Lasers, Lights and Other Technologies

Maria Claudia Almeida IssaBhertha Tamura Editors

Clinical Approaches and Procedures in Cosmetic Dermatology

Clinical Approaches and Procedures inCosmetic Dermatology

Series EditorsMaria Claudia Almeida IssaDepartment of Clinical Medicine – DermatologyFluminense Federal UniversityNiterói, RJ, Brazil

Bhertha TamuraClínicas Hospital of São Paulo of the University of Sao PauloSao Paulo, SP, Brazil

Barradas and Bourroul’s Ambulatório de Especialidades in Sao PauloSao Paulo, SP, Brazil

Sorocaba’s Ambulatório de Especialidade in SorocabaSao Paulo, SP, Brazil

The series Clinical Approach and Procedures in Cosmetic Dermatologyintends to be a practical guide in cosmetic dermatology. Procedures in cos-metic dermatology are very popular and useful in medicine, indicated tocomplement topical and oral treatments not only for photo-damaged skin butalso for other dermatosis such as acne, rosacea, scars, etc. Also, full-facetreatments using peelings, lasers, fillers, and toxins are increasingly beingused, successfully substituting or postponing the need for plastic surgeries.Altogether, these techniques not only provide immediate results but also helppatients to sustain long-term benefits, both preventing/treating dermatologicaldiseases and maintaining a healthy and youthful skin. Throughout this series,different treatments in cosmetic dermatology will be discussed in detail,covering the use of many pharmacological groups of cosmeceuticals, thenew advances in nutraceuticals, and emerging technologies and procedures.

More information about this series at https://link.springer.com/bookseries/13496

Maria Claudia Almeida IssaBhertha TamuraEditors

Lasers, Lights and OtherTechnologies

With 279 Figures and 25 Tables

EditorsMaria Claudia Almeida IssaDepartment of ClinicalMedicine – DermatologyFluminense Federal UniversityNiterói, RJ, Brazil

Bhertha TamuraClínicas Hospital of São Paulo of theUniversity of Sao PauloSao Paulo, SP, Brazil

Barradas and Bourroul’s Ambulatório deEspecialidades in Sao PauloSao Paulo, SP, Brazil

Sorocaba’s Ambulatório de Especialidadein SorocabaSao Paulo, SP, Brazil

ISBN 978-3-319-16798-5 ISBN 978-3-319-16799-2 (eBook)ISBN 978-3-319-16800-5 (print and electronic bundle)https://doi.org/10.1007/978-3-319-16799-2

Library of Congress Control Number: 2017951225

# Springer International Publishing AG 2018This work is subject to copyright. All rights are reserved by the Publisher, whether the whole orpart of the material is concerned, specifically the rights of translation, reprinting, reuse ofillustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way,and transmission or information storage and retrieval, electronic adaptation, computer software, orby similar or dissimilar methodology now known or hereafter developed.The use of general descriptive names, registered names, trademarks, service marks, etc. in thispublication does not imply, even in the absence of a specific statement, that such names are exemptfrom the relevant protective laws and regulations and therefore free for general use.The publisher, the authors and the editors are safe to assume that the advice and information in thisbook are believed to be true and accurate at the date of publication. Neither the publisher nor theauthors or the editors give a warranty, express or implied, with respect to the material containedherein or for any errors or omissions that may have beenmade. The publisher re-mains neutral withregard to jurisdictional claims in published maps and institutional affiliations.

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Foreword

When I received the invitation from Maria Claudia Issa, M.D., Ph.D., andBhertha Tamura, M.D., Ph.D., to write one of the chapters of this marvelousbook, I was very happy. Later, upon receiving the mission to write the prologueof this book, whose editors, with numerous publications in the internationalscientific field of cosmetic dermatology, dignify the Brazilian dermatology, leftme extremely honored. In this book, some of the leading medical doctors andresearch scientists from Brazil and from all over the world present theirprofessional experience in the cosmetic dermatology area.

Cosmetic dermatology is constantly evolving. Procedures for rejuvenatingthe skin are actively sought by people, nowadays. As dermatology grows as aspecialty, an increasing proportion of dermatologists will become proficient inthe delivery of different procedures. Even those who do not perform cosmeticprocedures must be well versed in the details to be able to guide their patients.

Numerous major advances in the field of the cosmetic dermatology area,including botulinum exotoxin, soft tissue augmentation, chemical peels, cuta-neous lasers, light source–based procedures, and the state of the art of derma-tologic and cosmetic prescriptions, have been developed and enhanced bydermatologists and plastic surgeons.

Lasers, lights, and related energies are routinely used in cosmetic derma-tology. These are very important tools in the armamentarium of the dermatol-ogy. Very interesting results in the treatment of photoaging, rosacea, scars, andstretch marks, among others, can be obtained with these procedures. However,accuracy in its management as well as the knowledge of possible complica-tions and their management are of extreme importance. In this volume,different types of devices are thoroughly discussed.

The series Clinical Approach and Procedures in Cosmetic Dermatologyoffers a wonderful and embracing text. It was a pleasure to contribute in thisunique book with so many well-renowned authors.

This work project is a text certainly of inestimable value for those who wishto deepen their knowledge in the field of cosmetic dermatology.

Hoping that you will enjoy learning a lot from this book!

Mônica Manela Azulay, M.D., Ph.D.

v

Preface

Nowadays, life expectation had increased and for a better quality of life, peopleare looking for beauty, aesthetics, and health. Dermatologists and plasticsurgeons who work with cosmetic dermatology can help patients to maintaina healthy and youthful skin. Topical and oral treatments associated with full-face procedures using peelings, lasers, fillers, and toxins are increasingly beingused, successfully substituting or postponing the need for plastic surgeries.

This series of book is very special among other ones already published as itencompasses all subjects related to this area of dermatology. All authors areexperts in the field of cosmetic dermatology. Literature review and its corre-lation with authors’ experience is a differential feature of this work.

This work had been divided into four volumes due to the breadth of thesubjects, which cover skin anatomy and histopathology, physiology, patient’sapproaches, common cosmetic dermatosis, topical and oral treatments, andcosmetic procedures.

Over the last decades, laser technology had great improvement. Thisvolume on Lasers, Lights and Other Technologies was designed to bring abasic structural framework of the use of lasers, lights, and related energies incosmetic dermatology. Here, Prof. Maria Issa, Prof. Bhertha Tamura, andcollaborators discuss different types of devices with their indications, param-eters to achieve better results, and management of possible complications.Some particularities including the use of lasers for different phototypes andbody areas are also described.

The Clinical Approach and Procedures in Cosmetic Dermatology wasprepared to be a guide in cosmetic dermatology. It can be considered acomplete encyclopedia in the field of cosmetic dermatology and, for thisreason, it is extremely useful for those who already work with cosmeticdermatology as well as for beginners in this field. This is a new referencework project, and we are delighted to have you on board.

Maria Claudia Almeida Issa, M.D., Ph.D.Bhertha Tamura, Ph.D.

vii

Acknowledgments

When we were invited to write a book about cosmetic dermatology, we couldnot imagine the dimension of this work project.

After drawing the program content, we realized that a comprehensivehandbook series in this field would be built. Nevertheless, it would not bepossible without the efforts and experience of our invited partners. Theydeserve our acknowledgment and our deep appreciation.

To all collaborators, our very special thanks.

Maria Claudia Almeida IssaBhertha Tamura

ix

Contents

Part I Biophotonics, Lights, Ablative and Non-ablativeLasers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Biophotonics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Álvaro Boechat

Intense Pulsed Light for Photorejuvenation . . . . . . . . . . . . . . . . . . 49Sílvia Karina Kaminsky Jedwab and Caio Roberto Shwafaty deSiqueira

Intense Pulsed Light for Rosacea and Other Indications . . . . . . . . 61Juliana Merheb Jordão and Luiza Pitassi

Light-Emitting Diode for Acne, Scars, and Photodamaged Skin . . . 73Luiza Pitassi

Non-ablative Lasers for Photorejuvenation . . . . . . . . . . . . . . . . . . . 89Maria Angelo-Khattar

Non-ablative Lasers for Stretch Marks . . . . . . . . . . . . . . . . . . . . . . 105Luciana Archetti Conrado, Melina Kichler, Priscilla Spina, and IsisSuga Veronez

Non-ablative Fractional Lasers for Scars . . . . . . . . . . . . . . . . . . . . 113Roberto Mattos, Juliana Merheb Jordão, Kelly Cristina Signor, andLuciana Gasques de Souza

Q-Switched Lasers for Melasma, Dark Circles Eyes, andPhotorejuvenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127Juliana Neiva, Lilian Mathias Delorenze, andMaria Claudia AlmeidaIssa

Erbium Laser for Photorejuvenation . . . . . . . . . . . . . . . . . . . . . . . . 141Alexandre de Almeida Filippo, Abdo Salomão Júnior, Paulo SantosTorreão, Lilian Mathias Delorenze, and Maria Claudia Almeida Issa

Erbium Laser for Scars and Striae Distensae . . . . . . . . . . . . . . . . . 153Paulo Notaroberto

xi

CO2 Laser for Photorejuvenation . . . . . . . . . . . . . . . . . . . . . . . . . . 165Jackson Machado-Pinto and Michelle dos Santos Diniz

CO2 Laser for Stretch Marks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171Guilherme Almeida, Elaine Marques, and Rachel Golovaty

CO2 Laser for Scars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181Thales Lage Bicalho Bretas, Aline Tanus, Marcia Linhares, andMaria Claudia Almeida Issa

CO2 Laser for Other Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . 195Emmanuel Rodrigues de França, Alzinira S. Herênio Neta, andGustavo S.M. de Carvalho

Fractional Ablative and Non-Ablative Lasers for Ethnic Skin . . . . 213Paulo Roberto Barbosa, Tais Valverde, Roberta Almada e Silva, andFabiolla Sih Moriya

Laser for Hair Removal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223Patricia Ormiga and Felipe Aguinaga

Laser on Hair Regrowth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233João Roberto Antonio, Carlos Roberto Antonio, and Ana LúciaFerreira Coutinho

Laser Lipolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245Paula Amendola Bellotti Schwartz de Azevedo, Bianca Bretas deMacedo Silva, and Leticia Almeida Silva

Laser Treatment of Vascular Lesions . . . . . . . . . . . . . . . . . . . . . . . . 253Andréia S. Fogaça

Laser for Onychomycosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267Claudia Maria Duarte de Sá Guimarães, Taissa Vieira Machado Vila,and Sergio Bittencourt-Sampaio

Lasers for Aesthetic and Functional Vaginal Rejuvenation . . . . . . 285André Vinícius de Assis Florentino, Thales Lage Bicalho Bretas, andMaria Claudia Almeida Issa

Laser Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297João Paulo Junqueira Magalhães Afonso and Meire Brasil Parada

My Personal Experience with Laser . . . . . . . . . . . . . . . . . . . . . . . . . 309Neal Varughese and David J. Goldberg

Part II Photodynamic Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313

Daylight Photodynamic Therapy and Its Relation toPhotodamaged Skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315Beni Moreinas Grinblat

Actinic Cheilitis: Efficacy and Cosmetic Results . . . . . . . . . . . . . . . 321Marco Antônio de Oliveira

xii Contents

Photodynamic Therapy for Photodamaged Skin . . . . . . . . . . . . . . 329Ana Carolina Junqueira Ferolla and Maria Claudia Almeida Issa

Photodynamic Therapy for Acne . . . . . . . . . . . . . . . . . . . . . . . . . . . 343Ann-Marie Wennberg Larkö

New Substances and Equipment Developed in Brazil:Photodynamic Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349Cristina Kurachi, Kleber Thiago de Oliveira, and Vanderlei SalvadorBagnato

Part III Ablative and Non-ablative Radiofrequency . . . . . . . . . . 359

Non-ablative Radiofrequency for Facial Rejuvenation . . . . . . . . . . 361Célia Luiza Petersen Vitello Kalil, Clarissa Prieto Herman Reinehr,and Celso Alberto Reis Esteves Jr.

Non-ablative Radiofrequency for Cellulite(Gynoid Lipodystrophy) and Laxity . . . . . . . . . . . . . . . . . . . . . . . . 375Bruna Souza Felix Bravo, Carolina Martinez Torrado, and MariaClaudia Almeida Issa

Non-ablative Radiofrequency for Hyperhidrosis . . . . . . . . . . . . . . . 389Mark S. Nestor,, Alexandria Bass, Raymond E. Kleinfelder,Jonathan Chan, and Michael H. Gold

Ablative Radiofrequency in Cosmetic Dermatology . . . . . . . . . . . . 395Tania Meneghel and Maria Letícia Cintra

Part IV Ultrasound and Cryolipolysis . . . . . . . . . . . . . . . . . . . . . . . 403

Ultrasound for Lipolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405Shirlei Schnaider Borelli, Maria Fernanda Longo Borsato, andBruna Backsmann Braga

Ultrasound for Tightening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411Guilherme Bueno de Oliveira and Carlos Roberto Antonio

Cryolipolysis for Body Sculpting . . . . . . . . . . . . . . . . . . . . . . . . . . . 421Roberta Bibas, Alexandra Cariello Mesquita, Diego CerqueiraAlexandre, and Maria Claudia Almeida Issa

Ultrasound-Assisted Drug Delivery in Fractional CutaneousApplications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429Joseph Lepselter, Alex Britva, Ziv Karni, andMaria Claudia AlmeidaIssa

Part V Transepidermal Drug Delivery . . . . . . . . . . . . . . . . . . . . . . . 445

Transepidermal Drug Delivery: Overview, Concept, andApplications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447Andrés Már Erlendsson, Emily Wenande, and Merete Haedersdal

Contents xiii

Transepidermal Drug Delivery with Ablative Methods (Lasersand Radiofrequency) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 463Maria Claudia Almeida Issa and Paulo Santos Torreão

Transepidermal Drug Delivery and Photodynamic Therapy . . . . . 473Marianna Tavares Fernandes Pires, Livia Roale Nogueira, andMaria Claudia Almeida Issa

Microneedling for Transepidermal Drug Delivery onStretch Marks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 487Gabriela Casabona and Paula Barreto Marchese

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 503

xiv Contents

About the Editors

Maria Claudia Almeida Issa is among the leading dermatologists in Braziland Latin America, especially in what regards to cosmetic dermatology.Dr. Issa holds a Ph.D. in Dermatology from the Federal University of Rio deJaneiro (2008) and an M.Sc. in Dermatology from the Fluminense FederalUniversity (1997). Dr. Issa is currently an Associate Professor within theDepartment of Clinical Medicine – Dermatology, at the Fluminense FederalUniversity, Brazil. Her research focuses on photodynamic therapy,nonmelanoma skin cancer, lasers, photoaging, and dermal remodeling. Finally,Dr. Issa has an extensive clinical experience in cosmetic dermatology, beingregistered as a dermatologist at the Brazilian Society of Dermatology since1995 and member of the American Academy of Dermatology.

xv

Bhertha Tamura has M.Sc. and Ph.D. degrees in Dermatology from theHospital das Clínicas de São Paulo – Universidade de São Paulo. Specialist ingeneral surgery and dermatology. Counselor for the Brazilian Society ofDermatologic Surgery and for the Brazilian Society of Dermatology. Memberof the Scientific Commission of the Brazilian Society of Dermatology. Chief ofthe Department of Dermatology at the Complexo Hospital Heliopolis (SãoPaulo, Brazil). Member of several international dermatological societies.

xvi About the Editors

Contributors

Felipe Aguinaga Instituto deDermatologia Professor RubemDavidAzulay –Santa Casa de Misericórdia do Rio de Janeiro, Rio de Janeiro, RJ, Brazil

Diego Cerqueira Alexandre Fluminense Federal University, Niterói, RJ,Brazil

Roberta Almada e Silva Brazilian Society of Dermatology, Clínica deDermatologia Paulo Barbosa – Centro Odontomédico Louis Pasteur, Itaigara,Salvador, BA, Brazil

Guilherme Almeida Department of Dermatology, Hospital Sirio Libanes,Brazil – Private office: Clinica Dermatologica Dr Guilherme de Almeida, SaoPaulo, Brazil

Alexandre de Almeida Filippo Santa Casa de Misericórdia do Rio deJaneiro (Laser Sector), Rio de Janeiro, Brazil

Leticia Almeida Silva Brazilian Society of Laser in Medicine and Surgery,Rio de Janeiro, RJ, Brazil

Maria Angelo-Khattar Aesthetica Clinic, Dubai, UAE

João Roberto Antonio Faculdade Estadual deMedicina, Hospital de Base deSão José do Rio Preto, São Paulo, Brazil

Carlos Roberto Antonio Faculdade de Medicina Estadual de São José doRio Preto – FAMERP, São José do Rio Preto, SP, Brazil

Hospital de Base de São José do Rio Preto, São Paulo, Brazil

Vanderlei Salvador Bagnato São Carlos Institute of Physics, University ofSão Paulo, São Paulo, SP, Brazil

Paulo Roberto Barbosa Brazilian Society of Dermatology, Clínica deDermatologia Paulo Barbosa – Centro Odontomédico Louis Pasteur, Itaigara,Salvador, BA, Brazil

xvii

Alexandria Bass Center for Clinical and Cosmetic Research, Aventura, FL,USA

Paula Amendola Bellotti Schwartz de Azevedo Brazilian Society of Der-matology and Brazilian Society of Dermatology Surgery, Rio de Janeiro,Brazil

Roberta Bibas Brazilian Society of Dermatology, Rio de Janeiro, Brazil

Sergio Bittencourt-Sampaio Department of Histology and Embryology,UFRJ, Souza Marques School of Medicine, Rio de Janeiro, RJ, Brazil

Álvaro Boechat BLB Fotomedicina LTDA, Sao Paulo, Brazil

Shirlei Schnaider Borelli Brazilian Society of Dermatology, Private Officein São Paulo, São Paulo, Brazil

Bruna Backsmann Braga Brazilian Society of Dermatology, Private Officein São Paulo, São Paulo, Brazil

Meire Brasil Parada Universidade Federal de São Paulo, São Paulo, Brazil

Bruna Souza Felix Bravo Instituto de Dermatologia Prof. Rubem DavidAzulay – Santa Casa da Misericórdia do Rio de Janeiro, Rio de Janeiro, RJ,Brazil

Bianca Bretas de Macedo Silva Brazilian Society of Dermatology, Rio deJaneiro, Brazil

Alex Britva Laser and Ultrasound Laboratory, Alma Lasers Ltd., Caesarea,Israel

Alexandra Cariello Mesquita Brazilian Society of Dermatology, Rio deJaneiro, Brazil

Gabriela Casabona Clinica Vida – Cosmetic, Laser and Mohs SurgeryCenter, São Paulo, Brazil

Jonathan Chan Center for Clinical and Cosmetic Research, Aventura, FL,USA

Maria Letícia Cintra Pathology Department, Medical Sciences School,Unicamp, Campinas, SP, Brazil

Luciana Archetti Conrado São Paulo, SP, Brazil

Gustavo S. M. de Carvalho Department of Dermatology, University ofPernambuco – UPE, Recife, PE, Brazil

Kleber Thiago de Oliveira Department of Chemistry, Federal University ofSao Carlos, São Carlos, SP, Brazil

Guilherme Bueno de Oliveira Faculdade de Medicina Estadual de São Josédo Rio Preto – FAMERP, São José do Rio Preto, SP, Brazil

MarcoAntônio de Oliveira A. C. Camargo Cancer Center, São Paulo, Brazil

xviii Contributors

Luciana Gasques de Souza Mogi das Cruzes University, São Paulo, Brazil

Lilian Mathias Delorenze Hospital Universitário Antonio Pedro,Universidade Federal Fluminense – Niterói, RJ, Brazil

Michelle dos Santos Diniz Santa Casa de Belo Horizonte, Belo Horizonte,MG, Brazil

Andrés Már Erlendsson Department of Dermatology, Bispebjerg Hospital,University of Copenhagen, Copenhagen, Denmark

Ana Lúcia Ferreira Coutinho Instituto de Dermatologia Professor RubemDavid Azulay do Hospital da Santa Casa da Misericórdia do Rio de Janeiro,Rio de Janeiro, Brazil

André Vinícius de Assis Florentino Department of Gynecology, Faculdadede Ciências Médicas de Campina Grande, Campina Grande, PB, Brazil

Brazilian Federation of Gynecology and Obstetrics, São Paulo, SP, Brazil

Andréia S. Fogaça Dermatology/Medicine, University Santo Amaro(UNISA), São Paulo, São Paulo, Brazil

Michael H. Gold Gold Skin Care Center, Nashville, TN, USA

David J. Goldberg Skin Laser and Surgery Specialists of NewYork and NewJersey, New York, NY, USA

Department of Dermatology, Icahn Mount Sinai School of Medicine, NewYork, NY, USA

Rachel Golovaty Clinica Dermatologica Dr Guilherme de Almeida, SaoPaulo, Brazil

Beni Moreinas Grinblat Department of Dermatology, Hospital das Clínicasda Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

Claudia Maria Duarte de Sá Guimarães Rio de Janeiro, Brazil

Merete Haedersdal Department of Dermatology, Bispebjerg Hospital, Uni-versity of Copenhagen, Copenhagen, Denmark

Alzinira S. Herênio Neta Department of Dermatology, University of SaoPaulo, Sao Paulo, SP, Brazil

Maria Claudia Almeida Issa Department of Clinical Medicine – Dermatol-ogy, Fluminense Federal University, Niterói, RJ, Brazil

Sílvia Karina Kaminsky Jedwab Escola Paulista de Medicina,Universidade Federal de São Paulo, São Paulo, Brazil

Skinlaser Brasil, São Paulo, Brazil

Juliana Merheb Jordão Skin and Laser Center of Boom, Boom, Belgium

Department of Hospital Universitário Evangélico de Curitiba, Curitiba, PR,Brazil

Contributors xix

Abdo Salomão Júnior Universidade de São Paulo, MG, Brazil

Ana Carolina Junqueira Ferolla Medical Ambulatory of Specialties,Barradas, São Paulo, Brazil

João Paulo Junqueira Magalhães Afonso Universidade Federal de SãoPaulo, São Paulo, Brazil

Ziv Karni Laser and Ultrasound Laboratory, Alma Lasers Ltd., Caesarea,Israel

Melina Kichler São Paulo, SP, Brazil

Raymond E. Kleinfelder Center for Clinical and Cosmetic Research, Aven-tura, FL, USA

Cristina Kurachi São Carlos Institute of Physics, University of São Paulo,São Paulo, SP, Brazil

Thales Lage Bicalho Bretas Universidade Federal Fluminense, Niterói, RJ,Brazil

Joseph Lepselter Laser and Ultrasound Laboratory, Alma Lasers Ltd.,Caesarea, Israel

Marcia Linhares Brazilian Society of Dermatology, Rio de Janeiro, RJ,Brazil

Maria Fernanda Longo Borsato Brazilian Society of Dermatology, PrivateOffice in São Paulo, São Paulo, Brazil

Jackson Machado-Pinto Dermatology, Santa Casa de Belo Horizonte, BeloHorizonte, Brazil

Paula Barreto Marchese Clinica Vida – Cosmetic, Laser and Mohs SurgeryCenter, São Paulo, Brazil

Elaine Marques Clinica Dermatologica Dr Guilherme de Almeida, SaoPaulo, Brazil

Carolina Martinez Torrado Instituto de Dermatologia Prof. Rubem DavidAzulay – Santa Casa da Misericórdia do Rio de Janeiro, Rio de Janeiro, RJ,Brazil

Roberto Mattos Mogi das Cruzes University, São Paulo, Brazil

Tania Meneghel Clínica Renaissance, Americana, SP, Brazil

Juliana Neiva Brazilian Society of Dermatology (SBD) and American Acad-emy of Dermatology (AAD), Rio de Janeiro, Brazil

Mark S. Nestor Center for Clinical and Cosmetic Research, Center forCosmetic Enhancement, Aventura, FL, USA

Department of Dermatology and Cutaneous Surgery, University of Miami,Miller School of Medicine, Miami, FL, USA

xx Contributors

Department of Surgery, Division of Plastic Surgery, University of Miami,Miller School of Medicine, Miami, FL, USA

Livia Roale Nogueira Universidade Federal Fluminense, Niterói, RJ, Brazil

Paulo Notaroberto Serviço de Dermatologia, Hospital Naval Marcílio Dias,Rio de Janeiro, Brazil

Patricia Ormiga Rio de Janeiro, RJ, Brazil

Célia Luiza Petersen Vitello Kalil Department of Dermatology, Santa Casade Misericórdia de Porto Alegre Hospital, Porto Alegre, Brazil

Brazilian Society of Dermatology, Porto Alegre, Brazil

Marianna Tavares Fernandes Pires Universidade Federal Fluminense,Niterói, RJ, Brazil

Luiza Pitassi Division of Dermatology, Department of Medicine, State Uni-versity of Campinas (UNICAMP), Campinas, SP, Brazil

Clarissa Prieto Herman Reinehr Brazilian Society of Dermatology, PortoAlegre, Brazil

Celso Alberto Reis Esteves Jr. Brazilian Society of Dermatology, PortoAlegre, Brazil

Emmanuel Rodrigues de França Department of Dermatology, Universityof Pernambuco – UPE, Recife, PE, Brazil

Caio Roberto Shwafaty de Siqueira Faculdade de Medicina de Botucatu,Universidade Estadual Paulista, São Paulo, Brazil

Kelly Cristina Signor Mogi das Cruzes University, São Paulo, Brazil

Fabiolla Sih Moriya Brazilian Society of Dermatology, Clínica deDermatologia Paulo Barbosa – Centro Odontomédico Louis Pasteur, Itaigara,Salvador, BA, Brazil

Priscilla Spina São Paulo, SP, Brazil

Isis Suga Veronez São Paulo, SP, Brazil

Aline Tanus Brazilian Society of Dermatology, Rio de Janeiro, RJ, Brazil

Paulo Santos Torreão Hospital dos Servidores do Estado do Rio de Janeiro,RJ, Brazil

Tais Valverde Brazilian Society of Dermatology, Clínica de DermatologiaPaulo Barbosa – Centro Odontomédico Louis Pasteur, Itaigara, Salvador, BA,Brazil

Neal Varughese Skin Laser and Surgery Specialists of New York and NewJersey, New York, NY, USA

Contributors xxi

Taissa Vieira Machado Vila Laboratory of Cell Biology of Fungi, CarlosChagas Filho Institute of Biophysics, Federal University of Rio de Janeiro,de Janeiro, Brazil

Emily Wenande Department of Dermatology, Bispebjerg Hospital, Univer-sity of Copenhagen, Copenhagen, Denmark

Ann-Marie Wennberg Larkö Department of Dermatology andVenereology, Institute of Clinical Sciences, Sahlgrenska Academy, Universityof Gothenburg, Gothenburg, Sweden

xxii Contributors

Part I

Biophotonics, Lights, Ablative andNon-ablative Lasers

Biophotonics

Álvaro Boechat

AbstractLight is one of the most beautiful forms of pureenergy, we know some of its therapeutic prop-erties, but there is still much to be explored.The aim of this chapter is to provide a betterunderstanding of the best known light toolsused in modern medicine, such as laser, intensepulsed light, the advent of fractional systems,radio frequency, and hybrid systems, whichcombine light and radio frequency, how theywork, how to select which device will be betterfor your application, and how light and RFinteract with the skin. Thus, this will enablethe improvement of current treatment tech-niques as well as broaden the horizons of appli-cations of these devices.

KeywordsDermatological laser • Laser physics • Types oflasers • Pulsed light • IPL • Treatment plat-forms • Light-tissue interaction • Selectivephotothermolysis • Relaxation time • Radiofrequency • Fractional lasers • Penetrationdepth • Ablative laser • Non-ablative laser •Sublative • Fractional radio frequency • ELŌS

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

Stimulated Emission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

Light Amplification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Characteristics of a Laser Light . . . . . . . . . . . . . . . . . . . . 7

Energy, Power, and Fluency . . . . . . . . . . . . . . . . . . . . . . . . 8

Operating Modes of a Laser . . . . . . . . . . . . . . . . . . . . . . . . 11Q-Switched: Nanosecond Laser . . . . . . . . . . . . . . . . . . . . . . 12Mode-Locked: Picosecond Laser . . . . . . . . . . . . . . . . . . . . . 12

Laser Types . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13Gas Lasers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15Liquid Laser . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16Solid-State Laser (Crystal) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

LED: Light-Emitting Diode . . . . . . . . . . . . . . . . . . . . . . . . . 21

Intense Pulsed Light . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

Treatment Platforms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

Light-Tissue Interaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

The Melanin “Curtain” . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

Light Penetration Depth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

“Ablative” and “Non-ablative” SkinRejuvenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

Fractional Laser Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

Radio Frequency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34Monopolar RF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35Bipolar RF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35Multipolar RF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37Unipolar RF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37Fractional RF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

Hybrid Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43Á. Boechat (*)BLB Fotomedicina LTDA, Sao Paulo, Brazile-mail: alvboechat@gmail.com; alvaro.boechat@skintec.com.br

# Springer International Publishing AG 2018M.C.A. Issa, B. Tamura (eds.), Lasers, Lights and Other Technologies, Clinical Approaches and Procedures inCosmetic Dermatology 3, https://doi.org/10.1007/978-3-319-16799-2_1

3

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

Take Home Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

Introduction

The laser and pulsed light are simply sources ofnatural light. The visible light that we experiencein our day to day is only one facet of a muchbroader physical phenomenon known as “electro-magnetic radiation.”

As shown in Fig. 1, the electromagnetic spec-trum (Siegman 1986) includes several well-known phenomena, such as TV and radio waves,microwave, infrared, and, on the other side of thespectrum, ultraviolet and X-ray. However, oureyes are sensitive to only a very narrow range ofthe spectrum, which forms the visible light fromviolet to red. It is important to realize that eachvisible color or each emission spectrum is associ-ated with a frequency or wavelength.

Thus, the differentiation between blue andgreen, for example, is related to their frequencies.It is similar to the musical notes; the difference ofthe note “do” (C) from the note “sol” (G) or “fa”(F) is their frequencies; one is low pitched and theother high pitched. Drawing a parallel with them,we can see that, in the light spectrum, the higherfrequencies correspond to blue and violet and, onthe other side of the spectrum, the lower frequen-cies correspond to red. As light frequencies arevery high, of the order of millions of hertz, theyare characterized by their wavelength or the dis-tance between two adjacent peaks in the waveillustrated in Fig. 2 (Siegman 1986; Arndt et al.1997).

Light radiation may be defined as the point-to-point power transmission in space, regardless ofthe medium in which it is being propagated. Lightor electromagnetic radiation propagates at a highspeed in the open space independent of the trans-mission medium in the form of waves that cantravel in the vacuum or in spaces containing mat-ter, such as gases, liquids, or solids. As it enters, ormoves from, a different medium, it will sufferchanges in direction and speed of propagation.

Lasers are sources of electromagnetic radia-tion, or light, with some special characteristicsthat are different from other light sources, suchas a car headlight or a lamp.

The word laser is an acronym for light ampli-fication by stimulated emission of radiation.We can divide this acronym into two well-definedparts: the stimulated emission phenomenon andthe light amplification.

Stimulated Emission

Light is a form of energy generated, emitted, orabsorbed by atoms or molecules. To emit energy,the atom or molecule is raised to an excitationenergy level, above its natural resting state(in which there is excess energy to be discharged).Atoms cannot maintain the excitement for longperiods of time. Consequently, they have a naturaltendency to eliminate the excess energy in theform of emission of particles or packets of lightwaves called photons (Fig. 3a). This phenomenonis called spontaneous emission of light. The wave-length (λ), or the frequency of the emitted pho-tons, is related to the photon energy through therelationship:

Ephoton ¼ hc=λ

h – Planck universal constant= 6.6260693 � 10�34 J.s

c – Speed of light = 300,000 km/sλ – Wavelength of the light (nanometers – nm)

We can draw an important conclusion from thisequation: long wavelengths of light, such as red,carry less energy than shorter wavelengths, suchas blue, which is at the other end of the spectrum.

Each atom or molecule in nature has differentenergy levels of excitement. Consequently, eachelement emits photons with different energies anddifferent wavelengths (frequencies). All these pri-mary radiations are monochromatic. The fact thatthe sunlight is polychromatic indicates that it iscomposed of a mixture of several distinctelements.

4 Á. Boechat

Another important relationship is the fre-quency with wavelength (Siegman 1986):

f ¼ c=λ

f – Frequency of the light wave (Hz)c – Speed of light = 300.000 km/sλ – Wavelength of the light (nanometers – nm)

We see that these two quantities are inverselyproportional; that is, the higher the frequency, thesmaller the wavelength. For example, the

frequency of visible light, which is very high ofthe order of Terahertz, has a very small wave-length, being the size of a molecule. As an anal-ogy, a FM radio wave, of the order of Megahertz,has a wavelength the size of a two-story house.

Atoms can be excited by different mecha-nisms: heat, mechanical shocks with other parti-cles as an electrical discharge (collision withelectrons), or when they selectively absorb elec-tromagnetic radiation energy from other photons.This is a natural process that occurs all the timearound us, but as its magnitude is very small and

103

1 kilometer

Long Wavelenghts

700 nanometers

Broadcastband

Radar

Radio(MHz)

Infrared(IR)

Ultraviolet(UV)

Visible Light

Microwaves(GHz)

Ultraviolet(GHz)

Gammarays

Cosmicrays

Infrared(IR)

X-rays

600 nanometers 500 nanometers 400 nanometers

Short Wavelenghts

100

1 meter10–3

1 millimeter10–6

1000 nanometer10–9

1 nanometer10–12 meters

Fig. 1 The electromagnetic spectrum

Fig. 2 Electromagneticwaves of photons thattransport energy

Biophotonics 5

very narrow in the visible spectrum, we cannot seeit. The location on Earth where we can more easilyobserve this phenomenon is, for example, near theNorth Pole, with the famous Northern Lights orauroras. It is produced by the impact between airmolecules and cosmic particles from the Sun thatconstantly bombard Earth, producing a phenome-non of luminescence in the upper atmosphere(Fig. 3b).

However, atoms can also decay producing lightradiation in a stimulated form. In 1917, AlbertEinstein postulated and proved the existence ofthis mechanism (Siegman 1986; Wright and Fisher1993; Arndt et al. 1997). When an excited atomcollides with a photon, it instantly emits a photonidentical to the first (Fig. 3a). This stimulated emis-sion follows the following basic laws:

(a) The stimulated photon travels in the samedirection of the incident.

(b) The stimulated photon synchronizes its wavewith the incident; in other words, the waves ofthe two photons align their peaks adding theirmagnitudes and thereby increasing the inten-sity of the light. Photons with aligned peaksproduce a coherent (organized) light. In acoherent beam, light travels in the same direc-tion, in the same time, and with the sameenergy.

The end result of a stimulated emission is thena pair of photons that are coherent and that travelin the same direction. The stimulated emission oflight is the working principle of a laser, inventedmore than 50 years after the discovery of Einstein.

Fig. 3 (a) Spontaneous emission of light. (b) Northern Lights, or aurora borealis, an example of spontaneous emission oflight

6 Á. Boechat

Light Amplification

To illustrate the generation of light inside a laser,let us first imagine a rectangular box or a tube, as astraight cylinder, with a large amount of identicalatoms or molecules, as an example, a fluorescentlamp tube with its gas. At each end of the tube, weplace mirrors, which because of the constructionwill be parallel to one another. At one end, themirror is totally reflective (100 % mirror), and atthe other end (the exit window of the light – outputcoupler), the mirror is partially reflective (80 %mirror), so that part of the light is reflected back tothe tube and part is transmitted through the mirrorto the outside (Wright and Fisher 1993; Kulick1998; Boechat 2009; Raulin and Karsai 2011;Kaminsky Jedwab 2010).

Let us also imagine that the atoms are excitedto a higher-energy level by an external source(a light source or an electrical discharge), as ifwe had activated the switch turning on the lamp.Through the mechanism of spontaneous emission,which takes place completely randomly, the atomsemit photons that begin traveling in various direc-tions within the tube. Those hitting against thetube wall are absorbed and lost as heat,disappearing from the scene. In the case of alamp, they leave the tube into the environment,illuminating the room. On the other hand, theemitted photons traveling parallel to the tubeaxis are likely to find other excited atoms andthus stimulate the emission of additional photons,which are consistent with the stimulating photonand travel in the same direction – i.e., along thelongitudinal axis of the tube. These two photonscontinue their journey, again with the likelihoodof stimulating, through a similar process, twoadditional photons – all consistent with eachother and traveling in the same axis. The progres-sion continues indefinitely and 8, 16, 32, 64, etc.,photons are produced, all traveling in the samedirection, as illustrated in Fig. 4.

It is clearly established a light amplificationprocess that generates a large luminous flux inthe longitudinal direction of the tube.

The mirrors perpendicular to the tube axisreflect the photons back intensifying this effect

of amplification. Each of these reflected photonstraveling along the axis in the opposite directioncontributes to the chain reaction effect generatinga stream of coherent photons.When they reach thepartially reflecting mirror, 80 % of the photonsreturn to the tube continuing the amplificationeffect. The remaining 20 % goes out forming thelaser beam (Fig. 5a, b). They represent in absoluteterms a very intense beam of photons produced bythe amplification effect. The tube and its excitedmedium, together with the mirrors, are called theresonator (or oscillator) which is the basic com-ponents of a laser in addition to the excitationsource.

Characteristics of a Laser Light

As described above, the laser light has uniqueproperties that make them different from otherlight sources (Goldman and Fitzpatrick 1994;Arndt et al. 1997; Kaminsky Jedwab 2010;Sardana and Garg 2014):

(a) Monochrome: it is generated by a collectionof identical atoms or molecules; thus, all pho-tons emitted have the same wavelength, asingle frequency. This feature is importantbecause of the selective absorption of thehuman tissue, which will be presented in thenext section.

(b) Coherent: because of the stimulated emissionand the way the light is amplified, which isonly in the longitudinal direction inside theresonator, the photons are organized, as sol-diers marching in a military parade. This iscalled spatial and temporal coherence. At anypoint of a laser beam, the photons (or light):(a) Have the same power(b) Travel in the same direction(c) Travel at the same time

Being coherent, light from a laser is calledcollimated. Traveling parallel to the tube axis,the laser beam has a very small divergenceangle, i.e., the light does not spread; the photonbeam is collimated (parallel). The small

Biophotonics 7

divergence allows the use of a lens system toconcentrate all the energy of the laser in a preciseway on a small focal spot (spot size), achieving agreater concentration of light energy or bright-ness. Optical laws tell us that the smaller thedivergence, the smaller the focal point. When wefocus a common light source such as a lamp, ofincoherent light, the focal point will be too largeand imprecise, whereas when using a laser, wehave a very fine and extremely precise focal pointand therefore a much more intense effect on thetissue.

Energy, Power, and Fluency

The increase of temperature or the effect of treat-ment on the tissue depends on the amount ofenergy that it receives. The energy, power, andfluency (energy density) are the physical parame-ters that control the treatment effect and determinethe eventual increase in temperature.

Energy Is measured in Joules (J)

Power Is measured in Watts (W)

These are different parameters and they arerelated trough the following equation:

Energy Jð Þ ¼ power Wð Þ � time sð Þ

Thus, energy is the amount of power delivered tothe tissue in a given time or the laser pulse

duration. The thermal effect of the laser is highlylocalized. In this way, the physical quantity thatgoverns the thermal response of the tissue is theamount of energy delivered to a certain area, theoverall size of the application area or the “spotsize” produced by the laser handpiece. Thus, theenergy density or fluency is measured in J/cm2

(Boechat et al. 1991):

Fluency J=cm2� � ¼ Energy Jð Þ=Area cm2

� �

The higher the fluency, the faster the temperatureincreases in the tissue and consequently the inten-sity of the desired effect. The effect of the treat-ment is achieved both by varying the laser outputenergy and the laser pulse duration, at the tissueapplication area. All commercial lasers allow us tochange easily and continuously the energy.

For a fixed operating power, we can vary thefluency in the tissue by changing the applicationarea (spot size – changing the lens that focus thelaser beam in the handpiece) or by varying thedistance of the handpiece from the tissue in a“focused” handpiece.

When we work with light in focus (Fig. 6), thepower density is at its maximum because all theenergy of the laser is concentrated in a small focalpoint (usually of the order of 0.1–1 mm), called“spot size.” At the focal point, it is possible toprecisely cut the tissue, and the application has itsmaximum effect. When we move the handpieceaway from the tissue to a defocus, or out of focus

Fig. 4 Chain reaction producing photons inside the laser resonator

8 Á. Boechat

position, the application area becomes largerreducing the power density (fluency) and increas-ing the temperature in the tissue. At this position,the effect becomes milder, producing a superficialeffect of vaporization and coagulation (used inskin rejuvenation – skin resurfacing).

Another widely used laser handpiece is called“collimated.”Here the laser beam remains parallel(collimated) and constant regardless of the

distance from the tissue. It is used in hair removalsystems and various types of skin treatment, suchas tattoo and melisma removal (Fig. 7).

It is important to note how the cutting effect iscontrolled when using a laser. The surgeon is usedto control the depth of the cut by the pressureexerted on the blade against the tissue. In thelaser, as there is no mechanical contact with thetissue, the cut is determined by two factors:

M1 – 100%a

b

M1 – 100%M2 – 80% M2 – 80%

M1 – 100%

(1)

(3) (4)

LASER RESONATOR

Fully ReflectingMirror

Laser Light

Partially ReflectingMirror

Excitation Energy

Stimulated Emission

Laser Medium

(2)

M1 – 100%M2 – 80% M2 – 80%

LaserBeam

Fig. 5 (a) Light amplification and laser beam formationinside a laser resonator. M1 is the 100 % reflection mirrorand M2 is the 80 % partial reflection mirror. The (1) and(2) are excited atoms that produce photons that begin to

travel longitudinally along the resonator between the mir-rors. The (3) and (4) are the photons traveling parallel to theaxis of the resonator that stimulate new photons, producingthe laser beam. (b) Schematic of the laser operation

Biophotonics 9

Handpiecein focus

HandpieceOut of focus

EpidermisDermis

Sub-Cutaneo

Spot-size and fluency change withhandpiece distance from skin

Fluency =Energy [J]

Spot size [Cm2]

Fig. 6 Focused headpiece. Laser in focus: power density is at its maximum (vaporizing, cutting). Out of focus: powerdensity is reduced (coagulation, milder treatment)

Fig. 7 Collimated handpiece. Regardless of the distancefrom the skin (touching or moving away), the spot size and

fluency remain the same. Some handpieces have a zoomeffect that allows the adjustment of the spot size

10 Á. Boechat

1. Hand movement speed2. Laser energy

The speed is linked to tissue exposure time,because if we keep the laser acting on a pointindefinitely, it begins to vaporize layer uponlayer of tissue increasing the depth of the cut.Thus, for a constant power, if the surgeon movesthe hand slowly, he or she will produce a deep cut.Likewise, for a movement with constant speed,the cutting will be deeper for a greater energy.

The laser exposure time also governs theamount of adjacent tissues which may be affected.Modern laser systems have mechanisms thatquickly deliver energy to the tissue minimizingthe thermal effect in adjacent areas. These mech-anisms can be through ultrafast pulses(“ultrapulse” laser) or computerized rapid laserbeam scanning systems (fractional scanners),used in skin rejuvenation treatments and morerecently in fractional treatment systems. The“scanner” divides and moves the laser beam athigh speed to position it over the skin minimizingdamage to adjacent tissues. They are controlled bycomputer and can execute different types of scan-ning, with great precision and control over theamount of tissue being vaporized (Goldman andFitzpatrick 1994; Arndt et al. 1997; Kulick 1998;Alster and Apfelberg 1999; Alster 1997).

Operating Modes of a Laser

Depending on the effect of the treatment we wantto obtain on the tissue, laser systems can operatein the following modes (Boechat 2009; Raulinand Karsai 2011; Kaminsky Jedwab 2010;Sardana and Garg 2014):

1. Continuous mode – CW: In this mode ofoperation (also known as continuous wave),the laser stays on, just as a normal lamp, andemits a light beam of constant energy, as long aswe keep the system powered by the foot switchor the power button on the handpiece (availableon some devices). It is widely used in surgeriesfor coagulation or vaporization of tissue.

2. Pulsed mode: This mode works as if weturned a lamp on and off; the laser is pulsedelectronically with the times and the intervalsbetween pulses controlled by the equipmentcomputer and selected via the panel. The rep-etition rate or frequency (given in Hz) of thelaser pulse can also be programmed. Mostlasers used in dermatology work with ultrafastpulses to vaporize the tissue faster than thethermal diffusion time of the skin in order tominimize damage to adjacent tissues, resultingin safe and effective treatments (Fig. 8).

Fig. 8 Comparison of tissue laser cutting, showing continuous wave (CW) and ultrafast pulses that minimize the thermaldamage to adjacent tissue

Biophotonics 11

According to the laser pulse duration, pulsedsystems can be classified into:

(a) Long pulses – 0.001 s, millisecond(ms) 10�3 s(i) Hair removal, varicose veins

(b) Quasi-CW – 0.000001 s, microsecond (μs)10�6 s(i) Skin rejuvenation, onychomycosis,

inflammatory acne(c) Q-Switched – 0.000000001, nanosecond

(ns) 10�9 s(i) Treatment of melasma, tattoo removal

(d) Mode-Locked – 0.000000000001, picosec-ond (ps) 10�12 s(i) Tattoo removal and pigmented lesions

(e) Femto – 0.000000000000001, femtosecond(fs) 10�15 s(i) Refractive surgery in ophthalmology

Q-Switched: Nanosecond Laser

This mode is achieved by placing an optical acces-sory inside the resonator, at the side of the lasercrystal, whose goal is to pulse optically the light(Siegman 1986; Goldman 1967; Raulin andKarsai 2011). It is generally used in crystal laserssuch as ruby, alexandrite, and Nd:YAG, describedbelow. The goal is to accumulate the laser energyat very high levels and release it at extremely rapidpulses. The result is a very high-peak-power laserpulse (often higher than the common pulse),which can penetrate deep into the tissue, withminimal side effects. Then a shockwave-inducedmechanical action caused by the impact of thelaser pulse onto the target tissue causes its frag-mentation. In the long and Quasi-CW pulsedmodes, the effect is purely thermal.

The Q-Switch can be passive, when using acrystal called “saturable absorber” that producesrapid pulses, or active, when using an electronicmodulator crystal called “Pockels cell.”

Passive systems using the saturable absorberare generally simpler and more compact resultingin smaller portable devices or systems installedinto handpieces incorporated to a platform. Theyare more limited as it is not possible to control

efficiently the stability of the fast pulse; the crystalis sensitive to higher energies, which limits themaximum working energy; and the applicationspot size is limited to a few millimeters(1–3 mm). They also fail to achieve high repeti-tion rates of pulses (high frequencies), working ina maximum of 2–3 Hz.

The active Q-Switch uses a Pockels cell whichis a crystal subjected to a high electric frequencyand is electronically controlled to produce a veryfast and stable light switching effect. The result isfaster pulses with very high peak powers that arenot possible with passive systems. Thus, they canhandle high energy, larger spot sizes (10 mm), andfaster repetition frequencies of 2–20 Hz. Equip-ment with active Q-Switch allow the device to beturned off, and thus the laser can also work in theQuasi-CW mode, with micropulse, giving greaterflexibility to the system (Fig. 9).

The classic application is in tattoo removal andthe treatment of pigmented skin lesions such asdark circles, postinflammatory hyperpigmentation,and melasma (Goldman 1967; Reid and Muller1978; Raulin et al. 1998; Chang et al. 1996;Shimbashi et al. 1997; Reid et al. 1983, 1990;Stafford et al. 1995; Ogata 1997; Chan et al.1999; Jeong et al. 2008; Mun et al. 2010) (Fig. 10).

Mode-Locked: Picosecond Laser

To achieve picosecond pulses, a technique called“mode-locking” is used (Siegman 1986; Raulinand Karsai 2011; Sardana and Garg 2014). Thebase is a Q-Switch system as described above, inwhich nonlinear effects of the Q-Switch crystal are

Fig. 9 Diagram of a Nd:YAG laser with Q-Switch (QS).M1 is the 100 % mirror; M2 is the output coupler

12 Á. Boechat

stimulated and modulated inside the resonator inorder to create faster pulses with a technique inwhich only they are amplified. It ismore commonlyused in crystal lasers as alexandrite and Nd:YAG.

There is the passive, with the saturableabsorber, and the active mode-locking, with thePockels cell electronically controlled. The limita-tions and benefits of each are the same as in theQ-Switched systems.

The picosecond lasers for dermatology providepulses ranging from 375 to 760 ps.

To understand the picosecond laser advantagesover a nanosecond device, we need to go back tothe relationship between energy, power, and pulseduration, described above. We see that the peakpower is inversely proportional to pulse duration.In other words, faster (shorter) pulses generatehigher powers for the same energy:

Power Wð Þ ¼ Energy JÞ=Duration of the Pulse sð Þð

A picosecond laser generates a very high peakpower, making the photomechanical fragmenta-tion of the target tissue and consequently the treat-ment more efficient. It also does not need high-energy levels. Working with very low energyresults in milder treatments and faster recoverytime. For example, in tattoo removal, a picosec-ond laser needs fewer sessions than a nanosecondsystem, and applications can be performed every15 days, while in nanosecond systems, sessionsare 45–60 days apart. The faster the system is, themilder and more effective is the treatment. That is

why the industry has been investing in the devel-opment of these ultrafast devices (Fig. 11).

Aswewill see in the following chapter, the pulseduration governs the way in which light interactswith the tissue (selective photothermolysis), and byvarying the pulse duration, we can completelychange the laser application in dermatology.

Laser Types

All laser devices consist of the following parts(Siegman 1986; Goldman and Fitzpatrick 1994;Boechat 2009; Kaminsky Jedwab 2010):

1. The resonator/oscillator – with mirrors (totaland partial reflectors) and active medium,which, when excited, produces the light andthus determines the wavelength

2. The excitation source (also called pumping) –which delivers power to the active mediumproducing the photons

Fig. 10 Laser tattoo removal

Fig. 11 Picosecond Laser PicoWay™ Nd:YAG/KTP(Syneron Candela)

Biophotonics 13

3. Laser beam delivery system from the source tothe hand of the operator

4. Handpiece, with focusing lens or a scanningsystem

The industry uses various elements in the man-ufacture of laser sources in order to cover a grow-ing range of electromagnetic wavelengths. Today,we have ultraviolet lasers, visible light, and infra-red. For this end, gases, liquids, crystals, fiberoptics, and semiconductors (electronic compo-nents) are used.

The pumping of each element also varies; thus,electrical discharges, radio frequency, and lightsources such as flash-lamps or even other lasersare used.

To carry the laser light from where it isgenerated in the resonator to the hand of theuser who is making the application, variousmechanisms are used depending on the wave-length and energy of the equipment. The mostcommon are:

Articulated arm – a set of multiple mirrors posi-tioned at the corners of articulated pipes toallow the freedom of movement in all direc-tions (Fig. 12).

Optical fiber – thin waveguide with a core madeof quartz covered with a thin layer called clad-ding, which is made of a slightly differentmaterial and encapsulated with plastic andmetal coatings to give it flexibility. It deliversthe laser beam by multiple internal reflections;that is, light enters the fiber, reflects on thecore/cladding interface and keeps movinguntil it exits the optical fiber. Note that at theoutput of the fiber the laser beam has a widedivergence and is no longer collimated. Inother words, the beam spreads, losing part ofits coherence (Boechat et al. 1991, 1993)(Figs. 13 and 14).

A handpiece is placed at the end of the beamdelivery system for either an articulated arm or anoptical fiber. It contains the lens system whichfocuses the laser light on the working area facili-tating the handling of the laser during treatment,as already described above. In fractional laserdevices, described below, the handpiece holdsthe scanning systems, or scanners, in addition tothe lenses.

Bellow we describe some typical commerciallaser systems used in medicine, groupedaccording to the laser medium (Alster and

Fig. 12 Diagram of anarticulated arm

14 Á. Boechat

Apfelberg 1999; Alster 1997; Boechat 2009;Raulin and Karsai 2011; Kaminsky Jedwab2010; Sardana and Garg 2014).

Gas Lasers

ExcimerGas molecules that exist only in the excited state,called “dimers,” form the excited medium; exam-ples are molecules such as halogens combinedwith noble gases (ArF, KrF, XeCl, Xef). Theword “excimer” is an abbreviation of the term“excited dimer.” The emission covers some wave-lengths in the ultraviolet range such as 193 nmArF, 222 nm KrCl, 248 nm KrF, and 308 nmXeCl. The pumping is usually made by electricdischarge or the shock of electrons with gas

molecules. Quartz optical fibers are used asbeam delivery system. Since the wavelength isvery small and carries a high energy, these lasersare widely used for high precision incisions ortissue ablation, such as in ophthalmic refractivesurgery (myopia). In dermatology, this system hasshown excellent results in the treatment of psori-asis and vitiligo (Zelickson et al. 1996; Guttman2000).

Fig. 15 RF-pumped CO2 laser with articulated arm,eCO2™ (Lutronic Inc.)

Fig. 13 Diagram of anoptical fiber showing thebeam divergence at theoutput

Fig. 14 Surgical laser with optical fiber

Biophotonics 15

Argon IonThe excited ionized argon gas, Ar+, forms thelaser medium. Pumping is made by electrical dis-charge. The wavelength can vary between 488 nm(blue) and 514 nm (green). It uses quartz opticalfiber as the delivery system (Siegman 1986;Boechat 2009).

Helium-Neon (He-Ne)The excited medium is a mixture of helium andneon gases. It is also pumped by electrical dis-charge. The wavelength is in the visible range,632.8 nm, i.e., red. These systems are generallyused for low-power applications such as cell stim-ulation and laser pointers or aiming systems forinfrared invisible lasers. It uses quartz opticalfibers (Siegman 1986; Boechat 2009).

Carbon Dioxide (CO2)The CO2 is still one of the most used lasers insurgery, dermatology, and industrial applications.Its power may vary from a few KWup to MW in acontinuous or pulsed manner. The laser medium isa mixture of gases including N2 (nitrogen – 13–45%), He (helium – 60–85 %), and CO2 (1–9 %).Pumping is achieved by high-voltage electric dis-charge or radio frequency (RF). The molecule ofCO2 is excited by mechanical shock with elec-trons, of the N2 and He molecules. The wave-length is in the infrared range at 10,640 nm. Thisis a relatively efficient laser (30 % of electro-optical conversion), and because of that, it haslow-power consumption and maintenance. Ituses an articulated arm and special dielectriccoated flexible hollow waveguides (Siegman1986; Kulick 1998; Alster and Apfelberg 1999;Alster 1997) (Fig. 15).

Liquid Laser

Dye LaserIt uses a liquid Rhodamine solution (R6G), whichis a fluorescent dye, as the laser medium. It ispumped by a flash-lamp or another laser. Thewavelength may vary continuously from 300 to1,000 nm, and the resonator can be tuned. It ismost commonly used in yellow (585–600 nm).Its main application is the treatment of vascular

lesions and inflammatory processes of the skin. Ituses quartz optical fiber (Siegman 1986; Reichert1998; Mcmillan et al. 1998; Reyes and Geronemus1990) (Fig. 16).

Solid-State Laser (Crystal)

Figure 17 shows the schematics of the most com-mon solid-state laser systems in the market. Themirrors, the laser rod (the crystal), and the flash-lamp, used for the pumping inside a cavity madeof a coated elliptical reflecting material – usuallyceramic or a large resistance metal such as gold –compose the resonator (Siegman 1986; Boechat2009).

Ruby: Cr3+:Al2O3

It was the first laser developed by Maiman in 1961(Siegman 1986; Goldman and Fitzpatrick 1994;Arndt et al. 1997) (Siegman (1986) Lasers), but itwas some time before this system started to be used

Fig. 16 Flash-lamp-pumped dye laser, Vbeam Perfecta™(Syneron Candela)

16 Á. Boechat

in medicine. The medium is ionized ruby crystal. Itis pumped by a flash-lamp. The wavelength is inthe red range of 694 nm. The nature of the crystalrequires high energy for pumping or high-powerflash-lamps. It uses fiber optics and articulated armfor laser delivery. It is generally used for the treat-ment of pigmented lesions and hair and tattooremoval (Goldman 1967; Reid and Muller 1978;Raulin et al. 1998; Chang et al. 1996; Shimbashiet al. 1997; Yang et al. 1996; Ono and Tateshita1998; Reid et al. 1983, 1990) (Fig. 18).

Alexandrite: Cr:BeAl2O4

The gain medium is chromium-doped chryso-beryl, the semiprecious stone alexandrite ionized.It is pumped by a flash-lamp. The wavelength is atthe end of the red range (755 nm). It uses flexibleoptical fibers or an articulated arm. This crystalhas better optical properties, which enables afaster and more efficient operation in a smallerdevice than the ruby. It is widely used for hairremoval and treatment of pigmented lesions(Siegman 1986; Finkel et al. 1997; Stafford et al.1995; Chan et al. 1999; Alster 1997) (Fig. 19).

YAG FamilyThe YAG abbreviation is short for yttrium alumi-num garnet, which is a synthetic crystalline struc-ture serving as host to the ion that will produce theradiation with the desired wavelength. It is

pumped by laser diodes or a flash-lamp, and itworks in the near-infrared spectrum. It uses opti-cal fiber and in some cases the articulated arm

Fig. 17 Schematics of a typical laser using a crystal rod

Fig. 18 Ruby laser with an articulated arm (AsclepionLaser Technologies)

Biophotonics 17

(high-energy pulsed laser – Q-Switched) as thebeam delivery system. The most common are(Siegman 1986; Goldman and Fitzpatrick 1994;Kulick 1998; Wong and Goh 1998; Ogata 1997;Chan et al. 1999; Boechat 2009; Raulin andKarsai 2011; Kaminsky Jedwab 2010):

– Nd:YAG – it uses the neodymium ion,with wavelengths of 1064 nm and 1320 nm,which is used for non-ablative skin rejuvena-tion (Muccini et al. 1998; Goldberg 1999,2000b).

– Nd:YAG/KTP – by placing a second crystal inthe laser resonator, in general the “famous”potassium-titanium-phosphate (KTP), it gener-ates the frequency-doubled Nd:YAG laser witha green wavelength at 532 nm. It is used forremoval of superficial pigmented and vascularlesions (Figs. 20 and 21).

– Nd:YAG/KTP + handpiece with crystal dye –a solid-state fluorescent dye handpiece canstill be added to these lasers in order to obtaindifferent wavelengths, such as 595 nm(yellow) and 650 nm (red), thus making themachine extremely versatile for the treatmentof pigmented lesions and the removal oflight color tattoos at different depths(Fig. 22).

– Ho:YAG – it uses holmium ions, with wave-length of 2,100 nm. It is excellent for treat-ments in bone and cartilage and for thefragmentation of kidney stones.

– Er:YAG – it uses erbium ions, with wavelengthof 2,940 nm. It is well known for its use in“skin resurfacing” (skin rejuvenation) (Flem-ing 1999; Weinstein 1998).

– Tm:YAG – it uses thulium ions, with wave-length of 1,927 nm. It is used for non-ablativeskin rejuvenation with a more superficialaction (Fig. 23).

Fig. 19 Alexandrite Laser, GentleLASE™ (SyneronCandela)

Fig. 20 (a) Schematics of a KTP laser pumped by aQ-Switched Nd:YAG laser. M1 is the 100 % reflectormirror; M2 is the partial reflector output coupler for theNd:YAG pumping laser; QS – Q-Switch; KTP – the KTP

crystal; OC – output coupler and wavelength selector for1,064 nm and 532 nm. (b) Laboratory prototype of a Nd:YAG pumped KTP laser with optical fiber outputconnection

18 Á. Boechat

Nd:YAPIt uses neodymium ions in yttrium aluminumperovskite crystal, with wavelength of 1,340 nm.It is used for non-ablative skin rejuvenation andchronic inflammatory diseases such as hidradenitis(Milanic and Majaron 2013; Antonio et al. 2015).

Er:GlassThegainmedium is changed for crystal glass,whichserves as host for the erbium ion. The wavelengthshifts to 1,540 nm, in the near infrared. It is used fordeeper skin rejuvenation and employed in fractionallaser systems (Mordon et al. 2000) (Fig. 24).

Er:YSGGThe gain medium is similar to the YAG crystal,and it uses the erbium ion in an yttrium scandiumgallium garnet (YSGG) host. The wavelength isalso in the near infrared, 2,790 nm, used in thePearl™ handpiece of Cutera. The main applica-tion is fractional skin rejuvenation. It is an alter-native to the Er:YAG laser skin resurfacing.

Semiconductor Laser– Diode – the laser medium is a semiconductor,

i.e., an electronic component. It is pumped byelectric current. The changing of the semicon-ductor achieves a wide range of wavelengthsranging from the visible, 450 nm, to the nearinfrared, 1,400 nm. The most common are alu-minum gallium arsenide (AlGaAs) with wave-lengths from red to near infrared, 620–900 nm,and gallium arsenide (GaAs) in the near infrared,830–920 nm. It has a very efficient electro-optical conversion (greater than 50 %); thus,generally it is a small and greatly simplifiedoperation system. It uses optical fibers or simplyfree, handheld devices. Some equipment manu-facturers provide systems with one or more laserdiodeswith differentwavelengths, increasing the

Fig. 21 Laser system Spectra XT™with twowavelengths:Nd:YAG (1,064 nm) and KTP (532 nm), Lutronic Inc.

Fig. 22 Crystal dyehandpieces, Laser SpectraXT™ (Lutronic Inc.)

Biophotonics 19

flexibility of the system. It is widely used for hairremoval, non-ablative skin rejuvenation, andtreatment of vascular lesions. It is also used forpumping other lasers such as Nd:YAG, Nd:YAG/KTP, and fiber-optic lasers, as we will seebelow (Siegman 1986; Goldberg 2000a; Rossand Hardway 2000; Lou et al. 2000) (Fig. 25).

Optical Fiber LaserExtremely robust, long-lasting, and highly reli-able, this technology employed in undersea opti-cal telecommunications cables has found anapplication in medicine in the development offractional lasers (Manstein et al. 2004;Geronemus 2006; Raulin and Karsai 2011).

– Y, Er:FIBER – the gain medium is a quartzoptical fiber measuring only 150 μm in diame-ter, containing erbium and yttrium ions. It ispumped by laser diodes. The wavelength is1,550 nm. The system does not need opticalcomponents such as mirrors, output couplers,flash-lamps, and cooling system, which signif-icantly reduces the need and cost of mainte-nance. This new technology producesmicroscopic focal points on the skin of theorder of 100 μm (approximately the thickness

Fig. 23 Er:YAG laser system, with articulated arm forablative skin rejuvenation (Fotona)

Fig. 24 Fractional Er:Glass laser system, Matisse™(Quanta System)

Fig. 25 LightSheer Duet diode laser, 810 nm (Lumenis)

20 Á. Boechat

of a human hair), since the light source is also amicroscopic fiber, leading to the advent offractional skin treatment (Figs. 26 and 27).

LED: Light-Emitting Diode

LEDs are electronic components, or semiconduc-tor diodes, that emit light when stimulated byelectric current. They may be considered as relate

to laser diodes, since they are manufactured withthe same materials, as GaAs, GaAlAs, GaInPAs,and thus provide the same wavelengths. However,they do not have the light amplification effectproduced by a laser resonator system. In thisway, an incoherent monochromatic light is pro-duced that diverges in various directions just as alamp of low intensity (Boechat 2009; Raulin andKarsai 2011; Kaminsky Jedwab 2010).

In order to concentrate and direct the emittedlight, they are manufactured with a parabolic plastichousing, which functions as a small lens (Fig. 28).

LED treatment systems use panels made of1,000–2,000 components in order to extend andoptimize the application area. Depending on theapplication or treatment, it is possible to changethe panel to a different wavelength. Some manu-facturers have integrated LEDs with differentwavelengths on the same panel thus avoiding theneed to change them (Fig. 29).

Some of the most common applications are inthe bio-modulation of cells, described below and inthe following chapters, such as anti-inflammatory

Fiber Laser SpoolPump Diodes

LD LD LD

LD LD LD

Steel Armored Fiber

Lens

LaserBeam

Fig. 26 Schematics of a laser diode array pumped, fiber laser

Fig. 27 Optical fiber laser, Mosaic™ (Lutronic Inc.)

Fig. 28 Example of LEDs

Biophotonics 21

effects and improved wound healing. It is also usedin photodynamic therapy and teeth whitening.

Intense Pulsed Light

It is a system that employs a flash-lamp for manyapplications, but it is not a laser light source, pulsedlight, or intense pulsed light – IPL. Dr. ShimonEckhouse at ESC Medical in Israel developed thisconcept, in the 1990s (Boechat 2009; Raulin andKarsai 2011; Kaminsky Jedwab 2010).

It uses an electronically controlled intenseflash-lamp. For this reason, it has distinct charac-teristics from a laser source:

(a) Polychromatic: it emits a broad spectrum ofwavelengths, generally in the range from400 to 1,200 nm. It uses band-pass filtersplaced in front of the lamp for wavelengthselection. These filters remove a band ofwavelengths, in general those below the filterspecification, letting through all the wave-lengths above it. Some machines use a

Fig. 29 (a) LED Panel, Hygialux™ (KLD). (b) LED Panels with different wavelengths (KLD)

22 Á. Boechat

more complex filter, which narrows theemission at a range of wavelengths, as illus-trated in Fig. 30. Even with a narrow emis-sion spectrum limited by the filters, theemitted energy disperse within several wave-lengths, that is those that will be absorbed bythe tissue to be treated and others that willhave no effect. Thus, the selectivity andeffectiveness of the treatment is reduced ascompared with a laser that has 100 % of theenergy concentrated in a single wavelength(monochromatic).

(b) Incoherent: different from a laser source, theIPL energy is emitted in all directions; itspreads. Mirrored surfaces placed behindthe lamp, similar to reflectors used in carheadlights, concentrate and direct the light.It will have a more superficial and mild effecton the tissue because it is less intense thanlaser light. The application will also be lesspainful.

The multiplicity of emitted wavelengths makesthese systems very versatile, being able to performseveral applications such as in hair removal,pigmented lesions, non-ablative rejuvenation,and vascular lesions, by simply changing the filterand pulse duration (Fig. 31).

These systems generally have a fixed pulse dura-tion already set by the manufacturer depending onthe application. To change the pulse duration, ingeneral, it is necessary to change the entirehandpiece. Pulse duration is restricted to the rangeof milliseconds because of the lamp characteristics;however, it suits most skin applications.

Figure 32 illustrates an IPL with various appli-cation filters. To change the spot size, it is neces-sary to change the handpiece for one with asmaller application area or use physical filters,such as a plate with a hole of different sizes placedin front of the lamp, as shown in Fig. 33. The platelimits the application area but significantlyreduces the treatment energy. In this way, theydiffer from lasers, in which a lens system locatedin the handpiece changes the spot size in a moreversatile manner, preserving the total energy ofthe laser beam.

Treatment Platforms

Following the trend of the market to produceincreasingly compact systems, which provide var-ious applications, the laser industry has developedthe concept of multi-application platform. Thesesystems consist of a base (platform) that carries theenergy source and cooling system. Then severalhandpieces can be connected to the base providingdifferent applications. Each handpiece may con-tain an IPL or a laser system. The most frequentapplications are hair: removal, skin rejuvenation,treatment of pigmented and vascular lesions, andtattoo removal (Raulin andKarsai 2011; KaminskyJedwab 2010; Sardana and Garg 2014).

These treatment platforms became very popularbecause of the excellent cost/benefit and versatilecombination of intense pulsed light and laser in thesame equipment. There are also platforms that haveonly lasers, or only IPL, and others that added a RFhandpiece for skin tightening.

On the other hand, one of the limitations of thisdesign is that it does not allow simultaneous treat-ments. For example, we need to finish the hairremoval treatment to perform the skin rejuvena-tion. For busy clinics performing several applica-tions at the same time, the choice of equipmentwith separate applications would be a better alter-native to increase revenues.

Another important point is that when using alaser as a platform handpiece, it suffers fromenergy and versatility limitations. For example,an Er:YAG laser equipment with its articulatedarm can provide more power, versatility, spotsize application, and pulse duration than wheninstalled in a platform handpiece. The same hap-pens with a Q-Switched laser, as it is very difficultto adapt an active Q-Switch in a simple handpiece.Therefore, on a platform, Q-Switched devicesusually are limited to the passive design (Fig. 34).

After becoming familiar with these technolo-gies and their operating principles, a questioncomes to mind: when and how to use each ofthese systems?

The application of each laser, IPL, or LED indermatology will depend on the response of thetissue to the wavelength being used.

Biophotonics 23

12000a

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Fig. 30 (a) General output spectrum of an IPL, (b) with a single 570 nm cut filter and (c) with a band-pass filter that limitseven further the output spectrum

24 Á. Boechat

Light-Tissue Interaction

Light can interact with living tissue in the followingforms (Anderson and Parrish 1981; Goldman andFitzpatrick 1994; Arndt et al. 1997; Kulick 1998):

Photothermal: light energy is absorbed by thetarget tissue (chromophore) and transformedinto heat, causing coagulation or vaporization.

Photomechanical: fragmentation by mechanicaleffect, as in the Q-Switch described above.

Photochemical:1. Direct breaking of chemical bonds between

atoms of a molecule produced by, for exam-ple, an ultraviolet excimer laser whensculpting a cornea, thus with great accuracy.

2. Light activates a chemical reaction that pro-duces reactive free radicals, as in photody-namic therapy (PDT), described in afollowing chapter.

Photobiomodulation: light is used to modulateintra- and intercellular activities. It employslow-power laser and LED panels. It has anti-inflammatory action and the effects of woundhealing and tissue regeneration (Lopes 1999).

Selective photothermolysis: it is the art of com-bining wavelength, pulse duration, and energyto obtain the desired effect on the target tissuepreserving adjacent areas, as described below.When a beam of light hits the tissue, it is

(Fig. 35) partially transmitted, reflected, spread(scattering), or absorbed.

Laser light will only produce a therapeuticeffect if the target tissue is “in tune” with theenergy that is being used, as in a mobile phone.At any given time, there are thousands of mobilephone waves passing where we are, but the phonedoes not ring. It will only be triggered when theemitted wave is in tune with the device. Similarly,we can place several wavelengths of light in theskin, but the target tissue will absorb only a

Operatingswitch

Parabolicreflector

Flashlamp

FilterLight

output

Fig. 31 Schematics of an intense pulsed light – IPL(Lumenis)

Fig. 32 IPL handpiece with different filters

Fig. 33 Physical filters that change the spot size of theoutput or the application area of an IPL in the tissue

Biophotonics 25

specific light. In particular, the energy depositedby the most commonly used lasers in medicine istransformed into heat and thus produces a temper-ature increase on the chromophore.

We can summarize the effect of the tempera-ture increase in the tissue in the following ranges:

1. 37–43 �C: accelerated cell metabolism, stimula-tion, contraction of elastic fibers, and skin tight-ening. There is less effect and it is reversible.

2. 44–45 �C: exponential increase in cell metab-olism acceleration, changes in protein, colla-gen stimulation, and cell apoptosis with longapplication time, because of hyperthermia.

3. 50–70 �C: protein denaturation, coagulation ofcollagen (which must be replaced – regenera-tion), cell membranes, and hemoglobin; per-manent contraction of collagen fibers.

4. 90–100 �C: formation of extracellular vacu-oles, evaporation of liquids.

5. Above 100 �C: vaporization of tissue, charring.

The laser parameter that most influences theabsorption factor, also called the “tuning” effect,is the wavelength of the light (its color; its fre-quency). Each part of our organism or componentof our skin responds differently or has affinity to aparticular wavelength. Certain tissues are trans-parent to a particular laser; others absorb itcompletely. Therefore, we can induce the neces-sary thermal effect to treat it selectively at a spe-cific point without affecting the surroundingtissue, giving rise to the phenomenon of the“selective photothermolysis” theory developedby Dr. Rox Anderson et al., in Boston, USA(Anderson and Parrish 1983, 1981; Goldmanand Fitzpatrick 1994).

The graph of Fig. 36 represents the fundamentalresult of the publication of Anderson et al. It showsthe variation with wavelength of the absorption

Fig. 34 Treatment Platform Harmony™ with severalhandpieces (Alma Laser)

Fig. 35 Light-tissueinteraction

26 Á. Boechat

coefficient of certain skin components, such asmelanin, hemoglobin, and water molecule. Wecan see thatmelanin has a high absorption for lasersin the visible range, such as green (KTP), whichcan be used, for example, in the treatment ofpigmented lesions. Hemoglobin has an absorptionpeak in the range of yellow light (dye laser), mak-ing it a good option for treating vascular lesions.The ruby laser, in the range of red light, is wellabsorbed by the melanin and dark pigment in theskin. On the other hand, it is positioned at a mini-mum for hemoglobin absorption, which explains inpart the difficulty that these systems have toremove red pigments in the treatment of tattoosand vascular lesions (low coagulation effect).

When the light of these lasers enter the skin infast pulses, or rather ideal pulses, it is able to crossthe skin without causing any damage and isabsorbed only by the target tissue with which ithas affinity. These components are referred to inthe literature as “chromophores.”

We also note from the graph that the absorptionof melanin in the visible and near infrared (invis-ible) is very wide which allows for a number of

different lasers to be used effectively for treatingpigmented lesions and hair removal, such as the810 nm diode laser and 1,064 nm Nd:YAG.Because of the its longer wavelength, the Nd:YAG penetrates deeper in the skin, as describedbelow, and its absorption coefficient for melanin islower when compared to visible lasers, such asgreen. These are properties that make these laserssuitable for a variety of treatments, since theypresent reduced risk of damage of the skin surface,because of the absorption of melanin, and areeffective for dermis treatments such as deep vas-cular lesions and melisma.

The Er:YAG (2,940 nm) and CO2 (10,600 nm),in the infrared, have high absorption coefficientsfor water molecule. As water is the major compo-nent of the cellular structures, its interaction withthese wavelengths is predominant. Therefore, thefirst layers of cells rapidly absorbs the energy fromthese lasers increasing their temperature to thevaporization level, making it an excellent toolfor cutting or precise and superficial tissueremoval, such as in laser skin resurfacing or frac-tional laser skin resurfacing. The Er:YAG laser

.110–4

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Fig. 36 Curve of the absorption coefficient of some tissue components as a function of wavelength, pointing out the mostpopular laser systems

Biophotonics 27

wavelength is at the peak of water absorption,with a coefficient at least ten times higher thanthe CO2 laser. Since its light is more rapidlyabsorbed, the energy penetrates less, what makesit have a more superficial action compared to CO2.The treatment will also have lees thermal effectbeing gentler to the skin (Chernoff et al. 1995;Alster et al. 1999; Weinstein 1998).

Another important aspect of light-tissue inter-action is the laser pulse duration (pulse length orexposure time). This must be such that the energyproduces an increase in temperature that is con-fined (concentrated) to the target tissue, with min-imal dispersion to the surrounding areas. In otherwords, the laser pulse duration has to be longenough to increase the temperature on the targettissue up to its destruction level, while being shortenough not to irradiate heat to the surroundingtissue. A similar situation happens when wewant to verify if the iron is hot enough for ironingclothes. Usually, we place the finger on the ironfor enough time to check that it is hot, but removeit very fast to guarantee that we do not burn it.

In order to achieve the correct pulse duration,we need to observe the thermal relaxation time(TRT) of the target tissue.

The TRT is the time the tissue takes to coolafter being intensely heated. Following the prin-ciples of physics, chromophores with large vol-umes or cross sections take longer to cool andtherefore have a higher TRT. For example, athick hair has an average TRT of 40 ms, whereasa thin hair has a TRT of 1–3 ms.

For a flat object, such as a melanosis, the TRTcan be estimated by the ratio (Anderson and Par-rish 1981; Goldman and Fitzpatrick 1994; Arndtet al. 1997; Lapidoth et al. 2015):

TRT ¼ d2=4a

where “d” is the thickness of the material and “a”is the thermal conductivity of the material.

For a cylindrical object, such as hair or vein:

TRT ¼ d2=16a

where “d” is the diameter of the object.

Thus, to confine the energy or heat in the targettissue, we need pulses that are less than or equal tothe chromophore TRT.

We can reach an important conclusion fromthis: by using the same wavelength (the samelaser), we can perform different treatments by sim-ply changing the laser pulse duration. For example,with a long-pulse Nd:YAG laser, in milliseconds,we can treat varicose veins or perform hair removal.Installing a Q-Switch, with nanosecond pulses,allows the removal of tattoos or melanosis, becausethe melanosome TRT is of the order of 100 ns.

From what is discussed above, the basic princi-ples of selective photothermolysis are (Andersonand Parrish 1983; Goldman and Fitzpatrick 1994):

(a) Ideal wavelength that is absorbed only by thetarget tissue or chromophore

(b) Ideal pulse duration that should be sufficientto produce the desired effect on any targettissue, but fast enough to cause minimal effecton the surrounding tissues, i.e., confining theenergy in the chromophore

(c) Energy enough to reach the treatment effect

In summary, the vast majority of treatments inphotomedicine happen as follows:

1. Light is absorbed by the target tissue orchromophore.

2. The absorption of light causes a selectiveheating of the target while preserving the sur-rounding tissues.

3. The chromophore selective heating causes itscoagulation or vaporization, reaching the goalof the treatment.

The Melanin “Curtain”

The curve of absorption of Fig. 36 (Anderson andParrish 1983, 1981) shows that skin melanin pre-sents absorption for most lasers on the visible andnear-infrared range. Thus, it is important to remem-ber that in applications where the target tissue isbelow the papillary dermis (hair, vascular lesions,pigmented lesions, etc.), or below the melanin layer

28 Á. Boechat

where we need greater light penetration, energywillalways be attenuated, reducing the efficiency of thetreatment. The melanin present in the top layers ofthe skin acts as a window curtain. Energy absorp-tion by this melanin “curtain” will increase withdarker skin patients or with patients at the higherpositions of the skin types on the Fitzpatrick scale.The absorbed energywill generate local heat, whichwhen excessive can generate unpleasant adverseeffects such as burns, hypochromic spots, or stimu-late melanocytes producing hyperchromic spots.

Thus, lasers and IPLs, which work with higherenergies, employ systems for the protection of theepidermis, ranging from simple solutions, such ascooling the area with cold gel or ice packs, to thesophisticated cooling systems coupled to thehandpiece. All are extremely necessary to dissi-pate some of the heat generated by light absorp-tion in the first layer of the skin.

Epidermal cooling systems can be (Waldorfet al.; Alster and Apfelberg 1999; Goldberg2000a; Ross and Hardway 2000; Klavuhn 2000):

1. Static: the handpiece has a sapphire windowcooled with water or cryogenic gas, whichremains in contact with the skin removingexcess heat during the laser pulse.

2. Dynamic: also coupled to the handpiece, thesystem triggers a cryogenic gas jet, whichfreezes the skin immediately before the laserpulse, which then rapidly brings the skin tem-perature back to normal. In this system, it is

possible to vary the duration of the gas jet(according to phototype and patient discom-fort), as well as the interval between the cryo-genic spray and the laser pulse.

3. Continuous/independent: a separate devicethat provides a cold air blast cooling the tissueduring the procedure and operating indepen-dently from the laser or pulsed light.

The advantages of using these devices are:

1. Possibility of using higher energies, increasingthe efficacy of the treatment

2. Reduction of patient discomfort and risk ofadverse effects

3. Possibility of treating darker skin types(Fig. 37)

Light Penetration Depth

Giving great importance to the effectiveness of thetreatment, light penetration depth is primarilygoverned by the wavelength, observing the fol-lowing factors (Anderson and Parrish 1981;Raulin and Karsai 2011; Sardana and Garg 2014;Lapidoth et al. 2015):

1. Scattering of light in the visible part of thespectrum.

Fig. 37 (a) Example of a dynamic cooling device coupledto the laser handpiece, DCD™ (Syneron Candela). (b)Working diagram of a dynamic cooling device, DCD™.A spray of cryogenic gas freezes the skin just before the

laser pulse (Syneron Candela). (c) Cool air jet system, Cryo6™, a stand-alone unit to cool the skin during treatment(Zimmer MedizinSysteme)

Biophotonics 29

2. Absorption by water in skin cells, particularlythe epidermal ones on the near-infrared wave-length range.

3. For a given wavelength, the higher is theenergy, the deeper the energy will reach.

Going back to the graph of absorption coeffi-cient of Fig. 36, we see that light scattering (bluecurve) becomes stronger for smaller wavelengthson the visible range. Therefore, for this part of thespectrum, regardless of the energy used, penetra-tion is usually very small as shown in the graph ofFig. 38. The scattering effect begins to reduce inred light (700 nm) and practically disappears inthe near-infrared range, around 900–1,100 nm,which allows these wavelengths to penetratedeeply into the tissue. After 1,200 nm, the absorp-tion of the water in the chromophore present inabundance in the skin cells starts to become sig-nificant, again reducing the light penetration.

As it penetrates the skin, light energy is absorbedand scattered along the way, decreasing the intensityuntil it disappears. The power distribution along thelight path in the tissuewill reduce as it penetrates theskin. The energy in the surface is always higher thanat any point within the tissue. Therefore, for a givenwavelength, light with higher energy at the surfacewill have a slight increase in tissue penetration.

In summary, visible wavelengths are ideal forthe treatment of superficial lesions such as spots orport-wine stains. It is common to observe in thetreatment of superficial pigmented lesions that

some spots do not clear completely. This canindicate that part of the spot is located on a deeperlayer where light does not reach.

Wavelengths on the range of 900–1,100 nm,near infrared, should be used for the treatment ofdeep lesions such as varicose veins or hemangi-omas and dermal melasma.

Another mechanism can control the light pene-tration depth. For a given wavelength and fluency(energy/application area), it is possible to achieve agreater energy penetration by increasing the spotsize. Figure 39 illustrates the effect of the spot sizeon light penetration. Using a small spot size, it isnot possible to achieve the concentration of lightdeep into the skin because of the scattering. For alarger spot size, the dispersion is the same, but itcompensates the scattering effect by achieving agreater energy concentration deeper into the skin.Therefore, the larger the spot size, the greater theenergy concentration, or the deeper the penetra-tion. This effect is important, for example, in laserhair removal, treatment of dermal melasma, andtattoo removal (Raulin andKarsai 2011; KaminskyJedwab 2010; Sardana and Garg 2014).

“Ablative” and “Non-ablative” SkinRejuvenation

A wide application of lasers working in the nearand mid-infrared, from 900 to 10,000 nm, andintense pulsed light (IPL) has revolutionized the

Fig. 38 Light penetrationdepth as a function of thewavelength

30 Á. Boechat

skin rejuvenation technique. By definition, anablative laser is one that removes the skin surfaceand produces controlled coagulation of the tissueunderneath. Non-ablative systems produce onlytissue coagulation, keeping the skin surface intact(Muccini et al. 1998; Goldberg 2000b; Khan et al.2005; Munavalli et al. 2005).

At the near-infrared range, the absorption ofmelanin reduces drastically. Moreover, theabsorption of water increases exponentially.Thus, through appropriate selection of wave-length and pulse duration, it is possible to varythe intensity of the heat generated in the skinchanging from non-ablative to an ablativeinteraction.

Therefore, the difference from a non-ablativeto an ablative laser is simply its wavelength andconsequent intensity of interaction with the waterin the chromophore. The graph of Fig. 40 showsthe curve of absorption of the water in the chro-mophore for two lasers used in skin rejuvenation,Er:Glass (1,540 nm) and CO2 (10,600 nm)(Anderson and Parrish 1983, 1981).

The absorption coefficient of water at the Er:Glass wavelength is approximately 10, while atthe CO2 wavelength, it is approximately 3,000, adifference of 300 times. Thus, for two lasers withthe same fluency, the Er:Glass will heat the skin toan average temperature of 60 �C, occurring onlycoagulation (cell death), while the CO2 laser willincrease the temperature of the tissue up to180 �C, leading to vaporization, since this value

is much higher than the boiling temperature ofwater. The histology of Fig. 41 shows the differ-ence of laser-tissue interaction for two fractionallasers, which will be described below.

The non-ablative treatment promotes the regen-eration of deep tissue, with collagen remodeling,promoting a natural filling effect of the skin. It has afast recovery time with little interference in thepatient routine. Treatment takes four to fivemonthly sessions. It improves fine lines, openpores, skin texture, and overall skin quality.

The ablative treatment promotes a skin surfaceremoval (resurfacing), regeneration of underneathtissue (same as the non-ablative effect), and skintightening, because of the high temperature reachedand the removal of a percentage of the skin by laservaporization. It promotes a more complete treat-ment than the non-ablative one, but with a longerrecovery time. Treatment takes two to three ses-sions with 45–60 days apart. It shows good resultsfor deep wrinkles, scars, tightening, texture, andoverall skin quality (Pitanguy et al. 1996; Chernoffet al. 1995; Alster et al. 1999; Lask 1995).

As the IPL systems employ a range of wave-lengths ranging from the visible to the near infra-red, they are able to treat many types of skinlesions simultaneously. While it improves skinquality with wavelengths in the near-infraredrange, the visible part of the spectrum removessuperficial pigmented lesions and small surfacetelangiectasia. However, it shows milder andmore superficial effects than lasers.

Fig. 39 Spot size effect onthe penetration depth of alaser beam with the samefluency

Biophotonics 31

Several manufacturers have produced lasersystems and pulsed light for this purpose; someexamples are:

CO2 (10,600 nm) – produces a balanced mix ofablation and coagulation of the tissue leadingto a complete rejuvenation result that is still thegold standard of the market.

Er:YAG (2,940 nm) – has ten times greaterabsorption coefficient for water than the CO2

laser and thus produces more ablation thencoagulation. Ablation is shallower and milder,with less collagen remodeling in the dermis.

Nd:YAG (1,064 nm and 1,320 nm) – a line of theNd:YAG laser, which typically produces1,064 nm, has its resonator altered to produce

.110–4

10–3

10–2

10–1

100

101

102

103

104

105

1

Protein

Scattering

Water

Melanin

Hemoglobin

2,94Er:YAG

1,54Er:GLASS

1,32Nd:YAG

1,064Nd:YAG

10,60CO2

10

Wavelength (mm)

Ab

sorp

tio

n C

oef

fici

ent

(1/c

m)

Fig. 40 Curve of absorption as a function of the wavelength of the laser showing the difference in the absorption of waterfor the Er:Glass laser (non-ablative) and the C02 laser (ablative)

Fig. 41 Skin histology showing the effect on tissue for:(a) non-ablative fractional Er:Glass laser (1,540 nm), withonly a coagulation column and the intact skin surface, and

(b) fractional ablative CO2 laser, with tissue vaporization atthe center of the column and coagulation around it

32 Á. Boechat

this new wavelength. It has non-ablative effectonly in the coagulation of the dermis (Mucciniet al. 1998; Goldberg 1999, 2000b; Goldbergand Whitworth 1997).

Tm:YAG – thulium laser working at 1,927 nm;non-ablative effect.

Diode – a compact system with wavelength of1,450 nm; non-ablative effect (Goldberg2000a; Ross and Hardway 2000).

Er:Fiber or Er:Glass – using the erbium ion, buton a different material, such as an optical fiberor a glass crystal, has the wavelength of1,550 nm or 1,540 nm. Both are non-ablative(Mordon et al. 2000).

Intense pulsed light – versatility, milder treat-ment, and good cost-benefit of these deviceshave led to the development of various devicesin recent years dominating the landscape ofnon-ablative skin rejuvenation, although theeffect is generally superficial.

Fractional Laser Systems

To appreciate the revolution introduced by thefractional laser technology, let us imagine apatient who seeks an aesthetic improvement ofthe skin as a family photograph that needs somefinishing touches. Today, a photograph is digitallyaltered pixel by pixel, to improve the appearanceof objects in the image. Likewise, damaged paint-ings are restored gently in a small area at a time.

This same concept is employed in systems thatuse the fractional photothermolysis technology.The laser produces microscopic thermal injurycalled microthermal zones (MTZs), approximately100–150 μm in diameter – the thickness of ahuman hair – and depth from 0.2 to 2.4 mm (IPLdevices in general achieve a maximum of 0.3 mmbelow the surface). TheseMTZs are surrounded byhealthy tissue that is not affected and will help inthe recovery of the micro-damaged area. The sur-rounding tissuewill also bemobilized in the overallskin regeneration process. The resulting rejuvena-tion effect is comparable to deep chemical peels ordermal mechanical abrasion, but with minimal sideeffects and little downtime (Fig. 42).

An intelligent scanning system (optical scan-ners) located on the handpiece ensures the even

distribution of MTZs. The operator can choosedirectly in the laser panel the amount of MTZsthat will be put on the skin or the percentage ofthe total skin area that will be stimulated, controllingthe aggressiveness of the treatment. More MTZsmeans greater stimulus, being more aggressive theapplication and consequently showingmore results.This leads to an application control that hitherto didnot exist in dermatological treatments.

The method was developed by the parents ofselective photothermolysis, Doctors Rox Ander-son and Dieter Manstein, at the Wellman Labora-tories in Boston, USA. The first fractional lasersystem, the Fraxel SR, was shown by ReliantTechnologies Inc. in the Congress of the Ameri-can Academy of Laser (ASLMS –American Soci-ety for Laser in Medicine and Surgery) in April,2004 (Laubach et al. 2005; Geronemus 2006;Raulin and Karsai 2011).

The system follows the principles of selectivephotothermolysis with wavelength in the1,550 nm range, where the water of the chromo-phore is present in the skin cells. In its originaldesign, the fractional systems perform anon-ablative treatment, preserving the skin sur-face, and the temperature of the tissue increasesonly up to the coagulation point, producingmicrothermal zones. Treatment takes three tofive monthly sessions.

Fig. 42 The science of fractional photothermolysis

Biophotonics 33

Beyond the minimum recovery time, theadvantages of this treatment include the possibil-ity to use the laser to treat other regions of thebody besides the face with safety and efficacy andto remove deep pigmented lesions, and also thereare surprising results on the improvement ofunaesthetic and acne scars. The following chap-ters will discuss in detail applications of fractionaltreatment.

Some commercial non-ablative fractional sys-tems are:

Fraxel re:Store – 1,550 nm wavelength, Er:Fiberlaser. It has a handpiece with an intelligent con-tinuous scanning system that measures thespeed of the application of the operator to dis-tribute the MTZs on the skin homogeneously.

Palomar Lux1540 – it has a fractional handpieceof the Palomar StarLux platform, whichemploys an Er:Glass laser. It uses a fixed filterat the output to split the beam and to generatethe fractional effect. Thus, the number ofMTZs and application area is fixed.

Lutronic mosaic – it is a fractional system fromLutronic Inc., which is a Korean company thatalso employs an Er:Fiber laser with wave-length at 1,550 nm. It uses the intelligent scan-ner at the handpiece; thus, it is possible tochoose the number of MTZs (density of thetreatment), and the application can be in a staticor continuous scan mode, as Fraxel (Fig. 27).

The great success of the fractional technologyled to the diversification and improvement of themethod originating the ablative fractional treat-ment. The laser drills micro-holes with controlleddepth in the skin, with a thin tissue coagulationzone around them. The surface is damaged pro-ducing small crusts and more persistent erythema.The recovery time is longer, and there are restric-tions on the skin type and body areas to be treated.The histology of Fig. 41 clearly demonstrates thedifference of a non-ablative and an ablativetechnology.

The ablative fractional treatment brought backthe CO2 laser to the rejuvenation scenery becauseit gave control, safety, and less restriction to theprevious efficient CO2 laser skin resurfacing that

still remains the gold standard of skin rejuvena-tion. Another advantage is that it can also beused for precise cuts and vaporization in minorsurgeries.

Bellow, we show some examples of commer-cial fractional ablative lasers:

Lutronic eCO2 – it is a CO2 fractional laser withstatic and dynamic scanning system (Fig. 7). Itis possible to program the diameter and densityof MTZs.

Fraxel re:pair – it is a CO2 laser, which uses thesame fractional technology as the non-ablativeFraxel re:Store with an intelligent continuousscanning system.

Lumenis Total Active FX – it also uses a CO2

laser with intelligent scanners, which allow forstatic and dynamic scanning modes. The diam-eter and density of MTZs can be programmed.

DEKA SmartXide (Boechat et al. 1991) DOT/RF – it is a CO2 laser with scanners and radiofrequency (RF) technology integrated in thehandpiece.

Alma Pixel CO2 – it is a CO2 laser with an arrayof micro-lenses on the tip to split the beam andto produce the fractional effect. The numberand diameter of MTZs are fixed although itoffers handpieces with different sizes.

Alma Pixel Handpiece – it is a fractionalhandpiece from the multiplatform harmonyemploying an Er:YAG wavelength of2,940 nm and a filter effect to split the laserbeam and to produce the fractional effect. TheMTZs are thicker than in the other devices, ofthe order of millimeters in diameter, and moresuperficial, reach only the epidermal layer,because of the wavelength and energy of thesystem.

Radio Frequency

Radio frequency (RF) consists of a high-fre-quency electric current, of the order of 1 MHz,and has been used in medicine for several years.Just for comparison, household appliances, suchas TVs and refrigerators, work with 50 or 60Hz,which are low frequencies.

34 Á. Boechat

Going back to Fig. 1, the chart of the electro-magnetic spectrum, we see that RF occupies thekHz to GHz range, used for radio communication,which gave it its name. Medical equipment uses aportion of the narrow band of this range – from200 kHz to 40 MHz – in different applications. Inthis frequency range, the effects of stimulation ofnerves and muscles decrease, and thus the energycan be applied gently to achieve different levels oftissue heating (Lapidoth et al. 2015).

The basic idea behind the use of RF on the skinis the ability to deliver volumetric heat in depth.The movement (current) of electrons (ions) causesthe heating of the tissue, unlike the light, in whichthe increase in temperature occurs by photonenergy absorption. There is no selectivity, i.e.,the high-frequency current heats the tissue as awhole regardless of the skin type. There are alsono losses by reflection or scattering as with a laserlight. It is safe for dark skin types and effective forclear chromophores. Energy diffusion dependsonly on the tissue conductivity.

As we saw earlier, the concentration of lightenergy (fluency), or power density, controls theeffect on the tissue. The same is true with RF. Ahigh power applied over a large area using largeelectrodes will cause a mild heating, but whenconcentrated in small areas, as an electrode inthe form of a needle, it will cause the ablation ofthe tissue.

The penetration of the RF energy into the tis-sue, or instead the attenuation of the energy as itpenetrates the tissue, will depend on the fluencyused, the configuration of the electrodes(monopolar, bipolar, or unipolar), the anatomy ofthe area being treated, and the characteristics ofconductivity of the tissue.

The RF systems can be “monopolar,” “bipo-lar,” “multipolar,” and “unipolar” (Lapidoth et al.2015).

Monopolar RF

These devices use an active electrode to apply theRF to the area of treatment, in the form of ahandpiece, and a return electrode, usually in theform of a grounding pad with a large contact area,

which is placed far from the treatment zone(Fig. 43).

A high RF current density is created at theactive electrode, and the current diverges as itpenetrates the tissue going toward the large returnelectrode. Therefore, the heat is generated near theactive electrode, and it does not depend on thesize, shape, or position of the return electrode.

The RF current diverges rapidly away from theelectrode thus the heating effect decreases. At adistance equal to the electrode size, heatingbecomes insignificant. The heat zone can be esti-mated as half the size of the electrode. Thereforeby controlling the RF power and the geometry andsize of the electrode, it is possible to control thepenetration depth and the effect on the tissue.

Popular monopolar system uses are in surgeryfor the cutting and coagulation of blood vessels. Indermatology, there is the application for skintightening and collagen remodeling, as the geom-etry of the large electrode targets the deeper tis-sues of the dermis (Fig. 44).

Bipolar RF

This configuration uses two electrodes which areplaced close to each other and in contact with thetreatment zone. The RF current flows between the

Fig. 43 Basic configuration of a monopolar device

Biophotonics 35

electrodes and does not spread to other parts of thebody as in themonopolar configuration. This geom-etry creates a more uniform heating at the treatmentzone compared to the monopolar devices (Fig. 45).

Both electrodes create an equal thermal effectnear them, and the divergence of the RF current isreduced because of the small distance betweenthem. Therefore, most of the heat is concentrated

near the electrodes, thus allowing a greater controlover the size of the treated volume.

The penetration depth is a function of the size ofthe electrodes and the distance between them. Byincreasing the separation of the electrodes, the RFcurrent can go deeper, but the divergence alsoincreases thus reducing the desired heating effect.If the separation is too high compared to the elec-trode size, the heating profile will be similar to twomonopolar electrodes. When the separation of theelectrodes is comparable to the size of the electrode,the penetration depth is approximately half of thedistance between them (Lapidoth et al. 2015).

The penetration depth can also be controlled byvarying the operating frequency of the system,and thus treatment can occur at different depthswithin the limits imposed by the separation of theelectrodes, as shown in the diagram in Fig. 46. In

Fig. 45 Schematic of a bipolar RF system

Fig. 46 (a) Variation ofheating effect with theoperating frequency of thesystem, 2.45 Mhz, 1.7 Mhz,and 0.7 Mhz, Reaction™.(b) RF + Suction,Reaction™ (Viora)

Fig. 44 Example of monopolar device used for skin tight-ening, Thermage ThermaCool, Solta Medical

36 Á. Boechat

this way, the higher the frequency, the shallowerthe heating effect.

The folding of the skin between the elec-trodes, for example, by applying negative pres-sure (in the form of vacuum), allows a uniformheating of a large tissue volume that can reach upto a few centimeters. This technique is used indevices for body contouring and cellulite such asReaction™ of Viora (Fig. 46b) and VelaShape™,which uses the Electro-Optical Synergy (ELŌS)technology developed by Syneron Candela,describe below.

Bipolar RF also presents reduced energy loss,because of the proximity of the electrodes, andreduced energy density at the area of treatment,with subsequent reduction in the risk ofoverheating and burning of the skin below theelectrode. The application is better tolerated andcause less pain.

It has also allowed the development of fractionalbipolar RF technology as we describe it bellow.

Multipolar RF

It is an interesting approach to the bipolar RFgeometry. In this case, a series of bipolar elec-trodes are used in a circular or linear configura-tion. The RF current flows between them,producing a more homogeneous heating effectover a larger tissue volume and variable penetra-tion depths, as shown in Fig. 47. It also quicklyreaches the desired treatment endpoint tempera-ture, since more electrodes are used simulta-neously (Fig. 48).

Unipolar RF

This RF configuration uses a single electrode thatworks, in some ways, as an antenna for electro-magnetic energy coupling in the skin. It is differ-ent from monopolar RF, which uses one activeelectrode and one return electrode, and in thiscase, the RF current flows into the skin (Fig. 49).

The electromagnetic field coupling in humantissue produces heat. The RF heating effectdepends on the operating frequency of the device.There are two mechanisms of heating biologicaltissue containing water: ionic current, which isproduced bymoving charged particles (electrons),and rotation of dipoles of water molecules. Thesetwo forms of interaction lead to heating and con-sequent increase in temperature of the biologicaltissue.

The RF configurations described so far –monopolar, bipolar/multipolar – utilize lower fre-quencies, 1–3MHz, and the dominant mechanismin these cases is the ionic current hitting the skinmolecules, which in turn vibrate producing heat.

At frequencies around 10 Mhz and above, therotation of water molecules starts to be noticeable,and at frequencies greater than 30–40 Mhz, thismechanism is the predominant cause of heating ofthe tissue (Lapidoth et al. 2015).

Unipolar devices use high frequency of RF,from 20 to 40 MHz, so that the electromagneticfield produces the rotation of the molecules toinduce the heating of the tissue.

The penetration depth in this case depends onthe operating frequency, geometry and configura-tion of the electrode, input power, and the time

Fig. 47 Schematics of a multipolar RF configuration showing RF current flow between electrodes at different penetrationdepths

Biophotonics 37

and mode of treatment (stationary – using a panelwith electrodes over the treatment area – ormotion, moving the electrode over the skin).

As it happens with the ionic current heating,the penetration depth of the energy in unipolar RFalso decreases with higher frequency. Therefore,by operating with different frequencies, it is pos-sible to concentrate a key volume of energy in aspecific skin layer. For example, by working withhigh frequencies such as 40 MHz, the main effectis skin tightening since the energy is mainly con-centrated in the dermal area. Lower frequencies,such as 27 MHz, will deposit the energy in adeeper layer, which works for body contouringand fat destruction (Fig. 50).

It is importance to note that the effect of thetreatment (skin tightening, collagen remodeling,and fat reduction) is not only a function of thetemperature but also of the length of time that thistemperature is applied, or the RF pulse duration.Exposure to a temperature of 70–90 �C for a fewmilliseconds causes tissue coagulation, while theapplication of a lower temperature such as 42 �Cfor tens of minutes also causes irreversible dam-age to sensitive cells. For example, fat cells areespecially sensitive to temperature changes. Byusing the correct electrode geometry, low inputpower (in order not to overheat the skin surface)and long application time (several minutes), it is

Fig. 48 Freeze™multipolar RF and itsapplicators, from VenusConcept

Fig. 49 Schematics of a unipolar RF generator

38 Á. Boechat

possible to cause apoptosis of fat cells in bodycontouring procedures. The skin damage functioncan be described by the Arrhenius equation(Lapidoth et al. 2015):

D ¼ Atexp �ΔE=RT½ �

The degree of damage (D) is a linear function ofexposure time, or pulse duration (t), and an exponen-tial function of the tissue temperature (T) (Fig. 51).

Fractional RF

Fractional bipolar RF (FRF) was developed fol-lowing the same concepts and success of frac-tional lasers as described previously and isgaining great popularity in dermatology. The pro-cedure is based on the heating or ablation ofmultiple small points in the skin (MTZ), with aspot size of 100–400 μm, leading to improvements

in the quality of the skin, wrinkle reduction, treat-ment of acne scars, and stretch marks (Lapidothet al. 2015; Brightman et al. 2009; Rongsaard andRummaneethorn 2014).

The RF has the potential to provide differentpatterns of energy and heat distribution from theMTZ shape interaction of fractional lasers. Incontrast to lasers where the thermal effect is lim-ited to the periphery of the ablation crater (ablativeprocedure) or the coagulated column (in non-abla-tive procedures), the RF energy flows through theentire dermis, adding volumetric heating to thefractional treatment. This produces a more effec-tive effect of skin tightening.

There are mainly two types of RF fractionaltechnologies:

1. A matrix of bipolar microelectrodes applyingthe RF energy from the surface

2. A grid of microneedles which internallydeliver the RF energy within the dermis

Fig. 51 Vanquish™, from BTL Aesthetics, uses a fre-quency of 27 MHz, low power, and long exposure timefor fat reduction and body contouring

Fig. 50 The platform Accent Ultra™, from Alma Laser,with a unipolar handpiece operating at 40 MHz

Biophotonics 39

The surface electrodes provide a more superfi-cial effect improving texture and lines, treatingstretch marks and smoothing acne scars. Thebipolar RF is applied with a matrix of activemicroelectrodes as shown in Fig. 52.

A normal bipolar device, described above, usesa large-area electrode and has low-power density,and the current and subsequent heating effect is

limited to the tissue between the electrodes. InFRF, the active electrode is converted into a seriesof microelectrodes, which increases the energydensity, thus producing an ablation effect nearthe electrode, and as the energy flows to thelarge return electrode, it spreads, reducing theeffect which is limited to skin coagulation andskin tightening (Fig. 53). This action is similar to

Fig. 52 Schematics of a fractional RF device

Fig. 53 Impact of the fractional RF in the tissue

40 Á. Boechat

a water nozzle. If we approach the nozzle, and thewater jet is concentrated, we can become exces-sively wet. As we move away from the nozzle, thewater spreads and only a few drops can reach us.

An interesting variation of the fractional bipo-lar RF was developed by Syneron Candela, the“Sublative RF,” used in the Matrix RF andeMatrix devices. The proposal is to deliver heatenergy to the dermal layer of the skin with mini-mal epidermal damage. By controlling the RFcurrent energy and delivery pulse, it is possibleto correct epidermal defects and promote aggres-sive remodeling of the deeper dermis. Since theeffect on the epidermis is minimal, the recoverytime is shorter and it also reduces the risk ofinfection and pigmentary changes (Fig. 54).

The RF microneedle approach is based on theintroduction of a set of fine dielectric coated nee-dle electrodes deep into the skin, which is thenactivated to deliver energy producing a strongdermal remodeling. Since the energy is directlydeposited into the deep dermis, there is no effectin the epidermis, which is preserved. Side effectsand recovery time are minimal. Compared to thesurface fractional RF application, microneedlescan produce higher temperatures in the deep der-mis and therefore stronger collagen contraction,which leads to the improvement of deep wrinklesand skin tightening (Lapidoth et al. 2015).

The RF energy penetration depth is controlledby adjusting the size of the needle, and the effect isconfined to the skin between the electrodes(Fig. 55).

The combination of a superficial fractionaltreatment (Sublative), improving epidermis andcollagen remodeling in the upper dermis, withdeep dermal remodeling produced by themicroneedle device, represents a high potentialfor a complete skin improvement with minimaladverse effects and recovery time.

It is often said that fractional RF is safe for allskin types because of its “color-blind” characteris-tic. However, it should be noted that, while the RFinteraction with skin does not depend on the pres-ence of melanin or any other chromophore, darkerskin types and tanned skin are still susceptible topost-inflammatory hyperpigmentation (PIH). TheFRF will heat and induce a wound healing processresponse in the skin; therefore, it is wise to treatthese high-risk skin types with greater caution.

Another important characteristic of the skinthat influences the RF current treatment is itsconductivity or its resistance (impedance). TheRF current works somehow as water; it flowsthrough the path of less resistance. For example,a piece of metal is an excellent electric conductor(low impedance/resistance), as current easilyflows even with low energy and there is little

Fig. 54 The eMatrix™ and the Sublative™ tip, from Syneron Candela

Biophotonics 41

heat dissipation. On the other extreme, a piece ofplastic does not conduct electricity (high imped-ance). Our skin is located somewhere in the mid-dle between a metal and a plastic, and somecharacteristics can change skin impedance. Ayoung skin, with good vascularity and well mois-turized, is a good electrical conductor (as a metal),while an aged, dry, and poor vascularized skinbehaves more as a piece of plastic. In this case,higher energy is needed for the current to flow,and there is heat dissipation.

The graph of Fig. 56 shows how the conductivitychanges for some skin components as a function ofthe RF operating frequency.We can see that blood isa good conductor than wet skin, and finally fat cellsare bad conductors (Lapidoth et al. 2015).

Temperature also changes the conductivity ofthe skin or its impedance. The RF current prefersthe heated, warm tissue, as shown in the graph ofFig. 57 (Lapidoth et al. 2015).

Therefore, by changing the temperature of thetissue, we can “direct” the RF current. In other

00.01

0.1

Con

duct

ivity

(S

/m)

1

Wet skin Fat Blood

1 2

RF frequency (MHz)

3 4 5 6

Fig. 56 Variation ofconductivity of skincomponents with RFoperating frequency

Fig. 55 INFINI™ skin treatment platform, with surface fractional RF and microneedle handpieces, from Lutronics Inc.

42 Á. Boechat

words, we can force the current to flow or beconcentrated in given parts or layers. For exam-ple, by using a cooling contact tip on the surfaceof the skin, the RF current flows deeper into thedermis. It also can generate certain selectivity, asthe RF current will be concentrated or flow pref-erentially on the skin layer or tissue, whichever ishotter. This technique is the basis for the Electro-Optical Synergy (ELŌS) system developed by

Syneron Candela, which we will present bellow(Fig. 58).

Hybrid Systems

Looking to overcome limitations and to expandthe safety and efficacy of treatments with laser orintense pulsed light (IPL) systems, the industryhas diversified technology associating light toother forms of energy creating the so-calledhybrid systems.

An example of great success of this diversifi-cation is the Electro-Optical Synergy (ELŌS™)technology synergy of light with radio frequency(RF) developed by the inventor of the intensepulsed light, Dr. Shimon Eckhouse, in SyneronCandela, Israel (Doshi and Alster 2005; Sadicket al. 2005; Lapidoth et al. 2005; Sadick andTrelles 2005).

The ELŌS™ technology employs a bipolar RFwith a water-cooled tip simultaneously with thelaser or IPL pulse, as illustrated in Fig. 59.

Fig. 58 Effect of a cooling contact tip on a bipolar RF current

Fig. 57 Variation of tissue impedance with temperature

Biophotonics 43

Following the principle of selectivephotothermolysis, light heats the chromophorepreserving the surrounding tissue. A cool tip pro-tects the surface of the skin and “pushes” the RF todeeper layers. The RF will be concentrated in theheated tissue because it has better conductivity,and this will cause the chromophore to overheatleading to the desired therapeutic effect.

Figure 59 illustrates this synergic effect in hairremoval treatment, but the same occurs in thetreatment of pigmented and vascular lesions,skin rejuvenation, and tightening (in which aninfrared light source in the range from 700 to200 nm is used with bipolar RF) (Fig. 60).

The main advantage of the ELŌS™ is thereduced optical fluency needed for the treatment,thus minimizing patient discomfort during thesession and increasing safety for darker skintypes. Because of the RF action, simultaneouseffects such as skin tightening during a treatmentof pigmented lesions can also happen.

Other applications of this technology are cir-cumferential reduction, cellulite treatment, andskin tightening. In this case, bipolar RF is associ-ated with an infrared source, a lamp emitting from700 to 2,000 nm, or a high-power LED (870 nm),rotating cylinders, which produces massage,drainage, and suction. The cylindrical rollers arethe RF electrodes. The suction causes a skin fold,which increases the penetration of the RF andlight as explained before (Alster and Tanzi 2005;Wanitphakdeedecha and Manuskiatti 2006;Boechat 2009) (Fig. 61).

The goal is to increase the temperature of (up to43 �C) deep tissue, which accelerates the metab-olism of fat cells and thereby reduces their sizeleading to circumferential reduction. For a longerexposure time and higher temperature (45 �C), itis possible to produce apoptosis of fat cells sincethey are more sensitive than skin cells thus reduc-ing localized fat. The effect of skin tighteningoccurs because of the stretching of elastic fibersand the remodeling of collagen, improving theoverall skin quality.

Conclusion

Laser and intense pulsed light systems are purelight sources with important properties, whichallow us to treat accurately and selectively differenttypes of tissue damage, preserving the surroundinghealthy tissue. Synergy with radio frequencyshows how this equipment can still evolve becom-ing safer and more efficient. With the advent offractional skin treatment, a new horizon of appli-cations that are at the same time gentle and effec-tive have emerged in dermatology.

In many applications, light appears as the onlyeffective solution, as in the case of flat vascularlesions in the face, or port-wine stains. It hasbrought a rapid and long-lasting result forunwanted hair removal, the treatment ofpigmented lesions, and tattoo removal. It is usedin skin tightening, cellulite treatment, circumfer-ential reduction, and localized fat reduction. In a

Fig. 59 The ELŌS™ effect, synergy of bipolar RF + light in hair removal

44 Á. Boechat

number of applications in dermatology, lightemerges as an important complement to theexisting techniques, as is the case of rhytidectomyin plastic surgery. It also improves body areas thatnormally are not treated by surgery, such as neck,chest, hands, and arms using ablative ornon-ablative fractional lasers.

The future will certainly bring more efficientand compact devices. We will have a wider rangeof applications and, among them, the develop-ment of lasers that have the ability to act at thecellular level, stimulating the production ofenzymes, which have the purpose of preventingskin aging and skin cancer. Systems that have the

subdermal fat as chromophore can open a newhorizon of applications for circumferential reduc-tion, cellulite treatment, and improved skin qual-ity. The diagnostic medicine will also benefit fromthis development.

The more we study about the effects of theinteraction of light with living tissue, the morewe learn on how to appreciate the variety andcomplexity of these critical interactions. Theresult will certainly open doors to a large numberof remarkable applications in the followingyears.

We only have to “tune in” with the energy oflight!

Fig. 60 (a) ELŌS Plus system, Syneron Candela –multiplatform with several handpieces including laser,IPL, infrared, all associated with bipolar RF, and a

fractional RF. (b) ELŌS handpiece showing the bipolarelectrodes and the IPL simultaneously

Biophotonics 45

Álvaro Boechat, M.Sc., Ph.D., is an electronicsengineer graduated from the Technological Insti-tute of Aeronautics (ITA), São José dos Campos,São Paulo, Brazil; he has a master’s degree (M.Sc.) in optoelectronics and Laser Devices and aPh.D. in Laser Engineering from the University ofHeriot-Watt in Edinburgh, Scotland.With special-ization courses in medical lasers from LaserIndustries in Tel Aviv, Israel, he is currently aconsultant for photomedicine.

Take Home Messages

1. The visible light that we experience in our dayto day is only one facet of a much broaderphysical phenomenon known as “electromag-netic radiation.” The difference between eachlaser or every color of light we see is its wave-length or frequency.

2. All laser devices consist of the resonator/oscil-lator –with the active medium, which producesthe light and thus determines the wavelength;the excitation source (also called pumping) –which delivers power to the active mediumproducing the photons; laser beam deliverysystem from the source to the hand of theoperator; and the handpiece, with focusinglens or a scanning system.

3. Best way to determine which laser or IPL isbest for a given application is to use the prin-ciples of selective photothermolysis: the wave-length that will be only absorbed by the targettissue, pulse duration that will confine the heatto the chromophore, and sufficient energy toreach the desired effect.

4. Radio frequency effect on skin does notdepend on chromophore absorption, whatmakes it safe to treat all skin types.

5. The radio frequency effect in the skin is a linearfunction of time and an exponential function oftemperature. A small change in treatment tem-perature by a few degrees will increase the tissueeffect by several times; on the other hand, it isnecessary to increase the application time byseveral minutes or hours to get the same effect.

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48 Á. Boechat

Intense Pulsed Lightfor Photorejuvenation

Sílvia Karina Kaminsky Jedwab andCaio Roberto Shwafaty de Siqueira

AbstractIntense pulsed light (IPL) is a non-laser, versa-tile light technology that is a key tool in derma-tology. It is widely used for the treatment ofphotoaged skin. Also, it is used for hair removal,acne treatment, and treatment of vascularlesions. IPL works through selective photo-thermolysis to reduce dark spots, telangiectasia,wrinkles, and skin laxity (photorejuvenation)caused by chronic sun exposure. This chapterwill discuss all the aspects about the physicsbehind the IPL technology, clinical indications,treatment, and possible complications.

KeywordsIPL • Photorejuvenation • Photoage • Darkspots • Telangiectasia • Wrinkles • Skin laxity

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

Basic Concepts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49The Biology of Photoaging . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

The Biophysics Behind IPL . . . . . . . . . . . . . . . . . . . . . . . . . 50

The Clinical Aspects of IPL on the DailyPractice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

Take Home Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

Introduction

The appearance of the skin has been a constantgrowing reason to visit dermatologist’s clinics notonly for aesthetics reasons aiming youth but alsofor medical reasons, such as treat and prevent skindiseases. Therefore, the number of procedures toimprove the quality of the skin with laser andnon-laser light devices grows each year(El-Domyati et al. 2015).

Themain goal of this chapter is to discuss all theissues regarding the use of intense pulsed light(IPL) for photorejuvenation of the skin. Thismodal-ity of treatment is popular because it doesn’t causeepidermis disruption, limiting adverse effects andminimizing downtime (El-Domyati et al. 2015).

Basic Concepts

The Biology of Photoaging

The aging process of the skin reflects both extrin-sic and intrinsic factors (Table 1) (Balibas et al.2010; Friedmann et al. 2014).

S.K.K. Jedwab (*)Escola Paulista de Medicina, Universidade Federal de SãoPaulo, São Paulo, Brazil

Skinlaser Brasil, São Paulo, Brazile-mail: silvia@skinlaser.com.br

C.R. Shwafaty de SiqueiraFaculdade de Medicina de Botucatu, UniversidadeEstadual Paulista, São Paulo, Brazile-mail: caioshwafaty@me.com

# Springer International Publishing AG 2018M.C.A. Issa, B. Tamura (eds.), Lasers, Lights and Other Technologies, Clinical Approaches and Procedures inCosmetic Dermatology 3, https://doi.org/10.1007/978-3-319-16799-2_2

49

The intrinsic factors are related to chronolog-ical senescence of dermal fibroblasts, leading tolower collagen and hyaluronic acid productionthat leads to poor extracellular dermal matrix(Goldberg 2012; Friedmann et al. 2014).

The extrinsic factors are related to long-term,chronic ultraviolet (UV) light exposure (usuallyby the sun), pollution, and tobacco smoke. All ofthem enhance the breakdown and fragmentationof collagen fibers through the production of reac-tive oxygen species and activator protein-I, whichupregulates abnormal expression of matrix meta-lloproteinases, the main reason that destroys col-lagen fibers (El-Domyati et al. 2015; Friedmannet al. 2014).

In normal skin, the transforming growth factor-β (TGF-β) upregulates the collagen production(Ali et al. 2013). At the photo-damaged skin,TGF-β1 has its levels decreased, causing reducedcollagen production. This results in poor levels ofcollagen I and III at the dermal matrix (Ali et al.2013; El-Domyati et al. 2015).

Also, it is well-known that the chronic inflam-matory response to long-term UV light exposureleads to permanent DNA damage. Locally at theskin, UV light may trigger DNA photoproducts,isomerization of trans- to cis-isoform of urocanicacid in the stratum corneum, and UV-inducedalteration of the membrane redox potential. Allthese events lead to UV-induced immuneresponse that causes immunosuppressive effects,UV mutagenesis, and UV carcinogenesis. TheDNA repair pathways no longer are capable ofdetecting and repairing effectively the DNAdefects, leading to replication and transcription

of damaged genes. Besides the obvious carcino-genic and mutagenic consequences, these eventsalso change the normal half-life time of epidermalcells, leading to excessive (or even abnormal)proliferation of melanocytes and keratinocytes atthe basal and Malpighi’s layers, respectively(Bolognia et al. 2008).

Clinically, all these events result in laxity, chronictanned skin, wrinkles, telangiectasia, rough and sag-ging skin, andmelanocytic lesions (like lentigos andephelides), all together named photoaging (Goldand Biron 2013; Sasaya et al. 2011).

The Biophysics Behind IPL

IPL devices are non-lasers, non-ablative sourcesof high-intensity light that use a high-outputxenon flash pump light source to produce a poly-chromatic, noncoherent, non-collimated diffusedlight with broad wavelength (500 nanometers(nm) – 1,300 nm). There are simultaneous emis-sions of green, yellow, red, and infrared wave-lengths (Mattos et al. 2009; Balibas et al. 2010;Goldberg 2012; Ali et al. 2013; El-Domyati et al.2011; Friedmann et al. 2014).

IPL was first approved by the Food and DrugAdministration (FDA – USA) in 1998 on thetreatment of photoaged skin.

Nowadays, there are more than 300 differentIPL devices available on the market. The lastgeneration of devices is much safer because allof them have protective features to prevent epi-dermal damage by excessive heat. Most of themuse cooling systems of sapphire or quartz

Table 1 Biologic factors behind skin aging

Intrinsic factors Extrinsic factors

Chronological senescence of dermal fibroblasts Chronic exposure to UV light

Lower production of collagen and hyaluronic acid Pollution

Poor extracellular dermal matrix Tobacco smoke

Production of reactive oxygen species and activator protein-I

Higher expression of metalloproteinases

Higher fragmentation of collagen fibers

Decreased TGF-β1 levels

Chronic inflammatory response

Defects on DNA repair system

UV ultraviolet, TGF transforming growth factor, DNA deoxyribonucleic acid

50 S.K.K. Jedwab and C.R. Shwafaty de Siqueira

interface to promote this safety at the epidermallayer (Goldberg 2012). The light pulse is usuallysingle, but they can be double or triple dependingon the device, with smooth delivery of energy,with peak flow occurring at the early shot, squaredshaped. It is not possible to deliver energy innanoseconds as the Q-switched lasers. This sys-tem prevents prolonged heating of epidermis,treating the majority of the chromophores at thesame time with one single shot. The pulse dura-tion time should be equal or below the thermalrelaxation time (TRT) of the target structures toprevent unselected damage to the surroundingtissue, but should be at least 50 % of the TRT’stargets to generate their cell death (Mattos et al.2009; Balibas et al. 2010; Goldberg 2012). Thenormal skin has an average of 10 milliseconds(ms) of TRT. Vessels with diameter of 0.1 mmhave TRT of 10 ms; larger vessels (0.3 mm) haveTRT of 100 ms (Goldberg 2012).

The handpiece allows the physician to choosewhich wavelength will be applied into the patients’skin. These cut-off filters block the lower wave-lengths that are not desired to the treatment, butdon’t filter the higher wavelengths. The usual fil-ters available on the market are 400 nm, 515 nm,540 nm, 550 nm, 560 nm, 570 nm, 590 nm,595 nm, 615 nm, 650 nm, 695 nm, and 750 nm(Fig. 1). The energy fluency varies from 8 to100 joules (J), and the pulse time varies from 5 to100 ms, depending on each device.

IPL works at skin sites based on the principleof selective photothermolysis, first described byAnderson and Parrish with pulsed dye lasers(Railan and Kilmer 2000). The normal skin con-tains substances that act as chromophores (i.e.,substances that absorb energy depending on theirintrinsic color, transforming them into heat), suchas hemoglobin, carotene, melanin, and water(Fig. 2) (Goldberg 2012). Each substance hastheir own curve of maximum and minimumabsorption of light (medium wavelengths of lightabsorption for deoxyhemoglobin are 550–560 nm,for oxyhemoglobin are 540 nm and 575–580 nm,and for vascular lesions and melanin are400–755 nm) (Friedmann et al. 2014). The photo-damaged skin contains higher amounts of thesechromophores, distributed in different forms(localized spots or diffuse, multiple-layer manner).These substances have the capacity to absorb thephotons, transforming it into heat, which destroysthe colored target and dissipates the heat into thesurrounding area, promoting the activation of col-lagen production by the fibroblasts (collagen I andIII) through cytokine activation and upregulationof TGF-β1 (Balibas et al. 2010; Ali et al. 2013).

IPL light targets all the chromophores at thesame time, specially melanin and hemoglobin.The overall immediate end point after the appli-cation of IPL into the skin is darkening ofmelanocytic lesions, blurry telangiectasia, andlight redness through all skin surface treated.

Fig. 1 Figure showingspecial smaller tips (on theleft) and cut-off filters(on the right)

Intense Pulsed Light for Photorejuvenation 51

The goal of treating vascular lesions is to raisethe blood vessel temperature high enough to causeits coagulation, leading to its destruction andreplacement by fibrous granulation tissue. Oxyhe-moglobin (red lesions), deoxygenated hemoglobin(blue lesions), and methemoglobin can be targetedby IPL (peak absorption of 418 nm, 542 nm, and577 nm, respectively). Therefore, the best IPL filtersto treat vascular lesions stay between 400 and600 nm. Some devices allow the adjustment of avascular tip into the handpiece, to increase thedelivered energy only at the desired target (Fig. 1).

The goal of treating pigmentary lesions is toelevate the rapid differentiation of keratinocytesinduced by thermal heating, using melanin astarget. This results in an upward transfer ofdestroyed and non-destroyed melanosomesalong the necrotic keratinocytes, resulting intheir elimination as crusts that can be seen on thedays after the treatment session. Lower cut-offfilters are the usual best choice for treatingmelanocytic lesions, usually around 400–540 nm(Goldberg 2012).

The goal of treating skin laxity and wrinkles is toheat dermal water to stimulate dermal fibroblasts,which increases the synthesis of extracellularmatrixproteins, such as collagen I and III and elastin. Thehigher cut-off filters are the best choice to achievethese goals, usually around 600–1,200 nm (Gold-berg 2012; El-Domyati et al. 2011).

The histopathology findings that confirm allthese changes are seen as an increase in the num-ber of fibroblasts associated with an increase incollagen compaction, thickening, and density.This also indicates collagen remodeling. Also,

the dermal papillae and the interpapillary crestsare more pronounced, showing the higher deposi-tion of collagen after IPL treatments. The melaninpigment has a more homogenous distribution atthe basal layer. The number and diameter of bloodvessels from the superficial plexus reduced, aswell, in one-third of treated patients (Fig. 3)(Scattone et al. 2012; Friedmann et al. 2014).

The Clinical Aspects of IPL on the DailyPractice

IPL is a key tool in the treatment ofphotoaged skin.

In the first place, the physician should establishthe skin color type of the photoaged skin accord-ingly to Fitzpatrick’s classification for skin types

400 500 600 700 800 900 1000

(1064)(810)

(755)(585, 595)

Absorptioncoefficient

1100nm

Melaninwateroxihemoglobin

Wavelength (nm)

Fig. 2 Figure showing the absorption curves of skin chromophores

Fig. 3 Patient laid down, with thin layer of transparent gelat the skin face, receiving IPL treatment with IPL 695 nmfilter, sapphire cooling system on

52 S.K.K. Jedwab and C.R. Shwafaty de Siqueira

(Table 2). The use of IPL on higher skin colortypes (� IV) and on highly photo-damaged skin(too much targets) demands lower fluencies,higher milliseconds, cooling systems on, and mul-tiple treatment sessions.

Pregnancy, lactation, infected skin, use ofphotosensitizing medications or oral retinoid,photosensitivity by any disease, surreal expectan-cies, keloids, hypertrophic scars, suntan, andphoto-induced skin disorders are exclusioncriteria for treatment (Table 3) (Balibas et al.2010).

The number of sessions varies depending oneach patient, i.e., it depends on the skin color typeand the degree of photoaging. Usually four to sixsessions are required to achieve the overallimprovement of the skin (Fig. 4).

Before the treatment starts at the office, oneshould lay down the patient into a comfort officechair; clean the skin area to be treated with lotionswithout high concentrations of alcohol, removingmakeup and sunscreen. Photos should be taken, asa term of consentient should be signed explainingthe possible outcomes and results from the treat-ment, as well as possible complications. The useof topic cream with anesthetics is not necessary. Infact, they can cause vasoconstriction, decreasing

the quantity of hemoglobin at the target site,reducing overall results (Mattos et al. 2009).

The patient and the staff must use eye protec-tion at all time during application. The skin shouldbe covered with a thin layer of transparent gel(like those used for ultrasound exams), cooledor not.

Before initiating the treatment, the doctor musttell the patient that the light will be triggered toreduce patient anxiety (Fig. 5). Usually we startthe application with the chosen parameters at theborder of the area to be treated, specially coveredareas, to prevent any complications on exposedsites (Balibas et al. 2010). The handpiece shouldbe applied perpendicularly to the skin surface,gently touching it. After three to four shots, weshould stop the treatment and look into the skin.The immediate end point should be slight rednessof the skin, darkening of brown spots, and blurri-ness of telangiectasias (Fig. 6). Each spot shouldoverlap the previous one by 10 %. When treatingisolated and resilient lesions, the physician mayuse a perforated plastic shield with varying aper-ture sizes (Fig. 7) or small special tips applied intothe handpiece (Fig. 1), to deliver higher energyonly to that target (Balibas et al. 2010). If one seesurticarias, blistering (Fig. 4), or gray-toned skin,then the treatment should stop immediately, theparameters should be reviewed, and ice or coolingsubstances and topic corticosteroid creams shouldbe immediately applied, because these are signs ofexcessive heating of the skin, with possibleburning.

In the areas that more results are needed, onecould apply the shots twice, but the second appli-cation should be perpendicular to the first one,avoiding “zebra marking.” Usually the patientsfeel little discomfort, little heat, and little pain

Table 2 Fitzpatrick’s skin color classification

Skin type Skin color Characteristics

I White; very fair, red or blonde hair; blue eyes; freckles Always burns, never tans

II White, fair, red or blond hair; blue, hazel or green eyes Usually burns, tans with difficulty

III Cream white, fair with any eye or hair color (common) Sometimes mild burn, gradually tans

IV Brown; typical Mediterranean Caucasian skin Rarely burns, tans with ease

V Dark brown; mid-eastern skin types Very rarely burns, tans easily

VI Black Never burns, tans very easily

Table 3 Exclusion criteria’s for IPL treatments

Pregnancy

Lactation

Infected skin

Photosensitizing medications/oral retinoid

Photosensitivity

Surreal expectancies

Scars: keloids, hypertrophic

Suntan

Photo-induced skin disorders

Intense Pulsed Light for Photorejuvenation 53

during the session. Anything different from thatshould alert the doctor to review the parametersthat has been used, because it can mean excessiveheating of the skin.

At the end of treatment, the staff should applyspray thermal water and soothing creams toreduce skin redness and discomfort and alsobroadband sunscreen creams.

Overall, the physician should keep in mind thatthe targets should be treated in layers, because thisis actually how the excessive pigments aredisplayed on the skin. First, we should reducedarker brown spots and superficial telangiectasia,and then we can stimulate collagen at the deeperlayers. Most of the complications occur when onetries to destroy all the targets, at all layers, at thesame time, with the same high energy. Anotherreminder is that one should reduce the parameters

(lower energies, higher pulse time duration) whenthe patient has too much targets at the skin area tobe treated, to prevent excessive heating of the skin.

For skin color types � III, we can start thetreatment by choosing the 515–540 nm filters,10–20 ms, 10–15 J/cm2. If there is too muchtargets, one should use 15–20 ms, 8–13 J/cm2

(Table 4). With the progression of the treatment,targets at the middle layers will reduce, so thephysician can elevate the energy delivered andreduce the pulse duration to target the remaininglighter chromophores (localized vessels, lighterdark spots) at the superficial layers, using lowerfilters, usually applied specifically at the target.Also, the physician can elevate the energy deliv-ered to the deeper layers, using higher filters andhigher milliseconds to stimulate the overall skintightening.

Fig. 4 (Left) Histopathology of photoaged skin (A)before and (B) after 3 IPL treatments, stained with hema-toxylin and eosin (HE), x 200. Note that were increase ininterpapillary crests. (Right) The same sample as before,stained with Masson´s trichrome, x 200. (A) before treat-ment and (B) after 3 IPL treatments, showing thickening

and compaction of collagen fibers. (Adapted from ScattoneL, Alchorne MMA, Michalany N, Miot HA, Higashi VS.Histopathologic Changes Induced by Intense Pulsed Lightin the Treatment of Poikiloderma of Civatte. DermatologicSurgery. 2012;38:1010-1016.)

54 S.K.K. Jedwab and C.R. Shwafaty de Siqueira

For skin color types � IV, we can start treat-ment using 570–695 nm filters, trying to avoid thenatural higher concentrations of melanin pre-sented at the basal layer of the epidermis onthese color skin types, 20–100 ms, 6–10 J/cm2

(Table 4). With the progression of the treatment,targets will reduce, so the physician can elevatethe energy (but maintaining the long millisec-onds) and deepen the light penetration usinghigher filters.

The healing process of facial skin differs fromthe skin of other areas, because the higher densityof sebaceous glands at the facial skin providesquicker healing by prompt cell restoration. So,application of IPL outside the facial skin demandshigher caution, lower fluencies, higher pulse time

durations, and overlapping the application of thelight so it doesn’t cause “zebra effect.” Usually ittakes 7–10 days to complete healing of the facialskin; it may double that time of heal outside thefacial area.

The authors use mostly the 540 nm and 695 nmfilters at their routine dermatologic practice,because these two filters targets both superficialand deep chromophores in a global manner.

IPL can be associated with other treatments,with or without devices, at the same session. Wemust advise that the parameters chosen for thesemultiple simultaneous treatments should be moreconservative, since we are combining differentways of treating the whole skin at the same timesession.

Fig. 6 Perforated plastic shield with varying aperturesizes to isolate specific targets

Fig. 7 (Left) Pretreatment and (Right) after treatment with IPL Harmony (Alma Lasers – Israel) 540 nm, 12 a 14 J/cm2,12 ms

Fig. 5 Immediate end-point after IPL treatment: slightlyredness skin, darkening of brown spots, blurriness oftelangiectasias

Intense Pulsed Light for Photorejuvenation 55

The authors have experience in combining atthe same session IPL with lasers, chemical peel-ings, and laser hair removal.

Laser Alexandrite 755 nm may be used whendark spots are resilient to IPL or to epilate fewfacial hairs before any other laser is applied, forangiomas or for larger telangiectasias.

Laser Ruby 694 nm Q-switched (QS) andLaser KTP (potassium titanyl phosphate)532 nm QS may be used to treat lighter brownspots resilient to IPL and Laser Alexandrite.

Laser Nd:YAG (neodymium-doped yttriumaluminum garnet) 1,064 nm long-pulsed may beused for telangiectasias larger than 0.1 mm and forepilation of facial hair in dark-skinned patients.

Laser Nd:YAG QS device may be used for skintightening, to treat lighter freckles and dark spotsand reduction of skin sebaceous pores.

Laser fractionated ablative (CO2 10,600 nmand erbium 2,940 nm) may be used for skin tight-ening, wrinkle reduction, comedone reduction,and rough-aged skin improvement.

Also, IPL can be associated with all types ofchemical peelings, such as retinoid acid, glycolicacid, Jessner Solution (combination of resorcinol,salicylic acid, and lactic acid), salicylic acid, tri-chloroacetic acid (TCA), phenol acid, mandelicacid, and so on. One must point out that theassociation between IPL and chemical peelingsshould not occur when the end point has alreadybeen achieved by the IPL itself and/or the patientrefers that the skin is burning too much after IPLtreatment. Therefore, we prevent complicationsthat may arise from overtreatment of the skin.

Applications with botulinum toxin andhyaluronic acid fillers may be associated withIPL sessions, usually right after this ends.

After treatment at home, patient must use prod-ucts to minimize excessive inflammation. For allsituations, patient should use broadband sun-screen, cleansing gel to wash the treated skin,spray thermal water for burning relief, topicallow-potency corticosteroid cream if the patientpresents with higher burning sensation or itchingsensation, and herpes simplex prophylaxis if thereis personal history of this disease (Balibas et al.2010). If the patient was treated only with IPLand/or non-ablative lasers, one should use simplecreams or gel creams, usually containing alpha-bisabolol, vitamin C, and essential oils (grapeseeds, sunflower seeds). If the patient was treatedwith IPL associated with ablative lasers, oneshould use creams or ointments containinghealing substances, as well antimicrobials agents(copper, zinc, triclosan, vaseline).

During the 7–15 days after the session, thetreated skins will peel off gently. The dark spotswill become darker with little crusts, and thevanished telangiectasias may reappear blurred orbluish. After the minimum period of 7 days afterinitial treatment, the patient can be submitted toother healing/tightening procedures, like radio-frequency and micro-focused ultrasound.

Possible side effects are (Table 5) blistering,purpura, excessive crusting, persistent erythema,dyschromias, irritating contact dermatitis, atro-phy, scarring, hypertrophy scarring, keloid forma-tion, and infection (bacterial and/or viral) (Balibaset al. 2010; Friedmann et al. 2014). All of thesecan be prevented through correct indication andindividualization of parameters and respect to theskin color type of the patient. We can divide thesecomplications in two groups: immediate compli-cations and late complications.

Table 4 Initial parameters suggested for IPL treatments

Targets Skin color type � III Skin color type � IV

Little to moderate quantity 515–540 nm 570–695 nm

10–20 ms 20–100 ms

10–15 J/cm2 6–10 J/cm2

Moderate to high quantity 515–540 nm 570–695 nm

15–20 ms 100 ms

8–13 J/cm2 6–8 J/cm2

IPL intense pulsed light, nm nanometers, ms milliseconds, J joule

56 S.K.K. Jedwab and C.R. Shwafaty de Siqueira

Immediate complications are those related toexcessive energy delivered into the skin. Possiblecauses are the following wrong parameters: exces-sive joules delivered or little time for thermalrelaxation, skin tanned or too many targets at theskin location, andmisclassification of the true skincolor type of the patient.

The patient may present with acute burningpain, urticarias, purpura, gray skin, and blistersright after the treatment (Fig. 4).

When these occur, the physician must imme-diately stop the procedure, apply cooling sub-stances, and apply high-potency corticosteroidcream into the skin site. Low-intensity laser(LIL) can be applied into the burned areas, in adaily basis, until total healing, because this modal-ity of treatment blocks excessive inflammation.Patient should maintain use of medium- to high-potency corticosteroid creams at home, twice aday, until total healing (usually 7–10 days), andavoid sun by physical blocking and the use ofbroadband sunscreens.

Late complications are scars (atrophy, keloids,hypertrophic scars), infections, allergy anddyschromias, and both postinflammatory hyper-cromia (PIHE) and hypochromia (PIHO). Theseusually are transient complications, resolvingspontaneously within 2–3 months after it started.

The scars (Fig. 8) usually occur after episodeswith burned skin, especially after blistering. Over-all, the scars may become white and atrophic.Depending on the personal background of thepatient, keloids and hypertrophic scars candevelop on specific locations (the jaw line, ear-lobe, chest, back, neck, upper arms, and abdo-men). Just after the healing process has endedafter the immediate complications, the skin may

show persistent erythema. This may sign out thatexcessive inflammation is taking on, which maytrigger the formation of the mentioned scars. Toprevent them, besides treating the immediatecomplications, the physician should apply at thepersistent erythematous area IPL as photody-namic therapy every week (very low fluencybetween 6 and 10 J, filters 540–695 nm, 100 msof time pulse), LIL on daily basis, and anti-inflammatory creams (medium-potency cortico-steroid creams, rose hip oil, silicone oil). If keloidscars or hypertrophic scars occur even after thepreventive treatment, the physician may treat thescars with local infiltration with injectable corti-costeroids or bleomycin, once a month until totalregression. For cases of keloid scars resistant toinfiltration therapy, surgical options may be indi-cated, like shaving of the lesion associated withbeta therapy. If atrophic scars occur, the physicianmay treat them with fractional ablative lasers andchemical peelings (like chemical reconstructionof skin scars [CROSS] chemical peeling), in mul-tiple sessions, once a month (Fig. 9).

Infections are rare complications, but they canbe devastating since they may arise suddenlywithout warnings. The most common one is acti-vation of herpes simplex virus, which may lead tolocal or widespread infection at the treated area(simulating Kaposi varicelliform eruption seen onatopic skin). Bacterial infections are rare, takingplace most often around contaminated skin sites

Table 5 Possible side effects of IPL treatment

Blister

Purpura

Excessive crusting

Persistent erythema

Dyschromias

Irritating contact dermatitis

Scars: atrophic, hypertrophic, keloid

Infections

Fig. 8 Acute immediate complication of IPL treatment:blister and urticaria over a hemangioma lesion at the face ofa male patient

Intense Pulsed Light for Photorejuvenation 57

(perioral, paranasal, perineum, hands, feet, axil-lae, skin site with bacterial folliculitis, or any otherbacterial skin infection), usually by Gram-positive bacteria (Streptococcus sp., Staphylococ-cus sp.). Risk factors for them are high-energyablative fractionated lasers, high-energy IPL,burning complications, medium-potency chemi-cal peelings (Jessner Solution associated withTCA), and large areas treated at the same time.The most important measure to prevent them is toanticipate them, by prescribing herpes simplexprophylaxis for the patients with this backgroundwhen they are submitted to the treatments abovelisted (to be initiated 1 day before the treatment),as well as prescribe topical and/or oral antibioticsor antimicrobial topic creams to use after theprocedure, until total healing of the treated skinsite. We don’t recommend treating any skin sitewith IPL with evident infection of any kind.

Allergies are rare, it may occur when epidermaldisruption is seen, leading to possible higherabsorption of allergens and/or of irritating sub-stances. In all cases, the physician should not useknown allergenic substances referred by thepatient; after the treatment, the use of creams forbetter healing of the skin minimizes the risks ofallergic contact dermatitis and/or irritating contactdermatitis. If it happens, the patient should applyto the skin low- to moderate-potency corticoste-roid creams, twice a day, for 7–10 days.

Dyschromias are the most common late compli-cation seen after IPL treatments. Persistent PIHE

can be treated with superficial chemical peelings(like retinoid acid and Jessner Solution), asso-ciated or not with Laser Nd:YAG QS 1,064 nm.At home, patients should use Kligman’s formularetinoid acid 0, 05%ð þhydroquinone 4% þacetonide fluorcinolona 0:05 % creamÞ or simi-lar formulas. Persistent PIHE will heal within3–12 months after the complication.

When persistent PIHO occurs, the physicianmust examine the site through Wood’s lamp(WL). If the area is highlighted by the WL, itindicates that the hypochromia may be really per-sistent; so it should be treated with phototherapynarrowband UVB, weekly, until total healing.

If the area is not highlighted by the WL, itindicates that it is transient, so the physician mayobserve the natural healing or try to make thesurrounding skin lighter with IPL and/or chemicalpeelings.

For all cases of PIHO, patients should alsoavoid direct sun exposure, use broadband sun-screens, and use Kligman’s formula at home.PIHO usually will heal within 3–15 months.

IPL treatment sessions can be repeated at30–45 days intervals. Normally, patients requirethree to six sessions to achieve global improve-ment, but this must be pointed out that it dependson individual characteristics. Overall, treatmentresults in better clinical appearance in skin tex-ture, reduction in mottled appearance, and clear-ance of pigmented and vascular lesions (Scattoneet al. 2012; Gold and Biron 2013).

Scars

Hypertrophic /Keloid Persistent ErythemaAtrophic

- Fractionalablative Lasers

-ChemicalPeelings

- Infiltration

- Shaving

- Betatherapy

- IPL as FDT

- LIL

- Topictreatment

Fig. 9 Flowchart on howto proceed on scars afterIPL treatments

58 S.K.K. Jedwab and C.R. Shwafaty de Siqueira

Take Home Messages

– IPL is a key treatment for patients withphotoaged skin.

– IPL devices are versatile, but one should alwayskeep in mind that the individualization of treat-ment should be the leading role to success onachieving the goals of youth and healthy skin.

– Defining the true patient’s skin color type is themain measure to avoid complications and toachieve the main goals of the treatment.

– As with lasers, IPL works through selectivephotothermolysis, in which the skin chromo-phores absorb photons from the IPL light,causing heat damage.

– The treatment support after sessions should beemphasized, because this measure helps thequick healing of the skin, reducing the chancesof all complications.

References

Ali MM, Porter RM, Gonzalez ML. Intense pulsed lightenhances transforming growth factor beta1/Smad3 sig-naling in acne-prone skin. J Cosmet Dermatol.2013;12:195–203.

Balibas P, Schreml S, Szeimies RM, Landthaler M. Intensepulsed light (IPL): a review. Lasers Surg Med.2010;42:93–104.

Bolognia JL, Jorizzo JL, Rapini RP. Dermatology. 2nded. London: Mosby; 2008. p. 1321–31.

El-Domyati M, El-Ammawi TS, Moawad O, Medhat W,Mahoney MG, Uitto J. Intense pulsed light photo-rejuvenation: a histological and immunohistochemicalevaluation. J Drugs Dermatol. 2011;10(11):1246–52.

El-Domyati M, El-Ammawi TS, Moawad O, Medhat W,Mahoney MG, Uitto J. Expression of transforminggrowth factor-β after different non-invasive facialrejuvenation modalities. Int J Dermatol. 2015;54:396–404.

Friedmann DP, Fabi SG, Goldman MP. Combination ofintense pulsed light, sculptra, and ultherapy for treat-ment of the aging face. J Cosmet Dermatol.2014;13:109–18.

Gold MH, Biron JA. Safety and cosmetic effects of photo-dynamic therapy using hexyl aminolevulinate andintense pulsed light: a pilot study conducted in subjectswith mild-to-moderate facial photodamage. J ClinAesthet Dermatol. 2013;6(10):27–31.

Goldberg DJ. Current trends in intense pulsed light. J ClinAesthet Dermatol. 2012;5(6):45–53.

Mattos R, Filippo A, Torezan L, Campos V. Non-laserenergy sources on rejuvenescence: part II. Surg CosmetDermatol. 2009;1(2):80–6.

Railan D, Kilmer S. Treatment of benign pigmented cuta-neous lesions. Goldman’s cutaneousand cosmetic lasersurgery. Elsevier; 2000. p. 93–108.

Sasaya H, Kawada A, Wada T, Hirao A, Oiso N. Clinicaleffectiveness of intense pulsed light therapy forsolar lentigines of the hands. Dermatol Ther.2011;24:584–6.

Scattone L, Alchorne MMA, Michalany N, Miot HA,Higashi VS. Histopathologic changes induced byintense pulsed light in the treatment of poikilodermaof civatte. Dermatol Surg. 2012;38:1010–6.

Intense Pulsed Light for Photorejuvenation 59

Intense Pulsed Light for Rosaceaand Other Indications

Juliana Merheb Jordão and Luiza Pitassi

AbstractIntense pulsed light (IPL) treatment is one of themost effective procedures for patients with vas-cular and pigmented lesions as well as for pho-toaging. The nonablative nature of IPL makes itan increasingly attractive alternative for patientsunwilling to accept the adverse effects associatedwith other procedures. ILP has been used widelyto treat a number of lesions, including benignpigmented lesions, inflammatory acne, hypertro-phic scars, hair removal, and a variety of vascularlesions such as port-wine stains, hemangiomas,telangiectasias, poikiloderma of Civatte, androsacea. In the last years, many studies and casereports have been written with different indica-tions for IPL expanding its use. Those studiesshowed that IPL represents a valid therapeuticsupport with excellent outcomes and low sideeffects. However, it should be underlined thatthe use and the effectiveness of IPL are stronglyrelated to the operator’s experience.

KeywordsIntense pulsed light • IPL technology •Rosacea • Vascular lesions

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62

History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62

Basic Concepts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63Intense Pulsed Light Wavelengths . . . . . . . . . . . . . . . . . . . . 63Pulse Duration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

Selectivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63Treatment Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

Mechanisms of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

Rosacea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

Other Vascular Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65Hemangioma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65Poikiloderma of Civatte . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66Nasal Telangiectasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67Leg Telangiectasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67Striae Distensae (SD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67Port-Wine Stain (PWS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68Hypertrophic Scars and Keloids . . . . . . . . . . . . . . . . . . . . . . 68

Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69

Side Effects and Their Managements . . . . . . . . . . . . . . 69

Take Home Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70

J.M. Jordão (*)Skin and Laser Center of Boom, Boom, Belgium

Department of Hospital Universitário Evangélico deCuritiba, Curitiba, PR, Brazile-mail: dra.julianajordao@hotmail.com

L. PitassiDivision of Dermatology, Department of Medicine, StateUniversity of Campinas (UNICAMP), Campinas, SP,Brazile-mail: luiza@luizapitassi.com.br; pitassi@yahoo.com

# Springer International Publishing AG 2018M.C.A. Issa, B. Tamura (eds.), Lasers, Lights and Other Technologies, Clinical Approaches and Procedures inCosmetic Dermatology 3, https://doi.org/10.1007/978-3-319-16799-2_3

61

Introduction

Intense pulsed light (IPL) systems have evolvedsince they were introduced into medical practice20 years ago. IPL devices use flashlamps and band-pass filters to emit noncoherent, noncollimated,polychromatic light energy at different wave-lengths that target specific chromophores(González-Rodríguez and Lorente-Gualb 2015;Babilas et al. 2010). IPL systems mainly targethemoglobin and melanin, with greatest efficacy inthe treatment of color rather than texture, accordingto certain authors. However, despite discussionover whether they can remodel collagen, theyhave proved to be effective for skin rejuvenation(González-Rodríguez and Lorente-Gualb 2015).

This selective targeting capability makes IPL aversatile therapy with many applications such as thetreatment of unwanted hair growth, vascular lesions,pigmented lesions, and acne vulgaris and as a lightsource for photodynamic therapy (PDT) (González-Rodríguez and Lorente-Gualb 2015; Babilas 2010).

Similar to lasers, the basic principle of IPLdevices is the selective thermal damage of thetarget structure (Babilas 2010). The combinationof prescribed wavelengths, fluences, pulse dura-tions, and pulse intervals facilitates the treatmentof this wide spectrum of skin conditions. Thelarge spot size is also a great advantage in termsof treatment duration (Babilas et al. 2010).

IPL was first indicated for the treatment of vas-cular malformations (Babilas et al. 2010). Actually,it has been usedwidely to treat a number of vascularlesions, including port-wine stains, hemangiomas,telangiectasias, poikiloderma of Civatte, and rosa-cea (Ichikawa and Furue 2013). The Food andDrugAdministration (FDA) has approved intense pulsedlight devices for the treatment of this variety ofbenign pigmentary and vascular lesions, but therange of disease that can be treated with IPL con-tinues to expand (Wat et al. 2014).

History

Muhlbauer et al. first described the use of poly-chromatic infrared light in 1976 for the treatmentof vascular malformations (Babilas et al. 2010).

The effects produced by applying a light source totissue can be explained by the principle of selec-tive photothermolysis, as described by Andersonand Parrish (1983). Thus, the energy supplied to atissue has a selective action on a target molecule,denoted the chromophore, with no or minimalimpact on the adjacent structures. This selectiveaction is the underlying principle by which intensepulsed light works (González-Rodríguez andLorente-Gualb 2015).

In 1990, Goldman and Eckhouse described anew high-intensity flashlamp as a suitable tool fortreating vascular lesions (Goldman and Eckhouse1996; Babilas et al. 2010). In 1994, the Israeliengineer Shimon Eckhouse managed to producea broad-spectrum stimulated light emission,thereby creating IPL. The US Food and DrugAdministration approved the technique for thera-peutic ends in 1997, after the first article on theiruse in dermatology, when Raulin et al. used themsuccessfully to treat 14 patients with telangiecta-sias of the face and legs or with poikiloderma ofCivatte. Shortly afterward, the same authorspublished two cases of permanent hair removaland subsequently have conducted several morestandardized studies that have demonstrated theefficacy and safety of the technique (Raulin et al.1997; González-Rodríguez and Lorente-Gualb2015).

First-generation IPL devices emit light of theinfrared part of the spectrum, which prevalentlyled to epithelial damage and a high incidence ofside effects. Second-generation IPL devices usewater to filter off the infrared part of the lightspectrum, keeping the wavelength spectrumbetween 515 and 950 nm. This reduces the riskof side effects (Babilas et al. 2010; González-Rodríguez and Lorente-Gualb 2015). Coolingsystems are used to protect the epidermis in con-tact with the crystal (González-Rodríguez andLorente-Gualb 2015). In IPL devices, similar tolasers, the basic principle is the absorption ofphotons by endogenous or exogenous chromo-phores within the skin, generating heat and, sub-sequently, destructing target structure (Babilaset al. 2010).

In the following years, multiple technical mod-ifications allowed an easier handling, increased

62 J.M. Jordão and L. Pitassi

safety, and amplifying the spectrum of potentialindications. The emission spectrum of IPLsranges from 400 to 1,300 nm, and pulse durationranges from 2 to 200 ms. Convertible cutoff filtersof IPL devices can be easily adapted to the desiredwavelength, allowing certain versatility (Babilaset al. 2010; González-Rodríguez and Lorente-Gualb 2015).

Most IPLs have a single pulse, and the energyis proportional to the pulse duration. Some IPLshave multiple sequential pulsing, and some havethe ability to independently vary the pulse dura-tion, the energy fluence, or both in each pulse.Other variables include the cutoff wavelengths,spectral output, and size of the delivered light(Wat et al. 2014).

Basic Concepts

Intense Pulsed Light Wavelengths

Traditional indications of IPL consist in its abilityof targeting pigmented and vascular lesions.

In pigmented lesions, the target is melano-some, whose chromophore is melanin. Thisabsorbs the appropriate wavelength, transformingthe light into heat, causing target destruction. Thetransfer of melanosomes toward the upper layersaccompanies these processes, where they areeliminated along with necrotic keratinocytes(González-Rodríguez and Lorente-Gualb 2015).

In vascular lesions, IPL acts on three targetchromophores: oxyhemoglobin (predominantlesions of red appearance), deoxyhemoglobin(predominant in blue lesions), and methemoglo-bin (González-Rodríguez and Lorente-Gualb2015).

Oxyhemoglobin contained in red blood cellswithin blood vessels has a maximum peak ofabsorption around 540 nm (alpha peak) and580 nm (beta peak). This holds true of smallsuperficial vessels mainly located on the faceand the neck. Vessels on the legs are usuallylocated deeper and contain moredeoxyhemoglobin. This situation moves theabsorption curve to the right, from 800 nm to1,200 nm. Infrared wavelengths tend to be more

effective in treating deeper blue vessels, whileshorter wavelengths are more effective for super-ficial red telangiectasias (Adamic et al. 2007).

The longer the wavelength, the deeper it pene-trates into the skin (Adamic et al. 2007). Althoughthe peak of maximum absorption for oxyhemo-globin is around 418–540 nm, less penetration isachieved and a strong competition with melaninfrom epidermis occurs. At 577 nm, althoughabsorption is low, the degree of penetration isgreater, reducing melanin absorption andavoiding side effects, such as hypopigmentation.For this reason, current devices use longer wave-lengths (515–600 nm) to ensure deeper penetra-tion while still being absorbed by oxyhemoglobin(Fig. 4) (González-Rodríguez and Lorente-Gualb2015). The use of longer wavelengths ensures thesafety of IPL in higher phototypes.

Among these wavelengths, the patient’s skintype, the skin condition, and the target presentdetermine the choice of suitable cutoff filters andtherefore the spectrum of wavelengths to be emit-ted (Babilas et al. 2010).

Pulse Duration

Pulse duration can be set in relatively wide ranges(depending on the particular device) in the milli-second range. Similar to laser devices, pulse dura-tion should be equal to or lower than the thermalrelaxation time (TRT) of the target structure toprevent unselective damage to the surroundingtissue (Babilas et al. 2010).

For IPL systems, usually pulse duration isdetermined in milliseconds (ms).

For deep lesions, higher pulse durations aresuggested. For superficial lesions, smaller pulsedurations are recommended.

Selectivity

The key chromophores of the human skin (hemo-globin, melanin, water) show broad absorptionspectrums. Thus, monochromaticity is not arequirement for photothermolysis. As IPL devicesemit a spectrum of wavelengths, the three key

Intense Pulsed Light for Rosacea and Other Indications 63

chromophores can be activated with one singlelight exposure. This versatility implies in areduced selectivity (Babilas et al. 2010) and canexplain the need of long-term treatment for vas-cular lesions (Ichikawa and Furue 2013).

Treatment Principles

• Smaller vessels need shorter pulses; larger ves-sels need longer pulses.

• The deeper the blood vessel is located in thedermis, the larger the spot size, the longer thewavelength, and the longer the pulse durationshould be combined with cooling to protect theepidermis.

• Darker skin types need longer pulses and lon-ger wavelengths (Adamic et al. 2007).

Mechanisms of Action

Intense pulsed light systems use a flashlamp thatemits high-intensity, noncoherent, and polychro-matic broad-spectrum light. The emission spec-trum of IPLs ranges from 400 to 1,200 nm. Thelight is emitted in pulses with various pulse dura-tions and intervals in a large rectangular spot of upto 1 by 4 cm (Raulin and Greve 2003; Meesterset al. 2014).

The mechanism of action of IPL system uti-lizes the theory of selective photothermolysis(Anderson and Parrish 1983). The basic principleis the absorption of photons by skin chromo-phores, generating heat, which is responsible fortarget destruction and selective thermal damage ofthe target. Selective photothermolysis begins withlocal absorption of light energy in target chromo-phores such as hemoglobin in vascular lesions ormelanin in pigmented lesions (Babilas et al.2010).

The combination of prescribed wavelengths,fluences, pulse durations, and pulse intervalsfacilitates the treatment of a wide spectrum ofskin conditions. Various different wavelengths ofabsorption are emitted to treat various targets,using different filters in order to optimize treat-ment of different conditions. By selecting a cutoff

filter specific for the absorption wavelength of thechromophore, energy can be deposited in theblood vessels, preventing damage and subsequentscarring to the surrounding tissues (Kassir et al.2011).

For vascular lesions, the mechanism of actionof IPLs is related to their selective absorption byhemoglobin (oxyhemoglobin, deoxyhemoglobin,and methemoglobin) within the blood vesselswith peaks of absorption at 418 nm (blue),542 nm (green), and 577 nm (yellow). Successfultreatment depends on the type and size of thevessels (Babilas et al. 2010; Barikbin et al. 2011;Goldberg 2012).

Shorter wavelengths may be preferred forsuperficial vascular lesions such as facial telangi-ectasias. Lower cutoff filters are effective intreating smaller caliber vessel. For standard-sized small vessels in the papillary dermis with adiameter of 0.1 mm, IPL has been shown to be aneffective treatment. IPL is able to treat the surfacearea of telangiectasias and to diminish the inten-sity of erythema and flushing seen in patients witherythematotelangiectatic rosacea (Mark et al.2003; Goldberg 2012).

Indications

The conditions treated with IPL include, mainly,vascular lesions and pigmented lesions, as well asskin rejuvenation, inflammatory dermatoses, acnevulgaris, hidradenitis suppurativa, hair removal,hypertrophic scars, and keloids (Babilas et al.2010; Vrijman et al. 2011; Goldberg 2012; Watet al. 2014).

The IPL device had been originally developedfor the treatment of a wide range of benign vas-cular lesions, including telangiectasias and retic-ular varicose leg veins (Goldberg 2012; Meesterset al. 2014). There are multiple well-establishedIPL treatments for targeting blood vessels in theskin. IPL devices have been used effectively in thetreatment of facial telangiectasias, erythematote-langiectatic rosacea, spider nevi, erythrosis, hem-angiomas, venous and capillary malformations,and poikiloderma of Civatte (Acarturk andStofman 2003; Clementoni et al. 2005; Adamic

64 J.M. Jordão and L. Pitassi

et al. 2007; McGill et al. 2008; Li et al. 2010a;Nymann et al. 2010; Campolmi et al. 2011; Dan2011; Barikbin et al. 2011; Meesters et al. 2014).

Successful treatment of vascular lesionsdepends on the type and size of the vessels.Fodor et al. conducted a comparative study ofIPL and Nd:YAG laser and obtained better resultswith IPL for more superficial and smaller lesions.A study conducted by Murray et al. in 2012showed an improvement in systemic sclerosis-related telangiectasias; however, these improve-ments were not sustained during follow-up,suggesting that other treatments should beadded. IPL can also be useful in infants withsuperficial hemangiomas or rapidly growinglesions >1 cm (González-Rodríguez andLorente-Gualb 2015).

Rosacea

Intense pulsed light therapy is a safe and effectivetreatment for the signs and symptoms of rosacea.Several studies have demonstrated the successfuluse of intense pulsed light for the vascular com-ponents of erythematotelangiectatic rosacea,including facial telangiectasia and papular lesions(Schroeter et al. 2005; Papageorgiou et al. 2008;Bae et al. 2009; Babilas et al. 2010; Dahan 2011;Kassir et al. 2011; Liu et al. 2014).

Rosacea is a chronic cutaneous disease thatmanifests as facial flushing, persistent erythema,telangiectasia, papules, and pustules. Erythemato-telangiectatic rosacea is the most common andmay have the strongest vascular componentamong the four subtypes (erythematotelan-giectatic, papulopustular, phymatous, and ocular)(Crawford et al. 2004; Lim et al. 2014). Advan-tages of IPL include short downtime, mild adversereactions, and short duration of procedure due tothe large application area (Kawana et al. 2007;Babilas et al. 2010; Lim et al. 2014).

The ability to choose the duration of pulsesmakes IPL a versatile tool in the treatment ofrosacea. The possibility of different filter settingsallows a wider selection of the range color of thevascular system (Schroeter et al. 2005; Piccoloet al. 2014). IPL can improve rosacea treating

abnormal vessels and inducing collagenremodeling (Piccolo et al. 2014).

Various studies have demonstrated the effective-ness of IPL in reducing blood flow, telangiectasia,and severity of erythema in individualswith rosacea(Wat et al. 2014) (Fig. 1). Taub noticed a reductionof 83% of erythema, a reduction of 75% offlushing,and an improved skin texture (Taub 2003).

A prospective trial involving 60 patients ana-lyzed the effect of IPL on facial telangiectasias andfound that 77.8% of patients achieved greater than50% reduction of vessels after treatment. Theseresults were maintained during a 3-year post-treatment follow-up period (Schroeter et al. 2005).

Papageorgiou and colleagues confirmed theefficacy of IPL in the treatment of rosacea diseaseof phase I. It showed a significant improvement oferythema, telangiectasias, and flushing. Theseverity of rosacea was reduced more than 50%,and the results were sustained at 6 months(Papageorgiou et al. 2011).

IPL appears to be an effective, well-toleratedtreatment option for rosacea (level 2a evidence),with efficacy equal to that of pulsed dye laser.Typical reported improvement was in the 50%range (Neuhaus et al. 2009; Wat et al. 2014).

Other Vascular Lesions

Hemangioma

IPL has been shown to be applicable in infantswith superficial hemangiomas and appears as oneof the effective and safe treatments. Treating thevascular tumor at the earliest stage probably con-trols the excess in endothelial growth. IPL is lim-ited by the deep and mixed types of the vasculartumors and a size over 5 cm at initiation of treat-ment, as well as some locations including theeyelids, lips, nostril, and genitalia (Paquet et al.2014). Angermeier studied patients with differentvascular lesions with IPL. It demonstrated75�100% of clearance after one or two treatmentswith IPL in 174 of 188 patients with vascularlesions (45 cases of them had facial hemangi-omas) (Angermeier 1999).

Intense Pulsed Light for Rosacea and Other Indications 65

IPL has notably been used in a study of62 patients with infantile hemangiomas whoreceived four to five IPL treatments at 4-weekintervals with a clearance rate of more than 80%(Li et al. 2010a).

Treatment with IPL suggested that lesionslarger than 1 cm in diameter at the first visit orthose rapidly growing more than 0.5 cm over thefirst 6–8 months of life must be treated in order toavoid further physical and psychologicalsequelae. Treatment in an early stage of develop-ment with IPL appeared to stop the rapid growthand initiated involution in three treatment ses-sions, thus preventing any unpredictabledisfiguring impairment (Rafiq et al. 2014).

Poikiloderma of Civatte

Because of their ability to target vascular andpigment components simultaneously, IPL sources

(IPLs) have been utilized in the treatment ofpoikiloderma of Civatte (Fig. 2).

Weiss and coworkers have reported their5-year experience in treating poikiloderma ofCivatte of the neck and chest in more than100 patients. A clearance of more than 75% oftelangiectasias and hyperpigmentation wasobserved, with a 5% incidence of side effectsincluding pigment changes (Weiss et al. 2000;Goldman and Weiss 2001).

In 2008 Rusciani et al. studied 175 patientswith poikiloderma of Civatte of the neck andchest treated with various IPL settings. Eightypercent of the vascular and the pigmented compo-nents were cleared. Less than 5% of the individ-uals had side effects, which were minimal andtransient (Rusciani et al. 2008). Weiss et al.succeeded in reaching a clearance rate of75–100% in 82% of 135 patients after three treat-ments with PhotoDerm VL (Weiss et al. 2000).Goldman et al. achieved a 50–75% improvement

Fig. 1 Successful use of IPL for the vascular components of erythematotelangiectatic rosacea (facial telangiectasia andpapular lesions) (Photographs from personal archive of Dr. Luiza Pitassi)

Fig. 2 IPL treatment of poikiloderma of Civatte of the neck and chest showing immediately after treatment their ability totarget vascular and pigment simultaneously (Photographs from personal archive of Dr. Luiza Pitassi)

66 J.M. Jordão and L. Pitassi

in the extent of telangiectasias and hyper-pigmentation after an average of 2.8 treatments(Goldman and Weiss 2001). Schroeter et al. evenhad clearance rates of 90% in the vascular part in15 patients (Schroeter and Neumann 1998).

IPL can be considered a safe and effectivetherapy for poikiloderma of Civatte due to itswide range of wavelengths, which allows treatingboth the pigmentation and the telangiectasia at thesame time (Barikbin et al. 2011).

Take care in darker skin phototypes treatment,and during cervical area, treatment is necessary toavoid dischomia and scars. When correctlyperformed, IPL procedure can be considered asafe and effective therapeutic option forpoikiloderma of Civatte, allowing a markedimprovement of vascular and pigmented lesionswith minimal side effects (Rusciani et al. 2008).

Nasal Telangiectasia

Nasal telangiectasia can be treated with IPL. Highfluences and stacking pulses should be necessaryin resistant telangiectasias. For smaller vessels,short wavelengths and low pulse duration aresuggested. For thicker telangiectasias, biggerwavelengths and high pulse durations are moreeffective.

To be sure, that the telangiectasia was effec-tively removed is necessary to see the telangiec-tasia immediately disappearing (Fig. 3) or anedema in the path of the vessel or a purpura in

its place. Repeated sessions with 3 week intervalsare indicated as some telangiectasias reopen afterfew days.

Leg Telangiectasia

Studies demonstrated that IPL could be used formultiple forms of telangiectasia treatment. How-ever, clinical evidence for IPL in the treatment ofleg veins is scarce. In a multicenter trial of159 patients, Goldman reported 90% clearancerate with vessels smaller than 0.2 mm and 80%clearance rate with vessels 0.2–1 mm in diameter.Schroeter et al. reported immediate clearing in73.6% of patients and in 84.3% of patients after4 weeks (Goldman et al. 1996; Schroeter et al.2013; Meesters et al. 2014). Doctors have to takeinto account the skin phototype to avoid sideeffects.

Striae Distensae (SD)

The exact mechanism of action of IPL in thetreatment of SD is unknown, but it is probablyrelated to dermis remodeling, in which the activityof fibroblasts is increased and more collagenfibers are synthesized or rearranged within thestroma (Goldberg 2000; Al-Dhalimi and AboNasyria 2013).

Previous studies have demonstrated that IPLinduces neo-collagen formation and potentially

Fig. 3 Nasaltelangiectasias immediatelydisappearing after IPL540 nm treatment(Photographs from personalarchive of Dr. JulianaJordão)

Intense Pulsed Light for Rosacea and Other Indications 67

improves epidermal atrophy and dermal elastosis.Pérez et al. showed that SD improved clinicallyand microscopically after IPL with minimal sideeffects (Pérez et al. 2002).

A comparative study of the effectiveness ofintense pulsed light in the treatment of striaedistensae showed that both of the wavelengths(650 nm and 590 nm) were effective in the treat-ment of striae distensae and both of them resultedin statistically significant reduction in the number,the lengths, and the maximum widths of striae.For all of these assessed parameters, the wave-length 590 nm was more effective (Al-Dhalimiand Abo Nasyria 2013).

Port-Wine Stain (PWS)

Raulin and Goldman reported the first successfultreatment of an adult port-wine stain (PWS) withIPL (Raulin et al. 1997).

The pulsed dye laser represents the most com-monly used laser for treatment of PWS and has themost published literature supporting its use. IPLhas also been reported to be an effective alterna-tive to PDL for treatment of PWS. Although IPLhas been shown to be effective in the clearance ofpink and red PWS, a head-to-head trial comparingthe efficacy of IPL against PDL determined thatthe median clinical improvement was signifi-cantly better for PDL (65%) than IPL (30%)(Faurschou et al. 2009). Nevertheless, IPL canbe considered for treating PDL-resistant PWS(Ho et al. 2004; Ozdemir et al. 2008; Li et al.2010b; Adatto et al. 2010; Chen et al. 2012).

Bjerring and colleagues treated 15 patientswith PWS that had previously been resistant toPDL and found that IPL was able to achieve75–100% clearance in 46.7% of cases (Bjerringet al. 2003).

A randomized, controlled, single-blind head-to-head trial comparing PDL with IPL for thetreatment of PWS showed that both modalitieswere effective but that PDL was superior interms of median clinical improvement and patientpreference (Wat et al. 2014).

Recently, Wang and colleagues confirmed theefficacy of IPL in the treatment of facial and

extrafacial PWS in Chinese patients (Wang et al.2013).

There is reasonable evidence to suggest thatIPL is an effective, safe modality for the treatmentof capillary malformations (level 2a evidence). Itmay be especially useful for darker lesions thathave greater vascularity but minimal nodularity(Wat et al. 2014).

Hypertrophic Scars and Keloids

A recent report of IPL in 109 patients with hyper-trophic scars and keloids (due to traumaticwounds, burns, and surgical incisions) demon-strated improvement in 92.5% of subjects, interms of scar height, erythema, and hardness,with a high level of patient satisfaction (Erolet al. 2008).

In Fig. 4, it is possible to see a good result of atraumatic scar treated with eight sessions of IPL540 nm.

Hyperpigmented, erythematous, and prolifera-tive scars all demonstrated greater than 50%improvement after a mean of 2.97 sessions,whereas atrophic scars did not respond (Kontoeset al. 2003). A very recent pilot study has demon-strated the effectiveness of IPL in wound healingafter suture removal. The basic mechanism is not

Fig. 4 Traumatic scar treated with eight sessions of IPL540 nm (Photographs from personal archive of Dr. JulianaJordão)

68 J.M. Jordão and L. Pitassi

yet fully understood, but most probably an actionon vascular proliferation, essential for the growthof collagen, and on pigmentation resulting fromscar formation is involved (Erol et al. 2008; Pic-colo et al. 2014).

Kontoes et al. reported an improvement ofmore than 75% in the pigmentation of hypertro-phic scars, 50% higher than that in the scars fromasphalt, and 50% reduction in the size and thick-ness of hypertrophic scars. This is probably due tothe inhibition of the action of the vessel caused byIPL on scar tissue and on the subsequent prolifer-ation of collagen (Kontoes et al. 2003).

Contraindications

Pregnancy, breastfeeding, the intake of retinoidsor photosensitizing medications, diseases orgenetic conditions causing photosensitivity ortending to aggravate after light exposure(Roelandts 2000), as well as suntan are exclusioncriteria for IPL treatment. Patients suffering fromlong-term diabetes, hemophilia, or othercoagulopathies and patients with implants in thetreatment area or with a heart pacemaker shouldbe treated with special care. Patients with a historyof herpes simplex require an antiviral prophylaxisfor holohedral facial treatments (Adamic et al.2007).

The skin type of the patient has to bedocumented according to the Fitzpatrick scalebecause photophysical parameters need to beadjusted depending on the individual patient’sskin type. It is recommended to avoid sunlight,in addition to applying a broad-spectrum sun-screen. When treating areas close to tattoos, defin-itive makeup, ephelides, and nevus, cautionshould be taken to avoid a possible color changeor scar injury after treatment with intense pulsedlight at the site.

Recently, a series of home-use intense pulsedlight devices has been developed. These devices,in spite of being FDA approved, have scarce con-trolled studies related to the method’s safety andefficacy. All systems tested are attractively pack-aged with clear educational material for the cus-tomer regarding contraindications to treatment

such as too dark skin types, active suntan, andmedications (Town and Ash 2010).

Side Effects and Their Managements

After the administration of high fluences and shortpulse times, there have been reports of transient orpermanent pigment changes, edema, erythema,purpura, mild discomfort, blistering, and crusting.These findings typically resolved within 1–48 hbut sometimes lasted up to 1 week. These sideeffects are much more common with older,first-generation flashlamps which emit a higherproportion of infrared light (Wat et al. 2014).

The most common complication after IPLtreatment is changed pigmentation, with possiblehyper- or hypopigmentation. These are most com-monly seen in patients with a darker or recentlytanned skin. The skin must be sufficiently cooledduring treatment to protect the epidermis frombeing burned; the cooling can be performedusing cooling gels, ice gels, contact spray cooling,or special cooling handpieces (Raulin andGreve 2003).

Blistering and crusting are signs of over-fluenced treatment; in case of blisters and crusts,patients must strictly avoid scratching, which mayresult in infections and scar formation. Antimicro-bial ointments help loosening the crusts and pre-vent bacterial superinfections. Potential sideeffects that might last longer or may even beirreversible are pigmentary changes, such ashypopigmentation or hyperpigmentation.Adjusting wavelengths and fluences to thepatient’s skin type and treatment area can mostlyprevent these side effects. Unsuitable patients(due to suntan or skin type) are excluded fromtherapy as well as patients who are unable orunwilling to strictly avoid postoperative UVexpo-sition. Scarring occurs rarely and is almost alwaysevoked by overfluenced treatments or by crustingwith subsequent manipulation and infection. Ingeneral, the most important measure to preventside effects is the application of test shots forevery chosen set of parameters and even for thesame set of parameters applied at different parts ofthe body (Babilas et al. 2010).

Intense Pulsed Light for Rosacea and Other Indications 69

Safety and efficacy with IPL devices rely onthe appropriate use of device settings and suffi-cient operator experience (Wat et al. 2014).

Take Home Messages

• The main skin chromophores present in theskin are melanin and hemoglobin

• Delay the treatment in tanned skins• Photograph areas before treatment• The informed consent form should be provided• Use sunscreens with a high protection factor• In brunette skins, perform a previous test to

increase procedure safety• Eye protection is mandatory, both for the phy-

sician and the patient• Use the highest amount of safe energy for best

results• Scars are extremely rare, but these may occur

when excessive energies are used

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Intense Pulsed Light for Rosacea and Other Indications 71

Light-Emitting Diode for Acne, Scars,and Photodamaged Skin

Luiza Pitassi

AbstractLight-emitting diode therapy was discoveredin the late 1960s but only recently has it beenwidely applied in dermatology to treat a widerange of skin diseases including photoaging,scars, and acne. Since the introduction ofphotobiostimulation into medicine, the effec-tiveness and applicability of a variety of lightsources have thoroughly been investigated.Light-emitting diode photomodulation is anonthermal technology used to modulate cel-lular activity with light, and the photons areabsorbed by mitochondrial chromophores inskin cells. Various beneficial effects of light-emitting diode at relatively low intensities havebeen reported, especially in indications wherestimulation of healing, reduction of pain andinflammation, restoration of function, and skinrejuvenation are required. The light-emittingdiode therapy is safe, nontoxic, and noninva-sive with no side effects reported in thepublished literature.

KeywordsLight-emitting diodes • Photobiostimulation •Photomodulation • Low-level light therapy •Nonthermal technology • Cellular activity •

Mitochondrial chromophores • Inflammation •Restoration of function • Acne • Scars • Skinrejuvenation • Photodamaged skin

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73

History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74

Mechanisms of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78

LED for Acne, Scars and Photodamaged Skin . . . . 79Acne . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79Scars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81Photodamaged Skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84

Take Home Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84

Introduction

Light therapy has been used in many cultures forthousands of years as a therapeutic modality to treatvarious health conditions (Barolet 2008). Photo-biomodulation, also known as low-level light ther-apy (LLLT), is a medical technique in whichexposures to low-level laser light or light-emittingdiodes (LEDs) stimulate cellular function leading tobeneficial clinical effects (Dincer 2000).

The light-emitting diode (LED) is a semicon-ductor device available at wavelengths rangingfrom ultraviolet (UV) to visible to near-infrared

L. Pitassi (*)Division of Dermatology, Department of Medicine, StateUniversity of Campinas (UNICAMP), Campinas, SP,Brazile-mail: luiza@luizapitassi.com.br; pitassi@yahoo.com

# Springer International Publishing AG 2018M.C.A. Issa, B. Tamura (eds.), Lasers, Lights and Other Technologies, Clinical Approaches and Procedures inCosmetic Dermatology 3, https://doi.org/10.1007/978-3-319-16799-2_4

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(NIR) bandwidth that converts electrical currentinto a non-coherent narrow bandwidth of the elec-tromagnetic spectrum. LED appears to have awide range of applications of use in dermatology.Because of the combination of high degree ofpenetration in the skin and absorption by respira-tory chain components, light in the spectral rangefrom 600 to 1300 nm is useful for promotingwound healing, reduction of inflammation, relievepain, and skin rejuvenation (Anderson and Parrish1981; Barolet et al. 2009).

LED is not an ablative or thermal mechanismbut rather a photochemical effect comparable tophotosynthesis in plants whereby the light isabsorbed and exerts a chemical change. Photo-therapy is characterized by its ability to inducephotobiological processes in cells. The effectivetissue penetration of light and the specific wave-length of light absorbed by photoacceptors aretwo of the major parameters to be considered inlight therapy (Huang et al. 2011).

LED has an additional advantage over lasers asthey possess the possibility of combining wave-lengths with an array of various sizes, therebystimulating a broader range of tissue types. LEDdisperses over a greater surface area than mostlasers and can be used where large areas aretargeted, resulting in reduced treatment times(Barolet 2008).

The LED was invented in the late 1960s butonly recently has it been widely applied in derma-tology. Within the past 15 years, a better under-standing of photobiology and an increaseddemand for minimally invasive yet effective der-matologic treatments have led to a growing inter-est in LED devices (Opel et al. 2015).

LED photomodulation can be used both aloneand in combination with a variety of rejuvenationprocedures. In dermatology, LED has beneficialeffects on wrinkles, acne scars, hypertrophicscars, and healing of burns and can reduce UVdamage both as a treatment and as a prophylacticmeasure (Vecchio et al. 2013).

LED photobiomodulation is the newest cate-gory of nonthermal light therapiesand an effectivealternative for a variety of medical treatments,with no side effects reported in the publishedliterature when used correctly.

History

Sunlight benefits in treating skin diseases have beenused as the earliest form of light therapy in ancientEgypt, India, and China (Barolet 2008). In 1904Niels Finsen won the Nobel Prize for Physiologyand Medicine for his work on using arc lamps totreat cutaneous tuberculosis and red light to preventscarring from smallpox (Hamblin et al. 2015).

Low-level laser (light) therapy (LLLT) alsoknown as photobiomodulation was discovered inthe late 1960s by the surgeon Endre Mester inBudapest, Hungary.

Mester began a series of laser experiments toassess the carcinogenic potential of lasers byusing a low-energy ruby red laser (694 nm) onmice. To Mester’s surprise, the laser did not causecancer but instead improved hair growth aroundthe shaved region on the animal’s back. This wasthe first demonstration of photobiostimulation(Mester et al. 1968; Barolet 2008; Avci et al.2013).

In the 1990s, the National Aeronautics andSpace Administration (NASA) developed LEDsthat produced a very narrow spectrum of light thatin turn allowed for their first clinical applications(Calderhead 2007). The application of light ther-apy with the use of NASA LEDs will significantlyimprove the medical care that is available to astro-nauts on long-term space missions. NASA LEDsstimulate the basic energy processes in the mito-chondria (energy compartments) of each cell, par-ticularly when near-infrared light is used toactivate the color-sensitive chemicals (chromo-phores, cytochrome systems) inside. NASA LEDarrays have already flown on Space Shuttle mis-sions for studies of plant growth.

The US Food and Drug Administration (FDA)has approved human trials. The use of light ther-apy with LEDs is an approach to help increase therate of wound healing in the microgravity envi-ronment, reducing the risk of treatable injuriesbecoming mission catastrophes (Whelan et al.2000).

Whelan et al. have used the LED originallydeveloped for NASA plant growth experimentsin space to access the effects of near-infrared lighttreatment on wounds in a genetically diabetic

74 L. Pitassi

mouse model and have found that certain tissue-regenerating genes are significantly upregulatedupon LED treatment. NASA-developed LEDsoffer an effective alternative to lasers. Thesediodes can be configured to produce multiplewavelengths; can be arranged in large, flat arrays(allowing treatment of large wounds); and pro-duce no heat. It is also important to note thatLED light therapy has been deemed as a nonsig-nificant risk treatment by the FDA (Whelan et al.2003).

In the period of almost 50 years since Mester’sdiscovery, the number of diseases and conditionsthat can be effectively treated by LLLT has grownexponentially. No longer confined to woundhealing, pain, and inflammation, many majororgan systems of the body such as the heart,brain, eyes, spinal cord, digestive tract, and respi-ratory tract can be benefited by light therapy pro-vided the correct light source, parameters, anddelivery methods that are used (Hamblin et al.2015).

Mechanisms of Action

LEDs are complex semiconductors that convertelectrical current into incoherent narrow spectrumlight. Phototherapy is based on the direct transferof incident photon energy between the incomingphotons and the cellular energy pool resulting in aviable clinical reaction, but without heat or dam-age (Calderhead et al. 2015). The basic mecha-nism for phototherapy involves absorption of theincident photon energy (photoreception), trans-duction, and amplification of the signal withinthe target followed by a photoresponse (Karu1999).

Photobiomodulation is considered to stimulatefibroblast proliferation, collagen synthesis,growth factors, and extracellular matrix produc-tion and enhances cutaneous microcirculationthrough activating the mitochondrial respiratorysystem of the cells (Lee et al. 2007a).

LED photomodulation has an effect on thehuman skin that is nonthermal and most likelymediated by mitochondrial cytochrome lightabsorption, in particular cytochrome c oxidase

(CCO), which is contained in the respiratorychain. This complex enzyme has two differentheme centers and two different copper centers,each of which can be reduced or oxidized whichaffects the absorption spectrum. Consequently, acascade of events occurs in the mitochondria,leading to biostimulation of various processes(Mahmoud et al. 2008; Avci et al. 2013; Weisset al. 2005).

The mechanism of LLLT is the absorption ofred and near-infrared light by chromophores pre-sent in the protein components of the respiratorychain located in mitochondria (Mahmoud et al.2008). The main therapeutic target for the visiblelight wavelengths is the cytochrome c oxidaseenzyme in the mitochondrial respiratory chain inthe target cells, resulting in a photochemicallyinduced cascade leading to the production ofadenosine triphosphate (ATP) and eventual cellu-lar photoactivation (Karu 2007).

Respiratory chain activation is the central pointand can occur by an alteration in redox properties,acceleration of electron transfer, generation ofreactive oxygen species, as well as induction oflocal transient heating of absorbing chromo-phores. This leads to increased cellular metabolicactivity by targeted cells, such as increased ATP,modulation of reactive oxygen species, the induc-tion of transcription factors, alteration of collagensynthesis, and stimulation of angiogenesis(Barolet 2008;Weiss et al. 2005; Opel et al. 2015).

Activation of respiratory chain componentsstimulates the expression of genes related to cel-lular migration and proliferation, changes in thecellular homeostasis, alterations in ATP or cAMPlevels, modulation of DNA and RNA synthesis,membrane permeability alterations, alkalizationof cytoplasm, and cell membrane depolarization.It also alters the production of growth factors andcytokines (Mahmoud et al. 2008).

LEDs appear to affect cellular metabolism bytriggering intracellular photobiochemical reac-tions. Observed effects include increased ATP,modulation of reactive oxygen species, the induc-tion of transcription factors, alteration of collagensynthesis, stimulation of angiogenesis, andincreased blood flow (Barolet 2008; Opel et al.2015). LLLT stimulates the expression of genes

Light-Emitting Diode for Acne, Scars, and Photodamaged Skin 75

related to cellular migration and proliferation; italso alters the production of growth factors andcytokines (Mahmoud et al. 2008; Evans andAbrahamse 2008).

Important cell types for skin and tissue regen-eration are fibroblasts, keratinocytes, and immunecells (mast cells, neutrophils, and macrophages),which can be stimulated using specific wave-lengths with significant tissue penetration proper-ties (Huang et al. 2011).

LEDs are small, robust devices that emit anarrow band of electromagnetic radiation rangingfrom ultraviolet to visible and infrared wave-lengths. Emitted light are available at wavelengthsranging from ultraviolet (UV) to visible to near-infrared (NIR) bandwidth (247–1300 nm). LED isdifferent from other types of laser by having a lowintensity, which causes low-temperature changes(Weiss et al. 2005). A significant differencebetween lasers and LEDs is the way the lightenergy is delivered. The peak power output ofLEDs is measured in milliwatts, whereas that oflasers is measured in watts. LEDs provide a muchgentler delivery of the same wavelengths of lightcompared to lasers and at a substantially lower-energy output (Barolet 2008).

While laser procedures require intensive post-treatment care and prolonged downtime and maylead to complications, the LED therapy is aneffective, safe, and non-painful treatment(Wunsch and Matuschka 2014).

Other advantages over lasers include the pos-sibility to combine wavelengths with an array ofvarious sizes. LED disperses over a greater sur-face area than lasers and can be used where largeareas are targeted, resulting in a faster treatmenttime (Barolet 2008).

The absorption of red and near-infrared lightby photoacceptor molecules within the respiratorychains can cause alteration in the redox status ofthe cells and activate the nucleic acid synthesis toaccelerate cell proliferation (Karu 1987, 1999)

Different wavelengths have different chromo-phores and can have various effects on tissue.Wavelengths are often referred to using their asso-ciated color and include blue (400–470 nm), green(470–550 nm), red (630–700 nm), and NIR

(700–1200) lights. Depth of tissue penetration isprimarily dependent upon the wavelength of thelight (Barolet 2008). Wavelengths of 630–900 nmcan penetrate and be absorbed through the entirepapillary dermis.

For best effects, the wavelength used shouldallow for optimal penetration of light in thetargeted cells or tissue. Because cytochrome coxidase is the most likely chromophore in LLLT,two absorption peaks are considered in the red(~660 nm) and NIR (~850 nm) spectra (Karuet al. 2005; Barolet 2008).

Analysis of the gene expression profiles inhuman fibroblasts revealed an influence oflow-intensity red light with a 628 nm wavelengthon 111 different genes that are involved in cellularfunctions, such as cell proliferation; apoptosis;stress response; protein, lipid, and carbohydratemetabolism; mitochondrial energy metabolism;DNA synthesis and repair; antioxidant-relatedfunctions; and cytoskeleton- and cell-cell interac-tion-related functions (Zhang et al. 2003; Wunschand Matuschka 2014).

Red light (wavelength range from 620 to770 nm), which is part of the visible light spec-trum, is able to activate fibroblast growth factor,increase type 1 procollagen, increase matrixmetalloproteinase-9 (MMP-9), and decreaseMMP-1 of the skin dermis due to its capabilityto deeply penetrate the skin to about 6 mm; thus, itis favored in photodynamic therapy (PDT). Anincrease in fibroblast number and a mild inflam-matory infiltrate following exposure have beendemonstrated histologically (Barolet et al. 2009;Issa et al. 2009; Opel et al. 2015).

Red LEDs have the deepest tissue penetrationof the visible wavelengths and demonstrate sig-nificant reduction of the epidermis thickness,elastotic material, and the dermal inflammatoryinfiltrate as well as an increase of collagen andprocollagen type I and III in the upper dermis.TGF-β is a growth factor responsible for inducingcollagen synthesis from fibroblasts and is signifi-cantly increased after PDT (Karrer et al. 2013).

Because of the deeper light penetration into theskin, red light is widely preferred in PDTand mayalso exert anti-inflammatory effects via regulating

76 L. Pitassi

the release of inflammatory factors. Important celltypes for skin and tissue regeneration are fibro-blasts, keratinocytes, and immune cells (mastcells, neutrophils, and macrophages), which canbe stimulated using specific wavelengths withsignificant tissue penetration properties(Calderhead et al. 2015).

PDT typically involves the application of a top-ical photosensitizer such as 5-aminolevulinic acid(ALA) or its methyl ester (MAL), which is activatedby exposure to a visible light source. Followingactivation of a photosensitizer with light of theappropriate wavelength, ROS, in particular singletoxygen, are generated. As a consequence of thecombination of light, photosensitizer, and tissueoxygen, cytotoxic ROS are formed in diseased tis-sues, inducing necrosis and apoptosis of the malig-nant and premalignant cells (Hamblin andDemidova 2006). The oncologic indications, actinickeratoses, nodular or superficial BCCs, andBowen’s disease are approved indications for PDTwith ALA/MAL (Morton et al. 2002).

PDT in the treatment of acne is based on thefact that Propionibacterium acnes contain endog-enous porphyrins, in particular coproporphyrin III(Babilas et al. 2005). The red light module is usedto increase blue light phototherapy new tissuegrowth, enhance healing, and stimulate collagen,thereby reducing lines and wrinkles (Fig. 1).

The beneficial effect of red light on woundhealing can be explained by considering severalbasic biological mechanisms including theinduction of expression cytokines and growthfactors such as VEGF responsible for the

neovascularization necessary for wound healing(Hamblin and Demidova 2006).

Near-infrared light (IR), also known as mono-chromatic infrared energy is believed to stimulatecirculation by inducing the release of guanylatecyclase and nitrous oxide, which, in turn, promotesvasodilation and growth factor production as wellas angiogenesis, leading to subsequent woundhealing (Karu 1987; Opel et al. 2015) (Fig. 2).

IR LED constitutes the wave band longer than760 nm and can penetrate the skin between 5 and10 mm. Near-infrared light 830 nm has been usedto treat wound, pain, ulcers, recalcitrant lesions,skin rejuvenation, and acne vulgaris treatment(Opel et al. 2015).

A single treatment of the normal skin with830 nm LED-LLLT compared with unirradiatedcontrols demonstrated rapid photomediateddegranulation of mast cells at 48 h, accompaniedby an ultrastructurally demonstrated inflamma-tory response with the appearance of significantlygreater numbers of mast cells, macrophages, andneutrophils (Calderhead et al. 2008).

LED irradiation with a combination of wave-lengths, such as 630 or 660 nm combined with830 or 850 nm, increased cell number and type Icollagen expression more than treatment witheach wavelength alone and decreaseMMP-1expression (Tian et al. 2012).

Fig. 1 Red light LED treatment for photodamaged skin(Photograph from personal archive of Dr. Luiza Pitassi)

Fig. 2 Near-infrared light (830 nm) treatment after abla-tive laser resurfacing (Photograph from personal archive ofDr. Luiza Pitassi)

Light-Emitting Diode for Acne, Scars, and Photodamaged Skin 77

Lee et al. compared the effects among LEDtreatment with 633 and 830 nm on their own andthe combination of 830 and 633 nm with a controlgroup. Although all the LED-treated groups inthis study showed statistically significant grossand histological results compared with the con-trols, the 830 nm group proved superior to theother LED groups in all aspects includingcollagenesis, skin elasticity, expression of tissueinhibitors of matrix metalloproteinase 1 and sub-jective patient satisfaction (Lee et al. 2007a).

Blue light (wavelength range from 400 to480 nm) is UV-free irradiation and appears toexert its effect on acne via its influence on Pro-pionibacterium acnes and its anti-inflammatoryproperties (Fig. 3). P. acnes contains naturallyoccurring porphyrins, mainly coproporphyrinand protoporphyrin IX. Absorption of blue lightby these molecules is believed to induce a naturalPDT effect with destruction of the bacteria via theformation of oxygen free radicals (Dai et al. 2012;Opel et al. 2015).

One mechanism of action of phototherapy foracne is through the absorption of light (specifi-cally blue light) by porphyrins that have beenproduced by P. acnes as a part of its normalmetabolism and that act as endogenous photosen-sitizers (Lee et al. 2007a; Avci et al. 2013).Because of the effectiveness in reducing cellproliferation, blue light is also propitious totreat hyperplastic diseases and chronic skininflammation.

The use of a dual-wavelength (red and blue)LED light source enhances PDT results for acneand other sebaceous disorders. Red wavelength(630 nm) can reach the sebaceous glands, andblue (405 nm) light photobleaches any residualprotoporphyrin IX (PpIX) in the epidermis,thereby reducing posttreatment photosensitivity(Barolet 2008).

Also topical PDT is a treatment for non-melanoma skin cancer (NMSC) and the improve-ment of photoaging. PDT typically involves theapplication of a topical photosensitizer such as5-aminolevulinic acid (ALA) or its methyl ester(MAL), which is activated by exposure to a visi-ble light source. As a consequence of the combi-nation of light, photosensitizer, and tissue oxygen,cytotoxic ROS are formed in diseased tissues,inducing necrosis and apoptosis of the malignantand premalignant cells (Gold et al. 2006; Szeimieset al. 2012)

A number of studies have indicated that expos-ing patients to a combination of LEDwavelengthsis more effective than monotherapy. This syner-gistic effect has been investigated on a variety ofskin disorders (Russell et al. 2005; Goldberg et al.2006; Goldberg and Russel 2006; Lee et al.2007a; Park et al. 2014).

Indications

Review of the literature revealed that differingwavelengths of light-emitting diode devices usedin dermatology have many beneficial effects totreat a wide range of skin diseases (Table 1), includ-ing acne, scars, and photodamaged skin and sideeffects were either mild or not reported. It remainsprudent to screen individuals with photosensitivedermatoses, or those taking photosensitizing med-ications, as these are contraindications to treat-ment. Caution must be emphasized especiallyfor epileptic and photophobic patients especiallyif LEDs are pulsed (Barolet 2008; Opel et al.2015).

Wavelengths in the 600–700 nm range arechosen for treating superficial tissue, and wave-lengths between 780 and 950 are chosen for

Fig. 3 Blue light LED treatment for acne (Photographfrom personal archive of Dr. Luiza Pitassi)

78 L. Pitassi

deeper-seated tissues due to longer optical pene-tration distances through tissue. Because of thepossible existence of a biphasic dose-responsecurve referred to above, choosing the correct dos-age of light (in terms of energy density) for anyspecific medical condition is difficult (Hamblinand Demidova 2006) (Table 2).

LED for Acne, Scarsand Photodamaged Skin

Acne

Phototherapy with visible light (mainly blue light,red light, or combination of both) has been pro-posed as an alternative therapeutic modality totreat acne vulgaris. One mechanism of action ofphototherapy for acne is through the absorption oflight (specifically blue light) by porphyrins thathave been produced by P. acnes as a part of itsnormal metabolism and that act as endogenousphotosensitizers (Avci et al. 2013).

Blue light therapy (415 nm) is effective atactivating coproporphyrin III and protoporphyrinIX, subsequently destroying the P. acnes bacteria(Fig. 4). It has been shown to significantly reduceacne lesions in studies on mild-to-moderate,inflammatory, and pustular acne when irradiatingover eight to ten treatments (Goldberg and Russel2006).

Blue light treatment also appears to have anti-inflammatory effects on keratinocytes by decreas-ing the cytokine-induced production of IL-1 alpha

and ICAM-1markers (Shnitkind et al. 2006). BlueLED light (400–470 nm) has a maximal penetra-tion of up to 1 mm. It is best suited for the treat-ment of more superficial conditions, such as totarget P. acnes in acne vulgaris (Opel et al. 2015).Blue light illuminated to P. acnes colonies inducesphotoexcitation of bacterial porphyrins, stimu-lates the production of single oxygen, and, finally,results in the endogenous photodynamic destruc-tion of P. acnes (Lee et al. 2007b; Joo et al. 2012).

Shalita et al. demonstrated the use of blue light(405–420 nm) for acne treatment, using 10-minlight exposures twice weekly. A total of 35 sub-jects with lesions on the face and back weretreated over a 4-week period; 80% demonstrateda significant improvement of noninflammatory,inflammatory, and total facial lesions, with a

Table 1 Most frequent LED indications in dermatology

Wound healing

Photorejuvenation

Hypertrophic scars and keloids

Acne

Post-inflammatory hyperpigmentation

Erythema

Edema

Analgesia

Burn

Alopecia

Photodynamic therapy treatment (actinic keratosis,Bowen’s disease, and basal cell carcinoma)

Vitiligo

Psoriasis

Rosacea

Herpes simplex

Table 2 Led wavelengths of light-emitting diode devices used in dermatology

ColorWavelength(nm) Skin treatment Treatment time

Red 610–760 Skin rejuvenation, fine lines, roughness, skin tone, texture, pore size,depigmentation, wound healing, hypertrophic scars, keloids, edema,and erythema

20–30 minsession/two perweek

Blue 450–500 Acne, hyperpigmentation, keloids, fibrotic skin diseases 20–30 minsession/two perweek

Infrared 850–940 Skin rejuvenation, hypertrophic scars, keloids 20–30 minsession/two perweek

Light-Emitting Diode for Acne, Scars, and Photodamaged Skin 79

70% mean decrease in inflammatory lesion count2 weeks after the last treatment (Shalita et al.2001).

Morton et al. treated 30 patients with mild-to-moderate acne with 8-, 10-, or 20-min blue LED(415 nm) treatments over a period of 4 weeks. Theinflammatory lesion counts decreased, with mini-mal effect on noninflammatory lesions (Mortonet al. 2005).

Tremblay et al. gave patients with mild-to-moderate inflammatory acne two 20-min treat-ments of blue LED (415 nm) per week for4–8 weeks. Ninety percent of patients were satis-fied with the result. Objectively, patients had a50% reduction in lesion counts (Tremblay et al.2006).

The blue light treatment is associated withsignificant reductions in lesion size number,severity, and redness of flare-ups and improve-ments in the skin’s overall appearance, as well asin clarity, radiance, tone, texture, and smoothness(Ash et al. 2015; Opel et al. 2015).

Red light (633 nm) is less effective at activat-ing coproporphyrin III than blue light but is apotent activator of protoporphyrin IX, also foundin P. acnes bacteria. Since red light penetrates

deeper into the tissue than blue, it is possible thatred light actively destroys P. acnes bacteria resid-ing in the lower regions of the sebaceous gland(Goldberg and Russel 2006).

Red light is believed to stimulate cytokinerelease from various cells including macrophagesand reduce inflammation. The effect of visible redlight on the local vasculature is also well recog-nized. The red light will bring more oxygen andnutrients into the area, further helping to reduceinflammation and enhance the wound repair pro-cess (Goldberg and Russel 2006; Sadick 2008;Avci et al. 2013; Sawhney and Hamblin 2014).

The combination of LED for the treatment ofacne is also promising. Phototherapy with mixedblue–red light, probably by combining anti-bacterial and anti-inflammatory action, is a safe,effective, and non-painful treatment for mild-to-moderate acne vulgaris, with no significantshort-term adverse effects (Avci et al. 2013;Opel et al. 2015).

Karu demonstrated thatwhenPropionibacteriumacnes was exposed to blue and red light simulta-neously in vivo, therewas amarked inhibition of cellactivity compared to that seen when red and bluelights were delivered independently (Karu 1999).

Fig. 4 Photoinactivationof P. acnes by its endogenicporphyrins wasdemonstrated afterillumination with blue lightat 405 nm for 30 min(Photographs from personalarchive of Dr. Luiza Pitassi)

80 L. Pitassi

Lee et al. treated patients with moderate acnewith a combination of blue (415 nm) and red(640 nm) LED devices. A 34% improvement incomedone count and a 78% improvement in thenumber of inflammatory lesions were observed.Most studies revealed that improvement in inflam-matory lesions was higher than the improvement incomedones (Lee et al. 2007b). Kwon et al. demon-strated a decrease of both inflammatory and non-inflammatory acne lesions by 77% and 54%,respectively, following home-use combined blueand red LED (Kwon et al. 2013).

Although blue light has been tried in conjunc-tion with ALA in the treatment of acne in20 patients, patients experienced greater sideeffects, and the results were not clinically signif-icant when compared with blue LED alone(Weinstabl et al. 2011; Opel et al. 2015).

Red light can prevent or treat acne post-inflammatory hyperpigmentation (PIH). On thebasis of photographic analysis and melanin con-tent measurements, most patients can achieve sub-stantial reduction or absence of PIH lesions in theLED-treated areas (Barolet 2008). Red light ther-apy is generally performed using wavelengthsfrom the visible spectrum, 670 nm, which is awavelength absorbed by melanin. The amount oflight energy being absorbed by pigments in theskin, such as melanin, should be taken intoaccount when designing a light therapy treatmentregimen for a patient. In order to achieve the sameenergy delivery to structures below the epidermis,patients with skin types in the range of 5 or 6 onthe Fitzpatrick scale will require a higher dose oflight (fluence) than patients with skin types in therange of 1 or 2 (Brondon et al. 2007).

Various LED wavelengths can affect melano-genesis in normal human melanocytes. LED irra-diation at 830, 850, and 940 nm reducedmelanogenesis through decreased tyrosinaseexpression without exerting any cytotoxic effects.The LED wavelength at 830 nm also reducesmelanin synthesis and might be helpful therapeu-tic tools for treating patients with hyper-pigmentation (Kim et al. 2012).

Papageorgiou et al. investigated the effects ofa combination blue and red light treatment in a

randomized study of 107 patients with mild-to-moderate acne. Results displayed a 76% reduc-tion in inflammatory lesions in the combinationgroup. This result was significantly superior tothat achieved by blue light alone (Papageorgiouet al. 2000).

Blue and red light combination LED photo-therapy is an effective, safe, and non-painful treat-ment for mild-to-moderately severe acne vulgaris,particularly for papulopustular acne lesions (Leeet al. 2007b).

Scars

Scars, hypertrophic scars, and keloids are cosmet-ically and psychosocially disfiguring and mayresult in patients seeking a variety of treatmentsto address the aesthetic and functional concernsattributed to scarring. Hypertrophic scars andkeloids can form after surgery and trauma andare characterized by fibroblastic proliferation andexcess collagen deposition (Uitto and Kouba2000; Lev-Tov et al. 2012).

Light-emitting diode devices have been shownto stimulate fibroblast activity and hasten woundhealing. Studies have revealed the possible benefitof red and infrared low-level light therapies toimprove scars. It has been reported that collagensynthesis is reduced, and interstitial matrix meta-lloproteinases (MMP-1), the collagenase involvedin normal turnover of skin collagen, areupregulated in aged skin (Brondon et al. 2007).

It has been proposed that interleukin (IL)-6signaling pathways play a central role in this pro-cess and thus that IL-6 pathway inhibition couldbe a promising therapeutic target for scar preven-tion. As LED therapy has been shown to decreaseIL-6 mRNA levels, it may potentially be pre-venting aberrant healing (Ghazizadeh et al.2007; Uitto 2007; Barolet 2008).

LED phototherapy using near-infrared 805 nmlight is a method to prevent or attenuate the devel-opment of hypertrophic scars or keloids inpatients that underwent surgical excision or CO2

laser ablation of keloids or hypertrophic scars(Mamalis et al. 2014).

Light-Emitting Diode for Acne, Scars, and Photodamaged Skin 81

In vitro studies demonstrate that LED photother-apy, at both red and near-infrared wavelengths, cansuppress fibroblast proliferation and may provide amechanistic foundation for future treatment ofkeloids (Barolet and Boucher 2010) (Fig. 5).

Scars treated for 15 min daily for 30 dayswith an infrared LED device (805 nm at30 mW/cm2) showed significant improvementwith no associated side effects as evidenced byimprovements in VSS score, measurement ofscar height by quantitative skin topography,and blinded clinical assessment of photographs(Mamalis et al. 2014).

A recent study has demonstrated that light-emitting diode blue can inhibit adult human skindermal fibroblast proliferation and migrationspeed and is associated with increased reactiveoxygen species generation in a dose-dependentmanner without altering viability. LED blue hasthe potential to contribute to the treatment ofkeloids and other fibrotic skin diseases (Mamaliset al. 2015).

The potential of PDT on scar tissue has beenpreviously investigated. In vitro studies haveshown that ALA-PDT induced collagen-degrading matrix metalloproteinase (MMP)-1and MMP-3 in dermal fibroblasts while reducingcollagen type 1 mRNA expression (Karrer et al.2003). A retrospective blinded study by Sakamotoet al. found aminolevulinic acid (ALA) or methylester aminolevulinic acid (MAL) combined withred LED to statistically improve scar appearance

after two or more treatments (Sakamoto et al.2012).

Nie et al. reported a positive effect of PDT in apatient with a persistent keloid which had notresponded to a number of routine therapies. Fol-lowing five MAL-PDT sessions, scar color hadimproved, and the keloid had reduced in size,become flatter, with reduced erythema in the sur-rounding margin (Nie et al. 2010).

PDT can reduce scar formation in keloid asevidenced by lack of recurrence and improvementin signs and symptoms as well as by decreasedblood flow, increased pliability, and decreased col-lagen and hemoglobin levels (Ud-Din et al. 2013).

Photodamaged Skin

The use of LEDs for skin rejuvenation is unique inthat it does not produce any thermal damage. It isproposed that specific LED light wavelengths areabsorbed in the skin and used to modulate cellfunction, proliferation, and repair in sun-damagedtissue, in a process termed photobiomodulation(Baez and Reilly 2007).

Photobiomodulation is considered to stimulategrowth factor production (i.e., fibroblast growthfactor, TGF, PDGF), extracellular matrix produc-tion, and increased synthesis of collagen and pro-collagen and enhances cutaneous microcirculationthrough activating the mitochondrial respiratorysystem of the cells (Lee et al. 2007a).

Fig. 5 Keloid treated for 30 min two times a week for60 days with a combination of red LED device (630 nm)and IR LED device (850 nm) showed significant

improvement after 6-month follow-up (Photograph frompersonal archive of Dr. Luiza Pitassi)

82 L. Pitassi

A number of clinical studies provide evidenceof the effectiveness of LED therapy in photo-rejuvenation using a variety of LED light sources.LEDs have been shown to improve UV-damagedskin conditions, including photoaging, suggestingthat the mechanism of action between LEDs andUV radiation is different (Kim et al. 2012).

Trelles has suggested that LED therapy repre-sents a potential approach in antiaging prevention.The prevention can be achieved via irradiatinglow-level photoenergy with specific wavelengthsthat, based on the photobiological findings, canstimulate both epidermal and dermal cells (Trelles2006).

Recent studies suggest that LLLT (specificallyred or NIR radiation) may provide effective pro-tection against UV-induced photodamage. This isbelieved to be due to the fact that, earlier or duringthe day (morning time), red/NIR wavelengths ofthe solar spectrum predominate and prepare theskin for the potentially harmful UV radiation thatpredominates later on in the day (noon/afternoon)(Barolet 2008; Sawhney and Hamblin 2014).

Irradiation with red light increased fibroblasticgrowth factor synthesis from photoactivated mac-rophages and accelerated mast cell degeneration(Lam et al. 1986).

The induction of collagen synthesis by LED inthe red spectrum has been shown to occur largelyin the papillary dermis. Barolet et al. showed thatLED therapy reversed collagen downregulationand MMP-1 upregulation. This could explain theimprovements in skin appearance observed inLED-treated individuals. These findings suggestthat LED at 660 nm is a safe and effectivecollagen-enhancement strategy (Barolet et al.2009).

The red light is used to increase new tissuegrowth, enhance healing, and stimulate collagen,thereby reducing lines and wrinkles. It also hasbeen used to improve skin roughness, depth ofrhytids, skin tone, texture, pore size,dyspigmentation, edema, and erythema (Sauder2010).

A split-face study of red LED (633 nm) inpatients who had undergone blepharoplasty andperiocular resurfacing demonstrated a statistically

significant improvement of edema, erythema,bruising, and pain on the treated side of the face(Opel et al. 2015).

Light at 830 nm (near-infrared) wavelength isabsorbed in the cellular membrane rather than incellular organelles which remain the target whenusing light in the visible spectrum. Irradiation at830 nm has accelerated fibroblast-myofibroblasttransformation and mast cell degranulation. Inaddition, chemotaxis and phagocytic activity ofleucocytes and macrophages are enhanced on cel-lular stimulation by this wavelength (Russell et al.2005).

Infrared wavelength phototherapy with anLED at 830 nm has anti-inflammatory effectsand is useful for the regeneration of damagedskin. The wavelength of 830 nm is well knownto dramatically increase the action potentials ofwound-healing cells, particularly those in theinflammatory and remodeling stages, and wouldtherefore cause a considerably faster resolution ofpost-laser adverse effects such as erythema andpain (Russell et al. 2005; Trelles 2006).

Previous work has been published on the com-bination use of 633 and 830 nm LED therapy inthe treatment of photoaged skin. Red (633 nm)light has been shown to increase fibroblast growthfactor and collagen synthesis in the skin (Baez andReilly 2007).

The 830 nmwavelength is well associated withphotobiomodulation of the wound-healing cells:the mast cells, neutrophils, and macrophages. Thesubsequent doses of 633 nm concentrate on thefibroblasts but maintain the reaction level in theother cells. Both wavelengths are well associatedwith increases in local blood flow rate and vol-ume, and 830 nm also stimulates the transitionalremodeling phase (Trelles 2006).

The synergy of 633 and 830 nm wavelengthlights will combine these effects to enhance fibro-blast proliferation and thus increase collagen syn-thesis, as well as stimulating inflammatory celllines such as mast cells and macrophages(Calderhead et al. 2015).

Goldberg et al. investigated the combination ofred (633 nm) and IR (830 nm) LED treatment onphotodamaged skin and reported softening of

Light-Emitting Diode for Acne, Scars, and Photodamaged Skin 83

periorbital wrinkles in 80% of subjects. There wassubjective improvement of softness, smoothness,and firmness. Histologic examination demonstratedincreased number and thickness of collagen fibrils(Goldberg et al. 2006).

An improvement in skin appearance in aged/photoaged individuals has been documented afterfull-face or split-face serial treatments with red(630, 633 nm) or red in combination with infrared(830 nm) light (Barolet et al. 2009).

Previousfindingswere able to correlatefibroblastactivity and dermal matrix remodeling processes,with an increase in intradermal collagen densityand reduced signs of aging (Lee et al. 2007a). Theproposed underlying mechanisms include thephotostimulation of terminal molecules in theelectron transport chain and the subsequent aden-osine triphosphate (ATP) concentration increase,along with the selective light-driven activation ofwater molecules, thereby enhancing metabolicexchange and influencing the ion transporter sys-tems found in cellular membranes (Wunsch andMatuschka 2014).

A prospective, placebo-controlled, double-blind, split-face trial by Lee et al. randomizedpatients with facial rhytids to receive red LED(640 nm), IR (830 nm), both, or sham treat-ments. Patients demonstrated a statistically sig-nificant reduction in wrinkle severity across alltreatment groups: 26%, 33%, and 36%, respec-tively. Skin elasticity also improved. Tissueassays were notable for an increase in collagenand elastic fibers adjacent to highly active fibro-blasts (Lee et al. 2007a).

A study performed with a light device combin-ing narrowband blue light (420 nm) and nearinfrared (850–890 nm), using 20 min exposureand a total dose of 60 J/cm2, has demonstrated adramatic improvement in skin photorejuvenationwhen associated with glycolic acid peels and top-ical vitamin C (Fournier et al. 2006). LED treat-ments work well after any procedure that causeserythema and irritation, including chemical peelsor ablative laser systems with extremely high sat-isfaction levels.

The combination of LED light wavelengthswas shown in in vitro results to improve the cell

shape homogenization, cell proliferation, and thelevel of major proteins involved in the healingprocess (Chabert et al. 2015). LED system isknown for its healing and anti-inflammatory prop-erties and also enhancing the results of facialcosmetic procedures.

Conclusion

LED phototherapy is a non-ablative, nonthermal,and nontraumatic treatment, which stimulatescell activities and functions through a photo-biomodulative effect.

Light therapy can be a safe and effective alter-native for treating acne, scars, and photodamagedskin and a variety of medical treatments with noadverse effects or downtime reported during orafter LED treatment.

Take Home Messages

• LED is non-ablative and nonthermal, making itsafe for all skin types.

• The treatment is hands-free with no need foroperator presence.

• The infrared spectrum is invisible to the eye.• Eye protection is mandatory, both for the phy-

sician and the patient.• LED can be used as an adjunctive treatment to

all laser• LED therapy helps wound healing after

surgery• The results are better when LED is used in

combination• LED therapy is an effective, non-painful, and

no-downtime treatment modality

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Light-Emitting Diode for Acne, Scars, and Photodamaged Skin 87

Non-ablative Lasersfor Photorejuvenation

Maria Angelo-Khattar

AbstractPhotoaging of the skin principally dependsupon the amount of melanin in the skin andthe degree of exposure to ultraviolet radiation.Solar damage to DNA leads to a reduction inthe skin’s collagen content and ultimately to adeficit in the structural integrity of the skin.This manifests as clinically visible skin atro-phy, lines and wrinkles, and dyschromias suchas telangiectasias and pigmented lesions.Photorejuvenation entails an improvement inthe tone, texture, and pigmentation of the skin.Various laser technologies are available thatrejuvenate skin by resurfacing the uppermostlayers and allow for the regeneration of newskin cells. The myriad of laser systemsincludes ablative and non-ablative lasers inboth fractionated and nonfractionated or con-ventional forms. In varying degrees, all ofthese lasers treat pigmented lesions, softenwrinkles, and reduce the appearance of scars.Although the ablative technologies yield moreeffective results in terms of the overall reduc-tion of photoaging, the non-ablative lasersallow for swift healing and are rarely associ-ated with any complications or downtime. Fur-thermore, non-ablative lasers offer a widerspectrum of clinical indications, since they

can be used to treat vascular lesions such astelangiectasia, generalized erythema, and rosa-cea that are commonly associated withaging skin.

Apart from photorejuvenation, non-abla-tive lasers have multiple applications includ-ing the reduction in sebum secretion in acneand the treatment of a variety of scars. How-ever, this review aims to give an overview andhighlight the clinical advantages of both frac-tionated and nonfractionated non-ablativelaser platforms in current use for the treatmentof photodamaged skin.

KeywordsPhotoaging • Photodamaged skin • Skin atro-phy • Aging skin • Wrinkles • Dyschromias •Pigmented lesions • Photorejuvenation •Resurfacing • Non-ablative lasers • Fraction-ated laser

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90

The Mechanism of Ultraviolet Damage tothe Skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90

History of Non-ablative Lasers . . . . . . . . . . . . . . . . . . . . . 91

Non-ablative Laser Photorejuvenation Mechanismof Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92

Non-ablative Nonfractional Lasers . . . . . . . . . . . . . . . . . 93Visible Light Lasers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93Near-Infrared Lasers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94Mid-Infrared Lasers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95

M. Angelo-Khattar (*)Aesthetica Clinic, Dubai, UAEe-mail: mkhattar@aestheticaclinic.com

# Springer International Publishing AG 2018M.C.A. Issa, B. Tamura (eds.), Lasers, Lights and Other Technologies, Clinical Approaches and Procedures inCosmetic Dermatology 3, https://doi.org/10.1007/978-3-319-16799-2_5

89

Non-ablative Fractional Lasers . . . . . . . . . . . . . . . . . . . . 95Concept of Fractional Photothermolysis . . . . . . . . . . . . 95Types of Non-ablative Fractional Lasers . . . . . . . . . . . . 97General Clinical and Treatment Considerations in

Non-ablative Resurfacing . . . . . . . . . . . . . . . . . . . . . . . . 100

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101

Take Home Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101

Introduction

The appearance of the skin in humans is integralto the perception of both health and beauty.Hence, in the vast majority of cases, it has agreat bearing on the individual’s overall well-being and self-esteem.

Skin aging is a complex biological processinfluenced by a combination of factors and maybe broadly categorized as chronological or intrin-sic aging and photoaging. Unlike intrinsic aging,which is determined by the individuals’ geneticpredisposition, photoaging depends mainly onthe degree of repeated sun exposure and theamount of melanin in the skin. In fact, skin injuryby the sun’s ultraviolet (UV) rays account forover 70% of skin aging (Kligman and Kligman1986).

Chronological and photoaging can be easilydistinguished clinically, but they share importantmolecular features. The clinical characteristics ofchronologically aged skin include fine wrinkles,laxity, xerosis, and the development of benignlesions such as solar lentigines, cherry angiomas,and seborrheic keratosis (Krutman and Gilchrest2006).

The features of photoaging include roughskin, wrinkles, deep furrows, pigmented lesions,telangiectasias, poikiloderma of Civatte, solarelastosis, precancerous lesions, and skin cancers(Yaar et al. 2002; Gilchrest 1990). Sun-exposedareas, such as the face, neck, décolleté, hands,and forearms, are most frequently affected. Fur-thermore, fair-skinned individuals with a historyof intensive sun exposure are more susceptible tosevere photodamage.

The Mechanism of Ultraviolet Damageto the Skin

Ultraviolet rays induce numerous changes in theskin including melanogenesis, angiogenesis,immune suppression, and degradation of connec-tive tissue, DNA mutations, and oncogenesis.

Advances in skin biology have increased ourunderstanding of the mechanism whereby UVradiation contributes to photoaging and cutaneousdisease.

UVB (280–320 nm) rays are reported to havedirect cytotoxic and mutagenic effects on skincells, while UVA (320–400 nm) rays exert theirdamaging effects predominantly through the pro-duction of reactive oxygen species (ROS). Anumber of transcription factors and inflammatorycytokines are released in response to ultravioletrays, which result in an increase in matrix meta-lloproteinase (MMP) production and ultimatelyaccelerated degradation of the dermal matrix.

The widely accepted pathway is via theupregulation of activator protein-1 (AP-1) andnuclear factor kappa B (NFk B). The latter playsa key role in the signaling pathway leading to theactivation of the inflammatory cascade that stim-ulates the expression of pro-inflammatory cyto-kines such as tumor necrosis factor alpha. Inaddition, activation of NFk B upregulatesthe expression of MMP-1, and consequently der-mal collagen is degraded. Furthermore, NFk Bdownregulates type I collagen synthesis (Rijkenand Bruijnzeel 2009) (Fig. 1). Ultraviolet radiationcan also upregulate c-Jun, a component of AP-1,and can downregulate retinoic acid (RA) receptors,which decrease RA inhibition of AP-1. This ulti-mately results in the loss of dermal bulk and skinthinning (Krutmann 2000).

Over the past several years, a plethora of bothenergy-based and nonenergy-based anti-agingstrategies have been developed to retard andreverse skin aging.

Both treatment categories work on the princi-ple of “controlled wounding,” whereby the induc-tion of skin trauma initiates a wound healingresponse and ultimately results in collagen

90 M. Angelo-Khattar

remodeling and dermal repair (Rivera 2008).Nonenergy-based treatments include chemicalpeels, dermabrasion, intradermal injection ofgrowth factors from autologous platelet-richplasma, fibroblast, and, more recently, stemcell transfer. However, the energy-baseddevices, which selectively target skin chromo-phores, have become the preferred treatmentmodality for many skin conditions includingpigmented lesions, telangiectasias, skin laxity,lines and wrinkles, as well as surgical scars,atrophic acne scars, and stretch marks. Theenergy-based systems include the full spectrumof ablative and non-ablative lasers, intensepulsed light systems, a variety of radio-frequency devices, and high-intensity focusedultrasound systems.

The focus of this chapter will be the full spec-trum of non-ablative lasers that are used forphotorejuvenation.

History of Non-ablative Lasers

The myriad applications of lasers in dermatol-ogy burgeoned with the milestone publicationby Anderson and Parrish on selective photo-thermolysis in 1983 (Anderson and Parrish1983).

Since then, over the last 30 years, there hasbeen a tremendous evolution in laser technologyand design, allowing better control of laser param-eters and a consequent increase in safety andefficacy of laser treatments.

Fig. 1 Molecular cascade in the skin following UVR via AP-1 and NFk B (Adapted from Rabe et al. 2006)

Non-ablative Lasers for Photorejuvenation 91

Non-ablative lasers are of two types: non-fractional or conventional lasers that act on theentire surface area of the skin and fractional tech-nologies that produce only small columns of ther-mal injury interspersed among predominantlyintact skin.

Historically, the use of lasers in the manage-ment of photoaged skin began with the introduc-tion of fully ablative skin resurfacing procedures.The mid-1990s saw the introduction of the carbondioxide (CO2) and erbium-doped:yttrium-alumi-num-garnet (Er:YAG) lasers (Alster 1999). Thesehigh-energy pulsed devices create full-thicknesswounds and yield impressive clinical outcomes(Alster and West 1996). To date, full resurfacingremains the gold standard for photodamaged skin.However, the procedure is associated with pro-longed recovery and poor patient tolerability.

In the late 1990s, Hsu and his colleagues firstdescribed non-ablative dermal remodeling due toan incidental observation of the reduction of wrin-kles in areas treated with the conventional pulseddye laser (PDL) for telangiectasias (Hsu et al.2005). Hence, this led to a move toward mini-mally invasive procedures, giving rise to a gener-ation of non-ablative resurfacing lasers such as the1450-nm diode, 1064-nm and 1320-nm neodym-ium:yttrium-aluminum-garnet (Nd:YAG) lasers,and 1440-nm, 1540-nm, and 1550-nm erbium-glass lasers (Tanzi and Alster 2004). However,this first generation of non-ablative systemsshowed only moderate efficacy. In 2004, the intro-duction of fractional photothermolysis (FP) byManstein and his colleagues (2004) revolution-ized the field of laser skin resurfacing and hasresulted in the development of numerous non-ablative and ablative fractional laser devices.The popularity of these technologies is due totheir ease of operation, lower risk of side effects,good patient tolerability, and relatively quickpatient recovery. It is widely accepted that thefractional ablative lasers offer superior efficacyin terms of skin rejuvenation; however, the gentlerfractional non-ablative lasers have the advantageof quicker healing and reduced downtime. Anincreased number of treatment sessions with thenon-ablative lasers may ultimately result in equiv-alent efficacy to ablative lasers.

Non-ablative Laser PhotorejuvenationMechanism of Action

Photorejuvenation consists of two essentialfactors:

1. The removal of epidermal signs of photo-damage by selective photothermolysis

Microscopic structures such as blood ves-sels and pigmented cells are photocoagulatedby selectively absorbed photons of light, henceresulting in the attenuation of solar lentigines,ephelides, and telangiectasias.

Laser energy absorbed by oxyhemoglobinresults in erythrocyte coagulation and thedestruction of ectatic vessels. This has beendemonstrated by the histological examinationof port wine stains after pulsed dye laser.Fibrin, thrombin, and agglutinated red bloodcells have been found in the superficial der-mal blood vessels (Stratigos and Js 2000). Asa consequence, neovascularization occurswith replacement of the destroyed abnormalvessels.

The precise molecular events involved inthe destruction of melanosomes by lasers areunknown (Santiagos et al. 2000), but it isbelieved that both photothermal and photome-chanical mechanisms are responsible (Araet al. 1990). A sudden rise in temperatureresults in the vaporization and expansion oftarget tissues with the consequent destructionof pigmentary lesions. Clinically, frosting isobserved immediately after pulsed lasers.This serves as a treatment endpoint and isproposed to be due to the formation of gasbubbles following a sudden increase in temper-ature of the target tissue (Santiagos et al. 2000).Histologically, destroyed melanosomes,vacuolization, and pigment leakage from cellshave been shown (Dover et al. 1989a).

2. Dermal remodeling resulting from patterns ofmicroscopic thermal injury to the dermis

The reduction in fine lines and wrinkles andoverall improvement in skin texture and tight-ening are due to new collagen formation anddermal thickening. The mechanism of dermalremodeling by non-ablative lasers centers upon

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the fact that the non-ablative resurfacing laserwavelengths are absorbed to varying extentsby intradermal water. Hence, this results inthermal injury to the dermis that is dependentupon both the amount of energy delivered andthe exposure duration. A critical intradermaltemperature of 60–80 degrees is required foreffective denaturation of collagen and initia-tion of the wound healing response (Paulet al. 2011). Temperatures above this rangecan lead to complete denaturation of collagenand result in scarring.

The non-ablative lasers treat photodamagedskin without physically removing or vaporiz-ing the skin as opposed to ablative proceduresthat literally vaporize a fraction or all of theepidermis and layers of the dermis. All of theselasers selectively utilize technology to cool andprotect the epidermis while creating controlledthermal injury to dermal structures.

Non-ablative Nonfractional Lasers

The first generation of non-ablative conventionallaser modalities entered the market in the late1990s primarily for the use of skin rejuvenation.These included lasers that emit light in the visible,near-infrared, and far-infrared spectrum (Table 1).This diverse group of laser technologies includesthe potassium titanyl phosphate (KTP; 532 nm),pulsed dye (PDL; 585 nm, 595 nm,), Q-switched(QS) ruby (694 nm), QS alexandrite (755 nm),long-pulsed and QS Nd:YAG (1064 nm), long-

pulsed Nd:YAG (1320 nm), long-pulsed diode(1450 nm), and erbium-glass (1440 nm and 1540nm) lasers.

Wavelengths within the visible light spectrumand specifically the QS lasers are mainly indicatedfor skin dyschromias, whereas the longer wave-length near-infrared and mid-infrared lasers arebetter suited for dermal remodeling.

Although the reversal of epidermal dys-chromias with the nonfractionated devices is rel-atively effective and predictable, the improvementin skin texture is much more subtle. Hence, non-ablative nonfractional skin resurfacing is ideal forthe patient with mild to moderate photodamageand early signs of skin aging.

Visible Light Lasers

These include the 532-nm KTP, 585-/595-nmpulsed dye, 694-nm Q-switched ruby, andQ-switched 755-nm alexandrite lasers.

These visible light lasers are commonly used totreat vascular and pigmented lesions since theirwavelengths are well absorbed by the variouschromophores in the skin, such as oxyhemoglobinand melanin. The lasers improve skin color byreducing dyschromias including solar lentigines,ephelides, telangiectasias, and generalized ery-thema. The visible light spectrum lasers shouldbe used with great caution in darker skin types dueto the risk of thermal damage of these shorterwavelengths.

An improvement in skin texture has also beenrepeatedly demonstrated with the visible lightspectrum lasers. The absorption of the 585-nmwavelength by oxyhemoglobin results in a ther-mal insult to the microvasculature and henceinitiates an inflammatory response that stimu-lates fibroblast activity and ultimately dermalcollagen synthesis. Bjerring et al. showeda 48% increase in type II collagen synthesisonly 2 weeks after a single session of pulseddye laser (Bjerring et al. 2002). Orringer et al.reported an increase in dermal remodeling due toan increase in type I procollagen mRNA, andZelickson et al. also showed that only one passwith the 595-nm pulsed dye laser was sufficient

Table 1 Non-ablative nonfractional lasers for skinrejuvenation

Visible lightlasers

Near-infraredlasers

Mid-infraredlasers

532-nm KTP585-/595-nmpulsed dye694-nmQ-switched ruby755-nmQ-switchednanosecond andpicosecondalexandrite

1064-nm long-pulsed andQ-switchednanosecond andpicosecond Nd:YAG

1320-nm Nd:YAG1450-nmdiode1540-nmerbium-glass

Non-ablative Lasers for Photorejuvenation 93

to improve dermal collagen (Orringer et al.2005; Zelickson et al. 1999).

Potassium Titanyl Phosphate Laser532 nm (Cynosure MedLite C6, RevLiteS1, and PicoSure; Syneron-Candela AlexTriVantage; Alma Harmony XL Pro)Current Q-switched KTP lasers include those inthe 5–15 ns range and the novel 350 picosecondlasers. The devices incorporate an Nd:YAG (1064nm) laser as the main source of light that isconverted by a KTP crystal to emit the halvedwavelength of 532 nm. This green light is wellabsorbed by hemoglobin and melanin; hence, theKTP can be used for the treatment of bothunwanted vessels and pigment. The short wave-length of the KTP laser is very well absorbed byepidermal melanin; hence, caution should beexercised in darker skin types (Weiss et al.2005). The KTP laser has only mild effects onthe improvement of skin texture (DeHoratius andDover 2007).

The 532 KTP laser has interestingly been usedfor lip color lightening, which is a common con-cern of darker-skinned individuals (Somyas et al.2001).

Pulsed Dye Laser 580–595 nm(Syneron-Candela VBeam)In the flashlamp-pumped pulsed dye, a flashlampis used to excite electrons in an organic dye,rhodamine, to emit light of yellow color. Theoriginal pulsed dye lasers had a wavelength of577 and pulse duration of 0.45 milliseconds,which resulted in intravascular thrombosis ofsmall vessels and purpura. Hence, the currentpulsed dye systems have wavelengths between585 and 595 nm and pulse duration of up to40 milliseconds. The longer wavelengths pene-trate deeper into the skin, and the longer pulsedurations allow for avoidance of purpura. Apartfrom the effect on vascular lesions, pulsed dyelasers do afford moderate skin rejuvenating effect(Bjerring et al. 2002).

Q-Switched Ruby Laser 694 nm (AlmaLasers, Sinon)The QS ruby laser emits red light and is hence notabsorbed by hemoglobin but selectively targets

melanin. It was, in fact, the first Q-switched laserdeveloped for epidermal and dermal pigmentedlesions. The very short, 20–50 ns, pulse durationsof the ruby laser selectively target melanosomes,resulting in the photoacoustic destruction of themelanosome cell membrane. This effect is pulsewidth dependent with shorter pulse durationsbeing more effective in melanosome destruction(Polla et al. 1987; Dover et al. 1989b). Cautionmust be exercised as darker phototypes maydevelop permanent hypopigmentation (Rinaldi2008; Kishi et al. 2009).

QS Alexandrite 755 nm (CynosureAccolade, Syneron-Candela AlexTriVantage, and PicoWay)The QS alexandrite laser, emitting light within thered spectrum and with pulse widths of 50–100 ns,selectively targets pigmented lesions by causingthe photoacoustic disruption of melanin.

A new picosecond QS alexandrite laser hasrecently been introduced on the market, and, thusfar, most of the studies with this novel device havebeen on its use in the treatment of tattoos. How-ever, the device shows promise in the effectivetreatment of pigmented lesions. A recent publica-tion has demonstrated the 755-nm ultrashort-pulsed 550 picosecond alexandrite laser withdiffractive lens array to be an effective option forrejuvenation of the photodamaged décolletage(Wu et al. n.d.).

Near-Infrared Lasers

1064-nm Long-Pulsed and QSNd:YAG Lasers (Palomar QYAG5,Syneron-Candela Alex TriVantage; AlmaHarmony XL Pro)Both the long-pulsed and QS Nd:YAG (1064-nm)lasers in the mid-infrared spectrum are used forphotorejuvenation. The incidental rejuvenatingeffect of long-pulsed lasers including the Nd:YAG1064-nm laser commonly used for other indicationsincluding hair removal and treatment of larger cal-iber blood vessels was recognized early on. Thisnear-infrared wavelength is absorbed by water inthe skin and hence effectively heats the dermis. Theresultant thermal injury to the dermis leads to a

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limited degree of neocollagenesis and skin tighten-ing (Weng et al. 2011).

The long-pulsed Nd:YAG laser handpiece maybe used in constant motion, delivering multiplepasses to the surface of the skin until a surfacetemperature of 39–42 degrees is attained. This isthe optimal temperature range for dermalremodeling. Above this temperature, dermal scar-ring may occur. Hence, prior to treatment with thislaser for rejuvenation, patients should not receiveany anesthetic, as excessive pain must be reportedto alert the practitioner and avoid epidermalinjury. Patients treated with long-pulsed Nd:YAG for rejuvenation exhibited a decrease inrhytids (Hong et al. 2015).

The QS Nd:YAG with pulse durations of5–15 ns, principally used for the treatment oftattoos and disruption of melanin in pigmentedlesions, may also be used in an in-motion manner,continuously treating the skin. Treatments may beperformed with or without the application of top-ical carbon solution, which is believed to improvethe penetration of the laser beam. A split-facestudy by Lee et al. demonstrated significantimprovement in rejuvenation effects after QSNd:YAG with no difference in improvement inskin texture after the application of topical carbonsolution (Lee et al. 2009). However, skin rejuve-nation treatments with the QSNd:YAGwere asso-ciated with a high degree of postinflammatoryhyperpigmentation at the 1-month follow-up eval-uation (Jun et al. 2014). Recently, picosecond Nd:YAG lasers in the 500–750 ps range have devel-oped for the removal of pigmented lesions. Todate, no studies have been published on the useof picosecond Nd:YAG laser system forpigmented lesions or skin rejuvenation.

Mid-Infrared Lasers

1320-nm Nd:YAG (Cooltouch CT3 Plus,Alma Harmony XL)This wavelength is well absorbed by water andeffectively heats the treated dermis. The ensuingthermal injury results, to a limited extent, in thestimulation of fibroblasts and the induction of“neocollagenesis.” Studies have shown an eleva-tion in basic fibroblast growth factor (bFGF) and

histological evidence for a reduction in skin agingby the stimulation of type I, III, and VII collagen(Zhenxiao et al. 2011; El-Domyati et al. 2011).

1450-nm Diode Laser (CandelaSmoothbeam)The mechanism of action of the 1450-nm diodelaser is similar to the 1320-nm Nd:YAG. Thismid-infrared wavelength creates wounding ofthe dermis due to its high water absorption coef-ficient, but the 1450-nm laser has been shown tobe more effective in inducing neocollagenesisthan the 1320-nm wavelength (Alster et al. 2007).

1540-nm Erbium-Glass Laser (QuantelAramis)The mid-infrared 1540-nm laser, which also tar-gets intracellular water, penetrates into the papil-lary dermis where collagen tightening andneocollagenesis are achieved. This allows formore effective treatment of solar elastosis.

The 1540-nm wavelength is only minimallyabsorbed by melanin; hence, it is safe for use bydarker phototypes.

This laser has been used for the treatment offine lines, wrinkles, and acne scars. Evidence fordermal remodeling with the 1540-nm laser hasbeen demonstrated by histologic studies as wellas ultrasound and profilometric analysis. A 40%reduction in wrinkles and 17% increase in skinthickness were shown after the fourth week oftreatment (Fournier et al. 2002; Lupton et al.2002).

Non-ablative Fractional Lasers

Concept of FractionalPhotothermolysis

Fractional photothermolysis (FP), first introducedby Manstein and colleagues in 2004, is one of themost significant milestones in laser technologyand resurfacing (Manstein et al. 2004). It has ledto a new era in the application of lasers in derma-tology and resulted in a tremendous developmentin fractional laser technology and numerous com-mercial fractional systems. Fractional lasers havenow become the laser modality of choice in the

Non-ablative Lasers for Photorejuvenation 95

management of photodamaged skin (Saedi et al.2012) . These devices bridge the gap in terms ofefficacy between the traditional ablative and non-ablative lasers (Alexiades-Armenakas et al. 2012).They are less aggressive than traditional ablativelasers and offer superior clinical outcomes to thenon-ablative systems but with the same level ofsafety. As opposed to the conventional ablativeand non-ablative lasers that produce layers of ther-mal heating, fractional lasers thermally denatureonly fractions of the skin.

They create micro-columns of thermal injuryreferred to as microthermal or microscopic treat-ment zones (MTZs) (Geronemus 2006). MTZs aretypically 70–150 μm wide and extend verticallyfrom the epidermis to the dermis at varying depthsof approximately 400–700 μm, determined byseveral laser parameters including laser outputenergy (Gold 2010). Fractional devices spareskin and stem cells in between the MTZs andhence allow for rapid recovery and increasedsafety (Fig. 2).

There are basically two types of fractional laserdevices: non-ablative and ablative, classifiedaccording to the type of MTZs that they produce(Fig. 2). Non-ablative fractional lasers (NAFLs)simply cause thermal injury to the dermis whilesparing the epidermis, whereas the ablative frac-tional lasers (AFLs) vaporize micro-columns ofepidermis and dermis (Alexiades-Armenakas

et al. 2008). The histologic changes due to non-ablative fractional photothermolysis (NAFP) andablative fractional photothermolysis (AFP) areshown in Figs. 3 and 4.

The repair of treated skin begins by the extru-sion of columns of necrotic skin, known as micro-scopic epidermal necrotic debris (MENDs), intothe stratum corneum (Manstein et al. 2004). Man-stein and colleagues (2004) showed that MENDsare button-shaped structures (40–80 μm diameter)that contain melanin and form beneath the stratumcorneum above each dermal wound. The produc-tion of MENDs indicates the participation ofintact keratinocytes, from uninjured skin, in theprocess of wound repair (Manstein et al. 2004).MENDs seen in histology correspond to thebrown spots observed via epiluminescencemicroscopy, and these are shed from the epider-mis within 7 days of FP (Manstein et al. 2004)(Fig. 5). This extrusion process of cellular debriswas confirmed by Hantash et al. (2006) who usedanti-human elastin antibody to demonstrate thetransdermal elimination of MENDs. Mansteinand colleagues (2004) showed clear evidenceof epidermal repair within the papillary andsuperficial reticular dermis as demonstrated byincreased mucin content as well as an increasedundulation in the rete ridge pattern of treated skinat 3 months posttreatment (Fig. 6) (Laubach et al.2006).

Fig. 2 Schematic representation of mode of action of fractional non-ablative and ablative resurfacing

96 M. Angelo-Khattar

Types of Non-ablative Fractional Lasers

All of the non-ablative fractional lasers emitwavelengths in the mid-infrared range that corre-spond to peaks on the water absorption curve. Byvirtue of the mechanism of action of the fractional

device, whereby only small fractions of the skinare resurfaced in each treatment session, typi-cally 4–6 treatment sessions are required toattain a positive clinical outcome in the treat-ment of photodamaged skin. The treatment isrelatively painful, requiring a combination oftopical anesthetic creams and cryoanesthesia.Posttreatment edema and erythema is noticeablefor 48 h, followed by skin desquamation overa few days.

1550-nm (Solta Fraxel Re:store, SoltaFraxel Re:store Dual) and 1540-nm(Palomar Starlux, Artisan, Icon)Erbium-Glass LasersThe first NAFL device to be developed in 2004was the 1550-nm erbium-glass laser that targetswater as a chromophore (Geronemus 2006). Thedevice is tunable such that the density of theMTZs and the energy can be adjusted. Most ofthe studies on NAFLs were performed with thisdevice (Tierney et al. 2009).

The initial clinical studies by Manstein et al.(2004) demonstrated significant improvement inskin periorbital lines and wrinkles. Many otherinvestigators consistently showed evidence ofcollagen remodeling as improvements in skin tex-ture and color. The initial results continued toimprove over 6–9 months posttreatment (Rahmanet al. 2006; Wanner et al. 2007). Non-facial areasare also effectively treated with this NAFL device.A study by Jih et al. (2008) on the hands of tenpatients showed 51–75% improvement in pig-mentation and 25–50% improvement in skin tex-ture at 3 months. DeAngelis et al. reported goodefficacy of the erbium-glass laser in the treatmentof striae rubra and alba ranging in maturation agefrom 1 to 40 years (de Angelis et al. 2011).

Wanner et al. showed fractional photothermolysisfor the treatment of facial and non-facial cutaneousphotodamage using a 1550-nm Er-glass fiber laser tobe a useful NAFL treatment (Wanner et al. 2007).

The upgraded version of this laser, the FraxelDual, has a dual wavelength of 1550-nm erbiumwith a 1927-nm thulium laser on one platform,allowing the operator to target different treatmentdepths. After a single treatment with the thuliumlaser, a mean of 69% of subjects at 1 month

Fig. 3 Histologic slide of human skin after NAFP (1550-nm erbium laser) demonstrating two columnar micro-lesions extending from the epidermis to the dermis(depth, 560 μm; width, 135 μm) (Adapted fromAlexiades-Armenakas et al. 2012)

Fig. 4 Histologic slide of human skin after AFL (2940-nmerbium laser) demonstrating a column of ablationextending from the epidermis to the dermis. (Adaptedfrom Geronemus 2006)

Non-ablative Lasers for Photorejuvenation 97

demonstrated a very significant improvement inlentigines and ephelides (Brauer et al. 2014).Hence, superficial treatment of pigmented lesionscan be achieved with the 1927-nm wavelength,and collagen remodeling is achieved with thedeeper penetrating 1550-nm wavelength.

1440-nmNd:YAG Laser (Cynosure Affirm)and 1440-nm Diode (Solta Clear +Brilliant)Fractional devices that deliver 1440-nm wave-lengths include the Nd:YAG and diode laser. Thecynosure device allows for uniform distribution

Fig. 5 Cross-polarized photomicrographs showing surfacehealing of forearm skin following FP: (a) pretreatment,(b) 1 dayposttreatment, (c) 1weekposttreatment, (d) 3months

posttreatment. Individual brown spots are visible at 1 day andbegin to slough by 1 week (Adapted from Manstein et al.2004)

Fig. 6 Histology of forearm skin: (a) pretreatment and (b) 3 months following FP demonstrating increased mucin contentin the superficial dermis and enhanced rete ridge patterning (Adapted from Manstein et al. 2004)

98 M. Angelo-Khattar

of the energy across the skin surface, at depthsof 300 um, via combined apex pulse (CAP)technology.

Clinical studies with both devices have shownthem to be only moderately effective in theremodeling of scars and treatment of photoagedskin (Marmon et al. 2014; Geraghty and Biesman2009).

Hence, manufacturers have upgraded the orig-inal systems to include dual wavelengths. Thecynosure system offers the multiplex technologythat combines a 1320-nm wavelength with a1440-nm laser, allowing for penetration to depthsof 1000–3000 um. The 1320-/1440-nm multiplexsystem resulted in greater skin tightening at6 months than the 1440-nm laser alone (Geraghtyand Biesman 2009).

A new version of the Clear + Brilliant, knownas the Clear + Brilliant Permea, includes bothdiode and thulium media, hence offering both1440-nm and 1927-nm wavelengths.

1565-nm Erbium-Doped Laser (LumenisResurFx)This wavelength has a slightly lower absorptioncoefficient for water than that of 1550 nm whichresults in greater skin penetration. The systemuses a sequential scanning system that allows fora variety of shapes, densities, and patterns ofdistribution of energy. It is also equipped withcontact cooling for greater patient comfort. Todate, there are no published studies demonstratingthe relative advantage of this laser system over theestablished fractional near-infrared devices(Sadick 2014).

1940-nm Alexandrite Fractional Laser(Syneron-Candela)This is a relatively novel thulium rod pumped by apulsed alexandrite laser emitting a wavelength of1940 nm, which corresponds to one of the waterabsorption peaks in the mid-infrared range. How-ever, the absorption of this wavelength is muchstronger than the other mid-infrared wavelengths(1400–1550) and weaker than the ablative wave-lengths (Er: YAG and CO2). A recent study dem-onstrated the skin rejuvenating effects of the1940-nm fractional device. Patient (n = 11)

received a total of three facial treatments,4–6 weeks apart, and outcome assessments weremade 3 months after the final treatment. Severalparameters were evaluated and the results showeda 21% reduction in pigmentation, 14.3% inrhytids, 8.9% in skin laxity, and 22.3% in solarelastosis (Miller et al. 2014).

1064-nm Fractional QS Nd:YAG laser(Alma ClearLift on Harmony XL Pro)This is a relatively new addition to the arsenal ofNAFR lasers that has gained popularity. The1064-nm laser beam is fractionated by a passiveoptical element into a 5 � 5 matrix of 25 micro-scopic perforations, each having a diameter of200 um. Each pixel receives an energy density inthe range of 6–13 J/cm2. A series of five differentfocusing tips allow for penetration of the QSnanosecond pulses to tunable depths, selectedaccording to the depth of the pathology beingtreated. The rapid laser pulses spare the epidermis,and, furthermore, since the 1064-nm wavelengthis poorly absorbed by melanin and hemoglobin,the pixels penetrate up to 3 mm into the papillaryand reticular dermis. Paasche, at the 2014 Amer-ican Society of Lasers in Medicine and Surgerymeeting, presented histological evidence ofmicrothermal injury deep into the reticular dermis(Paasch 2014). This is advantageous, since wenow know that to achieve skin firmness, penetra-tion to deeper levels is required.

Recently, a high-speed roller has been released,known as the iPixel Scan, which allows for effi-cient and fast treatment of off-the-face areas suchas photodamaged hands, arms, décolletage,and legs.

A pilot study by Luebberding and Armenakas(2012) showed an 11% improvement in superfi-cial rhytids on the face and neck following a seriesof three treatment sessions at 2–4 week intervals.Gold et al. (2014) investigated the effect of thefractional QS 1064-nm laser on several skinparameters. Patients received a total of four treat-ment sessions at 2–4 week intervals with a follow-up at 3 months post last treatment. They reportedan improvement of 70% in hyperpigmentation,80% in telangiectasias, 80% in skin laxity, and60% each in tactile roughness and actinic

Non-ablative Lasers for Photorejuvenation 99

keratoses. A further advantage of the treatmentwas found to be the fact that the treatment isrelatively pain-free, at a level of 0–2 on aten-point scale, and has absolutely no downtime.

General Clinical and TreatmentConsiderations in Non-ablativeResurfacing

Patient SelectionNon-ablative resurfacing is contraindicated dur-ing pregnancy, lactation, and in patients who havea history of keloid formation or those that have anactive infection. Patients who are on isotretinoincan only be treated 6 months after the completionof a course of treatment.

Ideal patients for non-ablative rejuvenation arethose with early signs of photodamage. These aregenerally younger patients ranging from 35 to50 years of age. Older patients with severe laxityand deep wrinkles will not benefit from non-abla-tive laser treatment and are candidates for ablativeresurfacing (Fig. 7).

It is important to ensure that patients haverealistic expectations and understand that skinrejuvenation with the non-ablative systemsrequires several treatment sessions.

Non-ablative resurfacing may be performed inpatients of all skin types, but particular cautionshould be exercised when treating darker skintypes. In these patients, visible light spectrumlasers that specifically target pigment must beused at conservative setting to avoid side effectssuch as hyper- or hypopigmentation, blisters, andscars. Although lasers in the near- andmid-infrared wavelengths are safer for darker-skinned individuals, caution must be exercisedwith respect to the settings. High laser fluencesas well as cryogen cooling with some systems canlead to postinflammatory hyperpigmentation.This is usually transient and can be treated withbleaching agents.

Treatment ConsiderationsPretreatment, the skin should be cleansed thor-oughly to remove oil, makeup, and any debristhat may impede the passage of the laser light.

Fig. 7 Photodamaged patient treated with non-ablative system for photorejuvenation: (a) pretreatment and (b)posttreatment

100 M. Angelo-Khattar

Topical anesthesia is generally required withmost of the non-ablative nonfractional and frac-tional lasers, the exception being the fractionalQ-switched Nd:YAG device. Various formula-tions and strengths of topical anesthetic creamshave been used, from 5% and up to 30%lidocaine. Fractional resurfacing with themid-infrared laser treatments requires the morepotent anesthetic formulations. There is somecontroversy regarding the application of topicalanesthesia as, with some devices, patient feed-back in terms of excessive pain is necessary toavoid epidermal injury.

The patient and all present in the laser roomshould wear protective eyewear as most of thewavelengths in the visible and near-infrared rangepose a risk to the retina, whereas the wavelength inthe mid-infrared range can damage the cornea.

Prophylactic treatment with oral antiviral med-ication is advocated to avoid a herpetic breakout,specifically in patients undergoing non-ablativefractional resurfacing.

Skin cooling during and posttreatment withthe use of a cool air blower or ice application isrequired for patient comfort and to minimizeposttreatment edema. Typically with the frac-tional non-ablative systems, edema and ery-thema resolve within 3 days. Patients arerequired to avoid the sun and apply sunscreendiligently to avoid the possibility of post-inflammatory hyperpigmentation. Additionally,in darker-skinned patients, bleaching creams arenecessary posttreatment to minimize the possi-bility of complications.

Conclusion

Non-ablative laser treatments are ideal for theimprovement of skin color, tone, and texture inrelatively younger patients with skin texturalimperfections associated with photoaging. Theseprocedures have a unique role in treating skindyschromias including vascular lesions in patientsof all ages. Evidence is mounting that non-abla-tive lasers may also result in skin tightening; how-ever, further studies are necessary to reinforce thistheory (Gold et al. 2014; Kauvar 2014).

Non-ablative systems are often used as main-tenance procedures following more aggressiveablative treatments. Furthermore, they play animportant role in the prophylaxis of skin agingas they can be performed regularly with little orno downtime. Non-ablative lasers have beenmainly used on facial skin; however, interest isrising in the role of these techniques on the neck,hands, arms, and other areas of the body.

Non-ablative skin resurfacing procedures pro-duce excellent clinical outcomes with minimalrisk and morbidity; hence, they are of particularimportance in the treatment of photodamagedskin.

Take Home Messages

• The visible light spectrum non-ablative lasers,and in particular the Q-switched devices, arethe lasers of choice for the treatment ofpigmented lesions.

• The pulsed dye laser offers a unique modalityfor the elimination of vascular lesions such astelangiectasias and generalized erythema asso-ciated with photodamage.

• Non-ablative nonfractional skin rejuvenationoffers only mild skin remodeling effects andis only suitable for patients with early signs ofskin aging.

• Non-ablative fractional lasers produce impres-sive clinical outcomes in skin rejuvenationwith respect to improvement in skin laxityand reduction in wrinkles.

• Non-ablative fractional lasers are associatedwith swift recovery, minimal complications,and little or no downtime.

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Non-ablative Lasers for Photorejuvenation 103

Non-ablative Lasers for Stretch Marks

Luciana Archetti Conrado, Melina Kichler, Priscilla Spina, andIsis Suga Veronez

AbstractStriae distensae (SD) or stretch mark (SM), acommon skin condition, does not cause anysignificant medical problem; however, it cancause significant distress to those affected.They are dermatologic lesions, usually asymp-tomatic, that often arise as a result of mechan-ical stress, certain endocrine conditions,pregnancy (striae gravidarum), or prolongedexposure to steroids. It can be initially ery-thematous (striae rubra) but over the timebecome atrophic with a white color (striaealba). Although there is no “gold standard”treatment for stretch marks, various laserparameters alone or in association with othermodalities of treatment have been studied.Over the years, the non-ablative fractionallasers have shown good clinical results andbecome very popular, especially because it iswell tolerated and safe, even in patients withhigher phototypes (IV E V). Post-inflammatory hyperpigmentation is the mostcommon complication; however, it is transi-tory in most cases and its incidence is lowerthan with ablative lasers. This chapter willapproach the use of non-ablative lasers forSD treatment.

KeywordsStriae distensae • Stretch marks • Striae rubra •Striae alba • Non-ablative fractional laser •Ablative fractional laser • Intense pulsed light •Pulsed dye laser • Photothermolysis

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105

Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106

Therapeutic Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110

Take Home Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111

Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111

Introduction

Striae distensae (SD), also known as stretchmarks, striae atrophicans, or striae gravidarum,are common skin lesions, which can pose a sig-nificant psychological burden for patients. It wasfirst histologically described in 1889 by Troisierand Menetrier, and until now it is a challenge interms of treatment and prevention. (Troisier andMenetrier 1889). Striae distensae are dermato-logic lesions that often arise as a result of mechan-ical stress (rapid weight change, puberty,pregnancy), certain endocrine conditions (like

L.A. Conrado (*) • M. Kichler • P. Spina • I.S. VeronezSão Paulo, SP, Brazile-mail: luciana@lucianaconrado.com.br;melcardoso7@hotmail.com; pri.spina@hotmail.com;isisveronez@gmail.com

# Springer International Publishing AG 2018M.C.A. Issa, B. Tamura (eds.), Lasers, Lights and Other Technologies, Clinical Approaches and Procedures inCosmetic Dermatology 3, https://doi.org/10.1007/978-3-319-16799-2_6

105

Cushing’s syndrome and Marfan syndrome), orprolonged exposure to medications such as ste-roids, whether topical or systemic. (Hexsel et al.2012).

It appears that the group at a highest risk ofdeveloping severe striae distensae is teenagers(Atwal et al. 2006). The prevalence is diversebetween adolescence, pregnancy, and obesitygroups and ranges from 43% to 88% and 6% to86% in pregnant women and adolescent, respec-tively. Among obese individuals the prevalencereported is 43% (Al-Himdani et al. 2014).Elbuluk et al. observed interracial differences inthe severity of SD and concluded that African-American women were more severely affectedthan white women within the same geographicalregion (Elbuluk et al. 2009). However, theauthors also did note that there was a differenceof body mass index and smoking status betweenthe two groups, which may indicate that otherfactors aside from race could be involved(Al-Himdani et al. 2014).

Anatomical regions can vary depending uponsex and age. In adolescent males, the lower backand knees are usually affected, while in femalesubjects, the thighs and calves are more ofteninvolved. Striae gravidarum occur in more than70% of pregnant women and are commonly foundon the abdomen and breasts, usually developingafter the 24th week of gestation (Atwal et al. 2006;Al-Himdani et al. 2014). They tend to appearsymmetric and bilateral (Hanauer et al. 2011)and are usually asymptomatic, but in the earlystages can cause some itch (Hexsel and Dal’Forno2013).

Striae distensae are linear atrophic scars, mostoften initially erythematous (striae rubra) but canalso have different colors such as purple and blueand then over the time become atrophic and hypo-pigmented and attain a white color (striae alba)(Alves et al. 2015; Malekzad et al. 2014).Hermanns and Piérard described two additionaltypes of SD, striae nigrae and striae caerulea,which occur in those with darker skin due toincreased melanization (Hermanns and Piérard2006). The color of the SD is related to the stageof evolution and to melanocyte mechanobiolo-gical influences (Al-Himdani et al. 2014).

Pathogenesis

A positive family history is an important riskfactor. In adolescents body mass index, childhoodobesity, and seborrhea and atopic dermatitis arealso reported as influences of developing SD. Onthe other hand, risk factors in pregnant womenmay be constitutional or pregnancy related. Con-stitutional factors include maternal age, smoking,and body mass index. Younger women are morelikely to develop SD, implicating a constitutionaldifference in the stretching ability of the skin.Pregnancy-related factors such as birth weight,gestational age, weight gain, and polyhydramniossupport the theory that changes associated withpregnancy can play a role in the developing ofSD. Others risk factors include medical conditionssuch as Marfan syndrome, Cushing syndrome,anorexia nervosa, typhoid fever, rheumatic fever,chronic liver disease, surgery and medicationslike systemic and topic corticosteroids, HIV ther-apy, chemotherapy, tuberculosis therapy, contra-ceptives, and neuroleptics (Al-Himdani et al.2014).

The pathogenesis of striae is still unknown butprobably relates to changes in the components ofextracellular matrix, including fibrillin, elastin,and collagen (Singh and Kumar 2005). There arethree main theories relating to SD formation thathave been described: mechanical stretching of theskin, hormonal changes, and innate structural dis-turbance of the integument. Mechanical stretchingof the skin is postulated due to perpendicularity ofSD to the direction of the skin. Hormonal alter-ations in adrenocorticotrophic hormone and corti-sol are thought to promote fibroblast activity,leading to increase protein catabolism and thusdecreasing deposition of collagen in the substanceof the dermal matrix (Al-Himdani et al. 2014;Khater et al. 2016).

Pregnancy-related hormones are also believedto influence SD formation. Cordeiro et al.described increased estrogen and androgen recep-tors in the skin exhibiting SD compared withnormal skin (Cordeiro et al. 2010). Lower serumrelaxin levels were demonstrated in pregnantwomen with SD compared with those withoutSD at 36 weeks gestation. SD may also present

106 L.A. Conrado et al.

altered gene expression, in similar way to keloiddisease and scleroderma, which are thought todevelop due to disordered gene expression ofextracellular matrix (Al-Himdani et al. 2014).

Striae rubra and alba are distinct forms ofSD. Their distinction has therapeutic implications(Al-Himdani et al. 2014). Usually the lesionmatures from rubra to alba in several steps similarto those of the wound repair mechanism fromwounding to scar formation (Ryu et al. 2013;Ud-Din et al. 2016). In early lesion development,there is a deep and superficial perivascular lym-phocytic infiltration with edema, vascular ectasia,and possible angiogenesis (Alves et al. 2015; Ryuet al. 2013). On electron microscopy, early histo-logical dermal alteration may be visualized bymast cell degranulation and macrophage activa-tion with release of enzymes such as elastases,which leads to elastolysis of the mid-dermis(Sheu et al. 1991). Inflammation resolves overtime, but collagen bundles in the reticular dermisstretch parallel to the skin, resulting in flatteningof the epidermis and elongation of rete ridges,absence of hair follicles, and reduction of mela-nocytes leading to leukoderma, followed by lossof collagen and elastic fibers in the substructures(Al-Himdani et al. 2014; Ryu et al. 2013).

Therapeutic Assessment

Because of the prevalence of SD and its impact onquality of life of patients, there is substantialdemand for a reliable treatment option.

Although there is no “gold standard” treat-ment for stretch marks, various modalities oftreatment have been tried. Not only outcomedepends on the type of SD but also the patients’Fitzpatrick skin type is important as well, sincemost of adverse effects, particularly withlaser, occur in patients with darker skin type(Al-Himdani et al. 2014).

There are a number of treatment optionsincluding topical agents, acid peels, micro-dermabrasion, radiofrequency, needling, andlasers and light therapies described in literature.

Topical agents such as tretinoin thought towork through its affinity for fibroblasts and

induction of collagen synthesis, and it has goodefficacy in striae rubra, but poor and unpredictableresponses in striae alba. Therefore, it offers onlymodest benefit in the early stages of the clinicalcourse. Topical creams, lotion, and ointments areused especially in pregnant women at risk ofdeveloping SD, but has no statistically significantevidence to support their use for prevention of SDaccording to a Cochrane review in 2012 (Brennanet al. 2012). Acid peel treatments such as glycolicacid and trichloroacetic acid are thought to actby increasing collagen synthesis. Micro-dermabrasion, which is a skin resurfacing tech-nique, has been reported to increase type Icollagen with a better efficacy on striae alba(Al-Himdani et al. 2014; Aldahan et al. 2016)(see chapter▶ “Microneedling for TransepidermalDrug Delivery on Stretch Marks”). Treatment withskin needling might be able to induce more colla-gen and elastin deposition beneath the epidermis asmicroneedling radiofrequency which can inducegrowth factor secretion by delivering higher volu-metric heating and deeper heat diffusion (Khateret al. 2016; Ryu et al. 2013). However, all of thesetreatments have inconsistent clinical outcomes(Aldahan et al. 2016).

Lasers and light therapies offer a variety ofwavelengths that can target specific chromophoresat varying fluences. This poses a theoretical advan-tage by allowing individualized treatments. Somewavelengths target blood vessels in striae rubra toreduce the appearance, and others induce collagenand elastin production in mature striae. Among thewavelengths that have been studied for striaedistensae UVB, UVA, excimer laser (308 nm),intense pulsed light (565, 590, 645, 650 nm), cop-per bromide (577 nm), pulsed dye laser(585, 595 nm), infrared, Nd:Yag (1064 nm), diode(1450 nm), Er:Glass (1540, 1550, 1565 nm), Er:Yag (2940 nm), and CO2 (10,600 nm) are included(Aldahan et al. 2016).

Ablative fractional lasers and intense pulsedlight (IPL) represent emerging therapies thathave demonstrated some success (Aldahan et al.2016). Non-ablative lasers have been studied inthe treatment of SD as well.

The 308 nm excimer laser is an ultraviolet laserand has been used to treat SD with improvement

Non-ablative Lasers for Stretch Marks 107

of the pigmentation on mature white striae, but thestudies shown that this pigmentation is only tem-porary requiring many treatment sessions beforesignificant improvement can be seen.

Pulse dye laser (PDL) can also be indicated. Itis commonly used for striae rubrae, treatment, asits target is dilated blood vessels (Aldahan et al.2016, Al-Himdani et al. 2014). Similar to pulseddye laser, Nd:Yag laser can be used to improvestriae rubra, but does not have the same result instriae alba (Aldahan et al. 2016).

The intense pulsed light is characterized by theemission of incoherent light, pulsed, and broadspectrum (515–1200 nm). It is used to treat vas-cularization of rubra striae, but some studies alsoshow clinical improvement and increased thick-ness of the collagen in striae alba. Repeated ses-sions may be required to maintain positive effects(Aldahan et al. 2016, Al-Himdani et al. 2014).

There are two types of fractional lasers used inthe treatment of striae distensae: ablative andnon-ablative. Fractional treatment is achievedthrough a pattern of microscopic thermal zones(deliver light energy into the tissue through mul-tiple microscopic columns surrounded byuntreated areas) produced by the laser beams atspecific depths in the dermis. Fractional photo-thermolysis stimulates the epidermal turnoverand dermal collagen remodeling (Mattos andJordão 2012).

Ablative lasers use long wavelengths to targetwater in the epidermis and dermis, thereby vapor-izing the cells. Available lasers in this categorythat have been studied for treating SD include theCO2 and Er:Yag (see chapter ▶ “CO2 Laser forStretch Marks”). These techniques provide imme-diate tissue tightening and induce more collagenstimulation than non-ablative lasers. On the otherhand, non-ablative fractional devices are associ-ated with minimal side effects and downtime(Aldahan et al. 2016; Alam et al. 2011; Khater2016; Tannous 2007).

For the treatment of both striae (rubra and alba),the fractional non-ablative Er:Glass (1540, 1550,1565 nm) is one of the most used (Table 1)(Stotland et al. 2008; de Angelis et al. 2011; TrettiClementoni and Lavagno 2015); however, othernon-ablative lasers are also used with good results.

Several sessions are necessary (Figs. 1–3) (seechapter ▶ “Erbium Laser for Scars and StriaeDistensae”).

De Angelis et al. treated SD in 51 patients withskin types II–IV, with two to four sessions of lasertherapy, spaced 4–6 weeks apart. All striae werereported to have a least 50% improvement. Histo-logically increased elastic fibers and neo-collagenesis were seen in the reticular dermis.Adverse effects were predominantly erythemaand edema; however, eight patients developedtransient post-inflammatory hyperpigmentation(de Angelis et al. 2011).

Clementoni and Lavagno evaluated the effec-tiveness and safety of a novel non-ablative frac-tional 1565 nm laser on the appearance ofSD. Good clinical improvement (between 51%and 75%) was observed in all patients. The aver-age pain during treatment was generally definedas tolerable and the average downtime was 4 days.Transient erythema and severe edema were notedimmediately after the procedure, but long-lastingor severe adverse effects were not observed. Allpatients noted a good improvement and were sat-isfied with the treatment and the results. Thus theyconcluded that the treatment with the 1565 nmlaser resulted in improved pigmentation, volume,and textural appearance of SD (Tretti Clementoniand Lavagno 2015).

Malekzad et al. studied ten patients with striaealba using fluence of 50–70 J/cm2, and, amongthe other adverse events, related one patient whodeveloped acne in the treatment area. Unfortu-nately, this study demonstrated questionableresults with nine of ten patients with fair or poorimprovement (Malekzad et al. 2014).

Table 1 Parameters commonly used for SD treatmentwith different wavelengths

Laser –wavelength (nm) ParametersNumberof passes

Erbium glass – 1540 Energy= 12–55 mJDensity= 100–320

2–3

Erbium glass – 1550 Energy= 12–18 JDensity= 125–250

8–12

Erbium glass – 1565 Energy= 40–55 JDensity= 150–300

2

108 L.A. Conrado et al.

Alves et al. reported four patients with corti-costeroid induced striae rubra treated using1540 nm Er:Glass at 1 month interval. Afterthree sessions, 50% had marked improvementand the other two patients achieved similarimprovement for four and six sessions, respec-tively (Alves et al. 2015).

Bak et al. treated Asian patients with improve-ment in appearance clinically and histologically.An increase in average epidermal and dermalthickness was seen on posttreatment biopsy, espe-cially in striae alba (Bak et al. 2009).

Stotland treated 14 female patients with1550 nm erbium-doped fiber laser, only one patienthad striae rubra, and all the others had alba striae.He concluded a 26–50% of improvement in

pigmentation, with transient edema and erythemain most of them (Stotland et al. 2008).

Guimaraes et al. studied the 1550 nm Er:Glass laser in ten patients with striae rubra ofthe breast with 4–8 sessions performed at 4-weekintervals. Patients who had total improvementreceived at least six laser sessions (Guimaraeset al. 2009).

Wang et al. compared 1540 nm and 1410 nmnon-ablative fractionated laser in nine patients,with abdominal striae. Each one was treated forsix sessions – half of the abdomen with each laser.All subjects demonstrated clinical improvementbilaterally after treatment. Skin biopsies showedan increase in epidermal thickness and collagenand elastin density when compared with baseline.

Fig. 1 Non-ablative laser(erbium glass 1540 nm) –fluence, 70 mJ/cm2; pulseduration, 15 ms for SDrubra on the right thighbefore and after threesessions

Fig. 2 Non-ablative laser(erbium glass 1540 nm) –fluence, 70 mJ/cm2; pulseduration, 15 ms for SDrubra on the left thighbefore and after threesessions

Fig. 3 Non-ablative laser(erbium glass 1540 nm) –fluence, 70 mJ/cm2; pulseduration, 15 ms for SDrubra on the left arm beforeand after three sessions

Non-ablative Lasers for Stretch Marks 109

However clinical and histological differencesbetween the two lasers were not statistically sig-nificant (Wang et al. 2016).

Based on the number of studies alone, it isclear that the treatment of SD with non-ablativefractional lasers is popular, safe, and well toler-ated by patients, with minimal adverse events.Mature striae alba have shown to be the mostdifficult type to be treated successfully with frac-tional lasers (Shin et al. 2011). However, thisalso occurs with other therapeutic modalities(Tannous 2007).

Post-inflammatory hyperpigmentation (PIH) isthe most common complication in patients withFitzpatrick skin types IV–VI; however, its inci-dence is lower when compared to ablative lasers.Although melanin does not absorb the1.540–1565 nm wavelength, pigmentary changescan still occur (Sherling et al. 2010). The degree ofPIH has been found to be directly proportional toboth the energy and density of the treatment,although density appears to be particularly impor-tant (Chan et al. 2007). Thus, it is important tostart out using conservative settings in thesepatients, even when using non-ablative lasers(Shah and Alam 2012).

To reduce the incidence of hyperpigmentation,many dermatologists use bleaching creams likehydroquinone, tretinoin, or glycolic acid (beforeand/or after the procedure). Although studies areinconclusive as to whether these topical agents arecapable of preventing hyperpigmentation, theymay be effective when instituted postoperativelyas a component of the skin care regimen(Manuskiatti et al. 2010; Sriprachya-anunt et al.2002). In combination with non-ablative devices,it is easier to prescribe these bleaching agents, asthe epidermis is maintained after laser (Shah andAlam 2012).

Studies comparing the clinical efficacy of theablative vs. non-ablative fractional photothermolysissystem for the treatment of striae distensae have beenconducted.

One of these studies compared the effect ofablative CO2 fractional laser with that ofnon-ablative 1550 nm erbium (ER)-glass frac-tional laser on SD in Asian patients. (Yang andLee 2011). Although CO2 laser resurfacing

might promise better clinical improvementbecause it may induce more dermal extracellularmatrix remodeling than the non-ablative lasertreatment, this study failed to prove statisticalsignificant difference between the two devices.However, treatment with the ablative CO2 frac-tional laser was considered more painful than thetreatment with the non-ablative fractional laserand resulted in more post-inflammatory hyper-pigmentation and longer posttreatment erythema(Yang and Lee 2011).

When the efficacy of these two methods,ablative vs. non-ablative fractional laser, iscompared for alba type of striae distensae, apoor clinical improvement is observed for bothlaser types. On the other hand, both laser treat-ments have moderate successful for immaturestriae distensae (rubra type) treatment (Gungoret al. 2014).

Unfortunately, there are some limitations whencomparing laser techniques due to variationsbetween study protocols. Parameters such asfluence, pulse, duration, and spot size are differentbetween many devices, making comparison verydifficult. Treatment intervals and number of ses-sions are also an important variable to be consid-ered (Aldahan et al. 2016).

We have good results with erbium-glass1540 nm for SD treatment, mainly for SD rubra.Parameters commonly used are fluence, 70 mJ/cm2; pulse duration, 15 ms; and three sessions(Figs. 1, 2 and 3).

Conclusion

A variety of laser parameters have been studiedeither alone or in combination with other modal-ities for the treatment of SD, as topics (retinoicacid and glycolic acid), chemical and mechanicalpeels (microdermabrasion), intradermotherapy,radio frequency, pulsed dye laser, and intensepulsed light. Although there is no “gold standard”treatment for stretch marks, the treatment of SDwith non-ablative fractional lasers is becomingincreasingly popular, especially because thisapproach is generally safe, even in higher photo-types. It is also well tolerated by patients with few

110 L.A. Conrado et al.

side effects (fewer crusts, erythema, and edema)and fast healing time.

Striae rubra are muchmore amenable to laser andlight therapy, probably because of their predominantvascular components. SD rubra can be successfullytreated with non-ablative fractional lasers but alsowith non-ablative and non-fractional lasers as Nd:Yag, pulsed dye laser, and intensed pulsed light.Post-inflammatory hyperpigmentation is the mostcommon complication; however, it is transitory inmost cases and its incidence is lower than withablative lasers.

Combination therapies may be the future fortreating SD; however, for further conclusions, it isnecessary to standardize study protocols, with alarger number of patients and long-term follow-upevaluation.

Take Home Messages

• Striae distensae can be cause by mechanicalstress, endocrine conditions, pregnancy, orprolonged exposure to steroids.

• It can be rubra or alba.• The pathogenesis is still unknown but probably

relates to changes in the components of extra-cellular matrix, including fibrillin, elastin, andcollagen.

• There is no “gold standard” treatment, buttreatment with non-ablative fractional lasers isbecoming increasingly popular, as it can besafely used by patients with high phototypes.

• Better results are achieved for SD rubratreatment.

• Post-inflammatory hyperpigmentation is themost common complication, but usually tran-sitory and less frequent comparing with abla-tive lasers.

Cross-References

▶Erbium Laser for Scars and Striae Distensae▶Microneedling for Transepidermal Drug Deliv-ery on Stretch Marks

▶CO2 Laser for Stretch Marks

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Elbuluk N, Kang S, Hamilton T. Differences in clinicalfeatures and risk factors for striae distensae in AfricanAmerican and white women. J am Acad Dermatol.2009;60(3 suppl 1):60–2.

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Malekzad F, Shakoei S, Ayatollahi A, Hejazi S. The safetyand efficacy of the 1540 nm non-ablative fractional XDprobe of star lux 500 device in the treatment of striaealba: before-after study. J Lasers inMed Sci. 2014;5(4):194–8.

Manuskiatti W, Triwongwaranat D, Varothai S, Eimpunth S,Wanitphakdeedecha R. Efficacy and safety of a carbon-dioxide ablative fractional resurfacing device for treat-ment of atrophic acne scars in Asians. J Am AcadDermatol. 2010;63(2):274–83.

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1,550-nm fractionated laser and its applications in der-matologic laser surgery. Dermatol Surg. 2010;36(4):461–9.

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112 L.A. Conrado et al.

Non-ablative Fractional Lasers for Scars

Roberto Mattos, Juliana Merheb Jordão, Kelly Cristina Signor,and Luciana Gasques de Souza

AbstractThe knowledge of microenvironment of tissuerepair enables better understanding of thehealing process and the techniques currentlyemployed for its correction. There are differenttypes of scars and the treatment should bechosen according to lesion. Laser mechanismof action on scars is based on two pillars, toreduce blood flow and to reorganize collagenfibers. Devices available for scar treatmentinclude intense pulsed light (IPL), in the vas-cular mode, non-ablative lasers, and ablativelasers. In this chapter we are going to discussnon-ablative lasers for scar treatment.

KeywordsNon-ablative laser • Non-ablative scars •Keloids • Tissue repair • Blood flow • Collagenreorganization • Skin remodeling

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114Stages of the Healing Process . . . . . . . . . . . . . . . . . . . . . . . 114

Scars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115

Lasers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116Equipment Available for Scars Treatment . . . . . . . . . . . 116Flashlamp-Pumped Pulsed-Dye Laser

(585 and 595 nm) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116Q-Switched Frequency Doubled Nd:YAG

532 nm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117Diode Laser (Laser-Assisted Skin Healing

810 nm) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117Non-ablative Fractional Lasers . . . . . . . . . . . . . . . . . . . . . . 117Laser Devices in the Market . . . . . . . . . . . . . . . . . . . . . . . . . 118

Treatment of Atrophic Scars . . . . . . . . . . . . . . . . . . . . . . 120

Treatment of Hypertrophic Scars . . . . . . . . . . . . . . . . . 120

Burn Scar Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121

Keloid Scar Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121

Procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122Before Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122Parameters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122Post-Procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123

Take Home Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124R. Mattos (*) • K.C. Signor • L.G. de SouzaMogi das Cruzes University, São Paulo, Brazile-mail: robmattos@uol.com.br; kellysignor@gmail.com;luhsouza@hotmail.com

J.M. JordãoSkin and Laser Center of Boom, Boom, Belgium

Department of Hospital Universitário Evangélico deCuritiba, Curitiba, PR, Brazile-mail: Dra.julianajordao@hotmail.com

# Springer International Publishing AG 2018M.C.A. Issa, B. Tamura (eds.), Lasers, Lights and Other Technologies, Clinical Approaches and Procedures inCosmetic Dermatology 3, https://doi.org/10.1007/978-3-319-16799-2_7

113

Introduction

In mammals, the wounds that occur in the fetusuntil the first trimester of pregnancy heal by regen-eration, creating tissue with the same characteris-tics of the original (Ferguson et al. 1996). However,after this period, the inflammatory process, with theaim to control infection, results in scar, which isdifferent from the surrounding skin. It can presentas atrophy, hypertrophy, or keloid scars (Fergusonet al. 1996; Mccalion and Ferguson 1996;Ferguson and O’kane 2004). Knowing the micro-environment of tissue repair, we can be able tounderstand the healing process and the techniquescurrently employed for its correction (Profyris et al.2012; Martin and Leibovich 2005).

Stages of the Healing Process

Healing is divided into three stages: inflammatory,proliferative, and remodeling. However, it is adynamic process, so at any point, a phase mayoverlap another (Profyris et al. 2012).

Inflammatory PhaseIt begins immediately after breaking the epithelialintegrity and lasts 1–3 days. When injury occurs,the immediate priority is hemostasis that isachieved through the extrinsic pathway activa-tion. It constitutes a hemostatic plug of fibrinthat is solidified by the arrival of platelets. It alsoacts as a mechanical barrier against microorgan-isms’ invasion and avoids bleeding. It is a tempo-rary matrix for cell migration and a reservoir ofcytokines and growth factors (Profyris et al. 2012;Werner and Grose 2003).

Once the bleeding risk is finished, the nextpriority is to remove dead tissue and to preventinfection. During the first 5 days, neutrophils andmacrophages reach the injury zone, and throughphagocytosis and production of local proteases,they eliminate microorganisms and remove deadtissue. They also secrete multiple growth factors,chemokines, and cytokines. These molecules areessential to signal the events that will occur in theproliferative phase (Profyris et al. 2012; Wernerand Grose 2003).

Proliferative PhaseIt has the function of wound healing. It beginsaround the fourth day and lasts about 3 weeks(Park and Barbul 2004).

Granulation tissue is the hallmark of prolifera-tive phase and has this name due to the granularfeature, formed by newly vessels (60% of itscomposition) (Dvorak 2005). It replaces hemo-static fibrin plug of the inflammatory phase (Parkand Barbul 2004).

The proliferative phase can be divided intothree steps:

The first step is represented by the increased vas-cular permeability induced by cytokines, asvascular endothelial growth factors (VEGF).Increased permeability of microvessels allowsextravasation of macromolecules, such asfibrinogen and other coagulation proteins,which results in extravascular fibrin deposition(Dvorak 2002).

In the next step, there are angiogenesis and migra-tion of endothelial cells. Many molecules havebeen implicated in this phase: fibroblastgrowth factors (FGFs), vascular endothelialgrowth factors (VEGF), transforming growthfactor (TGF) beta, angiogenin, angiotropin,and angiopoietin-1. In addition, platelet-derived growth factor (PDGF) is related tocell migration and fibroblast activation, pro-viding a structural network, over which endo-thelial cells proliferate and produce newvessels (Dvorak 2002).

Epithelialization is essential for reestablishing tissueintegrity. The epithelial coating cells, throughthe action of specific cytokines, proliferate andmigrate from the borders of the wound in anattempt to close it. This process is calledreepithelialization. The reepithelialization of awound by keratinocytes is performed by thecombination of the proliferative stage with themigration of cells near the lesion. The migrationof keratinocytes occurs in the direction of theremaining skin of the lesion to its extremities(Profyris et al. 2012; Dvorak 2002; Martin andLeibovich 2005). TGF beta is the mainly cyto-kine involved in this step (Werner and Grose2003; Santoro and Gaudino 2005).

114 R. Mattos et al.

Remodeling PhaseIt begins in the third week, lasts up to 1 year andmust be seen as an attempt of recovering the nor-mal tissue (Santoro and Gaudino 2005). The thirdphase of healing consists in remodeling, whichbegins 2–3 weeks after the onset of the lesion andcan last for 1 year or more. The core aim of theremodeling stage is to achieve the maximum ten-sile strength through reorganization, degradation,and resynthesize of the extracellular matrix. In thisfinal stage of the lesion’s healing, an attempt torecover the normal tissue structure occurs, and thegranulation tissue is gradually remodeled, formingthe scar tissue that is less cellular and vascular. Itexhibits a progressive increase in its concentrationof collagen fibers. At this stage, there is a deposi-tion of the matrix and subsequent change in itscomposition. With the closure of the wound, typeIII collagen undergoes degradation, and synthesisof type I collagen increases (Profyris et al. 2012;Mattos et al. 2009).

The main reason for failure in the reproductionof morphologically identical tissue during healingprocess is architectural layout of the new collagenin parallel bands instead of the network of normalskin, and, in addition, the absence of hair follicles,sebaceous glands, and sweat glands is remarkable(Profyris et al. 2012).

Scars

The clinical classification of scar guides the ther-apeutic choice (Mattos et al. 2009; Mutalik 2005).For treatment purposes, scars can be mainlydivided into three types (Osório and Seque 2012):

1. Hypertrophic2. Keloids3. Atrophic

Hypertrophic scars are erythematous, raised,firm nodular lesions. The growth of hypertrophicscars is limited to the sites of original tissue injury,unlike keloids that proliferate beyond the bound-aries of the initial wounds and often continue togrow without regression (Osório and Seque 2012;Sobanko and Alster 2012):

Keloid scars present as reddish-purple pap-ules and nodules, often on the anterior chest,shoulders, and upper back. They are more com-mon in darker-skinned persons and, like hyper-trophic scars, may be pruritic, anesthetic, andcosmetically disfiguring. While the histologyof hypertrophic scars is indistinguishable fromother scarring processes, the histology of keloidsmay be recognized by thickened bundles ofhyalinized collagen, haphazardly arranged inwhorls and nodules (Sobanko and Alster 2012;Osório and Seque 2012; Mattos et al. 2009;Mutalik 2005).

Atrophic scars, on the other hand, are dermaldepressions that result from the aforementionedacute inflammatory processes. The inflammationassociated with atrophic scars leads to collagendestruction with dermal atrophy. Atrophic scarsare initially erythematous and become increas-ingly hypopigmented and fibrotic over time. Themost common causes are acne, postsurgicalinjury, and burn (Osório and Seque 2012;Sobanko and Alster 2012).

Acne scarring is the result of a deviation in theorderly pattern of healing and can have profoundpsychosocial implications for patients. For this rea-son, they should be treated whenever possible.Atrophic acne scars are divided into three types:ice pick, rolling scar, and boxcar. Ice-pick scars arenarrow, v-shaped epithelial tracts that extend intothe deep dermis or subcutaneous tissue. Rollingscars are wide and undulating, due to their tetheringfrom the dermis below. Finally, boxcar scars aresharply delineated epithelial tracts that extend intothe dermis but, unlike icepick scars, do not taper atthe base. The use of this classification system allowsfor treatments to be indicated to the specific type ofscarring (Osório and Seque 2012).

Treatment of unsightly scars is a big challengefor the dermatologist. Till the date, there is notreatment considered ideal for scars. Gels or sili-cone tapes are commonly used and recommendedin recent scars. Intralesional corticosteroid infil-tration is the most common option for keloids andhypertrophic scars. Application peels, subcision,dermabrasion, and surgical excision are tradi-tional options for atrophic scars (Mattos et al.2009; Mutalik 2005).

Non-ablative Fractional Lasers for Scars 115

Incomplete scar removal, scar worsening, tis-sue fibrosis, and permanent pigmentary alterationhave limited the clinical utility of these treatments.Advances in laser technology have led researchersto study their potential use as a treatment for thistherapeutically difficult condition. Laser scar revi-sion is a well-tolerated procedure with clinicallydemonstrable efficacy and minimal adverseeffects and may be used in combination with theaforementioned scar treatments (Sobanko andAlster 2012).

In addition to its indication for treatingestablished scars, recent studies have brought anew therapeutic possibility: the prevention ofhypertrophic scars in predisposed patients (Mattoset al. 2009; Mutalik 2005).

Lasers

Much has been studied about the laser systems ofaction in treatment and prevention of scars. Themechanism of action of these technologies forscars is still poorly elucidated. It is believed thatthe therapeutic effect is based on two pillars:

1. Reducing blood flow: once the scars have fourtimes greater blood flow than the normal tissue,maintained by angiogenesis and VEGF pro-duction, therefore, the equipment should haveat least some ability to produce vascular injury(Mattos et al. 2009; Mutalik 2005).

2. Reduction, reorganization, and remodeling ofcollagen (Profyris et al. 2012).

Three genres of lasers have been shown toimprove scars, creating thousands to millions ofmicroscopic thermal wounds distributed through-out the dermis, with or without some epidermalinjury. First, millisecond-domain pulsed-dyelasers (PDLs) and similar devices produce selec-tive photothermolysis of small blood vessels. Sec-ond, nanosecond-domain Q-switched Nd:YAGlasers produce selective photothermolysis ofmicrovessels and pigmented cells. Third, ablativeand non-ablative fractional lasers (NAFLs) pro-duce arrays of nonselective, microscopic thermal

damage zones throughout the epidermis and der-mis (Profyris et al. 2012; Anderson et al. 2014;Kauvar 2014).

Equipment Available for ScarsTreatment

1. Intense pulsed light (IPL) in the vascular mode2. Non-ablative lasers:

• Pulsed-dye laser (PDL) 585 nm or 595 nm• Nd:YAG 1064 nm Long pulse• Nd:YAG 1064 nm Ultrapulsed (genesis)• Nd:YAG 532 nm• Diode 800 nm or 1340 nm• 755 nm alexandrite• Erbium glass: 1550 m and 1540 nm• Nd:Yap 1340 nm• Thulio 1927 nm

3. Ablative lasers:• CO2

• Erbium 2940 nm

Within the theme of this chapter, we discuss pref-erably treatment with non-ablative lasers,extending to vascular lasers given the importanceof the vessel approach, as stated earlier.

To determine which laser system is better forscar treatment, it is necessary to know the type andseverity of the scar and the patient toleration andexpectations. Dyschromia (erythema, hyper-pigmentation or hypopigmentation), scar type(hypertrophic, flat, or atrophic), scar body loca-tion (face, neck, or leg), and patient characteristics(skin phototype and comorbid conditions) shouldbe considered (Profyris et al. 2012; Sobanko andAlster 2012; Anderson et al. 2014).

Flashlamp-Pumped Pulsed-Dye Laser(585 and 595 nm)

There is no consensus on the precise mechanismwhereby the PDL exerts its effect on scars. PDLdemonstrates to reduce transforming growthfactor-b expression, fibroblast proliferation, andcollagen type III deposition. Other plausible

116 R. Mattos et al.

explanations include selective photothermolysisof vasculature, released mast cell constituents(such as histamine and interleukins) that couldaffect collagen metabolism, and the heating ofcollagen fibers and breaking of disulfide bondswith subsequent collagen realignment (Mattoset al. 2009; Mutalik 2005; Sobanko and Alster2012).

In fact, the PDL has been successful in improv-ing the depth of moderately atrophic facial acnescars, likely due to stimulation of collagenremodeling. In case of hypertrophic scars, mostevidence was found for the PDL 585 nm indi-cating that it is the best-investigated device forthis treatment. As a consequence of thisresearch, the laser of choice in treating hyper-trophic, erythematous acne scars and keloids isthe vascular-specific 585 nm PDL (Cynergy®).For the PDL 595 nm (VBean®), a moderateefficacy (34–66% improvement) was found(Gira et al. 2004; Sobanko and Alster 2012;Vrijman et al. 2011).

1. During implementation of PDL, the entire sur-face of injury should be treated by adjacentshots and not overlapping, single pass, oruntil it reaches purplish erythema (end point)(Gira et al. 2004).

Minimally purpuric settings have reduced ery-thema with minimal risks. Non-purpuric settingsalso improve erythema but appear to be associatedwith less redness reduction per treatment session(Anderson et al. 2014).

Parameters suggested are (Mattos et al. 2009):

• Fluency 6–7.5 j/cm2 with spot 5–7 mm.• 4.5–5.5 J/cm2 with spot 10 mm.• The most used pulse durations are 0.45 and

1.5 ms.• You should reduce fluency into 0.5 in higher

phototype patients, in more delicate areassuch as the neck, chest, and eyelids if vesi-cles and crusts are present in the previoussession.

• It is suggested to raise the fluency in subse-quent sessions if the previous was suboptimal.

To select the best treatment option, the scarsize is very important, since for very largescars, laser treatment may become impracticalby the higher costs of disposable (Gira et al.2004; Mattos et al. 2009).

Q-Switched Frequency Doubled Nd:YAG 532 nm

This laser is the only device that specifically tar-gets pigmentation. One clinical trial with a smallnumber of patients and a high risk of bias reportedlow improvement on the Vancouver General Hos-pital scale (Vrijman et al. 2011; Osório and Seque2012).

Diode Laser (Laser-Assisted SkinHealing 810 nm)

Its mechanism of action has not been fullyestablished yet. It generates heat that causesreleasing of cytokines and the synthesis of pro-teins involved into healing process (Osório andSeque 2012).

Parameters suggested are:

• 4 mm spot.• Fluency: 80–120 j/cm2 – Burn is reported with

higher fluences.

Non-ablative Fractional Lasers

Non-ablative fractional lasers possess superiorsafety profile than ablative ones (Tziotzios2012). This type of laser is better tolerated andless invasive compared to non-fractionated, withgood results in several indications (Osório andSeque 2012). It is considered safe even at higherskin types, being the first choice for these patients.

Non-ablative fractional laser comprises anarray of 30 devices, whose wavelength corre-sponds to the infrared, and its target is the water.The aim is collagen stimulation, normalization ofcolor, and scar remodeling (Tziotzios 2012).

Non-ablative Fractional Lasers for Scars 117

They causes coagulative, fractional, located,thermal injury and epidermal necrosis on micro-scopic treating zones (MTZ), separated by areasof normal skin. From this intact tissue, epidermalcells migrate into the damaged area performinghealing (Tziotzios et al. 2012).

The permanence of histologically intact stra-tum corneum characterizes it as a non-ablativelaser; allows re-epithelialization in 48 h, preserv-ing the epidermal barrier function; and minimizesside effects (Mattos and Jordão 2012).

In an attempt to elucidate its mechanism ofaction, Laubach et al. reported in 2006 thatnon-fractional ablative lasers perform micro-scopic epidermal necrotic debris (MEND) carry-ing depth melanin to the surface, what explainsthe improvement of skin color. Hantash et al.showed elimination of elastic fibers by MEND.Finally, Goldberg et al. showed that new melano-cytes and viable skin keratinocytes occupy theregion (Mattos and Jordão 2012).

Armann et al. have studied ex vivo NAFLeffects on skin morphology and molecular effectson gene regulation. Human three-dimensional(3D) organotypic skin models were irradiatedwith non-ablative fractional erbium glass lasersystems enabling qRT-PCR, microarray, and his-tological studies at the same and different timepoints. A decreased mRNA expression of matrixmetalloproteinases (MMPs) 3 and 9 was observed3 days after treatment. MMP3 also remaineddownregulated on protein level, whereas theexpression of other MMPs like MMP9 was recov-ered or even upregulated 5 days after irradiation.Inflammatory gene regulatory responses mea-sured by the expression of chemokine (C-X-Cmotif) ligands (CXCL1, 2, 5, 6) and interleukinexpression (IL8) were predominantly reduced.Epidermal differentiation markers such asloricrin, filaggrin-1, and filaggrin-2 wereupregulated by both tested laser optics, indicatinga potential epidermal involvement. These effectswere also shown on protein level in the immuno-fluorescence analysis. This study reveals erbiumglass laser-induced regulations of MMP and inter-leukin expression. The authors speculate thatthese alterations on gene expression level couldplay a role for dermal remodeling, anti-

inflammatory effects, and increased epidermaldifferentiation (Amann et al. 2016).

A number of studies have demonstrated mild tomoderate improvement in atrophic acne scarsusing these non-ablative lasers. In this case, onlypatients with boxcar and rolling acne scars areexcellent candidates for laser resurfacing as theyare distensible scars. Most ice-pick scars withdeep bases respond better to punch excision thanto fractional lasers, whereas rolling scars mightrequire subcision followed by fractional lasertreatment. Because acne scars are usually a mixof ice-pick, boxcar, and rolling scars, the finaleffect of fractional lasers would depend more onthe predominant scars than on the fractional laserused (Tziotzios 2012; Sobanko and Alster 2012;Sardana et al. 2014).

Recent studies have shown increasing evidenceof NAFL role in hypertrophic scars. Those oneyounger than a year have the best results. Scarpigmentation and elasticity are parameters thathave better response; vascularization and elevationare the items with most discrete results. Severalauthors suggest beginning laser treatment of scarsfor about 2–3 weeks after surgery (Tziotzios 2012).Some authors suggest the use of fractional ablativeor non-ablative laser to prevent the development ofhypertrophic scars after surgery. Jang J et al. havecompared the use of fractional ablative laser andfractional non-ablative laser in recent thyroidec-tomy scars. After four laser treatment sessions,both types of fractional laser treatments were suc-cessful; however, their results indicated that highereffectiveness may be obtained from the use of abla-tive and non-ablative lasers for hypertrophic scarsand early erythematous scars, respectively (Janget al. 2016). Keloid scars should avoid being treatedwith non-fractional ablative lasers by the risk ofworsening (Sobanko et al. 2015).

Laser Devices in the Market

• 915 nm diode: This laser was recently intro-duced in the market and associates fractionalnon-ablative laser with radiofrequency in thesame shot. It is widely used in localized areas(periocular and perilabial) to further warming

118 R. Mattos et al.

and improved outcomes. In bony areas, radio-frequency energy should be decreased becausethere is an increase in intensity of heat as wellas the risk of side effects. Erythema is fleeting(Sobanko and Alster 2012).– Long pulse 1320 nm Nd:YAG: It is associ-

ated with an epidermic temperature sensorand a cryogen spray for skin protection. Ithas a high diffusion rate of heat in dermis. Itis applied on a stamp mode, and spots varyfrom 3 to 10 mm. Prospective studies withthe 1320 nm Nd:YAG laser for atrophicacne scars have shown modest efficacywithout notable adverse events (Sobankoand Alster 2012).

– 1340 nm Nd:YAG: It has the lowest waterabsorption coefficient, which increases pen-etration in the dermis. Pulse duration rangesfrom 3 to 10 ms, handpiece’s density variesfrom 100 to 400 MTZ. The laser energy isdelivered to the dermis by the stamp mode.It is mandatory the use of epidermal coolerto protect the epidermal layer from burning.The most important advantage of this tech-nology is the absence of consumables(Mattos and Jordão 2012).

– 1440 nmNd:YAG: This very fast handpiecehas increased risk of burns and post-inflammatory hyperpigmentation. Pulseduration ranges from 3 to 10 ms; handpieceoptions are 10, 12, and 15 mm; energyranges between 2 and 80 mJ/microbeam.The tip has a cooling system to ensure theepidermal protection. These technologydoesn’t have consumables (Mattos andJordão 2012).

– 1450 nm diode: Its fluence ranges from 8 to25 J/cm2; handpiece options are 4 and6 mm; it is coupled to a cryogen spray.This diode laser showed greater clinicaleffect with less adverse effect (Sobankoand Alster 2012).

– 1540 nm Erbium glass laser: It is applied instamp mode; pulse duration ranges from10 to 100 ms; energy varies from 20 to100 mJ/cm2. It has sapphire cooled tip,slower speed of shots, and no consumables(Mattos and Jordão 2012).

– 1440 and 1540 nm in the same devices: Itprovides an increase of 20–50% in thermaldamage depth. It has cooled sapphire tip,which increases their safety (Mattos andJordão 2012).

– 1550 nm Erbium glass: It allows automaticcontrol of density width and depth of thecoagulation column. Its administration isquick, but painful. This NAFXL can deliverup to 70 mJ energy with 300–1400 mm ofdepth; selection of MTZ density is allowed,providing adjustment of the percentage ofskin treated to 5–48%. It is possible to applyseveral passes in different directions withsome cooling intervals to avoid side effects.Considering that the estimative of facialskin depth (forehead, nose, medial and lat-eral cheeks, lips, chin) is approximately2196 lm, which consists of the epidermis(105 lm), papillary dermis (105 lm), andreticular dermis (1986 lm), a recent reviewexamined the correlation between depth andenergy for all fractional lasers. This reviewfound that, for the 1550 nm fractional laser,for every mJ, the depth of coagulationincreased roughly by a factor of 10 lm(10 mJ/100–150 lm). Thus, with a dose of70–100 mJ, a depth of 700–1000 lm can beachieved, which would be sufficient to ame-liorate most superficial and some deep atro-phic scars (Sardana et al. 2014).

– Consensus guidelines on NAFXL (non-ablative fractional laser) treatment parame-ters for acne scars have been proposed fordifferent skin phototypes. Using 1550 nmErbium glass, for lighter skin phototypes(I–III), the recommended settings are30–70 mJ energy, treatment level of 7–11,and 8–12 passes. For darker skin photo-types (IV–VI), energy settings of30–70 mJ are advocated with fewer passesand lower treatment density in order todecrease postinflammatory hyper-pigmentation (Sobanko and Alster 2012).

– 1927 nm thulium laser and 1550 nm +erbium glass associated in the samehandpiece: The shots are quick in a scannerway. The integrated cooling system

Non-ablative Fractional Lasers for Scars 119

provides comfort and comes with systemwhere you can select the percentage of cov-erage and aggression. The number of passesis calculated by the device and requires theuse of different spot sizes according toselected energy. The combination of twowavelengths allows effective treatment forskin surface and dermis (Mattos and Jordão2012).

Treatment of Atrophic Scars

Atrophic scars are dermal depressions that resultfrom a relative paucity of collagen after an injuryor that are associated with conditions such asacne. The goal of laser treatment in this setting isto stimulate neocollagenesis and remodelingwithin the atrophic areas. New collagen synthesisis strongly stimulated by fractional laser therapy,and previous studies have demonstrated consis-tent efficacy for atrophic scars resulting from acneand trauma. For relatively atrophic, shallow, orflat scars, the NAFXL appears to achieve resultssimilar to those of the AFXL (ablative fractionallaser) (Vrijman et al. 2011; Anderson et al. 2014).

For acne scars in phototypes IV, V, and VI,including oriental skin, NAFXL is an effectiveand safe option compared to placebo (Yang et al.2016). Although NAFXL is generally better tol-erated than AFXL, more than one session may berequired (Vrijman et al. 2011).

Another option for atrophic scars is PDL, withsatisfactory results on improvement of depth ofmoderately atrophic facial acne scars, likely dueto stimulation of collagen remodeling (Vrijmanet al. 2011; Sobanko and Alster 2012).

Treatment of Hypertrophic Scars

On the basis of available data from randomizedcontrolled trials, silicone gel or sheeting is thepreferred first-line therapy for the treatment oflinear hypertrophic scars. In cases where a2-month course of silicone gel or sheeting doesnot prove effective or when the scar is severe,

pruritic, or both, adjunctive use of intralesionalcorticosteroid injection or 5-fluorouracil (5-FU)is indicated. For cases when the initial steps fail,laser therapy should be considered (Gold et al.2014).

The first lasers used in the treatment of hyper-trophic scars were ablative (CO2 laser) andshowed recurrence rates of 90% and higher(Vrijman et al. 2011). The incidence of adverseevents was also quite high. Therefore other alter-natives were developed (Tziotzios et al. 2012).Fractionated lasers and intense pulsed light (IPL)are relatively new techniques used to treat scars.

Another category that has been used for hyper-trophic scars is lasers with wavelength directedagainst oxyhemoglobin, as the PDL 585 nm or595 nm, 1064 long pulse, and phosphate-titanium-potassium (KTP) 530 nm. These lasersinjures the blood vessels, decreasing the eritema,telangiectasias and inflamatory process. Throughthe thermal damage, PDL act modifying collagenfibers. These sinergistic effects make PDL theideal treatment for hypertrophic scars and keloids(Mattos et al. 2009; Gira et al. 2004).

It is known that these technologies have avariable response in scars, depending on (Mattosand Jordão 2012):1. Thickness: better response in less thick scar2. Etiology: better response in organized scars,

like those by surgical procedure3. Maturity: superior results in recent scar

To improve the response of resistant hypertro-phic scars, a combination of silicone gel and lasertherapy is suggested. The use of concomitantintralesional corticosteroids or fluorouracil withPDL has been shown to provide additional benefitin proliferative scars. Intralesional injections ofcorticosteroids (20 mg/mL triamcinolone) aremore easily delivered immediately after (ratherthan before) PDL irradiation because the laser-irradiated scar becomes edematous (making nee-dle penetration easier). An additional consider-ation is that when corticosteroid injection isperformed before laser irradiation, the skinblanches and becomes less amenable forvascular-specific irradiation (Osório and Seque2012).

120 R. Mattos et al.

Burn Scar Treatment

1. Burn scar treatment is complex and it oftenrequires combination or alternative therapiesincluding silicone gel sheeting; individualizedpressure therapy; massage, physical therapy, orboth; corticosteroid application; and surgicalprocedures. Massage, hydrocolloids, and anti-histamines may be added to the therapeutic reg-imen to relieve pruritus (Michael et al. 2014).

The last clinical consensus for burn scar treatmentis that fractional lasers are significantly moreeffective for burn scar improvement than arePDL or Q-switched Nd:YAG lasers. Few con-trolled, prospective studies have evaluated thecomparative efficacy of various fractionaldevices, but early reports and our clinical experi-ences suggest that the AFXL has the capacity toinduce a more robust remodeling response thanthe NAFXL. Current AFXL devices have a sig-nificantly greater potential depth of thermal injurycompared with NAFXL devices (approximately4.0 and 1.8 mm, respectively) (Mattos and Jordão2012).

Most patients report significant improvementin pain, itch, and physical mobility within days toweeks after each treatment. Typically, rapidimprovement is seen in depigmentation, followedby gradual improvement in the texture and possi-bly range of motion. Pulsed-dye and fractionallasers have distinct and possibly synergistic rolesin burn scar treatment. Inflammatory, erythema-tous scars encountered within the first few years ofinjury are most amenable to treatment with PDL.Ablative fractional lasers typically produce thegreatest improvement for hypertrophic andcontracted scars, with or without the addition ofintralesional or topical medications (e.g., cortico-steroids) (Michael et al. 2014).

Non-ablative fractional lasers are effective andapproximately equivalent to AFLs for treatment ofatrophic orflat, mature scars. Pigmentary abnormal-ities (hypopigmentation, hyperpigmentation, ordepigmentation) seem to improve more rapidlythan the textural abnormalities during a course offractional laser treatments (Mattos and Jordão2012).

Early intervention (within weeks and monthsof injury) may be advantageous in mitigating scarcontracture formation and trajectory with signifi-cant benefits in patient rehabilitation, representinga potential breakthrough in the treatment of trau-matic scarring (Mattos and Jordão 2012).

The optimal time to begin fractional laser treat-ment is undetermined. However, in our opinion,AFXL and NAFXL appear to be well toleratedsignificantly earlier than 1 year after injury. Treat-ment of freshly healing wounds with unstableepidermal coverage in the first 1–3 months afterinjury may lead to unpredictable and potentiallyharmful outcomes. However, clinical experiencesuggests that wounds that are epithelialized andrelatively mature with focal erosions and ulcera-tions may experience more rapid healing afterAFXL treatment. Younger scars (within the firstyear of injury) are often less tolerant of aggressivetreatment than more mature scars, and laser vari-ables should be selected judiciously in regard tosettings and combination therapies. A minimumtreatment interval of 1 month between fractionallaser treatments is suggested, and the treatmentsare continued until a therapeutic plateau or treat-ment goals are achieved (Mattos and Jordão2012).

Keloid Scar Treatment

First-line therapy for the treatment of minorkeloids involves the combination of silicone gelor sheeting with monthly intralesional corticoste-roid injections. Contact or intralesional cryother-apy is a potentially useful adjunct for theselesions, but it has yet to reach widespread use forkeloid management in clinical practice. Adminis-tration of an oral analgesic and intranslesionallocal anesthesia can be used to reduce pain expe-rienced during cryotherapy. If improvement withconservative therapy is not observed within8–12 weeks, 5-FU in combination withintralesional corticosteroids and, ultimately, lasertherapy or surgical excision may be considered(Michael et al. 2014).

Keloids have unpredictable response to anytreatment. It may not have any answer to laser-

Non-ablative Fractional Lasers for Scars 121

reduced response in each session and is prone torelapse, especially when the sessions are notperformed at regular intervals (Mattos et al. 2009).

Procedure

Before Treatment

After choosing the laser, it is recommended totake photography before and after treatment toevaluate clinical response. Patient should signthe informed consent term. Past history of medi-caments and chronic diseases should also bequestioned (Gira et al. 2004).

Everyone in the procedure room must wearprotective eyewear.

The skin is cleaned and topical anesthetic solu-tion should be applied about 1 h before the proce-dure. Reducing laser speed application and usingcooler equipment may minimize patient discom-fort (Degitz and Hautarz 2015).

Parameters

The energy level depends on the device used andon the color of the lesion (amount of chromo-phore). The redder the lesion, the more the ves-sels, resulting in abundant target and higher heatproduction. In these cases, less energy should beused in the first session. Energy should be gradu-ally increased over the course of sessions(Michael et al. 2014).

It has been shown that the use of high-energysettings and multiple passes promotes better clin-ical results for rejuvenation and atrophic scars.For hypertrophic scars, it is the opposite: high-

energy settings and high density should worsenthe scar (Anderson et al. 2014).

High density is more likely to result inincreased incidence and severity of erythema,edema, and hyperpigmentation. For any equip-ment, lower parameters should be used forpatients with high skin phototype (Degitz 2015).

Safe treatment is based on the avoidance ofexcessive thermal injury. General principles appli-cable to laser selection and treatment techniquefor fractional laser therapy include minimizing thenumber of concurrent therapies, applying frac-tional treatments at low densities, using a narrowbeam diameter, applying a short pulse width, andminimizing the number of passes. Higher pulseenergies require a concomitant decrease in treat-ment density to minimize the risk of worseningscarring. Results are frequently optimized with aseries of treatments. Although individual treat-ment courses vary widely, patients most com-monly receive a series of three to six treatments(Michael et al. 2014).

Results

After the first session, the improvement is verydiscrete and the results become more visible aftertwo to five sessions (Figs. 1, 2, and 3). Hypertro-phic scars may show considerable improvementin the second session, but the response of keloidsis often unpredictable. Improvement can beobserved on the thickness, erythema, flexibility,texture, and scar itching (Michael et al. 2014).

As with other treatment modalities, betterresults are achieved with a combination of tech-nologies, such as combining laser and IPL (Degitz2015).

Fig. 1 Pulsed-dye laser695 nm. Fluence 7 J/cm2.Three treatments

122 R. Mattos et al.

Some studies have demonstrated better resultswhen associating laser with triamcinolone or5-FU infiltration comparing to each treatment iso-lated (Degitz 2015).

Post-Procedure

Edema and erythema are expected. The swellingusually improves within 48 h, and ice packs canbe used. Anti-inflammatories and oral steroids areindicated for intense edema (Anderson et al.2014).

Erythema usually improves within 3–5 daysand, in extra facial regions, can extend to 7 days.Recently, the use of LED (light-emitting diode)immediately after the use of NAFXL hasdecreased the duration of the erythema (Andersonet al. 2014).

The most common adverse effect for treatmentwith the PDL is postoperative purpura, whichoften persists for several days (Anderson et al.2014).

Complications

Complications are inherent of any technique.Focal hemorrhages can occur between 12 and24 h, with spontaneous resolution without sequel(Ha et al. 2014).

Superficial erosions may occur at an inappro-priate contact of the tip with the skin surface andthis may course without scars (Sobanko andAlster 2012).

Burns (bullous and indurated erythematousareas) are rare but can occur when a high energyis chosen or a technical error occurs. Hypo- orhyperpigmentation can occur as a burn evolution(Ha et al. 2014).

The post-inflammatory hyperpigmentationusually resolves spontaneously in a few monthsand can be prevented, preparing the skin usingbleaching (combination of hydroquinone withretinoic acid) and appropriate photoprotection. Itis more common in high phototypes, in the eyelidarea, or in areas that were used with high fluence(Kim and Cho 2009).

Fig. 2 Ultrapulsed NdYag.Fluence 16 J/cm2. Fourtreatments

Fig. 3 Non-ablativefractional laser 1550 nm.Fluence 45. Density 4. Fourtreatments

Non-ablative Fractional Lasers for Scars 123

The hypochromia is an unusual and late-onsetcomplication, appearing after a few weeks. It isusually related to high fluence, especially in highphototypes. It is commonly preceded by appear-ance of crusts. It is reversible with the use ofsteroids, with tacrolimus at the beginning, andwith retinoic acid in a later stage. In case ofresistant lesions, phototherapy can be a good alter-native (Ha et al. 2014).

Infections in the first week have the risk ofdelayed wound healing. The most commonpathogen is herpes simplex that can be avoidedfrom prophylaxis started 1 day before procedureand continued for 5–7 days. There is divergenceamong authors regarding the herpes prophylaxisin all patients or only in those with past historyof herpes or only when using ablative laser (Kimand Cho 2009). In our practice, herpes prophy-laxis is formerly recommended for patients withprevious herpes history in treatment with abla-tive laser.

Take Home Messages

1. There is no treatment considered ideal forscars.

2. The mechanism of action of lasers on scars isbased on two pillars: reducing blood flowand reorganization and remodeling ofcollagen.

3. The chosen laser system to be used dependsupon the type and severity of scar.

4. Non-ablative fractional lasers possess superiorsafety profile than ablative ones.

5. Non-ablative lasers are the first choice inhigher skin types.

6. Non-ablative fractional lasers appear toachieve results similar to those of the ablativefractional lasers for relatively atrophic, shal-low, or flat scars.

7. Lasers have a variable response in hypertro-phic scars. Better response is observed in lessthickness scar, in organized scars like those bysurgical procedure, and also in recent scars.

8. Keloids have unpredictable response to anytreatment.

References

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Non-ablative Fractional Lasers for Scars 125

Q-Switched Lasers for Melasma, DarkCircles Eyes, and Photorejuvenation

Juliana Neiva, Lilian Mathias Delorenze, andMaria Claudia Almeida Issa

AbstractMelasma is a common and persistent disorderof hyperpigmentation that affects a significantportion of the population, affecting mainlywomen. It is often a therapeutically challeng-ing disorder. Physical therapies such as chem-ical peels, dermabrasion, lasers, and intensepulsed light have also been used with varyingdegrees of success and side effects. Dark cir-cles eyes, also known as periorbital hyperpig-mentation, are a common condition that occursin both sexes with an increasing frequencyin females. Aesthetic treatments includemicrodermabrasion, chemical peels, lasers,radiofrequency, injectable fillers, surgery, fattransfer, and lightening topical products. Clin-ical signs of photoaging include coarse skintexture, irregular pigmentation, and laxity ofskin tone, as well as the appearance of finelines and wrinkles. Diverse treatment

modalities have been used to improve skinwrinkling and laxity, including chemical peel-ing, soft tissue filler, laser ablation, and faceliftsurgery. Lasers have revolutionized the treat-ment of many dermatological conditions. Dif-ferent types of lasers can be indicated forpigmentary disorders. Recently, Q-switchedlasers arose as a successful application inmelasma, dark circles eyes, and photoreju-venation due to its low fluence, short pulse,and specific wavelength.

KeywordsLasers • Q-switched laser • Melasma • Darkcircles eyes • Photorejuvenation

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128

Q-Switched Lasers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128QS Nd:YAG Laser . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128QS Ruby Laser . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129QS Alexandrite Laser . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129

Pretreatment Procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129

Melasma and Q-Switched Laser . . . . . . . . . . . . . . . . . . 129QS Nd:YAG Laser x Melasma . . . . . . . . . . . . . . . . . . . . . . 131QS Ruby Laser x Melasma . . . . . . . . . . . . . . . . . . . . . . . . . . 134

Dark Circles Eyes and Q-Switched Laser . . . . . . . . 136QS Nd:YAG Laser x Dark Circle Eyes . . . . . . . . . . . . . . 136QS RUBY Laser x Dark Circle Eyes . . . . . . . . . . . . . . . . 136

Photorejuvenation and Q-Switched Laser . . . . . . . . 136

J. NeivaBrazilian Society of Dermatology (SBD) and AmericanAcademy of Dermatology (AAD), Rio de Janeiro, Brazile-mail: judermo@gmail.com

L.M. Delorenze (*)Hospital Universitário Antonio Pedro, UniversidadeFederal Fluminense – Niterói, RJ, Brazile-mail: lili_delo@hotmail.com

M.C.A. IssaDepartment of Clinical Medicine – dermatology, FluminenseFederal University, Niterói, RJ, Brazile-mail: dr.mariaissa@gmail.com; maria@mariaissa.com.br

# Springer International Publishing AG 2018M.C.A. Issa, B. Tamura (eds.), Lasers, Lights and Other Technologies, Clinical Approaches and Procedures inCosmetic Dermatology 3, https://doi.org/10.1007/978-3-319-16799-2_8

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Complications and Post-procedure ofQ-Switched Lasers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138

Take Home Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138

Introduction

Lasers (light amplification by stimulated emissionof radiation) are sources of high-intensity mono-chromatic coherent light that can be used for thetreatment of various dermatologic conditionsdepending on the wavelength, pulse characteris-tics, and fluence of the laser being used and thenature of the condition being treated (Arora et al.2012).

Q-switched (QS) lasers deserve special atten-tion due to its recently uprising application in thetreatment of melasma, dark circles eyes, andphotorejuvenation.

Q-Switched Lasers

Lasers have demonstrated significant efficacy inthe treatment of hyperpigmented disorders byselectively destructing pigment cells with a shortpulse and low fluence. The effectiveness of lasertreatment for pigmented lesions is based on thetheory of selective photothermolysis introducedby Anderson and Parrish, which states that whena specific wavelength of energy is delivered over aperiod of time shorter than thermal relaxation time(TRT) of the target chromophore (Arora et al.2012; Anderson et al. 1989; Anderson and Parrish1983; Jang et al. 2011), heat and injury arerestricted to the target, with less damage to thesurrounding tissue (Anderson and Parrish 1983;Jang et al. 2011). The thermal relaxation time formelanosome with 1-μm diameter ranges from50 to 100 ns (Polder et al. 2011). Hence, a lasershould emit a wavelength that is specific and wellabsorbed by the particular chromophore beingtreated.

A selective window for targeting melanin liesbetween 630 and 1,100 nm, where there is goodskin penetration and preferential absorption of

melanin over oxyhemoglobin (Stratigos et al.2000). Absorption for melanin decreases as thewavelength increases, but a longer wavelengthallows deeper skin penetration. Shorter wave-lengths (<600 nm) damage pigmented cells withlower energy fluencies, while longer wavelengths(>600 nm) penetrate deeper but need more energyto cause melanosome damage (Arora et al. 2012).Besides wavelength, pigment specificity of lasersalso depends on pulse width (Chan et al. 2010).These lasers lead to a photoacoustic mechanicaldisruption of melanin caused by rapid thermaltissue expansion (Arora et al. 2012).

QS Nd:YAG Laser

The 1,064-nm Q-switched neodymium-dopedyttrium aluminum garnet (QS 1,064-nm Nd:YAG) laser is widely used in cosmetic laser der-matology (Arora et al. 2012; Chan et al. 2010) forpigmented and vascular lesions, removal of tat-toos, and unwanted hair (Chan et al. 2010).

With a wavelength of 1,064 nm, these devicesallow for much deeper energy penetration andminimal melanin absorption compared with QSruby laser or QS alexandrite laser. QS Nd:YAGlaser uses a collimated handpiece to deliver a highpeak power over very short pulse durations(�20 ns), maximizing selective photothermolysisof cutaneous melanosomes (Friedmann andGoldman 2015).

The 1,064-nmQSNd:YAG is well absorbed bymelanin, and being a longer wavelength causesminimal damage to epidermis and is not absorbedby hemoglobin. The deeper skin penetration isalso helpful to target dermal melanin. Low-doseQS Nd:YAG laser induces sublethal injury tomelanosomes causing fragmentation and ruptureof melanin granules into the cytoplasm (Aroraet al. 2012; Anderson and Parrish 1983; Lee2003). This effect is highly selective for melano-somes as this wavelength is well absorbed bymelanin relative to other structures. There is alsosubcellular damage to the upper dermal vascularplexus, which is one of the pathogenetic factors inmelasma (Kim et al. 2007). The subthresholdinjury to the surrounding dermis stimulates the

128 J. Neiva et al.

formation of collagen resulting in brighter andtighter skin (Schmults et al. 2004).

QS Ruby Laser

The Q-switched ruby laser (QSRL) was the firstlaser reported to be highly efficacious for thetreatment of benign epidermal-pigmented lesions(Park et al. 2008; Taylor and Anderson 1993;Nelson and Applebaum 1992).

The 694-nm wavelength of QSRLs is moder-ately absorbed bymelanin, yet poorly absorbed bycompeting chromophore such as hemoglobin(Friedmann and Goldman 2015; Taylor andAnderson 1993). Rapid delivery of high-intensityenergy at this wavelength disrupts melanosomeswithin keratinocytes, melanocytes, andmelanophages, making them ideal for pigmentedepidermal and superficial dermal lesions inFitzpatrick skin types I–II (Friedmann andGoldman 2015; Kopera et al. 1997).

QS Alexandrite Laser

The more deeply penetrating 755-nm wavelengthof the Q-switched alexandrite laser (QSAL) has alower absorption coefficient for melanin and isemitted over a longer pulse duration (50–70 ns)than that of QSRL, which may serve to decreaseadverse events (e.g., postinflammatory hyperpig-mentation (PIH)) in dark-skinned patients as aresult of gentler melanosomal heating. QSALtreatments of Fitzpatrick skin types of IV orlower are typically performed with 3- to 5-mmspot sizes and 4–8 J/cm2. Lower fluences maylead to equal efficacy with decreased PIH(Friedmann and Goldman 2015; Wang and Chen2012).

A novel QSAL with energy delivered in pico-seconds (as low as 550 ps) may produce greatertensile stress on melanosomes than nanosecondpulse durations, enhancing their photomechanicaland photothermal destruction. Collateral tissueheating and associated adverse events are mini-mized owing to the lower fluences required(Friedmann and Goldman 2015; Dover et al.

2012). As a result, potentially all skin types maybe treated with this device. A 3–5-mm spot sizeand 1.5–2.83 J/cm2 fixed fluence are favored(Friedmann and Goldman 2015).

Pretreatment Procedure

A history of keloids, conditions that may impairwound healing, recent oral retinoid use, preg-nancy, breastfeeding, photosensitivity, and/orabnormalities localized to the treatment area(active infections, malignant lesions, scarring, orburns) should be ruled out before undertaking anyprocedure. Prophylactic antiviral therapy for her-pes simplex virus is not routinely performedbefore QS lasers (Friedmann and Goldman2015). Topical depigmentation products can beused pre- and posttreatment (Arora et al. 2012).

All patients should have photographs and writ-ten informed consent obtained upon arrival (Aroraet al. 2012; Friedmann and Goldman 2015).Before treatment, the area to be treated should bewashed with a neutral cleanser to remove anymakeup or other impurities. Topical anesthesia isgenerally unnecessary given the limited treatmentarea, and it is usually bearable (Friedmann andGoldman 2015).

QS laser treatment of lower eyelid skin withinthe borders of the bony orbital rim requires intra-ocular metal eye shields (Arora et al. 2012).

Melasma and Q-Switched Laser

Melasma is a common and persistent disorder ofhyperpigmentation that affects a significant por-tion of the population, affecting mainly women(Werlinger et al. 2007; Park et al. 2011), beingmore common in Black, Latin, and Asiatic people(Kauvar 2012). Patients report that the conditionhas a markedly detrimental effect on their qualityof life (Park et al. 2011; Balkrishnan et al. 2003;Dominguez et al. 2006).

Melasma presents as symmetric, hyperpigm-ented macules and patches on the face, usuallyon the cheeks, bridge of the nose, forehead, chin,and upper lip (Kauvar 2012; Choi et al. 2010;

Q-Switched Lasers for Melasma, Dark Circles Eyes, and Photorejuvenation 129

Grimes 1995; Gupta et al. 2006; Zhou et al. 2011).Typically it affects more women at reproductiveage with Fitzpatrick type IV–VI, but can alsoaffect men (Sarkar et al. 2014). The ratio betweenaffected women and men is of 9:1 (Kauvar 2012).Although its photogenesis is not fully understood,pregnancy, sunlight exposure, birth control pills,hormone therapy, genetic factors, mild ovariandysfunction, and autoimmune thyroid diseasemay be implicated (Jang et al. 2011; Kauvar2012; Choi et al. 2010; Gupta et al. 2006; Sarkaret al. 2014; Lee et al. 2010). Sun exposure cantrigger melasma because it stimulates melano-cytes to produce increased melanin, and even asmall amount of sun exposure can worsen thecondition. Irritation or inflammation of the skincan also stimulate melanin production and worsenmelasma (Kauvar 2012; Grimes 1995). In somecases, it can disappear spontaneously, but in gen-eral, the condition remains for the rest of thepatient’s life (Zhou et al. 2011).

The most widely accepted classification ofmelasma in recent years is based on the patholog-ical manifestations (Zhou et al. 2011; Rigopouloset al. 2007), including the epidermal type withoutmelanophages in the dermis, the dermal type withmelanophages in the dermis, and the mixed typein which part of the lesion is of the epidermal typeand part of the dermal type (Kauvar 2012; Zhouet al. 2011). By Wood’s light (340–400 nm), theepidermal melasma can be visualized with brownpatches or macules, and the dermal types normallyare not visible except when they are present asblue or black (Kauvar 2012; Zhou et al. 2011;Sarkar et al. 2014).

The major clinical feature of melasma ishyperpigmentation in the form of patches or mac-ules, but it also has been observed that somepatients have an increased distribution of telan-giectatic erythema in the macules (Kim et al.2007).

In the histologic examination, it is possible toobserve that the quantity of melanocytes is notincreased; however, their size gets wider withmore dendrites. They are also more active. Thedermal pigment, when present, will normallyshow up at the middle dermis within themelanophages. These melanophages are usually

near to small and increased vessels, with few orno inflammation (Kauvar 2012; Zhou et al.2011).

It is known that melanocytes respond to angio-genic factors as they express receptors to vascularendothelial growing factor (VEGF). Kim et al.(2007) demonstrated that the area of melasmahas 33,89% more vessels than a near area withoutmacules and 16,28% of these vessels are thicker. Itis reported that the keratinocytes have an increasein the VEGF in melasma. The increase of thedensity and size of the vessels in the melasmaarea is directly related to the increase of the pig-mentation of the macules. Therefore, treatment ofthe vessels in melasma should be important (Kimet al. 2007).

Melasma is often a therapeutically challengingdisorder to the dermatologists. The most impor-tant thing to treat melasma is to understand thatthere are differences in the activity of the mela-nocytes between people. Despite of the treatment,it is very important not to irritate the skinwhen using acids. Patients should understandthe importance of treating melasma avoidingerythema.

Topical treatment melasma can be divided intwo groups: hydroquinone and non-hydroquinone(kojic acid, azelaic acid, ascorbic acid, or alphaarbutin). However, these kinds of treatment pro-vide only temporary results and can also producelong-term complications (Kauvar 2012; Guptaet al. 2006; Katsambas and Antoniou 1995;Jesitus 2014; Polnikorn 2011). Physical therapiessuch as chemical peels, dermabrasion, lasers, andintense pulsed light (IPL) have also been usedwith varying degrees of success and side effects(Park et al. 2011; Kauvar 2012; Katsambas andAntoniou 1995).

Physical methods are the only option toremove the melanin and destroy the melano-somes. Hence the treatment with laser is themost recommended since 2005, when the use offractional laser for the selective photothermolysisin the treatment of melasma began (Se-Yeonget al. 2008).

Various lasers that have been used for melasmainclude the following (Arora et al. 2012; Goldberg1997):

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– Green light: flashlamp-pumped pulsed dyelaser (PDL) (510 nm), frequency doubled QSNd:YAG (Q-switched neodymium:yttriumaluminum garnet – 532 nm)

– Red light: QS ruby (694 nm), QS alexandrite(755 nm)

– Near infrared: QS Nd:YAG (1,064 nm)

The green light lasers do not penetrate asdeeply into the skin as the other two groupsowing to their shorter wavelengths. They aretherefore effective only in the treatment of epider-mal melasma (Arora et al. 2012).

Since the green wavelength is also wellabsorbed by oxyhemoglobin, bruising and pur-pura may occur following laser irradiation. Thepurpura resolves in 1–2 weeks after treatment, andthe clinical lesions lighten in 4–8 weeks. Occa-sionally, the bruising can lead topostinflammatory hyperpigmentation. Greenlight lasers often have a variable response, andthus test spots may be prudent prior to treatingthe whole area (Arora et al. 2012; Goldberg 1997).

Red lasers have longer wavelengths and thusmay penetrate deeper into the dermis. They canalso be used to treat epidermal-pigmented lesionswithout bruising, as they are not absorbed byhemoglobin (Arora et al. 2012; Stratigos et al.2000). The pulse duration of the QS ruby laser(QSRL) varies from 20 to 50 ns and that of QSalexandrite laser (QSAL) from 50 to 100 ns(Arora et al. 2012).

Near-infrared lasers include QS Nd:YAG laser(1,064 nm) which has a pulse duration of10–20 ns. Despite less absorption of this wave-length by melanin compared with the green andred light lasers, its advantage lies in its ability topenetrate more deeply in the skin. In addition, itmay prove to be more useful in the treatment oflesions in individuals with darker skin tones(Arora et al. 2012; Goldberg 1997).

QS Nd:YAG Laser x Melasma

There have been several reports of treatingmelasma with the QS Nd:YAG laser. The mecha-nism of clinical improvement is proposed to be

due to its ability to induce nonspecific dermalwound with healing response and subsequentneocollagenesis (Chan et al. 2010). Mun et al.(2011) found that the treatment of melasma skinwith this laser resulted in the decreased number ofmelanocytic dendrites and altered ultrastructure ofmelanosome (Mun et al. 2011).

Its proposal is to describe a selective and morestable photothermolysis, minimally invasive, toremove the melanin and melanosomes. It happensdue to the use of low energy during the process(Kauvar 2012; Mun et al. 2011; Kang et al. 2011).

For the mechanism of photothermolysis to beefficient, an appropriate wavelength is necessary(1,064 nm is useful because it reaches the dermisand epidermis). The same way, the thermal dam-age of the emitted pulse must be enough to destroythe melanin. And, at last, the pulse duration mustbe as minimal as possible to avoid damages in thenear tissues. The ideal for melasma treatment is tocause the minimal thermal damage and the highestphotoacoustic damage possible (Mun et al. 2011).

QS Nd:YAG is the most widely used laser forthe treatment of melasma (Arora et al. 2012;Brown et al. 2011). In general the fluence used isless than 5 J/cm2, spot size 6 mm, and frequencyof 10 Hz. The number of treatment sessions variesfrom 5 to 10 at 1-week intervals (Arora et al.2012). Zhou et al. (2011) in their studies usedQS Nd:YAG laser at low energy levels (fluenceof 2.5–3.4 J/cm2) weekly for 9 sessions in thetreatment of melasma in 50 patients (Zhou et al.2011).

Choi et al. (2011) treated melasma lesions in20 patients older than 30 years with fluence2.0–3.5 J/cm2, spot size of 6 mm, and a repetitionrate of 10 Hz, in the whole face. The treatment wasperformed five times at 1-week intervals (Choiet al. 2010).

Over the last few years, QS Nd:YAG laser hasincreasingly been performed as “laser toning” or“laser facial” for non-ablative skin rejuvenationand melasma in Asian countries. In laser toning,multiple passes of low-fluence laser (e.g.,1.6–3.5 J/cm2) are delivered through a large spotsize (e.g., 6–8 mm) to optimize energy delivery(Arora et al. 2012; Chan et al. 2010). With aclinical endpoint of erythema plus lesional and

Q-Switched Lasers for Melasma, Dark Circles Eyes, and Photorejuvenation 131

hair whitening (Chan et al. 2010; Kauvar 2012),the QS Nd:YAG treatments involve 10, 20, ormore weekly treatments with as many 10–20laser passes per treatment (Arora et al. 2012;Chan et al. 2010; Kauvar 2012). For melasma,laser toning should be considered as a second-line therapy, since this treatment is unlikely to becurative and is not without risk (Chan et al. 2010).Complications from these high cumulativefluence procedures include pain, urtication,hyperpigmentation, long-term hypopigmentation(guttate leukoderma), and rebound of melasma(Arora et al. 2012; Chan et al. 2010; Kauvar2012; Kim et al. 2009, 2010).

Some publications try to compare the use ofdifferent types of laser in melasma treatment.Jalaly et al. (2014) compared low energyfractioned CO2 laser with QS Nd:YAG1,064 nm. In each side of the faces of the patients,one of these two lasers was applied. They weretreated for 3 weeks with five weekly sessions.Two months after the end of the treatment, thepatients were evaluated, and the side of the facetreated with fractioned CO2 had higher reductionof MASI (Melasma Area Severity Index) (Jalalyet al. 2014).

There is no relation between the therapeuticresponse between the QS Nd:YAG 1,064 nm andthe severity of the disease or the Fitzpatrick skinof the patients (Zhou et al. 2011). Some studiessuggest that more epidermal melasma respondbetter with topical treatment and intense pulsedlight and that the patients of Fitzpatrick phototypeIV respond better to the treatment in comparisonwith those of phototype III. However, as the QSNd:YAG 1,064-nm laser reaches the epidermis,even in dermal lesions, this relation is notobserved during or after the treatment.

In practice, the treatment of melasma consistsof two stages: whitening stage and maintenancestage.

The whitening of the lesions tends to startbetween the fourth and sixth weeks and increasesafter each session of the treatment. Xi Zhou et al.(2011) observed, after the nine sessions, 61.3%decrease of theMASI using QSNd:YAGwith lowenergy. Seventy percent of the patients improvedat least 50% of the lesions and 10% had 100%

improvement. They concluded that the QS Nd:YAG 1,064-nm laser with low energy andwide spot is the new method of choice formelasma treatment. The response is fast and sat-isfactory in the whitening of the pigment (Zhouet al. 2011).

Sim et al. (2014) evaluated the outcome of thetherapy of 50 patients treated with QS Nd:YAG1,064-nm laser with 8-mm spot and 2,8 J/cm2 offluence. The patients were treated weekly for15 weeks. Both patients and investigators havereported improvements of 50–74% of the lesions,what was confirmed by image. None of thepatients had severe adverse effect during the treat-ment. So, they judged the treatment to be safe andefficient with this kind of laser (Sim et al. 2014).

Other publications demonstrate thatQ-switched Nd:YAG 1,064-nm laser is safe andeffective in the treatment of melasma. Sun et al.(2011) evaluated 33 patients and the treatmentconsisted of 1 session per week, in a total of10 sessions. The reduction of MASI and the whit-ening of the lesions were perceptible from theseventh week on. The follow-up in the first, sec-ond, and third month after the end of the therapydemonstrated that the whitening process stillexisted at this period. In this work, no adverseeffect was noticed (Suh et al. 2011).

Jeon et al. (2008) published a work evaluatingthe use of Q-switched ND:YAG 1,064-nm laserwith 5-ns pulse in 27 patients. They used a 7-mmspot and 2–2.5 J/cm2 of fluence in 17 patients and1.6–2 J/cm2 in other 10 patients. The number ofpasses varied from three up to ten until reachingthe light erythema. Two months after the end ofthe treatment, 64.7% of the patients had recur-rences of the lesions, but the intensity of thepigment was lower than in the initial macules,and in 29.41% there were no recurrences(Se-Yeong et al. 2008).

This way, the treatment of melasma during thestage of whitening should be gradual with onesession per week for 10–12 weeks. It should beapplied the larger spot possible (6–8 mm), withpulse frequency of 5–10 Hz. The energy shouldvary from 0.8 up to 1.8 J/cm2 (400–900 mJ). Itshould be applied two to four passes per area untilthe erythema lightens with few overlap (10–15%).

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For a better result, the erythema should be ashomogenous as can be.

Some studies demonstrate that the use ofmicrodermabrasion before the procedure canhelp at the response of the laser. The use withone or two passes over the lesions isrecommended, followed by the application ofQS Nd:YAG 1,064 nm (Kauvar 2012). At theclinical practice, this kind of procedure seems tohelp cases of more laser-resistant melasma, oncethe decreasing of the cornea layer would ease thepenetration of laser into the skin.

Alsaad et al. (2014) applied a procedure ofmicrodermabrasion before the use of the QS Nd:YAG 1,064-nm laser with 5 ns of pulse, 6-mmspot, and 1.8–2.0 J/cm2 of fluence in 10 patients,and in other 17 patients, they used the QS Nd:YAG 1,064-nm laser with 50 ns of pulse, 5-mmspot, and 1.6 J/cm2 of fluence, along with the useof whitening cream at home. The patients werefollowed up for 3, 6, and 12 months after the endof the treatment. The patients who did three orfour treatments had better results than those whodid one or two treatments, all of them maintainingany kind of whitening until the completion of the12 months (Alsaad et al. 2014).

After the procedure, it is recommended to chillthe face for 10–15 min with cold mask or withcold air device. After it, a medium power corticoidcream and sunscreen lotion should be applied.The use of corticoids over the lesions can berecommended for up to 2 days after the sessionof laser, mainly in those lesions that seem to bemore instable and reactive to the procedure.

The sessions are usually well tolerated, and therecurrent adverse effects are erythema that can lastfor 1–3 h and prurience. The less frequent effectsare purpura, edema, acne, and decreasing andwhitening of the face hair. Postinflammatoryhypochromic and hypopigmentation-type guttateleukodermas are described as consequences of theuse of the laser with high energy and multiplepasses.

The reported cases of hyperchromic in somestudies can attack up to 10% of the treated patientsand can occur with few laser sessions, but usuallydue to the use of the QS Nd:YAG laser with thegoal of rejuvenation (Chan et al. 2010). In these

protocols, more passes or higher energy areapplied so the heat can stimulate the productionof collagen at the dermis. Many times, the pro-tocols exclude the use of QS; hence, the 1,064-nmlaser begins to have a bigger wavelength (e.g.,from 5 to 200 ms). In most of the cases, thehypopigmentation persists.

The recurrence of melasma is defined as theincreasing of the pigmentation or the increasingof the size of the lesion after the final treatment andstill is a problem to the therapy with QS Nd:YAG1,064-nm laser. The studies demonstrate that therecurrence of the lesions tends to occur from 2 to3 months after the last session and the characteris-tics of the lesions are the same of the beginning ofthe treatment. This return of the pigmentation atthe lesions occurs because the thermal effect overthe melanocytes is reversible as time goes by. Thisway, the association of the maintenance therapy isnecessary (Zhou et al. 2011; Se-Yeong et al. 2008).

The maintenance phase can cover QS Nd:YAG1,064-nm laser and/or topical creams and oralmedication. The eventual use of hydroquinoneduring and after the treatment is also describedfor the extension of the lightener response of thelaser, avoiding the association with retinoids.

Wattanakrai et al. (2010) carried a study withpatients with dermal or mixed melasma wherethey had, beyond the use of QS Nd:YAG1,064 nm, the daily application of hydroquinone2% versus the control group with patients that useonly the hydroquinone. The patients treated withlaser had five sessions of treatment using the spotof 6 mm and 3–3.8 Jcm2 of fluence along withcold air. After 12 weeks, 92% of the patients thathad association of hydroquinone with laserobtained a whitening of the macules. On theother hand, in the other control group, only19,7% of the patients had improvement of thelesions (Wattanakrai et al. 2010).

The topical application of arbutin, hydroqui-none, and vitamin C is convenient and preferred(Zhou et al. 2011).

In cases that the use of QS Nd:YAG 1,064-nmlaser for maintenance aims to increase the gapbetween the sessions, initially each 15 days for2 months and then one session each 30–60 days,according to the maintenance of the whitening.

Q-Switched Lasers for Melasma, Dark Circles Eyes, and Photorejuvenation 133

The use of the laser for maintenance demonstratedto be more effective than the use of isolated top-ical products as the melanocytes tend to stay lessactive and smaller in the lesions with the laser.

Melasma is a pigmentary disease of the skinwith many pathological and aggravating factorsinvolved. This way, a single treatment doesn’t getto be completely effective. The best treatment isthe combination of therapies, and, among those,the one that presents the best effectiveness andsafety in the whitening of the lesions today is theuse of low-energy laser Q-switched Nd:YAG1,064 nm (Figs. 1, 2, 3, and 4). The associationwith whitening creams, microdermoabrasion, and

peelings makes these results even better andlasting.

QS Ruby Laser x Melasma

The efficacy of QSRL for melasma is still contro-versial (Arora et al. 2012; Jang et al. 2011). Themechanism is the same as that of QS Nd:YAGlaser, that is, it causes highly selective destructionof melanosomes. QS ruby laser, having a wave-length of 694 nm, is more selective for melaninthan the QS Nd:YAG laser (1,064 nm) (Aroraet al. 2012).

Fig. 2 Melasma: before and after two and three sessions of treatment with fractioned QS Nd:YAG 1,064-nm laser(0.7 J/cm2 with three passes, alternating sides, each 30 days)

Fig. 1 Melasma: beforeand after three sessionstreatment with fractionedQS Nd:YAG 1,064-nmlaser (0.7 J/cm2 with threepasses, alternating sides,each 30 days)

134 J. Neiva et al.

So theoretically QSRL is expected to be moreeffective than QS Nd:YAG for melasma (Aroraet al. 2012), but severe postinflammatory hyperpig-mentation and hypopigmentation occurred in somepatients within a short period of time (Choi et al.2010; Hilton et al. 2013), suggesting that the high-energy mode of QS lasers is likely to be ineffectivefor melasma and therefore not a good choice fortherapy for this condition (Zhou et al. 2011; Taylorand Anderson 1994). The role of QSRL is

controversial with studies showing conflictingresults (Arora et al. 2012).

On the other hand, Jang et al. (2011) showedthat the use of multiple treatment sessions oflow-dose fractional QSRL may be an effectivestrategy for the treatment of dermal or mixed-type melasma (Jang et al. 2011).

More studies are needed to establish itsefficacy and safety in melasma (Arora et al.2012).

Fig. 3 Melasma: beforeand after ten sessions withcollimated QS Nd:YAG1,064-nm laser (5-ns pulse,1.1–1.6 J/cm2 of fluenceand 8 mm of spot)combined with daily topicalvitamin C

Fig. 4 Melasma: beforeand after ten sessions withQS Nd:YAG 1,064-nmlaser (5-ns pulse,1.1–1.6 J/cm2 of fluence).Maintenance stage withvitamin C and daily topicalwhitening agents

Q-Switched Lasers for Melasma, Dark Circles Eyes, and Photorejuvenation 135

Dark Circles Eyes and Q-SwitchedLaser

Dark circles eyes are also known as the periorbitalhyperpigmentation. It is a common condition thatoccurs in both sexes with an increasing frequencyin females (Friedmann and Goldman 2015; Rob-erts 2014). It can impart a fatigued and less youth-ful appearance to the face (Friedmann andGoldman 2015). Globally, skin-of-color patientsare affected more than Caucasians. There is mostlikely a familial component as it may be seen infamily members over generations (Roberts 2014).

The formation of dark circles is often multifac-torial, with a number of factors reported to play arole. Among these factors are hollowing/shadowing, dermal melanin deposition,postinflammatory hyperpigmentation secondaryto atopic or allergic contact dermatitis, prominentand superficial location of vasculature, and exog-enous causes (penicillamine-induced periorbitalpigmentation, bimatoprost-induced periorbitalhollowing, and hyperpigmentation) (Friedmannand Goldman 2015; Freitag and Cestari 2007;Roh and Chung 2009; Xu et al. 2011). It is impor-tant for clinicians, as it may be a sign of anunderlying systemic disease, skin disorder, aller-gic reaction, nutritional deficiency, or sleep dis-turbance (Friedmann and Goldman 2015; Xu et al.2011).

Dark circles eyes usually present as bilaterallysymmetric hyperpigmented patches around theeyes. One eye may be more involved than theother. It can affect either the upper or lower eyelidor both upper and lower. It may extend to involvethe glabella and upper nose (Roberts 2014).

Aesthetic treatments include microdermabrasion,chemical peels, lasers, radiofrequency, injectablefillers, surgery, fat transfer, hydroquinone, and topi-cal retinoids (Friedmann and Goldman 2015; Rob-erts 2014).

Cutaneous melanin has a broad, polychromaticabsorption spectrum that peaks in the UV rangeand declines steadily as a function of increasingwavelength. Although significantly attenuatedpast 755 nm, energy absorption is still likelywith wavelengths up to 1,064 nm, allowing fortreatment of deeper pigment and darker

Fitzpatrick skin types. Given that melanosomeshave thermal relaxation times of less than 1 μs,ultrashort pulse durations are required to selec-tively confine photothermal and photoacousticeffects to these structures (Anderson et al. 1989;Friedmann and Goldman 2015). ManyQ-switched lasers with nanosecond (and recentlypicosecond) pulse durations and wavelengthswithin the absorption range of melanin are cur-rently available. The typical clinical endpoint ofthese treatments is immediate lesion whiteningwithout pinpoint bleeding. Lower energy settingsshould be used initially to minimize the occur-rence of PIH (Friedmann and Goldman 2015).

QS Nd:YAG Laser x Dark Circle Eyes

As demonstrated in treating melasma, repeatedsessions with low-fluence, QS Nd:YAG treatmentscan decrease stage IVmelanosomes, damagemela-nocytes, and reduce expression of melanogenesis-associated proteins. Higher fluences (4–5 J) can beused with a 3-mm spot size for other types of lowereyelid hyperpigmentation (Friedmann andGoldman 2015) (Fig. 5).

QS RUBY Laser x Dark Circle Eyes

QSRL treatment is performed with 2–4 J/cm2

using a 5-mm spot size (or varied accordingly) at1.5 Hz. The clinical endpoint with this device isimmediate lesion whitening that resolves over20 min followed by erythema and edema. Com-bining QSRL with topical hydroquinone and tre-tinoin before and after treatment has also led tosignificant improvement in this location(Friedmann and Goldman 2015).

Photorejuvenation and Q-SwitchedLaser

Clinical signs of photoaging include coarse skintexture, irregular pigmentation, and laxity of skintone, as well as the appearance of fine lines andwrinkles (Hong et al. 2014; Yaghmai et al. 2010).

136 J. Neiva et al.

Diverse treatment modalities have been used toimprove skin wrinkling and laxity, includingchemical peeling, soft tissue filler, laser ablation,and facelift surgery. Recently, among thesemodalities, laser ablation has been highlighteddue to its relatively effectiveness and shorterrecovery time compared to other methods. It isclassified into ablative laser and non-ablativelaser. Generally, ablative lasers are consideredmore effective than non-ablative ones in treatingrhytides, but they have a prolonged recovery timeand more chance of complications, such aspostinflammatory hyperpigmentation due toexcessive thermal energy transferred to adjacenttissue (Hong et al. 2014).

Non-ablative lasers are thought to workthrough thermal energy transferred to small ves-sels and tissues in upper dermis, which stimulatedermal fibroblasts to induce collagen and elastinregeneration. Regarding the hypothesis above,long-pulse Nd:YAG lasers (LPND) have theadvantage of reaching deeply located blood ves-sels and transferring energy to collagen adjacentto vessels while bypassing the epidermis. Patients

with Fitzpatrick skin type III or more can betreated using with less risk because the wave-lengths of the infrared area are weakly attractedto melanin (Hong et al. 2014). Although the typ-ical response to this type of treatment is modestclinical improvement in mild to moderate facialrhytides, non-ablative therapy has gained in pop-ularity over the past few years for photoagingtherapy because of its little to no downtime.Laser systems, which have been traditionallyused for this approach, rely on thermal inductionfor tissue change. Introduction of Q-switchedlaser systems has added a photoacoustic elementto the dermal response. The Q-switched Nd:YAGlaser has been shown to improve photodamagechanges (Yaghmai et al. 2010; Goldberg andSilapunt 2001). With this laser system, relativelylower laser energies are needed resulting in mildimmediate side effects (Yaghmai et al. 2010).

Non-ablative laser therapy remains a veryadvantageous therapeutic approach for skin reju-venation. The potential of inducing beneficial tex-tural and pigmentary changes to sun-damaged andaged skin without the need of ablation will resultin dramatically less postoperative undesiredimmediate and long-term effects. Theseapproaches have resulted in collagen productionand subsequent dermal thickening with a reduc-tion of surface textural changes. In addition, bothpigmentary and erythematous changes can beimproved. All of this with minor immediate post-operative effects is generally limited to transienterythema and edema. Long-term undesired effectssuch as fibrosis, scarring, or persistent pigmentarychanges have been remarkably diminished rela-tive to ablative procedures (Yaghmai et al. 2010).

The Q-switched Nd:YAG laser has exhibitedthe ability to achieve clinically desirable improve-ment in many parameters of skin rejuvenation.Remarkably, this has occurred with a very accept-able adverse effect profile and, as importantly,patient tolerance and acceptability (Yaghmaiet al. 2010) (Fig. 6).

The authors have good experience with QSNd:YAG laser. Dr. Issa has good results using QS(Clearlift – Alma Lasers) for melasma (Figs. 1and 2) and dark circles eyes (Fig. 5). This deviceis a fractional (5 � 5 pixel) QSNd:YAG 1,064-nm

Fig. 5 Dark circle eyes: before and 30 days after foursessions of treatment with fractioned QS Nd:YAG 1,064-nm laser (1.2 J/cm2 with ten passes each side at a time, each30 days)

Q-Switched Lasers for Melasma, Dark Circles Eyes, and Photorejuvenation 137

laser with pulse duration of 20 ns, and its fluenceranges from 500 to 1,200 mJ/p. Regardingphotodamaged skin, the best results are observedon periocular area (Fig. 6). Dr. Neiva has goodexperience using QS Nd:YAG (Spectra-Skintech)for melasma (Figs. 3 and 4).

Complications and Post-procedure ofQ-Switched Lasers

As low energies are applied, the occurrence ofpost-procedure complications is very rare. Usu-ally, erythema resolves over minutes to few hoursand edema is not observed. The risk of blistering,PIH, and hypopigmentation is minimum due tothe low energy used at the treatment.

The authors reinforce the importance of usingsunscreen. Lightening creams can be used 24 hafter each session during the treatment.

Take Home Messages

1. Melasma is often a therapeutically challengingdisorder to the dermatologists. The same way,dark circles treatment and photorejuvenationare not easy to achieve.

2. Lasers have demonstrated significant efficacyin the treatment of hyperpigmented disorders,such as melasma and dark circles by selectively

destructing pigment cells with a short pulseand low fluence.

3. Q-switched (QS) lasers, such as QS Nd:YAG,QS ruby, and QS alexandrite lasers, deservespecial attention due to its recently uprisingapplication in the treatment of melasma, darkcircles eyes, and photorejuvenation.

4. Although QS lasers present the best effective-ness and safety in the whitening of the lesions,combined with other therapies, it can improvethe treatment of melasma, dark circles, andphotorejuvenation.

References

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Kim EH, Kim YC, Lee ES, Kang HY. The vascular char-acteristics of melasma. J Dermatol Sci. 2007;46:111–6.

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140 J. Neiva et al.

Erbium Laser for Photorejuvenation

Alexandre de Almeida Filippo, Abdo Salomão Júnior,Paulo Santos Torreão, Lilian Mathias Delorenze, andMaria Claudia Almeida Issa

AbstractThe use of ablative lasers for skin resurfacing isconsidered one of the gold standard treatmentsfor facial rejuvenation. Ablative fractionallasers, mainly erbium and CO2 lasers, weredeveloped to reduce side effects and patient’sdowntime. The fractional erbium laser pro-duces a thin ablation zone with little thermalinjury in the epidermis and superficial dermis.It is well indicated for skin rejuvenation,improving texture, pigmentation, and fine

lines. It can also be used for stretch marks andscars. In this chapter, we are going to describeerbium laser concept, mechanisms of action,protocols of treatment, side effects, andmanagement.

KeywordsErbium:yttrium-aluminum-garnet laser • Er:YAG laser • Facial rejuvenation • Resurfacingwith ablative lasers • Fractionated laser tech-nology • Rhytids • Wrinkle • Skin pigmenta-tion • Skin texture

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142

History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142

Laser and Tissue Interaction . . . . . . . . . . . . . . . . . . . . . . 143How Does Ablation Work? . . . . . . . . . . . . . . . . . . . . . . . . . . 143Fractional vs Non-fractional . . . . . . . . . . . . . . . . . . . . . . . . . 144Biologic Effects of the Treatment . . . . . . . . . . . . . . . . . . . 145

Laser Er:YAG Operator Modes . . . . . . . . . . . . . . . . . . . 145Ablative Mode or Cold Ablation . . . . . . . . . . . . . . . . . . . . 145Ablative/Coagulative Mode (Warm or Hot Ablation

Mode) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145Coagulative Mode or Smooth Mode . . . . . . . . . . . . . . . . 145Stacking Mode . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147Non-fractional Mode . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147

Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147

Pretreatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147

A. de Almeida FilippoSanta Casa de Misericórdia do Rio de Janeiro (LaserSector), Rio de Janeiro, Brazile-mail: alefilippo@gmail.com

A. Salomão JúniorUniversidade de São Paulo, MG, Brazile-mail: dr.abdo@usp.br

P.S. Torreão (*)Hospital dos Servidores do Estado do Rio de Janeiro,RJ, Brazile-mail: pstorreao@gmail.com

L.M. DelorenzeHospital Universitário Antonio Pedro, UniversidadeFederal Fluminense – Niterói, RJ, Brazile-mail: lili_delo@hotmail.com

M.C.A. IssaDepartment of Clinical Medicine – Dermatology,Fluminense Federal University, Niterói, RJ, Brazile-mail: dr.mariaissa@gmail.com; maria@mariaissa.com.br

# Springer International Publishing AG 2018M.C.A. Issa, B. Tamura (eds.), Lasers, Lights and Other Technologies, Clinical Approaches and Procedures inCosmetic Dermatology 3, https://doi.org/10.1007/978-3-319-16799-2_9

141

Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148

Posttreatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149

Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150

Take Home Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150

Introduction

There are many different treatment optionsfor skin rejuvenation, including medium anddeep chemical peels photodynamic therapy,radiofrequency (see chapters ▶ “Non-ablativeRadiofrequency for Facial Rejuvenation,” and▶ “Ablative Radiofrequency in Cosmetic Der-matology” in this volume), microneedling tech-niques and non-ablative and ablative lasers (seechapter Lasers, Lights, and Related Technolo-gies in Cosmetic Dermatology, this volume).Fractional ablative lasers are probably the mostefficient treatment available when we take intoaccount cost, safety, and results (Campos et al.2009; Holcomb 2011; Taudorf et al. 2014).

The fractional laser technology was introducedas safer alternative, being less operator dependentand with the aim of reducing the patient’s post-operatory restrictions (Sklar et al. 2014; Lee et al.2012; Kim et al. 2012). The fractional resurfacingmethod creates microscopic treatment zones(MTZs) with controlled width, depth, and density.These MTZs are surrounded by intact areas ofepidermis and dermis allowing for faster tissuerepair (Sklar et al. 2014).

Before the development of the pulse variationand the fractional technology, a long recoverytime and high frequency of side effects such asbleeding, persistent erythema, edema, and post-inflammatory hyperchromia were common.Those side effects were related to the extent ofepidermis ablation and to the almost purely abla-tive characteristic of the 2940 nm laser (Camposet al. 2009; Holcomb 2011).

Over the years, many operator “modes” havebeen developed allowing a variety of abilities forthe Er:YAG laser that were not present at the

beginning. The Er:YAG laser has the highestabsorption coefficient for water, which is the chro-mophore targeted in the resurfacing technique. Itis at least ten times higher than the CO2 laser.Biologically, it means that almost all the lightenergy delivered through the laser will beabsorbed by the water present in the skin andwill be converted to heat in an exothermic reaction(Holcomb 2011).

Those injuries will be repaired promotingskin rejuvenation (Holcomb 2011). The resultswith fractional lasers are less evident than thoseachieved with non-fractionated procedures;however, it is possible to have significantimprovement of the photodamaged skin (Kimet al. 2012).

History

The first erbium:yttrium-aluminum-garnet (Er:YAG) laser was approved by the Food and DrugAdministration in 1997 for tooth decay. It waslater approved for facial rejuvenation. The Er:YAG laser is made of a solid state crystal ofyttrium-aluminum-garnet doped with erbiumions (Er3+), and it is pumped by a pulsed broad-band flashlamp emitting a wavelength of2940 nm by the process of laser light amplifica-tion (Campos et al. 2009; Diaci and Gaspirc2012).

The 2940 nm laser was originally conceived asa device to ablate the entire epidermis, completelyexposing the dermis. For that reason, several post-operatory side effects were expected and limitedthe use of the device (Campos et al. 2009; Sklaret al. 2014).

The first generation was almost purely ablativelaser, requiring multiples passes for the end pointresult and inducing dermal bleeding. The secondgeneration was able to avoid unwanted bleedingby adding a long-pulse or a variable-pulse featuredesigned to promote tissue coagulation (Holcomb2011).

The variable pulse technology was the abilityto extensively control the pulse widths from very

142 A. de Almeida Filippo et al.

short pulses to very long pulses and the possiblecombinations of short and long pulses at onesingle laser shot. An even more developed controlover the pulses was called the variable squarepulse. It is the ability to deliver strictly the samepeak power as the average power during the pulse,which means that there is no rise or fall in thecurve that measures the power over time but asquare shape (Lukac et al. 2007, 2008) (Fig. 1).

More recently, in the beginning of the 2000s,the development of fractioned version of the2,940 nm laser was able to reduce skin surfacearea injured, preserving the efficacy of thenon-fractioned version of the laser (Camposet al. 2009; Holcomb 2011).

Laser and Tissue Interaction

How Does Ablation Work?

In order to choose a laser to promote skin rejuve-nation through ablation, the first thing that shouldbe taken in account is the wavelength. Water is amajor element present in the skin and is the targetfor all resurfacing laser. There are three majorlaser lengths that operate within absorptionpeaks for water: Er:YAG, Er:YSGG (yttrium-scandium-gallium-garnet), and CO2. When irra-diated with those wavelengths, the tissue gothrough three basic phases, as the energy in the

photons is transmitted to the water (Lukac et al.2007, 2008, 2010):

Phase 1: Direct heat within the optical absorp-tion depth. It happens when heat is transmitteddirectly and almost restrictedly to skin depth thatlight is capable of penetrating in the tissue, untilall the photons are completely absorbed andconverted to heat (Lukac et al. 2008).

The Er:YAG laser penetrates approximately3 μm in the skin as it has the highest coefficientof absorption for water, the Er:YSGG laser pene-trates 10 μm and has the intermediary coefficientof absorption for water, and CO2 laser penetrates30 μm into the skin with the lowest coefficient ofabsorption for water (Lukac et al. 2008, 2010)(Fig. 2).

So the highest the affinity for water and thehighest the absorption coefficients, the shallowerthe penetration of the laser, as all the energywithin the photons is better absorbed by thewater (Lukac et al. 2007, 2008, 2010).

Phase 2: Thermal diffusion. It happens whenthe heat is transmitted to deeper lying tissues,beyond the optical absorption depth. The longerthe pulse length, the more evident is the result ofthermal diffusion, tissue coagulation. Neverthe-less, the shorter the pulse length, the less evidentis the result of thermal diffusion as the pulse endsfaster than the ability of the tissue to transmit theheat within neighbor structures, like in Q-switchdevices (Lukac et al. 2008, 2010).

Time

Lase

r Pow

er

Variable pulse with square pulse technology : fast rise and short fall.

Variable pulse with conventional pulse technology (pulse forming network): intermediary rise and long fall.

Fig. 1 Diagram comparingthe behavior of the powercurve over time for thesquare pulse technologyversus conventional pulsetechnology (Adapted fromMatjaz Lukac et al. 2007)

Erbium Laser for Photorejuvenation 143

The smallest coagulation zone possible foreach laser wavelength is limited by the opticalpenetration depth, as it is an immutable character-istic of the wavelength determining howmuch thelaser penetrates the skin. But if we manipulate thepulse duration to last longer, heat is accumulatedwithin the tissue, making the coagulation zonethicker through thermal diffusion, beyond theextent of the optical absorption depth. So is notpossible to reduce the coagulation zone limited bylaser wavelength and the optical penetrationdepth, but it is possible to increase the coagulationzone through thermal diffusion principle, makingthe pulse width longer (Lukac et al. 2008, 2010).

This is what is done by Er:YAG lasers to emu-late the coagulative effect of the CO2 laser, furtherexplained below in the item Ablative/Coagulative Mode.

Phase 3: Tissue vaporization. It happens whenthe top part of the issue close to the surface isheated to a point where ablation occurs, and mate-rial is extruded leaving a small hole on the skinsurface, followed by tissue injured by the heat inthe surround area (Lukac et al. 2008) (Fig. 3).

Fractional vs Non-fractional

The fractional technology was first introduced in2004 by Dieter Manstein et al., in a pilot studywith wavelengths that varied from 1480 to1550 nm. The ability to reduce the resurfacingside effects maintaining its efficacy allowed thisnew technology to be develop into several laserwavelengths: initially the non-ablative lasers, thenthe fractional CO2 laser, followed by the frac-tional Er:YAG laser (Manstein et al. 2004).

When skin tissue is treated with fractionallasers, vertical channels are created by columnsof vaporization, drawing a grid of microscopictreatment zones, also called microthermal treat-ment zones or even microscopic thermal zones(MTZ). Each MTZ is composed of the ablatedchannels, also called microscopic ablation zones

3µm 30µm

CO

2 be

an

ER

:YA

G b

ean

Fig. 2 Diagram comparingthe optical penetrationdepth in the skin for the Er:YAG and CO2 lasers(Adapted from MatjazLukac et al. 2008)

Dermis

Ablated regionCoagulated region

Fig. 3 Diagram showing the effect of the laser treatmenton a schematic representation of a cross-sectional trans-verse view of a skin biopsy (Adapted from Holcomb 2011)

144 A. de Almeida Filippo et al.

(MAZ) and a border of coagulated tissue (Taudorfet al. 2014; Sklar et al. 2014; Skovbolling Haaket al. 2011).

Biologic Effects of the Treatment

Studies evaluating the efficacy of Er:YAGfractioned lasers have shown improvement of col-lagen arrangement and formation of new collagentypes I, III, and VII. Immunohistochemical stud-ies have shown total replacement of the MTZsinto new collagen 3 months after treatment. Fur-thermore, it has been reported that multiple treat-ments provide continuous new collagenproduction for more than 6 months allowing skinrejuvenation with shorter downtime and fewerside effects (Taudorf et al. 2014; Sklar et al.2014; Lee et al. 2012; Hammami Ghorbel et al.2014; El-Domyati et al. 2014).

Laser Er:YAG Operator Modes

The Er:YAG laser has several modes of operationand can be used in a non-fractioned or fractionedfashion, produce pure ablation, pure coagulation,and blends of ablation/coagulation at several dif-ferent ablation depths, and even capable of emu-lating a CO2 laser. Variations in pulse length,energy, fluence as well as pulse stacking and dif-ferent spots promote versatility to this lightsource. There are five primary operations modesunevenly presented in different devices and indus-tries (Holcomb 2011; Lukac et al. 2007, 2008).

Ablative Mode or Cold Ablation

It is the Er:YAG native and standard effect. Due tothe high affinity for water, the laser producessuperficial columns of almost pure ablation, capa-ble of reaching the epidermis to superficial dermis(with pulse stacking) (Holcomb 2011; Lukac et al.2008), as shown in Fig. 4. During the procedureareas of pinpoint bleeding may be observed, as inthis mode there is not coagulation of the bloodvessels. It is also used for drug delivery purposes

(Jang et al. 2014), mimicking the effect of a super-ficial microneedling, due to the superficial andpurely ablative laser profile, without barriers ofcoagulated tissue (Holcomb 2011).

Ablative/Coagulative Mode (Warm orHot Ablation Mode)

It is the most common mode used in many Er:YAG devices commercially available nowadays.It avoids bleeding by inducing greater thermaleffect and coagulation of dermis blood vessels.In this mode, the 2940 nm laser emulates theCO2 laser coagulative effect with the variablepulse or a long pulse operation, generated througha sequence of shots with different energies andpulse durations (Holcomb 2011; Lukac et al.2007).

There is a train of pulses where the first shotenergy is beyond the ablative threshold, and thesubsequent energy levels are always below theablative threshold, cumulating heat in the skinand producing coagulation (Lukac et al. 2007,2008, 2010) (Fig. 5).

In the warm ablation mode, there is an ablativepulse followed by sub-ablative long pulse, with amedium thick coagulation zone. In the hot abla-tion mode, there is an ablative pulse followed bylonger sub-ablative long pulse, with a thickercoagulation zone (Lukac et al. 2007, 2008, 2010).

This is the best 2940 nm mode addressed toinduce skin rejuvenation as there is greater ther-mal effect and more collagen remodeling, but itmay produce hyperchromias or hypochromias dueto the coagulation and heat produced during theprocedure (Holcomb 2011; Lapidoth et al. 2008).

It is the authors’ preference to use this modewhen rejuvenating the face with high fluences,3 to 5 pulse stacks and 2 to 3 passes. Fornon-facial areas low fluences, 2 stacks, and 1 or2 passes.

Coagulative Mode or Smooth Mode

In this mode, only sub-ablative fluences and ener-gies are used during the pulses, emulating the

Erbium Laser for Photorejuvenation 145

effect of non-ablative lasers (Holcomb 2011).This is also done through the variable-pulse orlong-pulse technology. For the coagulative effect,small amounts of energy are delivered within a

long pulse, normally a long train of sub-ablativepulses, building heat up into the tissue, promotingcoagulation without ablation or with very littleablation (Lukac et al. 2007, 2008, 2010) (Fig. 6).

Ablativethreshold

Time

Ene

rgy

or F

luen

ceT1: Short length, high energy, high fluence supra-ablative pulse for ablation.

Epidermis

Dermis T1

Ablated region

Fig. 4 Diagram showing a high energy, high fluence, andshort width pulse above the ablation threshold over timeand the effect of the Er:YAG laser on a schematic

representation of a cross-sectional vertical view of a skinbiopsy (Adapted from Matjaz Lukac et al. 2010)

Ablative threshold

Time

Ene

rgy

or F

luen

ce

T1: Short length, high energy, high fluence supra-ablative pulse for ablation.

T2: Long length, low energy, low fluence sub-ablative train of pulses for coagulation.

Epidermis

Dermis T1

Ablated region

Epidermis

Dermis T2

Coagulated region

Fig. 5 Diagram showing in T1 a high energy, highfluence, and short width pulse above the ablation thresholdover time; followed by in T2 a long pulse composed of fewshort pulses with low energy and low fluence below the

ablation threshold over time; and the effect of the Er:YAGlaser on a schematic representation of a cross-sectionalvertical view of a skin biopsy (Adapted from MatjazLukac et al. 2010)

146 A. de Almeida Filippo et al.

Stacking Mode

This is not essentially an operator mode as it canalso be present within the previous discussedmodes, as in the ablative and ablative/coagulative modes. During the pulse stacking,a train of high-energy, high-fluence, short-lengthpulses are delivered in sequenced manner, oneon the top of the other, without moving the laserhandpiece, so the ablation depth of each shot isadded to the previous ones, reaching deeperlayers in the skin. Again it can appear as anoperator mode or it can be hidden within othermodes automatically controlling the ablationdepth (Holcomb 2011; Lukac et al. 2007;Lapidoth et al. 2008).

Non-fractional Mode

In this mode, the laser beam is not fractioned insmaller lasers beans. Instead, the entire epidermisablated by the laser, leaving no areas of intactskin, as it was done originally at the Er:YAGfull-field resurfacing treatment regimens (Lukacet al. 2008, 2010).

Indications

The Er:YAG lasers can be used in a variety oflesions especially related to sun damage includingactinic keratoses, solar lentigines, superficial

rhytides, mild dyschromia, and Favre-Racouchotdisease. (Janik et al. 2007). Authors have goodresults for photodamaged skin treatment (Figs. 7and 8).

It can also be used for colloid milium, angio-fibromas, nevi, seborrheic keratosis, xanthelasma,syringomas, sebaceous hyperplasia, rhinophyma,atrophic facial acne scars, trichoepitheliomas,actinic cheilitis, Bowen’s disease, erythroplasiaof Queyrat. It has also been used associated withantineoplastic drugs as drug delivery purposes inthe treatment of actinic keratosis and superficialbasal cell carcinomas (Janik et al. 2007).

As the water is the main target, it is well toler-ated by higher phototypes patients, up to IV asshown by Lapidoth et al. and Lee et al. (2012).

Pretreatment

Patients should understand the mechanism ofaction of the proposed treatment, as well as itspossible side effects and complications. Derma-tologists should explain every step of the processfrom wound care to normal timelines for healing,diminishing excessive expectations and worriesrelated to the procedure and post-procedure(Holcomb 2011).

Patients must understand that it is normal tofeel bearable pain during the intervention andthat erythema, edema, and crusts are expectedside effects. The erythema can be prolongedaccording to the used settings. Dyschromias are

Ablativethreshold

Time

Ene

rgy

or F

luen

ce

T1: Long length, low energy, low fluence sub-ablative train of pulses for coagulation.

Epidermis

Dermis T1

Coagulated region

Fig. 6 Diagram showing in T1 a long pulse composed offew short pulses with low energy and low fluence belowthe ablation threshold over time and the effect of the Er:

YAG laser on a schematic representation of a cross-sectional vertical view of a skin biopsy (Adapted fromMatjaz Lukac et al. 2010)

Erbium Laser for Photorejuvenation 147

generally rare and tend to be transitory(Holcomb 2011).

The skin rejuvenation promoted by the erbiumlaser is significant, although several sessions maybe necessary to achieve optimal results and somedegree of photodamage may always persist(Holcomb 2011).

It is imperative for patients to start antiviraltherapy 2 days prior to the procedure (continuedfor 5–7 days after or until completereepithelialization), regardless of the previous his-tory of herpes simplex (Lapidoth et al. 2008).

Patients must also be instructed to use 0.05%tretinoin cream, nightly for 2–4 weeks, prior tolaser treatment and should stop few days prior

the procedure. (Papadavid and Katsambas2003)

Techniques

Topical anesthetic cream should be applied30 min before the treatment and removed justbefore the procedure.

There are several different techniques thatchange according to the authors. In 2008, Lapidothet al. (2008) reported results from a skin rejuvena-tion study with fractionated 2940 nm Er:YAG laser(Pixel, Alma Lasers Ltd.) in patients withFitzpatrick skin type II-IV. The authors have used

Fig. 7 Before and 90 daysafter Er:YAG intervention.Treatment regimen: firstpass with ablative modewith 15 mJ and 3 ms, andsecond pass withcoagulative mode 27.5 mJ e5 ms

Fig. 8 Before and 90 daysafter Er:YAG intervention.Treatment regimen: firstpass with ablative modewith 15 mJ and 3 ms, andsecond pass withcoagulative mode 27.5 mJ e5 ms

148 A. de Almeida Filippo et al.

two to four stacked passeswith a 7 � 7 tip (49-dot),which emits 28mJ/P (per pixel), with themaximumpulse energy output being 1.400 mJ/P. For the firstpass, a penetration of 20 μm of evaporative and30 μm of thermal, for the second pass respectively35 and 40 μm, for the third pass 50 and 45 μm, forthe fourth pass 60 and 50 μm, with a microzonediameter of 150 μm, and a mean number of 3.2sessions. Sixty days after the final treatment, allpatients showed clinical improvement greater than50%.

Goldberg and Hussain (2011) conducted astudy in patients with Fitzpatrick skin type I-III,utilizing Er:YAG laser 2940 nm with a full faceand single pass treatment, at low energy settingsof 15–30 mJ/microspot at 40 Hz, with 8–21%coverage, for six sessions. All patients presentedclinical improvement in the treated skin; halfreported over 50% improvement.

Karsai et al. (2010), studied the 2940 nm laserresponse on patients with Fitzpatrick skin typeI-III by applying a total fluence 60 J/cm2, withsix stacked pulses in single session. The outcomeof this study showed reduction of approximately10% of wrinkle depth.

A study performed in Korea, by Lee et al.(2012), in patients with Fitzpatrick skin typeIII-IV with Er:YAG laser (ACTION™, Lutronic,Korea), applied full face treatment, one or twopasses with 12–14 mJ per microspot, with250 μs pulse width and mean number of 2.3 ses-sions. The results showed an improvement greaterthan 26% in 62.5% of subjects.

El-Domyati et al. (2013) showed that bothmultiple sessions of fractional Er:YAG laser or asingle session, with multiple passes, of ablativeEr:YAG laser have comparable efficacy clinicallyand on dermal neocollagenesis, and multiple ses-sions of fractional Er:YAG laser resurfacing areeffective with higher safety and shorter downtime(El-Domyati et al. 2013).

Posttreatment

When using the pure ablative mode, pinpointbleeding is expected; therefore, wet gauze com-pression for several minutes post-procedure is

indicated (Campos et al. 2009; Holcomb 2011;Papadavid and Katsambas 2003).

After the laser session, topical semioccludeddressings (“closed” technique) or topical moistur-izers (“open” technique) are applied, as with CO2

laser postoperative care. It is the authors’ prefer-ence to apply a d-pantenol or sucralfate healingcream for 8 h and then after that period washingthe face with gentle cleanser and reapplying thehealing cream four times a day for 7–10 days. It isimportant to tell the patient not to remove crusts orscratch the skin (Campos et al. 2009; Papadavidand Katsambas 2003).

The use of physical sunscreen is advised andindicated 48 h after the treatment during theday. Antiviral therapy should be carried on forat least 5 days as mentioned earlier. It is impor-tant to have let the patient have an emergencynumber if the post-procedure goes not asplanned. Two weeks after laser treatment, asso-ciation of topical hydroquinone 2–5%, tretinoin0.05–0.1%, and hydrocortisone 1% cream isrecommended for 2–4 weeks (Papadavid andKatsambas 2003).

Complications

Unexpected side effects and complicationsinclude persistent erythema, milia, acneiformeruptions, eczema, infections, impaired healing,scars, and permanent hyper- or hypopigmentation(Janik et al. 2007).

Post-inflammatory hyperpigmentation is tran-sient. Late complications, such as hypo-pigmentation, are seen in very few patients (4%)treated with the Er:YAG laser. Hypopigmentationseems to be related to the ablation depth which isusually more superficial with the Er:YAG laser.The presence of bleeding forces the surgeon todiscontinue laser treatment and therefore preventsserious complications, due to the larger absorptioncoefficient for tissue water and the superficialpenetration of this wavelength. The risk of scar-ring and hypopigmentation could increase ifthe laser surgeon seeks to achieve considerableablation depths and more significant clinicalimprovement.

Erbium Laser for Photorejuvenation 149

Conclusion

The Er:YAG laser technology has been continu-ously developed since its beginning and nowa-days has become a powerful versatile tool for thedermatologist. This wavelength is capable of han-dling from photodamage wrinkles to basal cellcarcinomas.

The highest coefficient of absorption for wateramong ablative lasers assures the smallest pene-tration depth and the smallest unwanted thermaldissipation effects. Also, variations in pulsewidths can obtain deeper thermal effects whensuch treatment is desired. The Er:YAG laser istherefore the ideal laser for skin resurfacing.

Take Home Messages

– The resurfacing with ablative lasers is consid-ered one of the gold standard methods forfacial rejuvenation.

– It can promote improvement of facial rhytids,skin pigmentation, and skin texture.

– The usual treatment delivers short downtimeand few side effects.

– It is possible to have significant improvementof the facial photodamaged skin after just onesession.

– The Er:YAG highest coefficient of absorptionfor water, the smallest penetration depth, thesmallest thermal dissipation effects.

– Deeper thermal effects can be achievedthrough pulse widths variations.

References

Campos V, de Mattos RA, Fillippo A, Torezan LA. Laserno rejuvenescimento facial. Surg Cosmet Dermatol.2009;1(1):29–36.

Diaci J, Gaspirc B. Comparison of Er:YAG and Er, Cr:YSGG lasers used in dentistry. J Laser Heal Acad.2012;2012(1):1–13.

El-Domyati M, Abd-El-Raheem T, Abdel-Wahab H,Medhat W, Hosam W, El-Fakahany H, et al. Fractionalversus ablative erbium:yttrium-Aluminum-garnet laserresurfacing for facial rejuvenation: an objective evalu-ation. J Am Acad Dermatol [Internet]. 2013;68(1):

103–12. Available from: https://doi.org/10.1016/j.jaad.2012.09.014.

El-Domyati M, Abd-El-Raheem T, Medhat W, Abdel-Wahab H, Al AM. Multiple fractional erbium:yttrium-aluminum-garnet laser sessions for upperfacial rejuvenation: clinical and histological implica-tions and expectations. J Cosmet Dermatol. 2014;13(1):30–7.

Goldberg DJ, Hussain M. A study of multiple full-facetreatments with low-energy settings of a 2940-nm Er:YAG fractionated laser. J Cosmet Laser Ther [Internet].2011;13(2):42–46. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21401375

Hammami Ghorbel H, Lacour J-P, Passeron T. Treatmentof inflammatory linear verrucous epidermal nevus with2940 nm erbium fractional laser. J Eur Acad DermatolVenereol JEADV England. 2014;Vol. 28:824–5.

Holcomb JD. Versatility of erbium YAG laser: from frac-tional skin rejuvenation to full-field skin resurfacing.Facial Plast Surg Clin N Am [Internet] 2011 May;19(2):261–73. Available from: https://doi.org/10.1016/j.fsc.2011.04.005

Jang H-J, Hur E, Kim Y, Lee S-H, Kang NG, Yoh JJ. Laser-induced microjet injection into preablated skin for moreeffective transdermal drug delivery. J Biomed Opt.2014;19(11):118002.

Janik JP, Markus JL, Al-dujaili Z, Markus RF. Laserresurfacing. Semin Plast Surg. 2007;1(212):139–46.

Karsai S, Czarnecka A, Junger M, Raulin C. Ablativefractional lasers (CO(2) and Er:YAG): a randomizedcontrolled double-blind split-face trial of the treatmentof peri-orbital rhytides. Lasers Surg Med. 2010 Feb;42(2):160–7.

Kim SG, Kim EY, Kim YJ, Lee II S. The efficacy andsafety of ablative fractional resurfacing using a 2,940-nm Er:YAG laser for traumatic scars in the early post-raumatic period. Arch Plast Surg. 2012;39(3):232–7.

Lapidoth M, Yagima Odo ME, Odo LM. Novel use oferbium:YAG (2,940-nm) laser for fractional ablativephotothermolysis in the treatment of photodamagedfacial skin: a pilot study. Dermatol Surg. 2008;34(8):1048–53.

Lee HM, Haw S, Kim JE, Won CH, Lee MW, Choi JH,et al. A fractional 2940 nm short-pulsed, erbium-dopedyttrium aluminium garnet laser is effective and mini-mally invasive for the treatment of photodamaged skinin Asians. J Cosmet Laser Ther [Internet]. 2012;14(6):253–259. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23057489

Matjaz Lukac, Tom Sult, Robin Sult. New options andtreatment strategies with the VSP erbium YAG aes-thetics lasers. 2007;2007(1):1–9.

Lukac M, Vizintin Z, Kazic M, Sult T. Novel fractionaltreatments with VSP erbium YAG aesthetic lasers.J Laser Heal Acad. 2008;2008(6):1–12.

Lukac M, Perhavec T, Karolj Nemes UA. Ablation andthermal depths in VSP Er:YAG laser skin resurfacing.J Laser Heal Acad. 2010;1(1):56–71.

150 A. de Almeida Filippo et al.

Manstein D, Herron GS, Sink RK, Tanner H, AndersonRR. Fractional photothermolysis: a new concept forcutaneous remodeling using microscopic patterns ofthermal injury. Lasers Surg Med. 2004;34(5):426–38.

Papadavid E, Katsambas A. Lasers for facial rejuvenation:a review. Int J Dermatol. 2003 Jun;42(6):480–7.

Sklar LR, Burnett CT, Waibel JS, Moy RL, OzogDM. Laser assisted drug delivery: a review of an evolv-ing technology. Lasers Surg Med. 2014;46(4):249–62.

Skovbolling Haak C, Illes M, Paasch U, Haedersdal M.Histological evaluation of vertical laser channels fromablative fractional resurfacing: an ex vivo pig skinmodel. Lasers Med Sci. 2011;26(4):465–71.

Taudorf EH, Haak CS, Erlendsson AM, Philipsen PA,Anderson RR, Paasch U, et al. Fractional ablativeerbium YAG laser: histological characterization of rela-tionships between laser settings and micropore dimen-sions. Lasers Surg Med. 2014 Apr;46(4):281–9.

Erbium Laser for Photorejuvenation 151

Erbium Laser for Scars and StriaeDistensae

Paulo Notaroberto

AbstractScars are a very common complication of skininjuries such as burns, surgeries, and trauma (lac-erations or abrasions) affecting millions of peopleevery year. The appearance of scars can be verydisturbing to patients both physically and psycho-logically being aesthetically unacceptable andimpacting negatively on the quality of life. Treat-ment of scarringmay requiremanydifferent kindsof treatments, depending on the kind of scarringpresent; however skin vaporization and residualthermal damage can only be achieved by ablativelasers and explain the superiority of ablative lasertreatment over chemical peels and dermabrasion.The present chapter addresses the issue of ablativeErbium (Er:YAG) laser which is highly absorbedbywater and togetherwith the possibility of beingmodulated byvariations on pulse durationsmakesit a precise, safe, and effective tool on managingscars. The aims of ablative Erbium laser ontreating atrophic scars are reducing the depths ofthe scar borders and stimulating neocollagenesisto fill depressions.

KeywordsLaser • Erbium • Ablative • Ablation •Resurfacing • Scar • Striae distensae • Stretchmark

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153

Erbium 2,940 nm Photothermal Ablation . . . . . . . . 154

Protocols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156Resurfacing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156Post-trauma Scars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156Acne Scars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156Hypertrophic Scars and Keloids . . . . . . . . . . . . . . . . . . . . . 158Burn Scars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159Stretch Marks (Striae Distensae) . . . . . . . . . . . . . . . . . . . . 159

Post-Procedure Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160

Complications and Side Effects . . . . . . . . . . . . . . . . . . . . 160

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162

Take Home Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163

Introduction

Scars are a very common complication of skininjuries such as burns, surgeries and trauma (lac-erations or abrasions) affecting millions of peopleevery year. The appearance of scars can be verydisturbing to patients both physically and psycho-logically (Harithy and Pon 2012) being aestheti-cally unacceptable and impacting negatively onthe quality of life. Scars can also cause pruritus,tenderness, pain, sleep disturbance, anxiety, anddepression in postsurgical patients (Oliaei et al.2012).

Acne is a common disorder that affects up to80% of the people with age ranging between

P. Notaroberto (*)Serviço de Dermatologia, Hospital Naval Marcílio Dias,Rio de Janeiro, Brazile-mail: paulo.notaroberto@yahoo.com.br

# Springer International Publishing AG 2018M.C.A. Issa, B. Tamura (eds.), Lasers, Lights and Other Technologies, Clinical Approaches and Procedures inCosmetic Dermatology 3, https://doi.org/10.1007/978-3-319-16799-2_10

153

11 and 30 years (Oliaei et al. 2012; Fife 2011;Al-Saedi et al. 2014) and over 90% among ado-lescents (Fabbrocini et al. 2010). Several factorsare related in the pathogenesis of acne, but thesevere inflammatory response involved in theprocess may result in permanent scars, an unfor-tunate complication of acne vulgaris: permanentscar (Fife 2011). The incidence of acne scarringis not well studied, but it may occur to somedegree in 95% of patients with acne vulgaris.Studies report the incidence of acne scarring inthe general population to be 1–11%. Having acnescars can be emotionally and psychologicallydistressing to patients. Acne scars may be linkedto poor self-esteem, social ostracism, withdrawalfrom society, depression (Al-Saedi et al. 2014),anxiety, altered social interactions, body imagealterations, lowered academic performance, andunemployment and is a risk factor for suicide(Fife 2011).

There is no general consensus in the literatureas to what is the best treatment (Harithy and Pon2012). In the last 15 years, laser resurfacing hasemerged at the forefront of acne scar treatment.The first lasers to be used for acne scarring werethe ablative CO2 and Er:YAG lasers, which emitradiation at wavelengths of 10,600 and 2,940 nm,respectively; having high affinity for water, theyablate the epidermis and stimulate collagen syn-thesis (Hession and Grabber 2015) (see chapter▶ “CO2 Laser for Scars,” this volume). Deter-mining which laser system to use depends uponthe type and severity of acne scarring, the amountof recovery a patient can tolerate, and the ulti-mate goals and expectations of each patient(Sobanko and Alster 2012). No treatment is100% effective on “erasing” scars, and the bestresult is improvement, not perfection. Treatmentof scarring may require many different kinds oftreatments, depending on the kind of scarringpresent (Keyal et al. 2013); however, skin vapor-ization and residual thermal damage can only beachieved by ablative lasers and explain the supe-riority of ablative laser treatment over chemicalpeels and dermabrasion (Alster and Zaulyanov-Scanolon 2007).

The clinician who deals with scar treatmentmust understand the pathophysiology of scar for-mation. The process of wound healing is didacti-cally separated in three stages: inflammation,proliferation, and maturation (Harithy and Pon2012; Fabbrocini et al. 2010). By examiningbiopsy specimens of acne lesions from the backof patients with severe scars and without scars,Holland et al. found that the inflammatory stagewas stronger and had a longer duration in patientswith scars versus those without (Fabbrocini et al.2010).

Erbium 2,940 nm PhotothermalAblation

Erbium (Er:YAG) laser is a flashlamp-excitedsystem that emits light at an invisible infraredwavelength of 2,940 nm. The chromophore forablative lasers is water. It is not an exaggeration toaffirm that the laser target is the skin per se oncethe skin is made up of approximately 80% ofwater. Erbium 2,940 nm wavelength light isbetween 12 and 18 times better absorbed by tissuewater when compared to the 10,600 nm wave-length emitted by the CO2 laser. The first gener-ation of Erbium was approved for cutaneousresurfacing by the FDA (Food and Drug Admin-istration) in 1996 (Riggs et al. 2007), and it worksemitting a short pulse (SP) of 250–350 μs that isless than the thermal relaxation time of the skin,which is 1 ms (Al-Saedi et al. 2014). The ablationthreshold of the first-generation Er:YAG laser forhuman skin has been calculated at 1.6 J/cm2 ascompared with 5 J/cm2 calculated for high-energy, short-pulse CO2 laser systems. Becausethe Er:YAG laser is so exquisitely absorbed bywater, the SP Erbium laser causes 10–40 μm oftissue ablation and as little as 5 μm of thermaldamage on the surrounding tissue (Al-Saedi et al.2014). The second generation of Erbium lasershas variable and longer pulses (500 μs–10 ms)and was FDA approved in 1999. Longer-pulsedEr:YAG lasers have shown to increase the

154 P. Notaroberto

underlying thermal effect zone to approximately120 μm (Lukac et al. 2010), leading to coagulationand skin tightening but increasing risk of second-ary side effects such as erythema and dyschromia(hypo- and hyperchromia) (Alster and Zaulyanov-Scanolon 2007). Side effects and complicationsafter Er:YAG laser resurfacing are similar to thoseobserved after CO2 laser skin resurfacing, but theyuse to have less severe in duration, incidence, andintensity (Keyal et al. 2013; Alexiades-Armenakas et al. 2008).

Resurfacing lasers are high-energy pulsed lasersthat generate photothermal ablation that occurswith rapid heating when tissue absorbs enoughlaser energy leading to tissue vaporization. Thethermal effect also occurs in the area surroundingthe ablated zone due to thermal diffusion and (zoneof thermal damage). Modulated Erbium lasers withlonger pulse durations result in larger areas of ther-mal coagulation when compared to the first-generation SP Er:YAG 2,940 nm laser devices(Carrol and Humphreys 2006). Panzer and Golbergconducted a study on the histologic effect of avariable-pulsed Er:YAG laser and concluded thatthe thermal effect desired from CO2 can beobserved by using longer (50 ms pulse width) Er:YAG laser pulses (Pozner and Goldberg 2000;Khatri 2001). The ablative Erbium laser producesmoderate immediate intraoperative contraction, butsubsequentwound healing results in dermal shrink-age identical to that seen with CO2 ablative laserdevices (Sapijaszko and Zachary 2002).

Response rates to the first-generation short-pulse Er:YAG lasers ranged from 25% to 90%(Fabbrocini et al. 2010). In order to addressthese shortcomings, longer-pulsed Er:YAG laserswere developed. In a prospective study of35 patients with pitted acne scars, results wereexcellent (>75% improvement) in 36% ofpatients and good (50–75% improvement) in57% (Hession and Grabber 2015).

The combination of short pulses (for ablation)with longer pulses (for coagulation) is called dualmode Er:YAG, and the systems working this wayrange pulse durations from 500 μs to 10 ms. As agroup, these lasers have been shown to produce

deeper tissue vaporization, greater control of hemo-stasis, and collagen shrinkage leading to clinicalskin tightening. This translates into greater clinicalimprovement in mild to moderate acne scars thantheir short-pulsed predecessors and thus represent agood compromise between CO2 and the Er:YAGlaser from the first generation (Keyal et al. 2013).

The aims of ablative laser on treating atrophicscars are reducing the depths of the scar borders andstimulating neocollagenesis to fill depressions.Focused vaporization can be used for treating iso-lated scars, but performing the treatment over anentire cosmetic unit (field treatment) is highlyrecommended for increasing the overall collagentightening effect which promotes improvement ofdistensible scars. Field treatment also decreases thechance of a sharp demarcation between treated anduntreated sites (Alster and Zaulyanov-Scanolon2007). A feather treatment using gentler energyshould be performed on the periphery of the treatedarea with the goal of smoothing the transitionbetween treated and untreated areas.

The concept of ablative fractional photo-thermolysis (AFP) was introduced in 2003 as anoption for low-risk, short downtime and effectiveresurfacing techniques. Fractionated lasers workby thermally altering a “fraction” of the skin,leaving up to 95% of skin untouched, leading toa faster healing, shorter downtime, and lessadverse effects in comparison to non-fractionalablative laser devices (Loesch et al. 2014; Zgavecand Stopajnik 2014). AFP induces small three-dimensional zones of thermal damage known asmicroscopic treatment zones (MTZs) (Harithyand Pon 2012). In spite of not ablating a largesurface, AFP generates MTZs which are real “col-umns of heat” capable of generating collagencontraction (skin tightening) and inflammationwhich stimulates neocollagenesis. For AFP, thedepth of penetration is directly proportional tothe energy delivered in each MTZ, and the inten-sity of the treatment increases at the same rate thatthe density of spots is increased. Densities can bereported as either percentage of laser coverage in atreated area or number of MTZs per square centi-meter (Harithy and Pon 2012).

Erbium Laser for Scars and Striae Distensae 155

Protocols

Resurfacing

The treatment must be planned, executed, andfollowed up carefully in order to maximize resultsand minimize adverse effects.

The skin must be prepared with topical use ofglycolic acid or tretinoin associated with vitaminC at least 1 month prior performing the procedure.The topical use of hydroquinone on darker photo-types on the pretreatment period to minimize therisk of residual hyperchromia is not a consensus.All the patients should be advised about the needto use sunscreens with very high UVA and UVBprotection and to avoid sun exposure pre- (at least1 month) and posttreatment (at least 2 months).

Oral prophylactic anti-herpetic therapy regi-men should be started 2 days prior the procedureand must be sustained for 5 days, and it is manda-tory whenever there is a previous history of herpessimplex or when an aggressive treatment will beperformed (especially if the treatment affects theperi-oral area). The prophylactic antibiotic ther-apy is required when a non-fractional ablativetreatment will be performed.

Topical anesthesia used to be enough for paincontrol, but oral pain reliefs (such as trometamolketorolac), infiltrative anesthesia, or nerve blockscan be necessary. The use of corticosteroids (top-ically or orally) can reduce erythema and edemaon the posttreatment period, but its use is quitecontroversial because many doctors believe itmay prejudice the final outcome once the neo-collagenesis is mainly due to inflammation.

Ointments such as petrolatum must be usedduring the period of reepithelialization, whichtakes 2 or 3 days depending on the treatmentintensity.

Post-trauma Scars

Kim et al. conducted a prospective trial enrollingof 12 patients of Fitzpatrick skin types III–V with15 scars resulting from face trauma and repair bysuturing on the day of the trauma. Fractionated Er:YAG laser (LOTUSII, Laseroptek, Sungnam,

Korea) treatment was initiated at least 4 weeksafter the primary repair of the wound, and eachpatient underwent four sessions with 1 monthintervals. Two passes combining short (0.35 ms)and long (1 ms) pulses were performed in eachsession, and all the patients were submitted to thesame parameters of pulse and energy. This Koreanstudy demonstrated that ablative fractional Er:YAG laser treatment improved scars based onobjective results and patient satisfaction rates(Kim et al. 2012).

A study carried out in University of Verona(Italy) by Dr. Nocini et al. enrolled ten patientswith scarring after unilateral and bilateral cleft lipsurgery. All the subjects underwent four passescombining different depths of ablation and coag-ulation (first pass, 100 μm ablation without coag-ulation; second pass, 80 μm ablation, 50 μmcoagulation; third pass, 60 μm ablation, 25 μmcoagulation; and fourth pass, 40 μm ablation tosmooth the margins of the surgical area) per ses-sion. The authors related a clinical improvementof the non-fractional Er:YAG laser (Contour,Sciton, Palo Alto, California, USA)-treated scarsafter the first treatment, with continued improve-ment after the second laser session (Nocini et al.2003).

Acne Scars

Acne scarring can occur as a result of damage tothe skin during the healing of active acne and canbe classified into three different types dependingon whether there is a net loss or gain of collagen:atrophic, hypertrophic, or keloid. Atrophic acnescars are by far the most common type ragingbetween 80% and 90% of total acne scars andare divided into ice pick, boxcar, and rollingscars. Regarding atrophic scars, the ice pick typerepresents 60–70% of total scars, the boxcar20–30%, and rolling scars 15–25%. Ice pick scaris a narrow (less than 2 mm) punctiform and deepscar which does not undergo visible alterationwhen stretching the skin, and, typically, the open-ing is typically wider than the deeper infundibu-lum forming a “V” shape. Rolling scar is a resultof dermal tethering of the dermis to the

156 P. Notaroberto

subcutaneous tissue, and they are usually widerthan ice picks ranging 4–5 mm. These scars give arolling or undulating appearance to the skin andused to improve clinical appearance when beingdistended. Boxcar scar is round or oval and well-established vertical edges are known. These scarstend to be wider at the surface than an ice pick scarand do not have the tapering V shape. Instead,they can be visualized as a “U” shape with a widebase and can be shallow or deep (Fabbrocini et al.2010). Often the three different types of atrophicscars can be observed in the same patients, and itcan be very difficult to differentiate between them.As the skin ages, the appearance of acne scarsoften worsens due to a relative weakness in thedermis rather than fading (Fife 2011; Weinstein1999).

The pathogenesis of atrophic acne scarring isnot completely understood but is most likelyrelated to inflammatory mediators and enzymaticdegradation of collagen fibers. It is not clear whysome acne patients develop scars while others donot, as the degree of acne does not always corre-late with the incidence or severity of scarring.Once scarring has occurred, it is usually perma-nent (Fife 2011). Histologically, post-acne scarsare usually limited to the epidermis and upperpapillary dermis and, thus, amenable to treatmentwith a variety of techniques including ablative andnon-ablative lasers for skin resurfacing (Keyalet al. 2013).

After physical examination, understanding thepatient’s concerns and expectations relating to hisor her acne scars is the next step in the manage-ment of the acne scar and is determinant to thesuccess (Fife 2011).

A study conducted by Woo et al. in the KoreaUniversity included 158 Fitzpatrick skin photo-types III–V volunteers with atrophic acne scarswho were separated in three groups and treatedwith short pulse (350 μs – group 1), long pulse(7 ms – group 2), and dual-mode (350 μs followedby 8 ms – group 3) non-fractional ablative Erbium(2,940 nm) laser. The patients treated with short-pulsed Er:YAG showed a better improvement onthe ice pick scars when compared with the long-pulsed treatment. On the other hand, longer pulsesinduced higher improvement on deep and shallow

box scars and on rolling scar types when com-pared to short-pulse results. The group which wassubmitted to dual mode treatment showed the bestoverall improvement and for each type of scar(Woo et al. 2004). Jeong and Kye from the Uni-versity of Korea treated 35 patients presentingatrophic scars with a long pulsed (10 ms)non-fractional Er:YAG (2.940 nm) laser andobserved an excellent outcome in 36%, a goodin 57%, and fair in 7% (Jeong and Kye 2001).

Deng et al. performed a prospective study inShanghai Jiao Tong University, Shanghai (China),with 26 patients presenting moderate to severeatrophic acne scarring. Five treatment sessionswith a fractional Erbium laser device (Pixel2,940, Harmony, Alma Lasers, Ltd., Caesarea,Israel) and fluences ranging from 800 to1,400 mJ/cm2 at a 49 MTZ/cm2 and long-pulseduration (2 ms) were applied to the treated areausing 8–10 passes, with minimal discomfort andinsignificant collateral effects. The authorsobserved improvement of at least 50% in 100%of all subjects (Deng et al. 2009). Hu et al. fromTaiwan (China) conducted a study enrolling34 volunteers who were submitted to a singlesession of a fractional ablative Er:YAG laser(Profractional-XC, Sciton Inc., Palo Alto, Califor-nia, USA) providing 150 μm of thermal damage.This trial revealed a satisfaction rate of 72.7% ofpatients with minimal side effects (Hu et al. 2011).The fractional ablative Erbium treatment com-bines the gentleness of the fractional techniquewith a more intense coagulation mode promotingremarkable skin remodeling and dermal tighten-ing. Nirmal et al. from India performed a clinicaltrial including 25 patients and noticed that rollingand superficial box scars showed higher signifi-cant improvement when compared with ice pickand deep box scars after 2 ms pulse durationfractional ablative Er:YAG treatments (Nirmalet al. 2013).

Figures 1a, b and 2a, b illustrate my clinicalexperience with Erbium laser for acne scars treat-ment. These figures show improvement in severeacne scars after 3 treatment sessions with 1-monthineterval between them. A fractional Erbium laserdevice (Pixel 2,940, Harmony, Alma Lasers, Ltd.,Caesarea, Israel) was used with fluences of

Erbium Laser for Scars and Striae Distensae 157

1,400 mJ/cm2 at a 49 MTZ/cm2, long-pulse dura-tion (2 ms), and four overlapping “shots”(stacking).

Often a combination of techniques (e.g., submis-sion or filler injections combined with fractionalresurfacing) will ensure a better result compared toone procedure alone (Fife 2011). Yin et al.performed a prospective study enrolling 40 subjectspresenting severe acne. Patients were treated with15% 5-aminolevulinic acid (ALA) photodynamictherapy and subsequently received ablative frac-tional Er:YAG (2,940 nm) five times at a 4 weeksinterval. After 6 months, the lesions showed overallimprovement in all of subjects (good to excellent inacne inflammatory lesions), 80% overall improve-ment in acne scars. After 12 months, most of sub-jects had improved hypertrophic and atrophic scars(good to excellent in 85%), and no one had recur-rent acne inflammatory lesions. Patient self-evaluation also revealed good to excellent improve-ments (on average) in acne lesions and scarring,with significant improvements in self-esteem after6 months posttreatment. The authors suggested thatthe combination ALA-PDT and fractionalresurfacing Er:YAG is a promising option for the

management of severe acne preventing scar forma-tion (Yin et al. 2014).

Hypertrophic Scars and Keloids

Hypertrophic scars and keloids are not a hallmark onthe indications of ablative lasers. The Er:YAG lasersseem to be more suitable on treating hypertrophicscars and keloids because as it is 12–18 times moreselective for water than CO2 laser due to its shorterwavelength (2,940 nm), it has less residual thermalinjuries and less inflammation (Oliaei et al. 2012;Al-Saedi et al. 2014). Er:YAG at 5 J/cm2 vaporizestissue at depth of 20–25 μm with an additional of5–10 μm zone of thermal necrosis. Er:YAG lasershave showedmoderate improvement of hypertrophic

Fig. 2 Acne scars (lateral view). (a) Pretreatement.(b) Posttreatment 3 months after the third session with1 month of interval between each session

Fig. 1 Acne scars (front view). (a) Pretreatement.(b) Posttreatment 3 months after the third session with1 month of interval between each session

158 P. Notaroberto

scars and keloids. These ablative lasers target waterin the tissue, resulting in tissue vaporization (Harithyand Pon 2012).

Burn Scars

Treatment with ablative full-field CO2 and Er:YAG has been used to treat burn scars but hasbeen associated with prolonged recovery timesand contradicting results. Burn scars, especiallyones that are new, need to be treated gently.Ablative fractional lasers has the capability toact on a well-controlled skin percentage but canstimulate new collagen formation, remodel theburn scar tissue, and subsequently normalize thetexture, elasticity, and color of the scar. Fewcase reports have shown that ablative fractionalresurfacing is safe and effective in treatment ofburn scars; however further studies are neededto determine parameters (Harithy and Pon2012).

Stretch Marks (Striae Distensae)

Strech marks (also called striae distensae) arehistologically characterized as scars; althoughthere was no break in continuity of the epidermis,it demonstrates microscopic evidence of thinningand flattening of the epidermis, a normal ordecreased number of melanocytes, and thinningand retraction of the dermal collagen and elastin(Godberg et al. 2005; Maia et al. 2010). In theearly phase, inflammatory changes are remark-able, but later the epidermis is thin and flattened.Recent stretch marks show a deep and superfi-cial perivascular lymphocytic infiltrate. Colla-gen bands on the upper third of the reticulardermis are stretched and aligned parallel to thesurface of the skin. In the latter stages, there isthinning of the epidermis due to flattening of theepidermal ridges and loss of collagen and elas-tin (Elsaie et al. 2009). Clinically, stretch marksappear as erythematous (striae rubra) on theearly phase or hypopigmented (striae alba), lin-ear, dermal scars with epidermal atrophy on thelate phase.

There are few researches of good qualityfocused on the physiopathology of stretch marks(Cordeiro and Moraes 2009). Although the etiol-ogy of the stretch marks is not well understood, itis accepted that the combination of mechanicalstretching of the skin, genetic, endocrine disor-ders, and possibly secretion of relaxin duringpregnancy, alone or in combination, plays a rolein the physiopathology of striae distensae (Maiaet al. 2010).

The stretch mark treatment is based on stimu-lating neocollagenesis and restoring epidermalarchitecture. The use of ablative technologiessuch as the Erbium laser induces clinical improve-ment on body areas, but almost all patientsdevelop a significant post-inflammatory hyper-pigmentation, especially in darker skin tones.The sequence of Figs. 3, 4, 5, and 6 illustratesthe course of treatment of stretch marks on thethigh area of a type II Fitzpatrick’s skin phototypepatient. A non-franctional Erbium laser device(Fidelis, Fotona Lasers Ltd., Lujbljana, Slovenia)was used with the LP (long pulse) 600 μs pulseduration. Longer-pulse durations induce low abla-tion and intense coagulation and inflammation(Fig. 4). The residual post-inflammatory hyper-chromya is a hallmark of ablation on body areas(Fig. 5) despite the significant final result (Fig. 6).This is the reason that makes the use of sublativeand non-ablative lasers the first options on lasersfor managing stretch marks.

Fig. 3 Stretch marks (striae distensae) on the thigh area,pretreatment

Erbium Laser for Scars and Striae Distensae 159

Post-Procedure Care

The ablative laser procedure does not end whenthe surgical act is finalized. The post-procedurecare is an important subjacent part to guaranteethe expected aesthetic result, accelerating thehealing process with a smooth recovery, avoidingcomplications. Open wound care is performedwith frequent application of ointments on the sur-face of the treated area, while the occlusiveapproach requires the use of occlusive bandages.Open and closed wound care helps to control painand accelerates the healing process. Unlike opendressings, occlusive bandages increase the risk ofinfection (Costa et al. 2011) and do not allowvisualization of the wound.

Pain can be controlled with cold compresses orcold-water sprays (Costa et al. 2011) most of thetimes. Effective pain control can be achieved withthe use of oral analgesics (paracetamol, codeine)combined or not with an anxiolytic (lorazepan)(Costa et al. 2011). Edema can be managed withthe application of ice bags or cold water com-presses, but use of an oral (40–60 mg prednisonedaily for a variable period of 3–5 days) or intra-muscular corticosteroid can be useful in isolatedcases (Oliaei et al. 2012; Costa et al. 2011).Ointments and antihistamines can be used to reliefintense pruritus.

Complications and Side Effects

Ablative lasers induce thermal destruction of theskin with adjacent coagulation area. Thereforesome manifestations are expected and desirablein the post-procedure period. The recovering timedepends on the amount of energy targeted to theskin, the pulse duration, and the delivery system(full ablation or fractional). The healing processafter fractional treatment is significantly fastercompared with full ablative (non-fractional) treat-ment (Zgavec and Stopajnik 2014).

Erythema and minimal crusting whichdisappeared in 7 days are the expected sideeffects after fractional treatment (Zgavec andStopajnik 2014). The mean erythema durationused to be 2 days, and mean crusting is around

Fig. 5 Important post-inflammatory hyperchromia oneafter the first session

Fig. 6 Significant clinical improvement 3 months after asingle session

Fig. 4 Stretch marks (striae distensae) on the thigh area,immediately after the first ablative Erbium session withlong pulse duration

160 P. Notaroberto

5 days (Nirmal et al. 2013). On the other hand,extensive crusting after the treatment with thenon-fractionated handpiece is observed evenafter a 14-day follow-up (Zgavec and Stopajnik2014). Pain evaluated by the patients is milderwhen using fractionated handpieces in compar-ison with full ablative (Zgavec and Stopajnik2014) and disappears until the second day afterthe treatment (Zgavec and Stopajnik 2014;Costa et al. 2011). Pain rarely occurs after thesecond day of the postoperative period and mustbe investigated if it occurs (dryness and infec-tion are common causes) (Costa et al. 2011).

Edema usually varies from mild to moderate,with peaks on the second and the third day, andcan last for up to 1 week (Costa et al. 2011).Edema is usually more intense on the peri-orbitalareas and eyelids. Longer pulse durations withless ablation and more coagulation (deeperheating) usually lead to pronounced edema. Pru-ritus affects more than 90% of patients undergoingablative treatments on the first 2 weeks after pro-cedure, and it is due to the healing process (Costaet al. 2011). Once pruritus is intense and persis-tent, a secondary infection must be investigated.Desquamation and post-fractional, non-ablativelaser xerosis occur in 60% and 87% of cases,respectively (Costa et al. 2011). Purpura canoccur and recover spontaneously (Costa et al.2011).

Viral, bacterial, and fungal infections are raremanifestations that occur during the first post-procedure week and require proper identifica-tion and treatment to avoid further complica-tions (AlNomair et al. 2012) such as persistenteritema or scar formation. Infection must beconsidered when intense or persistent pain,eritema, and edema occur. The most commontype of infection after fractional laser skinresurfacing is caused by HSV and has beenreported in 0.3–2% of cases (Costa et al. 2011;AlNomair et al. 2012). Patients may not presentwith classic herpetiform vesicopustules butinstead may demonstrate only superficial ero-sions that develop during the first week aftertreatment (AlNomair et al. 2012). Given thatmost patients present subclinical levels of HSV,prophylactic use of oral antivirals such as

aciclovir, famciclovir, or valaciclovir is alwaysrecommended preventively in perioral or full-face ablative resurfacing. Prophylaxis with anti-virals taken on regular doses for HSV infectionmust start 1 or 2 days before the laser procedureand continue until the skin is completely healed.Prophylaxis notwithstanding, herpetic infectionsometimes does occur. In such cases, doses oforal antivirals equivalent to those used intreating the herpes zoster virus must be used(Zhang and Obagi 2009). Rates of bacterialinfection in traditional resurfacing tend to below (0.5–4.5% of cases) and even rare whenfractional, non-ablative lasers are used, occur-ring in only 0.1% of cases (Costa et al. 2011;AlNomair et al. 2012). Studies suggest that mostbacterial infections related to laser ablationoccur with the use of occlusive bandages onthe post-procedure period (Costa et al. 2011).When infection is suspected, secretions mustbe cultured, and an antibiogram test must becarried out and a wide-spectrum systemic anti-biotic (penicillin, first-generation cephalosporinor ciprofloxacin) is administered while waitingfor the results from the bacterial culture andantibiogram (Costa et al. 2011).

Candida albicans is the most frequent agentrelated to fungal infections occurring after skin abla-tion, and the infection starts between the first and thesecond weeks of the post-procedure period. Patientspresenting pruritus, pain, and whitish erosions on ahighly erythematous base as well as satellite lesionsoutside the treated area must be suspected to havefungal infection. A direct mycological examinationand culture for fungusmust be performed if infectionis suspected (Costa et al. 2011).

Acneiform eruptions have been described as afrequent complication of fractional skinresurfacing, and it can be a result of an aberrantfollicular epithelialization during healing or sec-ondary to the use of ointments during the recoverytime (Costa et al. 2011; AlNomair et al. 2012).The development of milia cysts has been reportedin as many as 19% of cases (AlNomair et al. 2012)and appears between 3 and 8 weeks after lasertreatment as a consequence of the use of occlusivebandages, oils, or creams during the healing pro-cess (Costa et al. 2011).

Erbium Laser for Scars and Striae Distensae 161

Post-inflammatory hyperpigmentation (PIH)after skin resurfacing can be transient or longlasting and is one of the most common post-ablative resurfacing complication (Costa et al.2011). Hyperpigmentation is much less fre-quent with fractional laser skin resurfacingthan with full-ablative resurfacing but isobserved in 1–32% of patients, depending onthe system used, parameters applied, and skinphototypes treated (AlNomair et al. 2012).Patients with darker skin phototypes(Fitzpatrick III–VI) or melasma have a higherlikelihood of developing post-inflammatoryhyperpigmentation (Costa et al. 2011;AlNomair et al. 2012). Some studies relate upto 68% of hyperpigmentation after skin abla-tion (Costa et al. 2011). Patients prone todevelop PIH must be prepared during the3 months prior to the procedure with a combi-nation of hydroquinone and glycolic acid ortretinoin or hydroquinone cream used alonebesides the use of sunscreens (Costa et al.2011). PIH must be treated as soon as possibleavoiding aggressive approaches beforereepithelialization is complete as they canworsen the condition (Costa et al. 2011). Theregular use of wide-spectrum sunscreen andavoiding exposure to the sun for at least 6 or8 weeks before and after the procedure areimportant on preventing PIH development(Costa et al. 2011). In addition to sunscreen,blemish agents such as hydroquinone, tretinoinand kojic, azelaic, and glycolic acids are alsofirst-line treatments. Superficial chemical peelsand microdermabrasion can be used to acceler-ate the whitening response (Costa et al. 2011).

Scarring is another known and rare complica-tion of fractional ablative resurfacing (AlNomairet al. 2012) with serious and devastating conse-quences (Costa et al. 2011) on the aesthetic finalresult. It is a more frequent complication in theCO2 laser when compared to the Erbium laserskin resurfacing. There are several potentialexplanations for hypertrophic scarring, includingthe use of excessively high-energy densities, post-operative infection of the skin, and lack of

technical skills. The neck is a well-recognizedsite that is especially susceptible to the develop-ment of scarring and synechia because of thesmall number of pilosebaceous units and poorvasculature in this region, which are essential forwound healing. In addition, the thin skin of theneck renders it more susceptible to thermal injury.Other scar-prone anatomic locations that requiremore conservative treatment protocols include theperiorbital, mandibular regions, chest, and otherareas over bony prominences (Fife 2011).

Conclusion

Ablative Erbium laser is highly absorbed by waterand together with the possibility of being modu-lated by variations on pulse durations makes it aprecise, safe, and effective tool on managingscars.

Take Home Messages

• Erbium (Er:YAG) laser is a flashlamp-excitedsystem that emits light at an invisible infraredwavelength of 2,940 nm, and it is highlyabsorbed by water.

• Erbium (Er:YAG) can be modulated by varia-tions on pulse durations making it a precise,safe, and effective tool on managing scars.

• The aims of ablative Erbium laser on treatingatrophic scars are reducing the depths of thescar borders and stimulating neocollagenesis tofill depressions.

• No treatment is 100% effective on “erasing”scars, and the best result is improvement, notperfection.

• Treatment of scarring may require many dif-ferent kinds of treatments, depending on thekind of scarring present; however skin vapori-zation and residual thermal damage can onlybe achieved by ablative lasers and explain thesuperiority of ablative laser treatment overchemical peels and dermabrasion.

162 P. Notaroberto

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Erbium Laser for Scars and Striae Distensae 163

CO2 Laser for Photorejuvenation

Jackson Machado-Pinto and Michelle dos Santos Diniz

AbstractThe CO2 laser is a powerful tool in the fightagainst aging including extrinsic aging. Theoperation of this laser is based on the principleof selective photothermolysis. Water is themain target of CO2 lasers operating at a wave-length of 10.600 nm, in the infrared portion ofthe electromagnetic spectrum. The rejuvena-tion observed after CO2 laser treatment is theresult of several phenomena that occur afterlaser interaction with the skin: collagen con-traction and neocollagenesis, photodamagedskin removal, and peripheric thermal damage.The most frequent complications are infec-tions, hypo- and hyperchromia, synechiae,and scarring. Fractionation of lasers greatlydiminished the risk of complications that aremore frequent in more aggressive treatmentsand when the laser is applied to non-facialareas. Although several devices and techniquesto treat photodamaged skin have been devel-oped, resurfacing with the CO2 laser remainsthe gold standard for the treatment ofphotoaged skin.

KeywordsLasers • Carbon dioxide • CO2 laser • Laserablation • Photorejuvenation • Adverse effects

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165

CO2 Laser for Photorejuvenation . . . . . . . . . . . . . . . . . 166Basic Concepts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166Indications and Contraindications . . . . . . . . . . . . . . . . . . . 167Laser Procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167

Side Effects and Their Management . . . . . . . . . . . . . . 167

Take Home Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169

Introduction

The CO2 (carbon dioxide) laser is a powerful toolagainst aging, including extrinsic aging thatincludes the cutaneous signs of aging that are notrelated to age, but to external factors the mostimportant of which are chronic sun exposure andsmoking. Contrary to what occurs with chemicalpeels, the CO2 laser allows an abrasion withstrictly controlled depth, which makes laser abra-sion or resurfacing a safer procedure that, in expe-rienced hands, gives the doctor and his patient agreat satisfaction. Although a variety of tech-niques and devices to treat photodamaged skinhas been developed, resurfacing with the CO2

J. Machado-Pinto (*)Dermatology, Santa Casa de Belo Horizonte, BeloHorizonte, Brazile-mail: jmsdermatologica@terra.com.br

M. dos Santos DinizSanta Casa de Belo Horizonte, Belo Horizonte, MG, Brazile-mail: michellesdmi@yahoo.com.br

# Springer International Publishing AG 2018M.C.A. Issa, B. Tamura (eds.), Lasers, Lights and Other Technologies, Clinical Approaches and Procedures inCosmetic Dermatology 3, https://doi.org/10.1007/978-3-319-16799-2_11

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laser remains the gold standard for the treatmentof photoaged skin (Duplechain 2013; Kilmer et al.2006; Hafner and Salomon 2006; Hunzeker et al.2009).

CO2 Laser for Photorejuvenation

Basic Concepts

The operation of the CO2 laser is based on theprinciple of selective photothermolysis, devel-oped by Parish and Anderson in 1983. This prin-ciple, which is a direct derivation of quantumtheory, says that, in order to obtain tissue ablation,it is important that the tissue receives a very highamount of energy in a very short time period.Water is the main target of CO2 lasers that operateat a wavelength of 10.600 nm, in the infraredportion of the electromagnetic spectrum. When aCO2 laser beam focuses on the skin, it vaporizesthe affected cells after they experience a tempera-ture rise up to 100 �C in 640 mcs (Omi andNumano 2014). The improvement of the cosmeticappearance observed after resurfacing can beattributed to various factors. The first is tissueablation by direct removal of the upper portionsof wrinkles after each successive laser exposure.This ablation results from the combination of tis-sue vaporization in the treated area that produces athermal coagulation necrosis of the cells belowand thermal denaturation of proteins of the extra-cellular matrix (Khatri et al. 1999). CO2 lasersremove between 25 and 50 um of tissue in eachpass (Weinstein 1998). This means that the clini-cal improvement observed in the wrinkles shouldalso be attributable to other reasons.

During the laser abrasion procedure, immedi-ate contraction of the skin can be observed.Although part of this contraction is due to dehy-dration by water evaporation, the instantaneousretraction of collagen can also occur, since it isknown that collagen shrinks when exposed totemperatures above 60 �C (Fitzpatrick 1996).However, although collagen contraction by dehy-dration or retraction lasts only 14 days afterresurfacing, a continued improvement up to ayear can be seen in patients (Seckel et al. 1998).

This improvement appears to be a result of thedeposition of newly formed collagen and reorga-nization of the dermis, the extent of which appearsto be dependent on the residual thermal damagecaused by the laser (Khatri et al. 1999).

The rejuvenation observed after CO2 lasertreatment is therefore a result of several phenom-ena that occur after laser interaction with the skin:collagen contraction and neocollagenesis, photo-aged skin removal, and peripheral thermal injury(Campos and Gontijo 2010; Omi and Numano2014). It is noteworthy that immediately after theprocedure, collagen contraction occurs, and3–6 months after the laser is applied to the skin,there is a new contraction secondary to theremodeling of collagen (Tierney and Hanke2011). Electron microscopy studies revealed adecrease in the average diameter of collagenfibrils consistent with deposition of collagentype III after performing fractional laser (Berlinet al. 2009).

History

The CO2 laser was one of the first lasers to beused. It was initially developed in 1964 by Pateland colleagues at Bell Labs in the USA. It wasconsidered the ideal laser for surgical treatmentdue to its high affinity for water (Kaplan 2007).

In the early 1990s, the CO2 laser was the big-gest advance among the treatments for epidermalablation and subsequent induction of a new skinwith a more youthful appearance. Later pulsedCO2 with a computerized scanner were usedwith excellent results. These first CO2 laserswere fully ablative and even though they providedextremely satisfactory results, the need for seda-tion, the great down time period, and the greatestrisk of complications such as scarring anddyschromias gave way to fractional resurfacing.

The ablative fractional laser was introduced in2006 and is responsible for localized disruptionsin the epidermis while keeping the skin aroundintact. Fractionation permits deeper layers of theskin to be reached (up to 1,500 um) depending onthe amount of energy delivered to tissue. Despitethe indisputable greater security of fractional laser

166 J. Machado-Pinto and M. dos Santos Diniz

compared to fully ablative CO2, the resultsachieved are not as efficient for rejuvenation andacne scars (Kaplan 2007).

Indications and Contraindications

Skin rejuvenation is the best indication for CO2

laser treatments. It can be used not only on theface but also on extra-facial areas like the neck,chest, hands, and arms due to fractionation.Besides rejuvenation, CO2 laser devices havebeen used to treat several other conditions suchas surgical and acne scars, stretch marks, actinickeratoses, seborrheic keratoses, warts,rhinophyma, sebaceous hyperplasia, nevi, andangiofibromas (Hunzeker et al. 2009; Omi andNumano 2014).

CO2 laser should be used with caution in higherphototypes (IV above) and is contraindicated inblack skin. It should not be done in patients withkeloids, vitiligo, and photosensitizing diseases andin patients with active infections including herpesvirus infections. It should not be done in patientstaking anticoagulants, and it is recommended towait 6 months after completion of oral isotretinoinbefore undergoing CO2 laser treatment.

Laser Procedure

Pre-laserPatients should be carefully oriented about theprocedure. The average downtime from the dailyactivities varies from 3 to 7 days depending on theintensity of treatment. Antiherpetic therapy is par-ticularly necessary in cases of recurrent herpeshistory and when more aggressive parametersare to be used. Either acyclovir, famciclovir, orvalacyclovir can be administered starting 3 daysbefore the procedure and being maintained up to4 days following the procedure or after completeepithelialization has taken place.

During the LaserThe duration of each application depends on theability of the laser surgeon. Care should be takento ensure that the patient is comfortable during the

procedure. Naturally, potent topical anesthesiashould be applied and fully and carefully removedbefore lasing. Often it is necessary to use tumes-cent anesthesia and nerve blockade. Devices thatrelease cold air and application of ice bags on thetreated area can be useful to help the patient tol-erate the treatment.

Post-laserImmediately after the procedure, cold compress ofsaline or thermal water may be used. Healingcreams and vaseline may also be used. The useof topical antibiotics is controversial. Sunscreensand makeup can usually be used after the thirdday. Close monitoring of patients is of the utmostimportance for early identification of any compli-cations (Figures 1, 2 and 3).

Side Effects and Their Management

The incidence of complications was greatlyreduced with the laser fractionation. However,they may still happen especially in moreaggressive treatments and when extra-facialareas are lased (Duplechain 2013; Campos andGontijo 2010). According to Shamsaldeen et al.(2011) and Campbell and Goldman (2010),complications occurred in 15% of the patientstreated.

The most commonly reported complication istransient hyperpigmentation, which takes placebetween 5% and 83% of patients, especiallythose with darker skin (types III and IV on theFitzpatrick classification) (Fitzpatrick et al. 1996).In another series with 749 patients, the most com-mon complication was persistent erythema, whichoccurred in all patients after the laser. After ery-thema, hyperchromia occurred in 32% of thesepatients (Berwald et al. 2004). Hyperpigmentationusually appears between 2 weeks and 2 monthsafter the disappearance of erythema. Dependingon the degree of skin irritation, topical tretinoinand hydroquinone should be started between2 and 6 weeks after the procedure or immediatelyafter completed re-epithelialization, in case ofpost-inflammatory hyperpigmentation (Ratneret al. 1999).

CO2 Laser for Photorejuvenation 167

Infections can also complicate resurfacingbetween 2 and 10 days after the procedure,increasing the risk of hypertrophic scars.S. aureus, P. aeruginosa, S. epidermidis, andCandida sp. are the most common agents. Thepresence of pustules in the early postoperative orpain indicates the need of cultures and anti-biograms to search for these agents. In mice,CO2 laser resurfacing reduces the microbialcount of microorganisms as compared to the

normal skin flora, which can explain the rarityof infectious complications in practice (Manoliset al. 2006). Infection with Candida species canbe controlled with oral or topical antimycoticssuch as itraconazole or fluconazole. Some rec-ommend the systematic use of an imidazolederivative in all patients after the laser. Simi-larly, herpesvirus infections can be seen, usuallyin the first week after the procedure Ratner et al.1999).

Fig. 1 Before and afterCO2 Laser

Fig. 2 Before and afterCO2 Laser

168 J. Machado-Pinto and M. dos Santos Diniz

Hypopigmentation, when it occurs, tends to bea late and permanent phenomenon in extremelyphotoaged patients after the disappearance of ery-thema. There is evidence suggesting that the sup-pression of melanogenesis instead of melanocytesdestruction is the most important mechanism(Helm and Shatkin 2006; Hunzeker et al. 2009.).

Synechiae may occur when two adjacent areashave lost their epithelium and remain in constantcontact during the re-epithelialization process andare more often observed on the upper eyelids. Acneand milia occur in up to 83.5% of patients, espe-cially those with very oily skin and when very thicksunscreen products are used. The most feared com-plication is the formation of hypertrophic scars.They occur only rarely and are usually due toimproper selection of patients for resurfacing, poortechnique, carelessness, or infection in the immedi-ate postoperative period. The more predisposedindividuals are those who were on systemic isotret-inoin up to a year before resurfacing or who havekeloids. Another complication appearing in patientspreviously subjected to blepharoplasty orrhytidectomy is ectropion. Although ectropionmay be transient, it does not always involute spon-taneously and sometimes requires surgical correc-tion (Ratner et al. 1999; Rendon-Pellerano et al.1999) (Figs. 1, 2, and 3).

Take Home Messages

• CO2 laser is the gold standard treatment ofphotodamaged skin.

• CO2 laser has water as a target and operates at awavelength of 10.600 nm.

• CO2 laser promotes collagen contraction andneocollagenesis addition to removing thephotodamaged skin.

• Fractional CO2 laser application is a safe pro-cedure and has a low complication rate.

• Treatment of extra-facial areas may be associ-ated with increased risk of complications.

References

Berlin AL, Hussain M, Phelps R, Goldberg DJ. A prospec-tive study of fractional scanned nonsequential carbondioxide laser resurfacing: a clinical and histopathologicevaluation. Dermatol Surg. 2009;35:222–8.

Berwald C, Levy JL, Magalon G. Complications of theresurfacing laser: retrospective study of 749 patients.Ann Chir Plast Esthet. 2004;49:360–5.

Campbell TM, Goldman MP. Adverse events of fraction-ated carbon dioxide laser: review of 373 treatments.Dermatol Surg. 2010;36:1645–50.

Campos VB, Gontijo G. Fractional CO2 laser: a personalexperience. Surg Cosmet Dermatol. 2010;2:326–32.

Fig. 3 Before and afterCO2 Laser

CO2 Laser for Photorejuvenation 169

Duplechain JK. Fractional CO2 resurfacing: has it replacedablative resurfacing techniques? Facial Plast Surg ClinNorth Am. 2013;21:213–27.

Fitzpatrick RE. Facial resurfacing with the pulsed CO2

laser. Facial Plast Surg Clin. 1996;4:231–40.Fitzpatrick RE, GoldmanMP, Satur NM, TopeWD. Pulsed

carbon dioxide laser resurfacing of photoaged facialskin. Arch Dermatol. 1996;132:395–402.

Hafner K, Salomon D. The role of surgery in the treat-ment of acne scars. Rev Med Suisse.2006;26:1100–3.

Helm T, Shatkin Jr S. Alabaster skin after CO2 laserresurfacing: evidence for suppressed melanogenesisrather than just melanocyte destruction. Cutis.2006;77:15–27.

Hunzeker CM,Weiss E, Geronemus RG. Fractionated CO2

laser resurfacing: our experience with more than 2000treatments. Aesthetic Sur J. 2009;29:317–22.

Kaplan I. The CO2 laser as a versatile surgical modality.Laser Ther. 2007;16(1):25–38.

Khatri KA, Ross EV, Grevelink JM, Magro CM, AndersonRR. Comparison of erbium: YAG and carbon dioxidelasers in resurfacing of facial rhytides. Arch Dermatol.1999;135:391–7.

Kilmer SL, Chotzen VA, Silva FK, McClaren ML. Safeand effective carbon dioxide laser skin resurfacing ofthe neck. Lasers Surg Med. 2006;38:653–7.

Manolis EM, Tsakris A, Kaklamanos E, Markogiannakis A,Siomos K. In vivo effect of carbon dioxide laser-skinresurfacing andmechanical abrasion oin the skin’smicro-bial flora in an animal model. Dermatol Surg.2006;32:359–64.

Omi T, Numano K. The role of the CO2 laser and fractionalCO2 laser in dermatology. Laser Ther. 2014;23(1):49–60.

Ratner D, Yardy T, Marchell N, Goldman MP, FitzpatrickRE, Fader DJ. Cutaneous laser resurfacing. J Am AcadDermatol. 1999;41:365–89.

Rendon-Pellerano MI, Lentini J, Eaglstein WE, Kirsner RS,Hanft K, Pardo RJ. Laser resurfacing: usual and unusualcomplications. Dermatol Surg. 1999;25:360–7.

Seckel BR, Younai S, Wang K. Skin tightening effects ofthe ultrapulse CO2 laser. Plast Reconstr Surg.1998;102:872–7.

Shamsaldeen O, Peterson JD, Goldman MP. The adverseevents of deep fractional CO(2): a retrospective studyof 490 treatments in 374 patients. Lasers Surg Med.2011;43:453–6.

Tierney EP, Hanke CW. Fractionated carbon dioxide lasertreatment of photoaging: prospective study in45 patients and review of the literature. DermatolSurg. 2011;37:1279–90.

Weinstein C. Carbon dioxide laser resurfacing: long termfollow-up in 2123 patients. Clin Plast Surg.1998;25:109–30.

170 J. Machado-Pinto and M. dos Santos Diniz

CO2 Laser for Stretch Marks

Guilherme Almeida, Elaine Marques, and Rachel Golovaty

AbstractStretch marks or striae distensae (SD) are awell-recognized, common dermatologic entity,which affect patients of all ages, genders, andethnicities and rarely cause any significantmedical problems but can have a deep psycho-logical impact on affected patients. Risk fac-tors have been reported, but much remains tobe understood about their epidemiology.Although there is no standard treatment forSD, many topical applications, peeling, light,and laser systems, have been tried. Consider-ing the many modalities used to improve SD,lasers have recently become a popular thera-peutic alternative. The aim of this chapter is todiscuss the causes and possible treatmentsdescribed in literature, to approach the clinicalefficacy and safety of fractional CO2 laser inthe treatment of SD, and to show 5 years of ourexperience using this device.

KeywordsStretch marks • Striae distensae • Striae rubra •Striae alba • Striae atrophicans • Striaegravidarum • Laser therapy • Light therapy •Acid peel treatments • Collagen injection •Laser lipolysis • Radiofrequency • Micro-dermabrasion • Nonablative lasers • Fractionallaser resurfacing

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171

Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172

Histopathogenesis of Striae Distensae . . . . . . . . . . . . . 173

Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174

Lasers and Light Devices . . . . . . . . . . . . . . . . . . . . . . . . . . 174

Author Experience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178

Take Home Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179

Introduction

Roederer first described striae in 1773, and Troisierand Menetrier made the first histological descrip-tions in 1889 (Troisier and Ménétrier 1889). Striaedistensae (SD), also denominated stretch marks(SM), striae rubra, striae alba, striae atrophicans,striae gravidarum (SG), are a well-recognized com-mon dermatologic entity, which affect patients of all

G. Almeida (*)Department of Dermatology, Hospital Sirio Libanes,Brazil – Private office: Clinica Dermatologica DrGuilherme de Almeida, Sao Paulo, Brazile-mail: dermaalmeida@uol.com.br

E. Marques • R. GolovatyClinica Dermatologica Dr Guilherme de Almeida, SaoPaulo, Brazile-mail: elainedermato@gmail.com;rachelaqueiroz@hotmail.com

# Springer International Publishing AG 2018M.C.A. Issa, B. Tamura (eds.), Lasers, Lights and Other Technologies, Clinical Approaches and Procedures inCosmetic Dermatology 3, https://doi.org/10.1007/978-3-319-16799-2_12

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ages, genders, and ethnicities. SD is common inadolescence, pregnancy, and obesity. Themost com-monly affected sites are the breasts, upper arms,abdomen, buttocks, and thighs. Initially, SD presentas edematous red or pink linear plaques called striaerubra. Over time, the color fades, and the lesionsbecome hypopigmented, atrophic, and permanent(striae alba). It is rarely caused by systemic diseasesbut commonly represents a deep psychologicalimpact on affected patients (Al-Himdani et al.2014; Watson et al. 1998; Ud-Din et al. 2016).

SD is a known feature of several clinical con-ditions, both chronic and acute, with very distinctpathophysiology (e.g., pregnancy, adolescentgrowth spurts, obesity, large weight gain, Cushingsyndrome, Marfan syndrome, diabetes mellitus,long-term systemic or topical steroid use), makingit difficult to determine their true etiology. MostSD research has focused on pregnant women andadolescents. A positive family history is a riskfactor in both of these groups alike. Among ado-lescents, BMI and childhood obesity both influ-ence risk of developing SD (Troisier andMénétrier 1889).

Epidemiology

The prevalence of SD reported in the literaturevaries a lot, ranging from 6% to 88% (Cho et al.2006; Sisson 1954; Kelekci et al. 2011; Thomasand Liston 2014; Chang et al. 2014; Ghasemi et al.2017; Osman et al. 2017; Davey 1972; Elton andPinkus 1966; García-Hidalgo et al. 1999; García-Hidalgo 2002). The prevalence ranges from 6% to86% in adolescents and from 43% to 88% inpregnant women (Cho et al. 2006; Chang et al.2014; Ghasemi et al. 2017; Osman et al. 2017;Atwal et al. 2006; Canpolat et al. 2010; Maia et al.2009; Jaramillo-Garcia et al. 2009; Cohen et al.1997). Among obese individuals with a BMI of27–51, the prevalence is reported to be 43%(García-Hidalgo et al. 1999). The prevalenceamong nonpregnant women and adult malevaries a lot in literature (Kelekci et al. 2011;

Elton and Pinkus 1966; Cohen et al. 1997; Mur-phy et al. 1992). Risk factors in pregnant womenmay be constitutional (maternal age and BMI)or pregnancy related (birth weight, gestationalage, weight gain during pregnancy, and poly-hydramnios) (Ghasemi et al. 2017; Osman et al.2017; Atwal et al. 2006; Canpolat et al. 2010;Murphy et al. 1992).

Many risk factors have been suggested for thedevelopment of SG, such as pregnancy maternalweight (Ersoy et al. 2016; Liu 1974; ThailandJ-Orh et al. 2008), weight gain during pregnancy(Osman et al. 2017), maternal age (Atwal et al.2006), skin structure (Ghasemi et al. 2017), familyhistory (Chang et al. 2014), race, and birth weight(Liu 1974). These have been investigated, buttheir effect has not been clearly proven (Davey1972; Liu 1974; Thomas and Liston 2014;Muzaffar et al. 1998; Kartal Durmazlar andEskioglu 2009). Surgical interventions and medi-cations have also been associated with SD(Osman et al. 2017; Pinkus et al. 1966; Di Lerniaet al. 2001; McKusick 1971; Rolleston and Goo-dall 1931; Shafir and Gur 1999; Tsuji and Sawabe1993; Gupta 2000).

Ersoy et al. (2016) published a new study todetermine individual risk factors related to SD andreported some preventive measures. This prospec-tive observational study included 211 primiparouspregnant women who were hospitalized for birthand did not have systemic diseases or other riskfactors (drugs use or polyhydramnios). The use ofpreventive oil or drugs, smoking status, skin type,water intake, and level of financial income did notsignificantly predict the appearance of SG.

According to the logistic regression analysis,including all variables found to be significant inone-by-one comparisons, i.e., age, pregnancyBMI, BMI at admission, abdominal circumfer-ence, birth weight, family history, sex of theinfant, and maternal education level, it wasestablished that each unit of decrease in maternalage increased the risk of SG by 1.15-fold(Ghasemi et al. 2017; Muzaffar et al. 1998; KartalDurmazlar and Eskioglu 2009; Thomas andListon 2014).

172 G. Almeida et al.

Histopathogenesis of Striae Distensae

Three main theories relating to SD formation aredescribed: mechanical stretching of the skin, hor-monal changes, and an innate structural distur-bance of the tegument. Mechanical stretching ofthe skin is postulated due to the perpendicularityof SD to the direction of the skin. However,contradictory studies dispute this theory(McKusick 1971; Nigam 1989). Adrenocortico-trophic hormone (ACTH) and cortisol arethought to promote fibroblast activity, leadingto increased protein catabolism, modifying col-lagen and elastin fibers (Klehr 1979). Pregnancy-related hormones are also believed to influenceSD formation (Osman et al. 2017; Nigam et al.1990; Cordeiro et al. 2010; Lurie et al. 2011).Disorder of extracellular matrix’s gene expres-sion is also postulated as a possible mechanisminvolved in SD formation (Etoh et al. 2013;Friedman et al. 1993).

The exact pathogenesis of striae is still contro-versial. Early histological dermal alterations maybe visualized on electron microscopy includingmast cell degranulation and macrophage activa-tion leading to elastolysis of the mid-dermis.Release of enzymes by mast cell, including elas-tases, is proposed as a key initiatory process in SDpathogenesis. The inflammatory process inducescollagen, elastin, and fibrillin modifications. Thereorganization of fibrillin and elastin are thoughtto play an important role in SD pathogenesis, andthose who are predisposed to developing SD mayhave an underlying deficiency of fibrillin (Watsonet al. 1998; Sheu et al. 1991).

A deep and superficial perivascular lympho-cytic infiltrate with occasional eosinophils anddilated vessels with edema of the upper dermisare characteristic of newly acquired striae. SD inthis stage is referred to as “striae rubra” (SR).

In late stage, elongated collagen bands are con-centrated within the upper third of the reticular der-mis and arranged parallel to the surface of the skin.In the “terminal” stages of SD, there is a thinning ofthe epidermis due to blunting of the rate ridges and apaucity of collagen and elastic fibers. SD in this

stage are classified as “striae alba” (SA) and areconsidered permanent (Watson et al. 1998;Ackerman Ab et al. 1997; Arem and Kischer 1980).

Striae distensae can be considered a form ofdermal scaring, and their clinical and histologicalare similar to those of scar remodeling. For what-ever reason, dermal collagen ruptures or separates,and the resulting gap is replacedwith newly formedcollagen that orients itself in the direction of localstress forces (Sisson 1954). Irrespective of theunderlying pathology that may incite a cascade ofuncertain events, a final common pathway resultsin the breakdown and tearing of the dermal matrix,which manifests clinically as SD.

A recent study investigates early molecularalterations that may promote laxity of maturestriae gravidarum (SG). They investigated thedermal elastic fibers network, which provideselastic properties of the human skin. Theyobtained skin samples of newly developed, ery-thematous abdominal SG in healthy pregnantwomen. Elastic fibers were examined by Verhoeffstain and immunofluorescence. The normal elasticfiber network appeared markedly disrupted in SG,compared with perilesional abdominal skin orcontrol (normal-appearing hip skin). This disrup-tion was accompanied by the emergence of short,disorganized, thin, threadlike “fibrils,” whichwere observed prominently in the mid-to-deepdermis. These fibrils were rich in tropoelastin(the main component of normal elastic fibers)and persisted into the postpartum period withoutforming normal-appearing elastic fibers. Theemergence of these fibrils was accompanied byincreased gene expression of tropoelastin andfibrillin-1 but not other elastic fiber componentssuch as fibrillin-2 and fibulin-1, fibulin-2, andfibulin-5. They concluded that in early SG, theelastic fiber network appears markedly disruptedand newly synthesized tropoelastin-rich fibrilsemerge as an uncoordinated synthesis of elasticfiber. Because they are thin and disorganized,tropoelastin-rich fibrils do not function as normalelastic fibers. These findings help to elucidate thepathogenic mechanism by which laxity occur inSG (Wang et al. 2015).

CO2 Laser for Stretch Marks 173

Treatment

Striae distensae is a considerable challenge interms of their treatment. They rarely resolvewithout intervention. Even with intervention,improvement rather than complete resolution is amore realistic goal. The best results are achievedwhen treating SD in the early phase. Once SDreaches a mature, static phase, they are signifi-cantly more resistant to treatment.

Various treatment modalities are reportedto treat or prevent SD. Among them are lasertherapy (Cho et al. 2006; Belo and Arceo-Cruz2009; Alexiades-Armenakas et al. 2011), lighttherapy (Sadick et al. 2007), chemical peelings(Mazzarello and Farace 2012), percutaneouscollagen induction (Aust et al. 2010), laser lipol-ysis (Freedman 2010), radiofrequency techniques(Suh et al. 2007), and microdermabrasion (Abdel-Latif and Albendary 2008). No single therapyhas been advocated to completely eradicatethese lesions (see also the following chapters:▶ “Non-ablative Lasers for Stretch Marks,” thisvolume; ▶ “Transepidermal Drug Delivery withAblative Methods (Lasers and Radiofrequency),”this volume).

Even when procedures are indicated, topicaltreatment is considered the most used treatmentand can be used before or associated with pro-cedures (Kelekci et al. 2011). A recent articleassessed the evidence for the use of topical treat-ments for SD. They reviewed the published liter-ature in English language, from 1980 onward(Kelekci et al. 2011). The products were catego-rized by their mechanisms of action, includingthose which acts in stimulating collagen produc-tion, increasing elasticity, and improving cellproliferation and those with anti-inflammatoryand rehydration properties. The results showedthat there are few studies (n= 11) that investigatethe efficacy of topical in management ofSD. Trofolastin and Alphastria creams demon-strated level 2 evidence of positive results fortheir prophylactic use in SD. Additionally, tretin-oin used therapeutically showed varied results,while cocoa butter and olive oil did not demon-strate any effect. Overall, there was a distinct lack

of evidence for each topical formulation. Themajority of topical products failed to mentiontheir effect on early SD vs. later stages of SD(striae rubrae compared to striae albae) and theirrole in both prevention and treatment. In conclu-sion, there is no topical formulation that is shownto be most effective in eradicating or improvingSD. A structured approach in identification andtargeted management of symptoms and signswith the appropriate topical is required. Random-ized controlled trials are necessary to assess theefficacy of topical products for treatment andprevention of different stages of SD (Ud-Dinet al. 2016).

Lasers and Light Devices

The 585 nm flash lamp-pulsed dye laser (PDL) atlow energy densities is commonly used totarget the dilated blood vessels of striae rubra.An increase in the amount of collagen has beenreported after a series of PDL treatment(McDaniel et al. 1996; Alster 1997). The PDLhas a moderate, beneficial effect in reducing thedegree of erythema in striae rubra but no apparentbenefit in striae alba. Because of the potential foradverse effects, PDL should be performed withextreme caution in patients with Fitzpatrick V-VIskin type. McDaniel et al. undertook a controlledof 39 patients with SD. Treatment sites includedthe abdomen, thighs, and breasts. Four treatmentprotocols were used with different spot distancesand fluences. Untreated SD was the control. Out-comes were measured by subjective analysis,shadow profilometry, and histological analysis.A significant reduction in skin shadowing wasreported in patients with SD in all proto-cols compared to controls. Additionally, elastinregained its normal appearance in SD treatedwith low-fluence PDL (McDaniel et al. 1996;Hernández-Pérez et al. 2002).

Intense pulsed light (IPL), characterized by anoncoherent filtered flash lamp with a broadbandspectrum (515–1200 nm), has been shown toreplace dermal elastosis with neocollagen, thus

174 G. Almeida et al.

improving the appearance of mature SD after aseries of treatments (Zelickson et al. 2004).

Radiofrequency (RF) devices produce heatwhich converts electrical current to thermalenergy that is uniformly dispersed to differenttissue depths. It increases collagen production byinducing collagen type I mRNA expression(Manuskiatti et al. 2009).

The long-pulse 1064 Nd:YAG is a nonablativetreatment for facial wrinkles, and an increase indermal collagen has been reported after treatment.It also has a strong affinity to vascular targets, mak-ing it a useful modality in the treatment of SR. The1064 Nd:YAG laser can be safely used, even inpatients with dark skin types (Goldman et al. 2008).

The 308-nm xenon-chloride excimer laser (XeCl)used in psoriasis, vitiligo, and post-inflammatoryhypopigmentation has been used to repigmentSD. Posttreatment biopsies showed increased mela-nin pigment, hypertrophy, and increased number ofmelanocytes; however, they failed to demonstrateany improvement in skin atrophy (Goldberg et al.2003, 2005). Alexiades-Armenakas et al. conducteda randomized-controlled trial of 31 patients withSD. Lesions were randomized by alternate allocationto receive treatment or not. Treatments wereperformed at biweekly intervals until a maximumof ten treatments were undertaken; 75% increase incolorimetric measurements relative to baseline or100% visual pigment correction was obtained. Out-come measures included visually assessed pigmentcorrection relative to control assessed by threeblinded observers and skin pigmentation levels mea-sured on a colorimeter. A statistically significantimprovement in pigmentation was identified intreated SD vs. site-matched controls. Improvedvisual pigmentation levels compared to controlswere also reported, but this declined toward baselineafter 6 months. Alternate allocations in this studywere blinded to treatment. Attrition bias may beanother concern as there is no report of how manypatients were in the final analysis (Alexiades-Armenakas et al. 2004).

Ablative lasers, as short pulse 10,600 nm CO2

laser, trigger epidermal vaporization and coagula-tion of the underlying dermis. They present a riskof hyperpigmentation, particularly in those with

dark skin (Alster and Lupton 2002; Lee et al.2010). Fractional photothermolysis (FP) wasdeveloped to overcome adverse effectsassociated with traditional ablative laserresurfacing and low efficacy of nonablative lasers(Lee et al. 2010; Geronemus 2006).

Fractional laser resurfacing can be delivered ineither an ablative or nonablative mode. These laserdevices generate focused laser energy that is deliv-ered in a microarray pattern, producing small col-umns of tissue destruction in the epidermis anddermis, termed microscopic treatment zones(MTZs), with intervening islands of healthy tissue.Within these cones of destruction, the induction oftissue remodeling and synthesis of new collagenand elastic fibers occurs. The surrounding unaf-fected, healthy tissue serves as structural scaffoldingaswell as provides nutritional support for the treatedzones, offering the advantage of significantlyreduced healing times (Fisher and Geronemus2005). The difference between ablative and non-ablative FP lies in the variable degree of vaporiza-tion of columns of tissue (ablative) versus thermalinjury with residual epidermal necrotic debris (non-ablative). The nonablative technique achieves onlyminimal efficacy and requires multiple treatmentsessions over an extended period of time, whilethe fractional ablative technique boasts superiorefficacy, however, with more discomfort, postoper-ative erythema, and recovery time (Suh et al. 2007).

Fractional laser resurfacing devices demonstratesuperior efficacy over other modalities of treatmenttechniques for photorejuvenation and have provenparticularly effectiveness for acne scars, deep facialrhytides and atrophic scarring. Given the clinicaland histologic similarity of striae to the dermalscarring characteristic of these conditions, compa-rable outcomes could theoretically be achieved inSD. The fractional ablative 10,600 nm carbondioxide CO2 laser has been shown to be highlyefficacious for skin resurfacing as well as for thetreatment of atrophic scars due to its ability tostimulate collagen and elastin regeneration andremodeling. Additionally, it has been documentedthat the fractional CO2 laser induces neocollagensisto a greater degree than the nonablative lasers(Rahman et al. 2009).

CO2 Laser for Stretch Marks 175

Due to the high risk of pigmentary alteration inethnic skin, the use of the CO2 laser in patientswith phototypes IV–VI has largely been discour-aged; however, when used with appropriate cau-tion, it appears that the fractionated CO2 systemsare safe and efficacious for the treatment of SDwith no appreciable increase in risk for PIH.

Combination therapy may be the future fortreating SD. Multiple simultaneous approachesmay afford the use of lower fluences, ultimatelydecreasing adverse effects. Strict adherence tolaser parameters and standardization of photogra-phy will be essential to ensure valid results. Whilea variety of energy devices could theoretically beused in combination, only a handful of well-powered studies have been performed, so it ishard to say which combination will be at theforefront (Aldahan et al. 2016).

Author Experience

In our daily practice, both striae rubra and striaealba, located in different areas of the body, havebeen treated with CO2 fractional laser (Ultrapulse,

Deep Fx) in the last 5 years. During this period,we have documented treatment of 500 Brazilianpatients (Fitzpatrick skin types III to V) with SDwho were followed up for 2 years.

For the treatment, topical lidocaina associ-ated with tetracaina cream was applied on theskin 20–60 min before laser therapy. Treatmentconsists of applying two passes of laser. The firstpass was performed over the SD using a linearpattern, energy of 5–20 mJ, density 5–15%, withsingle pulses. The second pass was performedusing a square pattern, energy of 2.5–10 mJ,densities 5–15%, with single pulses. This sec-ond pass was performed not only over the SD butalso around the SD. Patients were advised tokindly wash the area, to apply a healing creamtwice a day for 2 weeks, and to avoid sun expo-sure for 3 weeks. After this period, they wereoriented to wear chemical and physical topicalsunscreen.

Clinical results were evaluated 3 months and2 years after treatment, through image software,which quantifies SD volume before and after treat-ment through an overlap of before and after images.

Three months after treatment, 100% of patienthad improved. Among them, 15% was considered

Fig. 1 Before and 24 months after treatment: excellent improvement

176 G. Almeida et al.

excellent improvement, 65% good improvement,and 20% moderate improvement. These resultswere sustained during 2 years of follow-up(Figs. 1, 2, 3, 4, and 5).

Best results were achieved for striae rubra,compared with striae alba, and for SD located onthe breast. The second best anatomy region to

have good results was the abdomen and then thethighs.

Degree of patients satisfaction was consideredexcellent in 10% and great in 90%.

Post-inflammatory hyperchromia was a transi-tory side effect. To avoid dyschromia, we advo-cate the use of low densities.

Fig. 2 Before and 24 months after treatment: excellent improvement

Fig. 3 Before and 24 months after treatment: good improvement

CO2 Laser for Stretch Marks 177

Conclusion

Striae distensae are a well-recognized, commondermatologic entity, which affect patients of allages, genders, and ethnicities and rarely causeany significant medical problems but can have adeep psychological impact on affected patients.Many treatment modalities are available fortreatment and prevention; however, striaedistensae is still a challenge for dermatology.Laser treatment can be a good option whenperformed by experts. Fractional CO2 laser canbring very good results, but appropriated param-eters must be adjusted according to the device.Low density is an important parameter to avoidside effects.

Take Home Messages

• Striae distensae commonly occur in pregnancy,puberty, and obesity.

• Proposed etiological mechanisms are hor-mones, physical stretch, and structural alter-ations to the tegument.

• Striae distensae does not have one standard treat-ment but many different treatment modalities.

• Treatments include topical agents, radio-frequency, percutaneous collagen induction,microneedling, IPL, and nonablative and abla-tive lasers.

• Expectations must be realistic, but the frac-tional CO2 laser has recently shown improve-ment of these aesthetically distressing lesions.

Fig. 4 Before and 24 months after treatment: excellent improvement

Fig. 5 Before and 24 months after treatment: good improvement

178 G. Almeida et al.

• Best results were achieved for striae rubra,compared with striae alba, and for SD locatedon the breast. The second best anatomy regionto have better results was the abdomen.

• Parameters should be adjusted according to thedevice. Low density is advocated. Photo-protection and topical care are recommendedto avoid post-inflammatory hyperchromia.

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180 G. Almeida et al.

CO2 Laser for Scars

Thales Lage Bicalho Bretas, Aline Tanus, Marcia Linhares, andMaria Claudia Almeida Issa

AbstractScars result from the substitution of a damagedskin to a new and abnormal tissue following aninjury. Ablative devices, including the Erbiumand carbon dioxide lasers, have shown to beeffective in improving the appearance of scars,including mature burn scars. The CO2 laser pro-motes thermal fractionated ablation of the skin,and the resultant selective healing stimuliimprove the altered tissue. The scars, then,become more homogeneous with the surround-ing skin. The carbon dioxide laser can be com-bined to other interventions to achieve optimalresults. It can also be used to allow drug pene-tration into the dermis, homogeneously, a tech-nique called drug delivery. It has been reportedthe use of drugs such as corticoids to reduce thehypertrophic scars and poli-L-latic acid (PLLA)to increase collagenesis in atrophic scars. Inpost-procedure/post-treatment and burn scars,

the early use of the CO2 laser is important toremodel the tissue before the maturation of thescar, therefore bringing better cosmetic results.In this chapter, we will expatiate on the multiplekinds of scars, the ablative fractional carbondioxide laser CO2 peculiarities and the approachof different types of scars through the use of thistechnology.Wewill also discuss the precautionsto be taken before the procedure (pre-treatment),the procedure itself, the post-procedure/post-treatment care, the most commonly seen sideeffects and how to deal with them.

KeywordsCO2 Laser • Scars • Ablative • Fractional •Carbon dioxide

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182

Scars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182

Fractional CO2 Laser . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183Basic Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183Mechanism of Action of the Fractional CO2

Laser . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184

The Use of Fractional CO2 Laser in TreatingDifferent Kinds of Scars . . . . . . . . . . . . . . . . . . . . . . . . 185

Hypertrophic Scars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185Atrophic Scars in General and Atrophic

Acne Scars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187Postsurgical/ Post-Traumatic Scars . . . . . . . . . . . . . . . . . . 187Burn Scars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188

Preprocedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190

Procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190

T. Lage Bicalho Bretas (*)Universidade Federal Fluminense, Niterói, RJ, Brazile-mail: thalesbretas@gmail.com

A. Tanus • M. LinharesBrazilian Society of Dermatology, Rio de Janeiro, RJ,Brazile-mail: alinetanus@yahoo.com.br;dra.marcialinhares@yahoo.com.br

M.C.A. IssaDepartment of Clinical Medicine – Dermatology,Fluminense Federal University, Niterói, RJ, Brazile-mail: maria.issa@gmail.com; dr.mariaissa@gmail.com;maria@mariaissa.com.br

# Springer International Publishing AG 2018M.C.A. Issa, B. Tamura (eds.), Lasers, Lights and Other Technologies, Clinical Approaches and Procedures inCosmetic Dermatology 3, https://doi.org/10.1007/978-3-319-16799-2_13

181

Post Procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191

Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191

Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191

Take Home Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192

Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193

Introduction

The healing process involves the release ofinflammatory mediators, cytokines, and cell che-motaxis, leading to reepithelialization and depo-sition of types III and I collagen within the dermis,respectively. Scars are a consequence of abnormalsubstitution of damaged tissues after trauma, withmisbalance of collagen types and their fiber thick-ness within the dermis, as well as histologicaldisorganization. They represent unaestheticmarks capable of decreasing self-esteem and qual-ity of life, therefore demanding the start of anefficient treatment as quick as possible, in orderto offer the patient satisfactory and aestheticresults. Treating scars has never been an easytask for dermatologists, and it usually involvesmulti- therapeutic approach, with a combinationof drugs and technologies. There are unnumberedtreatments described, such as ablative and non-ablative lasers, corticosteroid injection,intralesional 5-fluorouracil or bleomycin, siliconpatches, cryotherapy, chemical peels, dermabra-sion, fillers, punch excisions, punch-elevations,micro needling, subcision, and many others(Ozog et al. 2013; Wolfram et al. 2009; Reishand Eriksson 2008).

In the past decades, the popping up of frac-tional lasers (ablative or not) took the scar man-agement to another level, offering good resultswith minimum invasive procedures. The recentuse of the carbon dioxide (CO2) ablative fractionallaser (AFL) for the treatment of scars has deliv-ered good results when correctly managed. Thislaser promotes thermal ablation of multiple smallchannels between nondamaged skin, calledmicrothermal zones (MTZ), causing healing stim-uli that results in neocollagenesis and remodelingof the altered tissue. The expression of some

cellular markers of dermal wound healing andneocollagenesis, such as collagen III, heat shockprotein 70, alpha-smooth muscle actin, and pro-liferating cell nuclear antigens have been reportedin treated areas. Therefore, scars becomeshallower and narrower, and their surface tend tolook more homogeneous with the surroundingskin (Manstein et al. 2004; Laubach et al. 2006;Walgrave et al. 2008; Alexiades-Armenakas et al.2011; Rkein et al. 2014).

The CO2 laser itself, without being combinedto other techniques, already offers visibly goodimprovement in the skin texture, shape and aspectof the scar, as well as its similarity to the surround-ing skin. But it has also been used concomitantlywith the application of several medications; henceit produces small channels that allow the penetra-tion of drugs into the dermis, homogeneously, atechnique called drug delivery. In hypertrophicscars, for example, the CO2 laser itself does notrepresent a good option as a monotherapy; it isoften used to deliver drugs such as corticoids andbleomycin that will act synergistically with thelaser to reduce the hypertrophy and improveeven more the aspects of the scar. This methoddemands special caution and knowledge from theoperator, as the laser itself could cause new scarsin a person who has some genetic tendency ofdeveloping hypertrophic scars, as well as itcould over stimulate those scar fibroblasts andworsen the fibrosis already generated by an over-reaction of that body to a previous damage stim-ulus. In atrophic and acne scars, the CO2 laser canalso be used with the delivery of drugs like poli-L-latic acid (PLLA) to increase collagenesis andfulfill the depressions of the scar tissue (Vrijmanet al. 2011; Shamsaldeen et al. 2011; Fife et al.2009; Avram et al. 2009).

Scars

Scars represent abnormal substitution of a dam-aged tissue after any trauma that reaches the der-mis. Functionally, they are less malleable than thenormal tissue and they lack cutaneous annexes,such as hair follicles, sebaceous and sweat glands.They can be either hypertrophic or atrophic and

182 T. Lage Bicalho Bretas et al.

are frequently generated by harms such as burns,surgery, tattoos, accidents, or some inflammatorydiseases like acne. There is also a particular kindof hypertrophic scar, known as keloid, which is aresult of very exacerbated inflammatory responseof the host to skin damages, and demands a dif-ferent and more cautious approach.

Hypertrophic scars result from uncontrolledproliferation of fibroblasts and extracellularmatrix. The reason why this abnormal prolifera-tion occurs is primarily genetic, and afro-descendants are usually more prone to this alter-ation. The hypertrophic scars are higher than thesurrounding skin, and they do not go further thanthe originating scar borders. Typically, hypertro-phic scars can be seen on the shoulders, superiortrunk, and ears (Alster and Tanzi 2003; Verhaegheet al. 2013; Kuo et al. 2004).

A keloid, for definition, goes over the bound-aries of the original injury, has a higher recurrenceindex, and represents a challenging task to derma-tologists. Besides its visual impairment, the keloidis usually painful, rigid, with thick fibrosis andlow mobility. It does not regress spontaneously,and the patients affected have a high genetic pre-disposition (Reiken et al. 1997; Alster and Wil-liams 1995; Sherling et al. 2010).

Atrophic scars result from inefficient collagenremodeling and abnormal regeneration of thefibrous tissue. They represent depressions on theskin surface and can be originated by unawarecare with a wound or also be influenced by geneticpredisposition (Vrijman et al. 2011).

Acne scars originated from moderate to severeacne in teenagers and young adults represent fre-quent and important complains in a dermatologicalconsultation. Their etiology is related to exagger-ated inflammatory reaction that lasts too long, inef-ficient immune response of the host to the tissuedamage, and anomalous healing capacity with lowcollagen synthesis (Jeremy et al. 2003; Taylor et al.2011; Fabbrocini et al. 2010; Holland et al. 2004;Sobanko and Alster 2012). Acne scars are classi-fied by the amount of collagen loss or gain by thetissue, by its thickness, its stretching capability, itsdepth, and its architecture.

Atrophic scars are the most common kind ofacne scars and occur because of the destruction

of dermic structures by the deep inflammatoryinfiltrate. They can be divided into ice pickscars, rolling scars, and boxcar scars (Fig. 1).Ice pick scars are narrow, spotted and deepscars, clinically shown as multiple small pointsof depression on skin surface. They usually haveless than 2 mm of width and grow verticallyuntil deep dermis or subcutaneous tissue, assum-ing a cone figure. Rolling scars are shallowerand wider, with a width of 4–5 mm, with slopingedges, and they occur when the dermis getsattached to the subcutaneous tissue, producinga superficial ripple. Boxcar scars are rounded oroval, with a various width, from shallow todeep, and diameter between 1.5 and 4 mm(Levy and Zeichner 2012; Jacob et al. 2001;Lee et al. 2013).

Fractional CO2 Laser

Basic Principles

The CO2 laser is an ablative fractional laser(AFL), with a wavelength of 10.600 nm, andits target is the water. The AFL produces

Fig. 1 Different types of atrophic acne scars

CO2 Laser for Scars 183

microscopic columns of ablated tissue, whichextends from the epidermis to the dermis (theso-called microthermal zones – MTZ), savinghealthy tissue areas between these columns. Col-lagen degeneration and focal epidermic necrosisstimulate a process of fast reepithelization pro-moted by the surrounding healthy skin cells. TheAFL technology gave us a new perspective forfacial resurfacing treatments, decreasing the sideeffects and complications of the standard ablativeresurfacing so far feared, since it did not use topreserve any healthy skin area. Other kinds ofablative fractional lasers are the Er:YAG (yttrium,aluminium, garnet) 2.940 nm, and the new Er:YSG (yttrium, sapphire, garnet) 2790 nm. Theyonly differ from each other in the wavelength andthe water absorption coefficient, as the target is thesame: the emanating energy is absorbed by theamount of water in the tissue (Manstein et al.2004; Laubach et al. 2006; Walgrave et al. 2008;Alexiades-Armenakas et al. 2011; Alster andNanni 1998).

The Er:YAG has the biggest water absorptioncoefficient, as it promotes immediate vaporizationof cells without thermic damage. It is capable ofabsorbing 12–18 times more water than the CO2.The pulse duration of the Er:YAG is much smallerthan the CO2 laser’s, resulting in less surroundingthermic diffusion. Nevertheless, the inability ofthe Er:YAG to cause thermic injury results inless collagen contraction, making it useless topromote per-operatory homeostasis (Alster andNanni 1998).

The CO2 laser device has a handpiece thatprojects small spots on the skin. Depending onthe model used, it is possible to adjust the shotformat (triangle, square, or round, for example),the spot density and the diameter of each spot,which can range from 125 μm to 1.25 mm. It hasthe smallest water absorption coefficient, caus-ing large collateral thermic damage and promot-ing excellent homeostasis when used in thestandard mode, nonfractional (Rkein et al.2014).

There are, basically, four or five parameters tobe adjusted in the CO2 laser, bearing in mind theskin area to be treated, the deepness, the diameterand the ablation degree:

– Energy: is the amount of power (in Watts)delivered to the tissue in a given time (thelaser pulse duration, in seconds). It is directlyproportional to the depth of penetration and thethermic injury promoted, meaning that thehigher is the energy, the deeper the laserreaches and the more injury it promotes in thesurrounding tissue.

– Fluency/Density: is the amount of energydelivered to a certain area – the overall sizeof the application area or the “spot size” pro-duced by the laser handpiece. Thus, theenergy density or fluency is measured inJ/cm2. The higher the fluency, the faster thetemperature increases in the tissue and, con-sequently, the bigger is the intensity of thedesired effect. The effect of the treatment isachieved both by varying the laser outputenergy and the laser pulse duration, at thetissue application area.

– Pulse duration: in milliseconds (ms), it isdirectly proportional to thermal injury of thetissue. The more the pulse lasts, the bigger isthe damage made in the target tissue andsurroundings.

– Distance between dots: determines the balancebetween the density of energy delivered andthe preserved skin in the treated area. It isinversely proportional to density, whichmeans that the smaller is the distance betweenthe dots, the more energy will be delivered intothe target area, with denser thermal ablation.Higher densities mean dots overlapping, leav-ing smaller healthy skin surface preservedand making the post procedure moreuncomfortable.

Mechanism of Action of the FractionalCO2 Laser

Heat shock proteins (HSP) are upregulated andhave their role in cutaneous remodeling after ther-mal injuries. They have anti-inflammatory andcell-protecting actions. Histologic studies havedemonstrated enhanced levels of HSP, such asHSP70 and HSP47, that promote the process ofcollagen generation, leading to dermal thickening

184 T. Lage Bicalho Bretas et al.

and improvement of scar appearance (Magnaniand Schweiger 2014). HSP70 is a procollagenchaperone and plays a crucial role in woundhealing, promoting neocollagenesis and theexpression of other growth factors, like trans-forming growth factor β (TGF-β), essential tohealing. HSP47 also plays a key role in promot-ing neocollagenesis. Its peak expression is at1-month posttreatment, and it remains high at3 and 6 months. Remodeling and new collagenformation was noted at 3 and 6 months postprocedure. The long-term expression of thesetwo heat shock proteins supports the long-termefficacy of fractional CO2 laser resurfacing(Xu et al. 2011).

The CO2 laser also enhances the expression oftissue collagenases, such as matrix meta-lloproteinases (MMP), that act in collagen degra-dation. As MMPs are not normally expressed inthe skin, the balance between collagen formationand degradation results in individual responses foreach patient (Vrijman et al. 2011).

As already mentioned before, the CO2 laserproduces small dots in between preserved skin inthe treated area, the MTZ, with vaporization of thecorneal layer upon these channels. An area ofundamaged tissue surrounds each ablative zone.Spared, viable keratinocytes in these areasmigrate to the MTZs and promote the healingprocess, with collagen formation andreepithelization. Immediately after the laserpulse, hypochromic dotted macules may be seenin skin surface, representing this corneal layer’svaporization. These macules evolve to erythema,more visible within 3 days after the treatment. Atthat time, serosanguinous drainage and swellingoccurs in various degrees, according to the param-eters used. Bleeding occurs between the stratumcorneum and stratum granulosum. Regenerationand desquamation of the epithelium is observed,with preservation of the basal lamina. There isalso disappearance of elastin in elastic fiberslocated in the superficial dermis of scar areas(Magnani and Schweiger 2014).

The healing process finishes with the forma-tion of small brown crusts, corresponding to theextrusion of damaged keratinocytes. Necroticdebris are eliminated within 1–2 weeks (can

take even longer in certain patients), leavingskin surface more “tanned” until its completeexfoliation (Rkein et al. 2014). Three weeksafter treatment, almost complete regeneration ofthe epithelium is observed. Microscopically,elastin can be seen in electron-dense deposits,and elastic fibers look fragmented and elaunin-like, which is indicative of the dermalremodeling process (Omi et al. 2011). A visibleimprovement of scars can be seen within3 months, but it has already been described upto 12–18 months after treatment, with neo-collagenesis and dermal remodeling evidencedby histological analyses.

The Use of Fractional CO2 Laserin Treating Different Kinds of Scars

Hypertrophic Scars

Although the CO2 laser has been used to treathypertrophic scars, the pulsed dye laser (PDL)585 nm has a higher evidence of efficacy basedon the recent findings of the literature. The over-expression and abnormal activity of TGF-β1 andTGF-β2 is enrolled in the pathogenesis of hyper-trophic scars and keloids. The mechanism ofaction of the PDL is not yet a consensus, but itis believed that it reduces the expression ofTGF-β, the fibroblast proliferation and the col-lagen III deposition in the scar. It is alsodescribed that, between the mechanisms ofaction of the PDL, are the selective photo-thermolysis of blood vessels, the release ofhistamine and interleukins by mast cells andthe collagen degradation with consequentreestablishment of the dermis (Alster andNanni 1998; Patel and Clement 2002; Reishand Eriksson 2008; Alster and Zaulyanov2007). Intralesional corticosteroid infiltrationaiming to inhibit collagen synthesis immediatelyafter the PDL section is technically easier due totissue swelling, offering less resistance to theneedle penetration into the scar (Mustoe et al.2002; Jalali and Bayat 2007; Roques and Téot2008; Manuskiatti and Fitzpatrick 2002; Guptaand Sharma 2011; Chowdri et al. 1999).

CO2 Laser for Scars 185

The Fractional CO2 laser is often used toimprove thickness, stiffness, and abnormal textureof more mature scars by ablative destruction andresurfacing (Waibel et al. 2013). The treatmentwith fCO2 ablative laser can be started from12months after injury or following the conclusionof PDL treatment, in case they are combined.Laser sessions are delivered with 4–6-week inter-vals until a plateau in improvement is observed.Generally, only one modality is used per session,but more than one platform can be used on differ-ent sites in the same session.

The microscopic thermal zones generated bythe CO2 laser have also been used as channelsto enhance the penetration of triamcinolone(Fig. 2a–c) and other topical drugs into theskin. This technique, called Drug Delivery, isless painful than the drug injection and allows amore uniform distribution of the medication

between the scar’s dermis, acting synergisti-cally with the laser. The corneal stratus is nor-mally impermeable to molecules weightingmore than 500 Da, nevertheless, the channelscreated by the laser allows higher penetrationand bioavailability of topic medications (Good-man 2006).

Having all that information in mind, the CO2

laser is usually combined with the Drug Deliverytechnique to achieve better results in treatingkeloids and hypertrophic scars (Fig. 3a, b). Know-ing that the laser itself can promote a high healingresponse in people who are already geneticallyprone to scar formation, it is always extremelyadvised to start slowly at the first few laser sec-tions, with low potencies/ fluencies and low pulsedurations not to worsen scars by feeding theirexacerbated inflammatory chain secondary tohealing stimuli.

Fig. 2 (a) Hypertrophic scar in malar region before lasertreatment. (b) Hypertrophic scar immediately after CO2

laser session associated with topical triamcinolone: drug

delivery. (c) Two years after CO2 laser treatment associatedwith triamcinolone: drug delivery

Fig. 3 (a) Hypertrophic scar on the left nasal wing before the CO2 laser session. (b) Hypertrophic scar on the left nasalwing after a single CO2 session and the use of Triamcinolona 20 mg/gl as a drug delivery

186 T. Lage Bicalho Bretas et al.

Atrophic Scars in General and AtrophicAcne Scars

Atrophic scars are better treated with AFL, like theCO2 laser, when compared to nonablative frac-tional lasers, because the energy reaches deep der-mis (1.5–1.6 mm of depth) and the remodelingprocess can last months. The AFL increases theheat shock proteins (HSP) expression, which inturn regulate the tissue response to thermal injurythrough activation of epidermic stem cells that willreplace the just damaged cells. IL-1, TNF-alfa,TGF, and MMP signalize the removal of the dam-aged cells and the neocollagenesis.

The CO2 laser treatment reduces scar’s widthand depth and stimulates the synthesis and orga-nization of collagen fibers, filling in atrophicareas. It is highly recommended to treat thewhole aesthetic unit surface, and neither only theaffected areas nor the scar itself, in order to avoidclear demarcation between treated and nontreatedareas. As a resurfacing method, the CO2 laser pro-motes a higher collagenesis stimuli and a betteraesthetic result. It improves the homogeneity ofthe skin, progressively making the atrophic areasseem more plane, shallower, superficial, andreintegrating them to the surrounding normal skin.

We shall never forget the possibility of the con-comitant use of drugs that stimulate collagenesisand reverse the atrophy through the drug deliverysystem with the homogeneous penetration of med-ications to improve the skin texture and regain itsvolume and vitality. In atrophic scars, the poli-L-latic acid (PLLA) is the actual substance used toimprove collagenesis through the drug deliverytechnique, straight after the laser section. PLLA,when introduced, induces local inflammatoryresponse with activation and production of colla-gen, acting in a synergic way with the laser.

Acne scars are mostly atrophic, subdivided indifferent types as already mentioned (icepicks, boxscar, and rolling scar). The great majority of theaffected patients have multiple types simulta-neously. With the resurfacing technique, there is agood improvement in the general aspect of thetreated aesthetic unit, but multiple laser sessionsare usually needed to achieve impressive results.All subtypes of acne scars experiment great

amelioration, but box scars are often better respon-sive. The patients shall be oriented about the needof subsequent sessions, from four to six, to get thebest outcome (Fabbrocini et al. 2010; Magnani andSchweiger 2014; Omi et al. 2011) (Fig. 4a, b).

Postsurgical/ Post-Traumatic Scars

Fast and early acting in these scars are essential toimprove their thickness and texture. Depigmenta-tion is the hardest alteration to treat. Due to thebigger depth they have in comparison to acnescars, the postsurgical scars usually reach worseresults. Fibroblasts and myofibroblasts startmigration during the first week, and begin toform a scar tissue after the second week. There-fore, the right approach shall be made readilywithin the first week after surgery.

Many studies use the Vancouver scar scale(VSS) to promote clinical evaluation of the scar,including the pigmentation (0= normal, 1=hypo-pigmentation, 2 = hyperpigmentation), vascular-ity (0 = normal, 1 = pink, 2 = pink to red,3 = red, 4 = red to purple, 5 = purple), pliability(0 = normal, 1 = supple, 2 = yielding, 3 = firm,4=banding, 5= contracture), andheight (0=nor-mal, 1 = <2 mm, 2 = 2–5 mm, 3 = >5 mm)(Chowdri et al. 1999).

Apparently, the CO2 laser can be used to treatpostsurgical and post-traumatic scars (Figs. 5a, b,6a, b, 7a, b, and 8a, b) as well as they can promotethe formation of a new scar. The occurrence ofhypertrophic scars secondary to the treatmentwith the CO2 laser has been reported. Manysuggested protocols for the laser treatment areavailable, but the energy delivered and the area tobe treated must be thoroughly chosen. Thesuggested densities to approach the face scarsrange from 30% to 50%, whereas in extrafacialareas they range from 20% to 30%, as the chancesof hypertrophic scars are higher at those areas,specially on the neck, as previously mentioned.Moreover, lower energies also offer the best resultsand lower the risks of erythema and permanentdepigmentation after the laser treatment (Roquesand Téot 2008; Manuskiatti and Fitzpatrick 2002;Sobanko et al. 2015; Zachariae 1988).

CO2 Laser for Scars 187

Burn Scars

Burn scars have a complex formation mechanismthat involves trauma responses, and their treat-ment must focus on aesthetics and functionalimprovements. Apart of all adequate surgicaland curative care, it is common to see the patient

complaining about local pain, burning, or itching.In managing burn scars, we shall focus onaddressing the aberrant collagen deposition typi-cally shown in mature scars. Mature scars, likeadult skin, have a predominance of type I collagenover type III, and this proportion is inverted infetal skins.

Fig. 5 (a, b) Before and 6 months after four sessions: (30 mJ; 100 density)

Fig. 4 (a, b) Atrophic acne scars before and after two sessions of CO2 laser with 3 months interval

188 T. Lage Bicalho Bretas et al.

The use of Fractional CO2 laser in burn scarshas been proved to decrease collagen I and increasecollagen III in the treated tissue, rearranging thescar tissue to reestablish the normal collagen

deposition seen in young and nondamaged skin.This finding might be the responsible for relatedgain in mobility of the scar region after thetreatment.

Fig. 6 (a) Scar after surgery: before treatment. (b) Scar after surgery after one section of CO2 laser

Fig. 7 (a) Scar after surgery before treatment. (b) Scar after surgery after one section of CO2 laser

Fig. 8 (a, b) Before and 6 months after four sessions: (30 mJ; 100 density)

CO2 Laser for Scars 189

Besides the improvement of the skin architec-ture, there is no way to regain the lost adnexalstructures, like hair follicles, sebaceous and sweatglands. Therefore, the aesthetic improvementmight be limited in cases of extensive skin areasaffected (Ozog et al. 2013).

Preprocedure

The procedure itself depends on each manufac-turer’s protocols. But there are some general pre-cautions and instructions to be followed, especiallybefore and after the procedure. Starting from aprevious well-done anamnesis and after a minimal-ist physical exam, dermatologists must pay specialattentions to the conditions mentioned bellow:

Active infections of any kind (fungal, bacterial, orviral) are relative contraindications to the laser,and should be treated properly ahead of thelaser session.

Inflammatory skin disorders on the area to betreated, like eczema or psoriasis, are not to besubmitted to the procedure until their completeresolution. Patients with inflammatory skin dis-eases that have Köebner phenomenon (lichenplanus, psoriasis, perforating dermatosis, viti-ligo, etc), even outside the area to be treated,shall be well informed of this possibility.

Active acne: Patients with acne scars and activedisease should be treated properly with topicalor oral treatment prior to proceed to the scarmanagement, in order to control the inflamma-tory lesions before the laser sessions. There isno point in treating acne scars when new onesare still popping up, since it would prolong thetreatment and make it inefficient.

Recent oral Isotretinoin use: Concerning thepossibility of healing impairment in patientstaking isotretinoin, as well as the risen risk ofkeloid formation, it is recommended to wait atleast 6 months after the end of the treatment tostart the laser sessions. There is still a lack ofstudies evaluating this wound healing impair-ment, but a consensual interval of 6 months hasbeen established (Zachary and Rofagha 2012).

Herpes simplex personal history: Patients withprevious history of herpes simplex infectionmust undergo a prophylaxis with antiviralagents. The duration is not yet a consensus,but oral Aciclovir (400 mg 8/8 h), Valacyclovir(1 g qd), or Famciclovir (250 mg 12/12 h)should be started at least 48 h prior to theprocedure, and be kept until reepithelization,usually 5 days following the laser session(Zachary and Rofagha 2012).

Higher skin phototypes (Fitzpatrick IV to VI):darker skin tones have higher risk of post-inflammatory hyperpigmentation related tothe procedure. Therefore, the procedure shallbe discouraged, since the risks would exceedthe benefits. If extremely necessary, lowerfluencies and densities can be used withcaution.

Procedure

Proceeding to the laser session, a topical anes-thetic should be applied in order to gently coverthe area to be treated. After its action time, theskin must be well cleaned and a small areamight receive the first laser shot to test theskin ablation and the patient’s tolerance to theprocedure.

The laser session is to be based on the manu-facturer’s orientations concerning the specificlaser device and its personal parameters to thepatient’s situation. Both the patient and the appli-cant must wear safety goggles. The skin, thus,receives the laser shots, and the operator mustavoid overlapping, since this practice can increasethe laser potency and cause harm to the skin.When a certain area is treated with multiple over-lapping, there is higher thermal damage, lesshealthy skin is left behind, hence elevating therisk of scar formation.

Immediately after the laser application, thedoctor has a chance to do drug delivery spreadingsome active ingredients over the ablated area,depending on the patient’s indications, like triam-cinolone or bleomycin for hypertrophic scars andPLLA for atrophic ones.

190 T. Lage Bicalho Bretas et al.

Post Procedure

Immediately after the laser section, the skin pre-sents with erythema and swelling due to the tissuevaporization and an exuberant serous discharge. Arefreshing and calming mask can be placed overthe patient’s face, since one can be experiencing aburning sensation. Meanwhile, orientations to thepost procedure are to be given to the patient, likehygiene routines and the application of topicalhealing creams on the treated area, twice a day,until complete reepithelization. The doctor mustbe sure that the patients know about the proce-dure’s downtime, recovery, precautions need to betaken at home and how to manage expectations.

It is very important to tell the patients that,during the first few days, the skin is going toseem worse than before the treatment, followedby the appearance of crusts that get better in7–10 days, when the healing and reepithelizationprocess is going to be completed.

The results are really promising and tend toimprove after subsequent sessions, with 2–6weeks of interval between them. Higher poten-cies can be progressively used depending onthe patient’s tolerance and response to thetreatment.

Side Effects

Aside the fact that the fractional CO2 laser offersmuch less side effects than the ablative standardCO2 laser, they can still occur. Some precautionsare to be taken in order to avoid them, such asusing lower energies and not overlapping morethan twice at the same place. Side effects occurmore often in patients submitted to either higherenergies or densities (Vrijman et al. 2011;Shamsaldeen et al. 2011; Fife et al. 2009; Avramet al. 2009; Alster and Tanzi 2003).

Secondary infection is the most related sideeffect, and the herpes simplex prophylaxis is usu-ally needed to avoid it. Erythema, swelling, andpain can be infection signs and the patient has tobe well oriented to readily contact one’s doctor incase of any of these changes.

Acneiform eruptions can either be a responseto thermal injury or a reaction to the greasyhealing creams prescribed after the procedure,and the latter must be replaced by more fluidoptions. The introduction of some soft topicalmedicines for acne also optimizes the resolutionof acneiform eruptions.

Occlusive band-aids and antibiotics can causecontact dermatitis, better treated with topical cor-ticosteroids. Late complications occur weeks afterthe procedure and include hyperpigmentation,persistent erythema, spotted appearance of theskin, ectropion, hypertrophic scars, and hypo-pigmentation. Hyperpigmentation and hypertro-phic scars are rare, becoming more usual inextrafacial areas (particularly the neck) and whenthere have been multiple overlapping or exces-sively aggressive parameters have been used.Hypopigmentation is even rarer. In cases ofdyschromia, topical agents like hydroquinone,retinoic acid, thioglycolic acid and others can beused. Lasers and light devices can also play animportant role in cases of persistent erythema(Intense Pulsed Light, Ruby, Alexandrite) andhyperchromia (Intense Pulsed Light, Q-switchedNd-YAG).

Conclusions

The CO2 laser offers a new and safe treatment tounaesthetic scars, with low incidence of sideeffects, good tolerance and high efficacy, makingit a promising technique to this common complaintin dermatology offices. When well indicated, theresults are really satisfying. Nevertheless, there aresome precautions to be taken before the applicationof the laser: evaluate skin type and patient’s expec-tations, antiviral prophylaxis when needed, andgood orientation of the patients. They need toknow about the downtime of this ablative laser,the possible side effects, how to deal with therecovery, and how to make it easier and faster,keeping the good results.

Concerning the laser device, each one carriestheir manufacturer’s manual, as well as their rightparameters taking the patients indication and skin

CO2 Laser for Scars 191

characteristics into account. However, concepts offluency, potency, energy, spot size, and pulse dura-tion are values that allow us to understand it as apatterned device: the higher the parameters are, thestronger and deeper the laser will reach the skin.

Take Home Messages

1. Scars are a consequence of abnormal substi-tution of damaged tissues after trauma.

2. The recent use of the carbon dioxide (CO2)ablative fractional laser (AFXL) has deliveredgood results when correctly managed.

3. Treating scars is never an easy task for der-matologists, and involves multi therapeuticapproach, with a combination of drugs andtechnologies.

4. The CO2 laser creates microthermal zones(MTZ) that stimulate healing process involv-ing heat shock proteins, metalloproteinases,cytokines and chemotaxis, with neo-collagenesis and reorganization of the scartissue and its surroundings.

5. The CO2 laser can be used to treat scars as amonotherapy or combined to other tech-niques, such as pulsed dye laser, corticoste-roid/bleomycin injections, topical drugs andothers to achieve better results, especially inhypertrophic scars.

6. The CO2 laser can also be used with theconcomitant application of topical drugs thatwill penetrate into the MTZ and reach thedermis, acting synergistically in a techniquecalled drug delivery.

7. In hypertrophic scars and keloids, the use ofthe CO2 laser must be even more careful,since it may stimulate the overreactinghealing inflammatory reaction found in genet-ically predisposed people.

8. In acne scars, there is usually concomitantpresence of multiple kinds of atrophic scars,with general improvement after the CO2 lasersession. The patients often need more thanone session, usually three to six, with1–3 months of interval. Ice picks scars arethe worst responders.

9. In postsurgical and burn scars, the early use isthe key for the success.

10. The patients must be very well orientedabout the procedure, its downtime, itspre and post precautions, as well as thepossible side effects and signs of infection/complications.

11. If the patient has personal history of herpessimplex infection, he/she must undergoprophylaxis schemes before the laserapplication.

12. The presence of infections or active inflam-matory diseases in the skin area to be treatedmust be completely solved before the lasersession, as well as inflammatory skin diseaseswith Köebner phenomenon shall be discour-aged of the procedure.

13. Before the laser application, topic anesthesiawith lidocain, tetracain and others must beapplied onto the skin area to be treated, andthen removed with correct asepsis of the skin.

14. The laser section should be based on themanufacturer’s protocol, considering thepatient’s Fitzpatrick’s skin type, the indica-tion and the parameters that match all theseinformations.

15. The post procedure evolves the use of restor-ative creams and general precautions like sunprotection. If the patient is currently underherpes simplex prophylaxis, it must becontinued until the complete skinreepithelization, around 5–10 days after thelaser session.

16. The most common side effects are infections,dyschromia, persistent erythema, hypertro-phic scarring, and hypopigmentation, the lat-ter being rare. The doctor must feel capable ofreadily handle these intercurrences.

Cross-References

▶CO2 Laser for Photorejuvenation▶Erbium Laser for Scars and Striae Distensae▶Light-Emitting Diode for Acne, Scars, andPhotodamaged Skin

▶Non-ablative Fractional Lasers for Scars

192 T. Lage Bicalho Bretas et al.

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CO2 Laser for Other Indications

Emmanuel Rodrigues de França, Alzinira S. Herênio Neta, andGustavo S. M. de Carvalho

AbstractThe CO2 laser is an ablative laser and has astrong affinity for water. It has been widelyused with the objective to promote therejuvenation or improve the appearance ofscars by stimulating new collagen. As well,its increasingly widespread use has allowedthe safe and effective treatment of variousdermatoses, from benign epithelial tumorsto melanocytic lesions to premalignantlesions (actinic cheilitis). Patient educationon pre- and post-laser care is essential tomaintaining good result. We discuss belowsome CO2 laser indications in routinedermatologist.

KeywordsCO2 lasers • Laser therapy • Lasers • Gas •Ablative laser

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196

Dermatosis Papulosa Nigra . . . . . . . . . . . . . . . . . . . . . . . . 196

Xanthelasma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197

Sebaceous Hyperplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198

Viral Wart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199

Genital Warts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200

Melanocytic Nevus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201

Verrucous Epidermal Nevus . . . . . . . . . . . . . . . . . . . . . . . 202

Syringoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203Surgical Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203

Fordyce Spots . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204

Seborrheic Keratoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205

Rhinophyma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205

Actinic Cheilitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206

Exogenous Ochronosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210

Take Home Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210E.R. de França (*) • G.S.M. de CarvalhoDepartment of Dermatology, University of Pernambuco –UPE, Recife, PE, Brazile-mail: emmanuelfranca@hotmail.com;gustavo.carvalho@msn.com

A.S. Herênio NetaDepartment of Dermatology, University of Sao Paulo,Sao Paulo, SP, Brazile-mail: niraherenio@hotmail.com

# Springer International Publishing AG 2018M.C.A. Issa, B. Tamura (eds.), Lasers, Lights and Other Technologies, Clinical Approaches and Procedures inCosmetic Dermatology 3, https://doi.org/10.1007/978-3-319-16799-2_14

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Introduction

Dermatologists and plastics surgeons oftenencounter in their clinical practice injuriesinitially considered as small, which frequentlyhave a difficult resolution. Pathologies assyringoma, sebaceous hyperplasia, verrucousepidermal nevus, acrochordon, and viral wartscan be solved by different methods, but thelaser, particularly the CO2, can be very useful,with surprising results. We will cover the mostcommon dermatologic conditions that can bebenefited by this method.

Dermatosis Papulosa Nigra

Dermatosis papulosa nigra (DPN) is a commoncondition in the black population, particularly inwomen, with prevalence of 35% in the African-American population (Kundu and Patterson2013). It begins in adolescence being the mostaffected women. The number and size of thelesions increase with age. Clinically, it isrepresented by multiple papules hyperchromic,asymptomatic, typically affecting the head andneck. It histologically resembles the seborrheic

keratosis showing hyperkeratosis, irregularacanthosis, horn cysts, and marked hyperpig-mentation of the basal layer. This is a benignlesion of genetically determined character –positive family history in around 40–54% ofcases (Hairston et al. 1964).

No treatment is usually indicated for DPN. Thecondition, though indolent, can sometimes besymptomatic or aesthetically undesirable. In suchcases, treatment options include shaving, curettage,cryotherapy, electrodessication, microdermabrasion,and laser. More aggressive approaches can becomplicated by postoperative hyperpigmentation,hypopigmentation, or scars. The keloid formationis a potential complication (Fig. 1).

The lasers have been cited in the literature asuseful therapeutic modalities for PDN, includingCO2 (Bruscino et al. 2014), Nd:YAG, diode,pulsed dye, and erbium lasers. Among them,the CO2 laser has been shown to be safe, withlow rates of recurrence or complications(scarring, hypo-/hyperpigmentation) and also ahigh degree of satisfaction by patients, even atthe highest phototypes (Ali et al. 2016). Thetopical anesthesia is sufficient in most casesand is indicated white petrolatum ointmentonce a day until reepithelialization of lesions.

Fig. 1 (a, b) Dermatosis papulosa nigra treated with CO2 laser (low fluence)

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There must be an interval of 3–4 monthsbetween the sessions.

Xanthelasma

This is a benign disorder characterized byyellowish plaques typically located in theperiorbital region, especially in the inner cornerof the eyes and upper eyelids; it is also the mostcommon form of skin xanthoma. The lesionshave a tendency to progress and coalesce withpermanent character.

They are due to accumulation of fat within thehistiocytes, known as foamy histiocytes, locatedmainly in the upper reticular dermis. The maincomponent is accumulated cholesterol, which forthe most part are esterified. In 50% of patients,normal serum levels of cholesterol are found. Themain association is with hypertriglyceridemia,found in 50% of cases. Reduced HDL level canbe found in some patients. In such cases, it may beconsidered a predictor of cardiovascular risk, severeischemic heart disease, and atherosclerosis,especially if combined with hypertension, diabetes,obesity, and smoking. It is a rare disease in thegeneral population and has a slight predominancein females. They have peak incidence between thefourth and fifth decade of life.

The diagnosis is clinical, but it should beremembered that about half of patients haveabnormal lipid levels; therefore, they shouldhave their values measured frequently. Somedrugs such as nilotinib, used to treat chronicmyelogenous leukemia, may developxanthelasma (Sayin et al. 2016).

The treatment is based primarily on dietaryrestriction and lipid-lowering drug if necessary.The aesthetics of xanthelasma is limited toisolated treatment of dyslipidemia. Numeroustherapeutic options for the aesthetic xanthelasmatreatment are available, such as surgical removal,electrosurgery, chemical cauterization withtrichloroacetic acid, and cryosurgery. Thepingyangmycin, family antibiotic bleomycin,can be injected into the lesions with good results(Wang et al. 2016). Electrocautery andcryosurgery can destroy superficial lesions, butrequire repeated treatments. Cryosurgery maycause scarring and hypopigmentation and shouldbe discouraged. The use of ablative lasers asultrapulsed CO2, Erb:YAG (Güngör et al. 2014),Q-switched Nd:YAG, diode, pulsed dye laser, andKTP laser has become popular in the treatment ofthese lesions. The CO2 ablative lasers areexcellent options for localized xanthelasmas andwithout involvement of muscles (Mourad et al.2015; Pathania et al. 2015) (Fig. 2).

Fig. 2 (a, b) Xanthelasma treated with ultrapulsed CO2 laser

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Surgical removal is best indicated for cases ofdiffuse xanthelasma, deep involvement of thedermis and/or muscle. Recurrence is common,with rate of about 40%.

Sebaceous Hyperplasia

It is a common benign condition of the sebaceousglands of middle-aged adults or older. Lesions maybe single or multiple and manifest themselves assmall yellowish or skin color papules of 2–9 mm,normally with a central umbilication, located on theface (particularly the nose, cheek, and forehead).Occasionally they are seen in the breast, areola,mouth, scrotum, prepuce, and vulva. Rarelyreported variants included a giant form, a lineararrangement or zosteriform, a diffuse form, and afamilial form. Some consider the rhinophyma aspecial form of sebaceous hyperplasia. Itsfrequency is about 1% in healthy elderly adults,but comes to be as high as 10–16% in patientsreceiving long-term immunosuppression withcyclosporin A. The neonates may present around43.7% of sebaceous hyperplasia. It has beenreported in association with internal malignancyin Muir-Torre syndrome. It must be distinguishedfrom basal cell carcinoma (BCC) – some papuleshave telangiectasia and molluscum contagiosum.

The histopathology represents amultilobulated sebaceous gland increased insize. The lobes have one or more layers of basalcells at its periphery with undifferentiatedsebocytes containing large nuclei and scant

cytoplasmic lipid, in contrast to normalsebocytes, which are filled with lipids. Thedecrease in levels of circulating androgens,associated with aging, appears to be the cause ofsebaceous hyperplasia. Ultraviolet radiation andimmunosuppression have been postulated ascofactors (Fig. 3).

Treatment

Therapeutic options include photodynamic therapy,cryotherapy, cauterization or electrocoagulation,chemical topical treatment with trichloroaceticacid (TCA), and treatment with argon laser, carbondioxide, and 1,450 nm and 1,720 nm diodes (No etal. 2004; Aghassi et al. 2000; Winstanley et al.2012; Simmons et al. 2015a). The complicationsof these destructive nonspecific therapies includedepigmentation and atrophic scarring. Oralisotretinoin has been shown to be effective inremoving some lesions after 2–6 weeks oftreatment, but the recurrence of the lesions iscommon after cessation of therapy.

Viral Wart

It is a frequent viral skin infection, with limitedcourse, caused by the human papillomavirus(HPV), being able to produce epidermalproliferation characterized by acanthosis,accompanied by papillomatosis, and it can befound in up to 10% of young adults and children.

Fig. 3 (a, b) Sebaceous hyperplasia treated with CO2 laser (low fluence)

198 E.R. de França et al.

It is caused by papillomavirus of the papovavirusgroup of double-stranded DNA capable ofeliciting cytolytic effect on the infected cells,causing their death.

Clinically, it is characterized by papules ornodules exophytic with roughened surface,sometimes with small darkened spots, whichrepresent thrombosed capillaries. They arecommonly located on the back of hands andfingers in the nail bed or periungual and kneesfolds. About 65% of common warts disappearspontaneously within 2 years. New warts maydevelop at sites of trauma, constituting theisomorphic Koebner phenomenon which isusually less pronounced than the flat warts.

Infection is acquired by direct contact withpatients with clinical and subclinical lesions throughobjects or contaminated surfaces (pools, gyms). It isbelieved that each new injury is a result ofautoinoculation. Minor traumas predisposes toinfection. Nail biting is associated with periungualwarts. The trauma while shaving can spread thefiliform warts of the beard area. Hyperhidrosis andflatfoot predispose to plantar warts. The averageincubation period is 3 months, but can rangebetween 1 and 20 months. The papillomas causedby HPVare initially benign.

The incidence of warts, its malignant potentialand regression, appear to be directly related toimmune disorders mediated by host cells. Wartsoccur more frequently, last longer, and appear inlarge numbers in patients with AIDS andlymphomas and those who take immunosup-pressant drugs.

Treatment

The lesions in patients with cell-mediated immunitydeficit are generally resistant to treatment. Moreover,treatment of a lesion can lead to regression of manyor all warts in immunocompetent individuals(Fig. 4).

The objective is to destroy the infected cellsusing substances such as fuming nitric acid,salicylic acid, lactic acid, TCA, cantharidin,podophyllin, 5-fluorouracil, or intralesionalbleomycin. We may use cryosurgery,photodynamic therapy, and even surgicalprocedures such as curettage and electrodes-sication. The surgery with suture and radiotherapyare contraindicated. Among the lasers is thedescribed CO2 laser or hyperthermia by Nd:YAG laser (Oni and Mahaffey 2011). HPV is

Fig. 4 (a, b) Verruca vulgaris treated with CO2 laser

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more vulnerable to hyperthermia than thecryotherapy. In the warts resistant flashlamppulsed dye laser (585 nm) has been used with80% efficiency.

The reoccurrence of the viral lesions(condylomas and warts) after treatment withCO2 laser have not been more frequent thanisolated techniques. One study showed norecurrence of lesions in 12 months of follow-upafter removal of warts with CO2 laser andimiquimod cream 5% after epithelialization,once a day, five times a week for 2 weeks (Zenget al. 2014).

Plantar WartPlantar warts are notoriously more difficult totreat and eradicate. The use of artificial dermis(curative) after the CO2 laser ablation, and use ofsalicylic acid in residual lesions, appears to beeffective in these situations. Mitsuishi provedthe absence of HPV DNA in the upper epidermisof the treated sites after this technique and theabsence of significant scarring or severe pain(Mitsuishi et al. 2010) (Fig. 5).

Genital Warts

The use of CO laser in genital warts is safe andeffective (Padilla-Ailhaud 2006). The cure rate in asingle session reaches 70%. Relapses are associatedwith multiple partners and involvement of the

cervix in women. Combination therapy with CO2

laser and photodynamic therapy with ALA(5-aminolevulinic acid) exhibits a lower rate ofrecurrence of lesions that isolate CO2 laser therapyfor refractory lesions (Huang et al. 2014). Thetreatment can be done during pregnancy (Savocaet al. 2001). In a study of 18 pregnant womentreated between 15 and 38 weeks of gestation,there were no abortions, premature birth, orcomplications (infection, bleeding) by theprocedure (Gay et al. 2003). The Bowenoidpapulosis corresponds to intraepithelial neoplasiagrade III of the penis or vulva and is stronglyassociated with HPV 16 (Fig. 6).

Considerations

During the use of the CO2 laser, emitted smokeconsists of gases and/or toxic vapors such asbenzene, formaldehyde and hydrogen cyanide,bioaerosols, steam, and live or dead cell remnants(including blood debris and viruses). The use ofsmoke filter vacuum cleaners, outdoor exhaustsmoke, gloves, and laser mask is advisable. Thehose can be handled by a helper 2 cm from theoperative field or be coupled to the handpiece.Several studies have shown that the smokeresulting from the vaporization of viral lesionsby CO2 laser is an aerosol containing viralparticles which are dispersed by a diametergreater than 2 m, even under vacuum,

Fig. 5 (a–c) Plantar wart treated with CO2 laser

200 E.R. de França et al.

contaminating the equipment and the peopleinvolved (skin and breast nasal) during surgery.For this reason, the CO2 laser is not a first-choicetreatment for viral lesions such as common wartsand genital warts. Studies analyzing the resultingsmoke from the vaporization of human viral wartswith Er:YAG laser did not detect the presence ofviral DNA; this laser is apparently safer than theCO2 laser. However, the case of a doctor whoused the Nd:YAG laser to treat perianal wartswas described and developed a laryngealpapillomatosis. Viral particles of HIV andhepatitis C virus were also found, in addition tothe HPV, in the smoke caused by CO2 laservaporization; therefore, it is not recommendedfor treatment of patients suffering from theseinfections by this process (Hallmo and Naess1991).

Melanocytic Nevus

Melanocytic nevus (MN) is a benign lesion ofnevus cells that arises as a result of theproliferation of melanocytes. There are twofundamental types: congenital melanocyticnevus and acquired melanocytic nevus.

Congenital melanocytic nevi are present sincebirth. They usually present as small blemishes orbrown papules with smooth or warty, sometimeshairy, even larger lesions that can occupy entire

members. When they are larger than 20 cm, theyare called giant melanocytic nevi (0.002% ofnewborns). The average nevus lesions and giantMN often have a hairy surface (95%) androughened with color ranging from brown toblack. Neurological disorders may be associatedwith giant MN according to the area mostaffected, such as spina bifida and meningocele,due to infiltration of melanocytes in the nervestructures, constituting the neurocutaneousmelanosis. Surgical excision is recommendeddue to the high risk of malignant transformation,but it is often a difficult treatment to be carried outdue to the extent of the injury, being necessary toresort to the use of expanders, patchwork rotation,and placement of grafts.

Other therapeutic options currently availablefor congenital MN include dermabrasion,chemical peels, and laser ablation. These methodsallow to improve the aesthetic appearance, butthey are not effective to completely remove thedeep nevus cells, since they are surfacetreatments. Only complete excision of the nevuswith clear deep surgical margins can effectivelyreduce or eliminate the potential for malignanttransformation in the future.

The MN acquired are common and usually occurbetween 12 and 30 years, although they can appearin childhood. They tend to decline slowly from theage of 35 and may increase in size during puberty,pregnancy, corticosteroids, and sun exposure.

Fig. 6 (a, b) Bowenoid papulosis treated with CO2 laser

CO2 Laser for Other Indications 201

Clinically they may present as flat lesions, warty,domed, or pedunculated. Histologically they can bejunctional, compounds, or intradermal.

Usually no treatment is necessary. In cases byremoval of various cosmetic reasons, methods havebeen used such as surgical excision, cryosurgery,electrodissection, and more recently laser. Thenevus lesion should be excised with a margin of1–2 mm and subjected to histopathological studyon suspicion of malignancy.

There are few data in the literature that supportthe use of laser in melanocytic lesions. Nonablativemethods produce selective photothermolysis ofmelanin pigment, with secondary destruction ofthe nevus cell, as performed by the Q-switchedruby, Nd:YAG, and alexandrite. These produce asurface whitening effect; althoughwith the cosmeticimprovement, there are recurrences in many cases,they may mimic a melanoma (pseudomelanoma)and change the potential for malignanttransformation, which requires long-term follow-up studies. When removing the possibility ofmalignancy, for clinical evaluation and dermoscopy,intradermal nevi and compounds may be removedby ablative lasers such as CO2 or Er:YAG laser withsatisfactory cosmetic results (Hague and Lanigan2008; Bukvić et al. 2010; Baba and Bal 2006).The CO2 laser is currently preferred to cause lessscarring, less bleeding, and simplicity of theprocedure. For more than 5 mm nevi, some authorssuggest serial ablation of the lesion at intervals of2–4 weeks between sessions, varying the number of

sessions according to the size of the lesion (Ozaki etal. 2014) (Fig. 7).

Verrucous Epidermal Nevus

They are hamartomatous circumscribed lesionsformed almost exclusively by keratinocytes. Theymay arise at birth and during childhood or onlybecome apparent in adulthood. Lesions are typicallyseen on the trunk, tend not to cross the midline, andfollow the Blaschko’s lines. The lesions on thelimbs tend to be linear and verticalized. Initially,they show up as streaks or pigmented plates, whichdarken with time and showmore and more keratoticsurface. When they reach one-half of the body, theyare called nevus unius lateris, and if widespread,ichthyosis hystrix.

A variant of verrucous nevus is ILVEN(inflammatory linear verrucous epidermal nevus)having constant itching and has aspect of a chroniceczematous dermatitis or psoriasis; women aremore affected. Clinically it is characterized by theappearance since the birth of recurrent chronicinflammatory phenomena, usually unilateral, withintense itching and refractory to treatment (Lee et al.2001). Another variant is the nevus comedonicuscorresponding to a set of papules with centralstoppers corneas.

There is no ideal treatment, and this may beoften disappointing because of relapses andunaesthetic scars. The therapy includes topical

Fig. 7 (a, b) Acquired melanocytic nevus treated with ultrapulsed CO2 laser

202 E.R. de França et al.

agents, dermabrasion, cryosurgery, photodynamictherapy, and laser cutting. The most commonlyused are the ablative lasers, such as CO2 or Er:YAG laser (Thual et al. 2006). The use of lasersallows satisfactory aesthetic results (Boyce andAlster 2002). The Er:YAG laser should be used inless warty lesions (Pearson and Harland 2004)(Fig. 8).

Syringoma

It is a benign tumor fairly common, usuallymultiple, represented by small rosy-yellowishpapules smaller than 3 mm, symmetrical,located in the lower eyelids and periorbitalregion, mainly in adult women. Sometimes itcan be translucent or cystic. They are largelyof cosmetic significance.

The syringoma usually appears first inpuberty; additional lesions may develop later.There is a form of sudden onset in adolescencethat affects the neck, chest, abdomen, and penisthat is the eruptive hidradenoma. It can also befound on the vulva, armpit, and back of hands. Itis characterized histologically by cystic ducts andcomma-shaped and solid epithelial cords

surrounded by fibrous stroma. The histogenesisof syringomas is probably related to eccrineelements or pluripotent stem cells.

Friedman and Butler classify syringoma infour variants: (1) localized form, (2) formassociated with Down’s syndrome (3),generalized form that encompasses multipleeruptive syringomas, and (4) a familial form.

Rarely, syringomas may be associated with theBrooke-Spiegler syndrome, an autosomal dominantdisease characterized by the development ofmultiple cylindromas, trichoepitheliomas, andoccasional spiradenomas. Syringomas occur withincreased frequency in patients with Down'ssyndrome (6–36% of cases), usually in womenover 10 years old (Fig. 9).

Surgical Care

The main reason for the treatment is cosmetic.Complete removal is often unsuccessful andrecurrence is common, as syringomas aregenerally in the dermis. Possible treatmentsinclude surgical excision with primary suture,electrocautery, cryosurgery, dermabrasion, TCA,carbon dioxide laser, or Er:YAG laser (Cho et al.

Fig. 8 (a, b) Verrucous epidermal nevus after treatment with CO2 laser

CO2 Laser for Other Indications 203

2011; Sajben and Ross 1999; Kitano 2016; Seoet al. 2016; Lee et al. 2015). Regarding the use ofthe CO2 laser, recurrence of the tumor is associatedwith a surface ablation, and complications such ashypopigmentation and atrophy are associated withdeeper ablation (Fig. 10).

Fordyce Spots

The Fordyce granules are asymptomaticsebaceous glands commonly found in the oralmucosa, upper lip, and retromolar region. Theyare characterized by multiple whitish or yellowishpapules with diameter from 0.1 to 1 mm whichoccasionally may coalesce and form plaques.Only visible sebaceous glands through the

epithelium should be considered as Fordycegranules. In children they usually are not noticeduntil puberty, but are histologically present. Itsincidence increases with age, especially after thehormonal stimulation of puberty. The prevalencein adults ranges from 70% to 85% with a slightpredominance in males. Histopathologically, thelesions are indistinguishable from the sebaceousglands, but are not associated with hair follicleand its duct opens directly onto the surface.

It is an entity of easy clinical diagnosis andadditional tests are not needed. The frameworkmust be distinguished from other lesions of theoral cavity: small colonies of Candida albicans,miniature lipomas, Koplik’s spots, warts, papularmucosal lesions of Cowden syndrome, lichenplanus, and leukoplakia. Despite its asymptomatic

Fig. 9 (a, b) Syringomas treated with CO2 laser

Fig. 10 (a, b) Syringomas treated with CO2 laser. Observe post-laser relative hypochromia, contrasting with thehyperpigmentation of the dark circle

204 E.R. de França et al.

nature and considered normal variants, somepatients seek treatment for cosmetic reasons.There are reports of cases where we used thedichloroacetic acid, CO2 laser (Ocampo-Candianiet al. 2003), photodynamic therapy using5-aminolevulinic acid, oral isotretinoin, andcurettage with electrocoagulation (Chuang et al.2004; Baeder et al. 2010) (Fig. 11).

Seborrheic Keratoses

Seborrheic keratoses are keratotic papules orplaques for limited arising from keratinocytesepidermal proliferation. The lesions usually appearafter age 40 and are more common in Caucasians.Its surface is rough and greasy, does not reflect

light, and can show corneal cysts or have acerebriform appearance. It has a very variablepigmentation that goes from light brown to blackand may be confused with actinic keratosis,melanocytic nevus, or lentigo maligna (Fig. 12).

They are located more on the trunk and face.They may be single or be tens and can beremoved by curettage, cryosurgery, electrocoa-gulation, or CO2 laser (Fig. 13).

Rhinophyma

Rhinophyma is a dermatologic benign disease ofthe nose that primarily affects Caucasian men ofthe fifth to seventh decades of life. There ishyperplasia of the sebaceous glands leading tothe appearance of peau d’orange. It ischaracterized by a slowly progressiveenlargement of the nose with irregular thickeningof the nasal skin and nodular deformation. It isone clinical type of rosacea.

The rhinophyma shows prominence of thesebaceous glands with the development ofthickened and disfigured noses in extreme cases.The condition usually does not produce scars.The rhinophyma can occur as an isolated entity,without other symptoms or signs of rosacea. Itcan be disfiguring and distressing to patients.

Fig. 11 (a, b) Multiple yellowish papules on the upper lip before and after use of the CO2 laser

Fig. 12 The histology of seborrheic keratosis showinghyperkeratotic surface and numerous corneal cysts

CO2 Laser for Other Indications 205

Some authors consider the rhinophyma a differentdisease. The main reasons that lead patients toseek help are aesthetic and functionalimpairments, such as nasal obstruction and sleepapnea. However, 46 cases of malignancies such asBCC and SCC have been found associated withrhinophyma, which leads us to examine allexcised tissue (Fig. 14).

Various methods have been used to correct themalformations produced by this disease in thenose as dermabrasion, electrocautery, and lasertherapy. The treatment of choice for rhinophymais removal surgery of the hyperplastic tumor. Theuse of CO2 laser for the treatment of rhinophymais an appropriate therapy with excellent aestheticresults, minimal surgical morbidity, and little risk.The pulsed dye laser can be used after the CO2

laser to improve vascular rhinophyma component(Moreira et al. 2010). We may also use the Er:YAG as ablative (Orenstein et al. 2001). Theelectrocoagulation and cold cut by scalpelprovide similar long-term results, but hemostasisis less efficient and the operating time is extended.The period of postoperative healing is faster andscars occur less in the case of CO2 laser (Meesterset al. 2015; Baró et al. 2015; Serowka et al. 2014).

Actinic Cheilitis

Actinic cheilitis (AC) is considered apremalignant lesion or an incipient and superficialform of squamous cell carcinoma (SCC) of thelip. Genetically predisposed keratinocytes

Fig. 13 (a, b) Seborrheic keratoses treated with CO2 laser

Fig. 14 (a–c) Rhinophyma treated with ultrapulsed CO2 laser

206 E.R. de França et al.

probably undergo molecular change induced byultraviolet light B yielding neoplastickeratinocytes. Therefore, AC is in fact the resultof clonal expansion of transformed keratinocytes,considered from the beginning of a SCC in situ. Itis commonly found in individuals whoseprofessional activities are related to chronic sunexposure, particularly redheads with light skinand lower lip eversion. The lower lip is morevulnerable to sunlight by having a thinepithelium, a thin layer of keratin, and a lowercontent of melanin. Smoke and lip infectionshuman papillomavirus can cause cytogeneticchanges and increase the risk of actinic cheilitisprogress to SCC (Wood et al. 2011).

Clinical signs include atrophic diffuse andpoorly demarcated plaques or erosive keratoticthat may affect all or some parts of vermilion.The definitive diagnosis is obtained by biopsy.Histopathological changes consist from atrophyto hyperplasia of the squamous epithelium on theborder of vermilion, with varying degrees ofkeratinization, disorderly maturation, increasedmitotic activity, and cytological atypia. Apoptoticcells are often present, but the basementmembrane is intact. The underlying connectivetissue shows basophilic degeneration (solarelastosis). Actinic cheilitis should be consideredas a SCC intraepithelial or in situ, based on theabovementioned microscopic changes (Fig. 15).

The risk of occurrence of AC progress to SCCvaries from less than 1% to 20%. Clinically, pain,induration, large size, marked hyperkeratosis,ulceration, bleeding, rapid growth, and recurrenceor persistence may be markers of progression ofAC for SCC. The risk of metastasis to the SCC

varies between 0.5% and 3%. However, lip SCCresulting from actinic cheilitis is more likely tometastasize than skin SCC, with rates rangingfrom 3% to 20% (Kwon et al. 2011). The treatmentis of crucial importance due to the potential formalignant transformation. Surgical excision of theentire vermilion (vermilionectomy) as histologicalexamination of serial sections is the preferredtreatment. Other possible treatments includeelectrodissection, cryosurgery, photodynamictherapy, topical treatment with the antineoplasticagent 5-fluorouracil or immunomodulatorimiquimod, and lasers such as CO2 and Er:YAG(Cohen 2013; Laws et al. 2000). However, withthese arrangements, the tissue is not available forhistological examination (Dinani et al. 2015). Theprevention of AC can be achieved through thereduction of cumulative exposure to UVBradiation. The use of protective clothing, reducingoutdoor activities, and the use of sunscreens shouldbe introduced very early in childhood andcontinuing throughout life.

Exogenous Ochronosis

Ochronosis is a grayish-brown pigmentation ofconnective tissues that can be classified asendogenous or exogenous. The endogenousvariety, also known as alkaptonuria, is a rare,congenital disorder and autosomal recessive,which results from the absence of the enzymethat converts homogentisic acid to acetoaceticacid and fumaric acids. Affected individualsdevelop accumulation of homogentisic acid, aninsoluble pigment that is deposited in various

Fig. 15 (a–c) Actinic cheilitis treated with ultrapulsed CO2 laser

CO2 Laser for Other Indications 207

tissues such as the cartilage, skin, and heart valves(Albers et al. 1992).

Exogenous ochronosis is clinically andhistologically similar to endogenous, but doesnot have systemic involvement. It is characterizedby blue-black or grayish asymptomatic hyperpig-mentation typically located on the face, neck,back, and extensor surfaces of the extremities. Itmost commonly follows the use of hydroquinone,but resorcinol, phenol, mercury, picric acid, andoral antimalarials may also be involved. It wasinitially considered to be caused only by the useof high concentrations of hydroquinone for anextended period, but there are reports of recentcases demonstrating the development of thispathology with use of hydroquinone 2% for aperiod not longer than 3 months. The hyperpig-mentation mechanism induced by hydroquinoneremains uncertain (Charlín et al. 2008). It isreported the possibility of activation of tyrosinaseby high concentrations of hydroquinone, leadingto stimulation of melanin synthesis. Other authorssuggest that the hydroquinone oxidase inhibitsthe activity of homogentisic acid in the skin,which leads to accumulation of homogentisicacid, which then polymerizes and formsochronotic pigment. Melanocytes could beinvolved; many cases are related to sun exposure,

and there is a reported case of ochronosis thatspared vitiligo area (Simmons et al. 2015b).

Clinical presentation: It can be identified intothree stages in the exogenous ochronosis. In stageI it occurs only as erythema and mildpigmentation of the face and neck. Increasingly,there are hyperpigmentation, “caviar-like”papules, and atrophy, which correspond to stageII. The last stage includes papulonodular,surrounded or not by inflammation injury.

Histopathological examination of exogenousochronosis lesions reveals yellow-brown filamentsor green with banana-shaped in the papillarydermis. These filaments undergo degenerationforming colloid milium with progression topapulonodular stage. In stage III there areinflammatory mediators, including giant cells,epithelioid cells, and histiocytes. Some biopsiesexhibit sarcoid-simile granuloma formationsurrounded by filaments. In severe cases it mayalso be described as transepidermal elimination ofpigment and pseudoepitheliomatous hyperplasia(Figs. 16, 17, and 18).

Therapy of exogenous ochronosis is difficult.Various treatments have been used, often withdisappointing results. Avoiding the use of disease-causing substances is beneficial, but it can takeseveral years for some result. The retinoic acid

Fig. 16 (a, b) Exogenous ochronosis treated exclusively with fractionated CO2 laser

208 E.R. de França et al.

was effective in some patients, but in others causedtransient hyperpigmentation. The results of thetreatments with sunscreens and low powercorticosteroids have been variable. There arereports of clinical improvement after use of oraltetracycline, dermabrasion, and CO2 laser;however, the results are not uniform. Regardingdermabrasion, there is a case report in which therewas removal of hyperpigmentation in a whitepatient. A combination of dermabrasion and CO2

laser with satisfactory results in the periorbital andnasal regions in a black woman was reported(Diven et al. 1990). The use of Q-switched (Q-S)laser for the treatment of pigmentary lesions and

tattoos are well documented in the literature. TheQ-S ruby laser 694 nm and 755 nmQ-S alexandritewere used to treat exogenous ochronosis with goodresults, based on the fact that the pigment ofexogenous ochronosis is deposited in the dermisin a manner similar to the tattoo pigment recently(Bellew and Alster 2004; Kanechorn-Na-Ayuthayaet al. 2013; Tan 2013).

There are reports on the effectiveness ofintense pulsed light (IPL), as the laser, for thetreatment of pigmented lesions. The mechanismof action of both is based on selectivephotothermolysis of pigmented cells. IPL hasthe advantage pulse width adjustment and

Fig. 18 (a, b) Ochronosis exogenous treated with fractionated CO2 laser, combined with IPL and Nd:YAG

Fig. 17 (a, b) Exogenous ochronosis also treated exclusively with fractionated CO2 laser

CO2 Laser for Other Indications 209

wavelength according to the skin type and thedepth of pigment deposition in the skin. TCApeeling in different concentrations has been usedfor many years for the treatment of photoaging,acne scars, and pigmentation disorders. The useof ATA in hyperpigmentation is related tocoagulative necrosis of the epidermal cellproteins, followed by cell death. The depth ofthe process depends on the concentration used.The ATA solution between 15% and 25% onlydetermines coagulative necrosis of the epidermis,resulting in surface peeling. In our recentlypublished work, the peeling ATA was used asadjuvant therapy applied immediately after theintense pulsed light sessions; it was observedthat this combination was effective for regressionof the lesions.

Exogenous ochronosis is a disease difficult totreat, requiring a combination of several methodsfor obtaining a satisfactory result (França et al.2010).

Conclusion

The CO2 laser has great versatility as to its use. Itis indicated in various scenarios involving skinexcision, vaporization, and coagulation; there areseveral forms of action for this laser such ascollagen stimulating and rejuvenation or removalof tumors and removal of warts, xanthelasmas,and keratoses among others. The CO2 laser is safesince it is used by trained dermatologist, allowinga dry surgical field, with limited blood loss andinduction of collagen and cicatrization. In thecase of viral lesions (warts and condyloma),laser can be used with the use of the smokeevacuator filter.

Take Home Messages

1. The CO2 laser is ablative with high affinityfor water, considered safe when used byproperly trained physicians.

2. The CO2 laser may be used in many scenariosas for removal of benign epithelial tumors,

keratoses, nevi, warts, and xanthelasmaamong others.

3. The CO2 laser has been shown to be safe inremoving DPN, with low rates of recurrenceor complications, and also has a high degreeof satisfaction by patients even at the highestphototypes.

4. The use of topical anesthetic to benignepithelial lesions is sufficient in most casesand is indicated with petrolatum ointmentonce a day until reepithelialization of lesions.

5. In cases of viral lesions, treatment of a lesioncan lead to regression of many or all warts inimmunocompetent individuals.

6. The CO2 laser is not the first choice in theablation of viral lesions, and the use of thesmoke filter vacuum cleaners, as well asgloves and goggles, is mandatory.

7. The surface ablation is associated withrecurrence in the treatment of syringomas ornevi with the CO2 laser, while complicationssuch as hypopigmentation and atrophy areassociated with deeper ablation.

8. The period of postoperative cicatrization isfaster in cases of rhinophyma treated withCO2 laser compared to electrocoagulation.

9. The CO2 laser permits removal of actinickeratoses, but there are no evaluation of thelesion margins.

10. Exogenous ochronosis is difficult to treat andthe results with the CO2 laser are not uniform.

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Fractional Ablative and Non-AblativeLasers for Ethnic Skin

Paulo Roberto Barbosa, Tais Valverde, Roberta Almada e Silva,and Fabiolla Sih Moriya

AbstractEthnic skin is a term used to define the darkerskin corresponding to Fitzpatrick’s IV, V, andVI skin types. Patients with ethnic skin have anincreased risk of problems related to pigmen-tation, such as post-inflammatory hyper-pigmentation or hypopigmentation. For along time, ethnic skin treatment with laserswas a big challenge, especially when referringto ablative technologies, a technique so widelyused and widespread in dermatological proce-dures. Over time, laser devices have evolved,and recent techniques make its use safer, withless downtime and, consequently, with lessdamage and risk of post-inflammatory pigmen-tation. When performed by skilled and well-trained dermatologists, the use of fractionalablative and non-ablative lasers can be consid-ered safe and viable for many different treat-ments. This chapter is going to discuss ethnicskin and the peculiarities of laser treatment.

KeywordsEthnic skin • Laser • Ablative technologies •CO2 laser • Erbium lasers • Fractional andnon-fractional ablative lasers

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213

Fractional Ablative Lasers . . . . . . . . . . . . . . . . . . . . . . . . . 214

Fractional Non-Ablative Lasers . . . . . . . . . . . . . . . . . . . 215

Indications for Laser Treatment in EthnicSkin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216

Pigmentary Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216Acne . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216Benign Cutaneous Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . 216Stretch Marks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217Rejuvenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217

My Experience with Lasers for Ethnic Skin . . . . . 217

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220

Take Home Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220

Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221

Introduction

The color or race of the Brazilian population isdiverse. Patients with dark color skin are morefrequent in the North and Northeast of our country,due to our colonization, and most of them areconcentrated at the north and northeast of the coun-try. They have an ethnic skin, a term used to definedarker skin and non-Caucasian, corresponding to

P.R. Barbosa (*) • T. Valverde • R.A. Silva • F.S. MoriyaBrazilian Society of Dermatology, Clínica de DermatologiaPaulo Barbosa – Centro Odontomédico Louis Pasteur,Itaigara, Salvador, BA, Brazile-mail: prbarbosa@uol.com.br; taisvalverde@yahoo.com.br; roberta.almadas@gmail.com; fabisih@yahoo.com.br

# Springer International Publishing AG 2018M.C.A. Issa, B. Tamura (eds.), Lasers, Lights and Other Technologies, Clinical Approaches and Procedures inCosmetic Dermatology 3, https://doi.org/10.1007/978-3-319-16799-2_15

213

skin types IV, V, and VI of the Fitzpatrick classifi-cation (IBGE 2000).

For a long time, treating ethnic skin with laserwas a challenge, especially when referring to abla-tive technologies. Although the main chromo-phore of this technique is the water and notmelanin, the heat generated by them can haveserious postoperative complications if not usedby trained professionals, making it necessary tohave thorough knowledge of the physical basicsof lasers (Battle and Hobbs 2003).

The number of melanocytes and the thicknessof the skin are approximately the same in all races,but ethnic skin has its own characteristics. We canfind in ethnic skin more and higher fibroblasts andbi- or multinucleated and hyperactive fibroblasts.This hyperactivity may explain the predispositionto keloid formation. It is also richer in sebaceousglands and has more collagen (Mateus andPalermo 2012).

The ranging is melanin production speed,number, morphology, size, density, and distribu-tion of melanosomes. Ethnic skin patients have ahigher risk to pigmentation problems because theskin melanin competes with main chromophore,increasing the risk of hyperpigmentation andhypopigmentation post. Moreover the risk of pig-mentary changes can also be correlated with thedepth of the laser injury as well as their effects ondermal heating. Post-inflammatory hyper-pigmentation is the most common complicationof facial resurfacing in patients with skin-type IV(4) (Sriprachya-anunt et al. 2002;Wat et al. 2017).

Fractional Ablative Lasers

Carbon dioxide (CO2) lasers are the main repre-sentative of ablative lasers and, although devisedin 1968, are still regarded as the gold standardtreatment for photoaging. Novel technologies arenow able to produce a column of ablation andcoagulation with rigorously controlled depth, pro-viding increased safety and reduced recoverytime. The method is based on the principle ofselective photothermolysis, developed by Parishand Anderson in 1983. The principle is the selec-tive and specific destruction of a target in the skin

with minimal thermal damage to the componentsin neighboring tissues. To achieve selectivephotothermolysis, the appropriate wavelength pri-marily absorbed by the target tissue or chromo-phore should be carefully chosen. For ablativelasers, the main chromophore is water (Riggset al. 2007; Tierney et al. 2011).

However, CO2 lasers show intense residual ther-mic effect, leading to a final result much broaderthan the tissue ablation observed at the end of theprocedure. Conversely, water is absorbed 13 timesless efficiently with CO2 than with Erbium lasers,which are more superficial and cause less thermaldamage (Kalil and Campos 2012).

A novel treatment concept was described byManstein et al. in 2004: fractional photo-thermolysis. In this procedure, the laser producesmicroscopic lesions, ranging from 100 to 150 μmin thickness and 0.2–2.4 mm in depth, termedthermal microzones (TMZ), which are merelyhighly controlled microperforations in the epider-mis and dermis that are, then, replaced by neworganized tissue rich in collagen. Fractionalphotothermolysis revolutionized laser treatments,allowing for a more efficacious dermal coagula-tion without major damage to the epidermal layer,thus decreasing the risk of nonaesthetic scarifica-tion and reduced recovery time when compared totraditional ablative procedures. Several ablativefractional photothermolysis devices are available,in three different wavelengths: 2790, 2940, and10,600 nm (Kalil and Campos 2012; Xu et al.2011; Macrene et al. 2012; Manstein et al. 2004;Wat et al. 2017).

In 2007, Hantash et al. described the use of anew CO2 ablative fractional laser that generates,by their TZM, ablation and coagulation columnsextending through the stratum corneum, epider-mis, and dermis. A CO2 laser beam is able toremove from 25 to 50 μm of tissue in each appli-cation, raising the temperature up to 100 �C in640 ms. The heat leads to an immediate contrac-tion in the skin, although partly caused by waterevaporation-driven dehydration and by collagencontraction, which retracts in temperatures higherthan 60 �C (Ciocon et al. 2011).

Despite long-lasting clinical improvement,the best results can be seen after 3 months

214 P.R. Barbosa et al.

posttreatment, mostly because of persistentinflammatory responses (demonstrated by thepresence of heat-shock protein 47) and by thecontinuous collagen remodeling observed in his-tological and immunohistochemical studies.Ortiz et al. reported that patients maintain 74%of improvement in the first 1–2 years offollowing-up (Ortiz et al. 2010).

Cellular markers for neocollagenesis, such asprocollagen III and collagen III, are found intreated areas, and the increase of both collagendensity and elastic fibers can be observed up to1 year posttreatment (Xu et al. 2011; Kim et al.2013; Orringer et al. 2004).

Currently there are various CO2 fractionaldevices in the market, which are characterizedby adjustable fluency and pulse length, allowingfor precise control of the level and depth of heat inthe dermis. These parameters – fluency, pulselength, potency, energy, and density – will deter-mine the effectiveness and safety of the treatment(Kadunc et al. 2012).

The erbium: yttrium–aluminum–garnet (Er:YAG) laser was approved by the FDA in 1996for skin resurfacing. Because its wavelength(2940 nm) is the closest to water absorption peak(3000 nm), all its energy is practically absorbed bythe epidermis and the papillary dermis, causingsuperficial ablation and less thermal damage thanCO2 lasers. Each Er:YAG short-pulse application(250–350 ms) ablates approximately 20–25 μm,utilizing 5 J/cm2 of energy. Thermal damagereaches 30–50 μm in depth with a fluency of5–8 J/cm2, which is smaller when compared tothose cause by CO2 lasers (50–200 μm in depthwith a fluency of 3.5–6.5 J/cm2). Even with mul-tiple applications, thermal damages caused by Er:YAG lasers are limited to 50 μm (Riggs et al.2007).

This technology, which acts within the infra-red spectrum, proved its higher ablation effectcausing negligible thermal damage (5 μm perapplication). Because of its wavelength withmaximum water absorption, short pulse length,and adequate energy, Er:YAG lasers are the pre-ferred technology for fine wrinkles, photoaging,and treatments that demand higher phototypes.Injuries to neighboring tissues are minimum

(maximum temperature reaches 30 �C), andbleeding spots started manifesting only afterseveral applications (4–5, depending of the sizetreated), indicating that the dermis–epidermisjunction was reached and therefore the laserapplication should be discontinued. Time forre-epithelization is around 2–4 days (Riggset al. 2007).

Another new type of laser, the Er:YSGG(erbium: yttrium, scandium, gallium, garnet) waslaunched in 2007. It emits energy in the 2790 nmwavelength and presents a coefficient of waterabsorption of 5000/cm2, an intermediate valuebetween those for CO2 and Er:YAG (1000 and12,500/cm2, respectively). Thus, the ablationcapacity of Er:YSGG lasers is higher than thoseof CO2 and lower than those of Er:YAG, withintermediate potential for thermal damageamong the ablative lasers. It treats the whole epi-dermis and causes homeostatic thermal stimuli,which cannot be obtained by Er:YAG lasers. Inaddition, it does not cause the common sideeffects observed during CO2 laser applications,such as thermal damage and long recovery time(Macrene et al. 2012).

The 2790 nm laser allows for two types ofablation (continuous and fractional) in the samesession. This combination causes both vaporiza-tion of the epidermal surface and coagulationzones in the dermis–epidermis (Munavalli et al.2011).

The fractional technique is able to produceablation columns of 300 μm diameter, with adepth of 300–1500 μm, and 40–60 μm of residualthermal damage (Munavalli et al. 2011).

Fractional Non-Ablative Lasers

After the establishment of the principle of frac-tional photothermolysis in 2004, there were thefirst lasers not ablative fractionated approved bythe FDA (Food and Drug Administration). Theprimary chromophore is water and includes wave-lengths ranging from 1064 to 1550 nm. Thesedevices differ from the ablative technology,which promotes epidermal vaporization. Thelaser works with irreversible thermal damage,

Fractional Ablative and Non-Ablative Lasers for Ethnic Skin 215

inducing a healing response in the papillary der-mis and upper reticular (coagulation zones),reaching temperatures between 50 and70 degrees. The coagulation generated by dena-turing collagen induces a located necrosis, withconsequently formation of a new collagen. Oncethis kind of lasers generate heat into the deeperlayers of tissue without affecting the integrity ofthe epidermal barrier, this technique can be con-sidered more secure when used in higher photo-type patients, reducing risks of unwantedcomplications when compared to ablative tech-niques. Coagulation columns can reach greatdepths in the skin, depending on the amount ofenergy used (fluence), the density of thermalmicrozones per application, and the number ofpasses (Macrene et al. 2012).

Indications for Laser Treatmentin Ethnic Skin

Pigmentary Disorders

Pigmentary disorders in ethnic skin are one of themost common complaints in dermatologicaloffices (Ortiz et al. 2010). Among them, melasmaand post-inflammatory hyperchromia are veryfrequent.

The treatment of melasma (chapter ▶ “Q-Switched Lasers for Melasma, Dark CirclesEyes, and Photorejuvenation” in volume “DailyRoutine in Cosmetic Dermatology”) is still a chal-lenge for dermatology despite of the skin photo-types, but it is still worse in ethnic skin. It isnot uncommon not to have any improvementafter treatment, as well as darkening of the areatreated. Post-inflammatory hyperchromia is a rela-tive common side effect after laser treatment (Jack-son 2003). Even though, the use of non-ablativefractionated lasers, Q-switched Nd-YAG laser,with low thermal damage, can be an option formelasma.

Microneedling technique with or without drugdelivery (TED) (chapters ▶ “Microneedling forTransepidermal Drug Delivery on Stretch Marks,”

this volume) is an excellent option for pig-mentary disorders, melasma, or post-inflammatoryhyperchromia. When associated with drug deliv-ery, hydroquinone, kojic acid, azelaic acid,and tranexamic acid are applied just before themicroneedling. These substances can be used iso-lated or combined. Light erythema is observedafter treatment. It lasts less than 24 h, withvery rapid recovery. Microneedling treatment orTED with microneedling can be associated withQS laser treatment alternating the sessions every2–4 weeks.

Some superficial chemical peels, combiningretinoic acid or alpha hydroxy acid with lighten-ing medications (hydroquinone, kojic acid, andtranexamic acid) can also be used as a comple-mentary treatment alternating with lasers. It is alsopossible to apply this peel above the skin, justafter QS laser treatment.

Acne

Acne commonly causes post-inflammatory pig-mentation and atrophic scars (Taylor et al. 2002).Fractionated non-ablative laser is very well indi-cated to induce skin remodeling, sparing the epi-dermis (Jackson 2003). This procedure has ashorter downtime and a fewer risk ofdyschromias; however it requires a greater num-ber of sessions when compared to ablative lasers.We also use ablative lasers, although conserva-tive parameters (low energy and low density)should be applied. Controlled radio-frequencymicroneedles and fractional ablative radio fre-quency are also excellent options to treat darkerskin.

Benign Cutaneous Tumors

Ablative lasers can be used to remove facialangiofibromas, syringomas keratosis seborrheic,as well as dermatosis papulosa nigra, keloidalfolliculitis of the neck, and dermatosis with higherprevalence in ethnic skin (Jackson 2003).

216 P.R. Barbosa et al.

In these cases, we use CO2 or erbium YAGlaser in surgical mode of operation, choosing theproper spot diameter according to the lesiondimension, avoiding perilesional thermal damage(Cole et al. 2009).

Stretch Marks

The literature reports numerous treatment optionsfor stretch marks, such as intense pulsed light,pulsed dye laser, ablative radio frequency, Er:Glass, Er:YAG, and CO2. However, very fewdiscuss those treatments on ethnic skin (Aldahanet al. 2016).

Some studies in Asians (phototype VI) suggestthat ablative and non-ablative fractionated lasersare promising technologies in the treatment of thiscondition (Kim et al. 2008; Lee et al. 2010). In2011, Yang and Lee (2011) compared the1550 nm (Er:YAG) laser to fractionated CO2 in astudy involving 24 Asian patients with whiteabdominal stretch marks. Treatments were ran-domized to each side of the body with three ses-sions every 4 weeks. Clinical improvement wassomewhat higher on the side whose treatment wasperformed with fractionated CO2, despite of moreadverse events in this group. Clinically, there wasa reduction in the width of the striae, and anincrease in the number of collagen and elasticfibers was observed in the histology study (Yangand Lee 2011).

We have experience with fractionated ablativelasers (CO2 and Erbium 2940) in treatment ofstretch marks in phototypes V. Our protocolincludes testing two different parameters in asmall area 30 days before the first session; usingcold air cooling before, during, and after proce-dure; and applying low energy and low density(Kono et al. 2007). Post-inflammatory hypo-chromia is a common and mostly transientadverse event.

Rejuvenation

Although relatively more risks of pigmentarydisorders and scars are described, effective

treatment with lasers can be achieved in patientswith higher phototypes (Bhatt and Alster 2008;Shah and Alster 2010). As an alternative toreduce these risks, non-ablative fractionatedlasers are an excellent option. The correctparameters are essential to reduce side effects.Both technologies can be used in different ses-sions, respecting the interval of 4 weeks betweenthe applications.

My Experience with Lasersfor Ethnic Skin

Treating ethnic skin with lasers is always chal-lenging. The first step is to evaluate the patientand the dermatosis to be treated and choose thebest technology to be applied. We often per-form a test treatment in a small area of theskin using two different parameters to checkthe effectiveness and to avoid side effects.This test is usually done 30 days beforetreatment.

The use of lightening cream, as hydroqui-none isolated or associated with retinoic acid,to prepare the skin before laser applicationis controversial, but it is part of our routine.We also use these medications 3–4 weeks aftertreatment.

All patients are photographed before the pro-cedure my experience with lasers for ethnic skin.Topical anesthetics are indicated to reduce thepain. During the procedure we use skin coolingequipment, as we believe that it can minimizeinflammation, burning, and pain.

We routinely use conservative parameters atthe first session, making adjustments in the sub-sequent sessions. Low fluence and low densityand are indicated to reduce thermal effects,avoiding dyschromia.

Just after procedure we apply steroid creamfor the first 3 days associated with a restorativecream, which is maintained until completehealing. After treatment, patients are advised towear sunscreens with broad spectrum, and it isfundamental to avoid sun exposure (Figs. 1, 2, 3,4, 5, 6, and 7).

Fractional Ablative and Non-Ablative Lasers for Ethnic Skin 217

Fig. 1 Acne scars: CO2 Exelo 2; E: 45 mJ; P: 2 ms; D: 250pt; 2 sessions (front view and lateral view)

Fig. 2 Dermatosispapulosa nigra: CO2 Luxar;F: 5W Mode: Dynamic(Cortesy by EmmanuelFrança)

218 P.R. Barbosa et al.

Fig. 3 Tuberous sclerosis –Angiofibromas: CO2 Luxar;F: 5W Mode: Dynamic(Cortesy by EmmanuelFrança)

Fig. 4 Striae: CO2 Exelo 2; E: 30 mJ; P: 2 ms; D: 250pt; 4 sessions

Fig. 5 Striae: CO2 Exelo 2; E: 20 mJ; P: 2 ms; D: 200pt; 1 session. Starlux 1540 nm 15 mm; 55 mJ; 10 ms; 1 session.Starlux 1440 nm 70 mJ; 10 ms; 1 session

Fractional Ablative and Non-Ablative Lasers for Ethnic Skin 219

Conclusion

Nowadays, ethnic skin patients are looking fordermatologic treatments, and according toadvances in lasers’ technology, the best resultscan be achieved. It is fundamental to photographthe patients before and after each procedure, touse the appropriate parameters according to theindications and to follow the patients during thepost-procedure period until complete skinrecovery.

Take Home Messages

– Ethnic skin is a term used to define the darkerskin corresponding to Fitzpatrick’s IV, V, andVI skin types.

– Patients with ethnic skin have an increased riskof problems related to pigmentation, such asand post-inflammatory hyperpigmentation orhypopigmentation.

– The risk of pigmentary changes is correlatedwith laser injury and thermal damage. It

Fig. 6 Post-inflammatory hyperpigmentation and varicella scars. Starlux G 28 J/cm – 20 ms (3 sessions). Starlux1540 nm 15 mm 15 mJ – 15 ms (3 sessions)

Fig. 7 Acne Scars: Starlux 1540 nm. 55 mJ; 15 ms (1 session) + 60 mJ; 15 ms (2 sessions)

220 P.R. Barbosa et al.

depends on laser wavelength, fluency, anddensity.

– Over time, lasers devices have evolved, andrecent techniques make its use safer, with lessdowntime and, consequently, with lessdamage and risk of post-inflammatorypigmentation.

– When performed by skilled, well-trained der-matologists, fractional ablative and non-ablative lasers become safe and viable formany treatments.

Cross-References

▶Microneedling for Transepidermal Drug Deliveryon Stretch Marks

References

Aldahan AS, Shah VV, Mlacker S, Samarkandy S,Alsaidan M, Nouri K. Laser and light treatments forstriae distensae: a comprehensive review of the litera-ture. Am J Clin Dermatol. 2016;17(3):239–56.

Battle Jr EF, Hobbs LM. Laser therapy on darker ethnicskin. Dermatol Clin. 2003;21:713–23.

Bhatt N, Alster TS. Laser surgery in dark skin. DermatolSurg. 2008;34(2):184–94.

Ciocon DH, Engelman DE, Hussain M, Goldberg DJ. Asplit-face comparison of two ablative fractional car-bon dioxide lasers for the treatment of photo-damaged facial skin. Dermatol Surg. 2011;37(6):784–90.

Cole PD, Hatef DA, Kaufman Y, Pozner JN. Laser therapyin ethnic populations. Semin Plast Surg. 2009;23(3):173–7.

IBGE – Brazilian Institute of Geografy and Statistics,Brazil 500 Years. Rio de Janeiro; 2000.

Jackson BA. Lasers in ethnic skin: a review. J Am AcadDermatol. 2003;48(Suppl 6):S134–8.

Kadunc B, Palermo E, Addor F, Hetsavaht L, Rabello L,Hattos R, Martin S. Textbook of dermatologic surgery,cosmiatry and laser. In: Osório N, Macéa J, editors.Ablative fractional lasers for photoaging. 1st ed. Riode Janeiro; 2012. p. 772. Elsevier.

Kalil C, Campos V. Practical laser handbook and othersources of electromagnetic energy. In: Boechat A, edi-tor. Laser and interaction whit tissues. 1st ed. Rio deJaneio; 2012. p. 19. Elsevier.

Kim BJ, Lee DH, Kim MN, Song KY, Cho WI, Lee CK,Kim JY, Kwon OS. Fractional photothermolysis for thetreatment of striae distensae in Asian skin. Am J ClinDermatol. 2008;9(1):33–7.

Kim JE, Won CH, Bak H, Kositratna G, Manstein D, DottoGP, Chang SE. Gene profiling analysis of the earlyeffects of ablative fractional carbon dioxide laser treat-ment on human skin. Dermatol Surg. 2013;39(7):1033–43.

Kono T, Chan HH, Groff WF, Manstein D, Sakurai H,Takeuchi M, Yamaki T, Soejima K, NozakiM. Prospective direct comparison study of fractionalresurfacing using different fluences and densities forskin rejuvenation in Asians. Lasers Surg Med. 2007;39(4):311–4.

Lee SE, Kim JH, Lee SJ, Lee JE, Kang JM, Kim YK,Bang D, Cho SB. Treatment of striae distensae usingan ablative 10,600-nm carbon dioxide fractional laser: aretrospective review of 27 participants. Dermatol Surg.2010;36(11):1683–90.

Macrene RA, Jeffrey SD, Kenneth AA. Fractional laserskin resurfacing. J Drugs Dermatol. 2012;11:1274–87.

Manstein D, Herron GS, Sink RK, Tianner H, AndersonRR. Fractional photothermolysis: a new concept forcutaneous remodeling using microscopic patterns ofthermal injury. Lasers Surg Med. 2004;34(5):426–38.

Mateus A, Palermo E. Cosmiatria and laser practice in thedoctor’s office. In: Almeida G, Golovaty R, Araújo R,editors. Dark skin. 1st ed. São Paulo; 2012. p. 504.Gen.

Munavalli GS, et al. Combining confluent and fractionallyablative modalities of a novel 2790nm YSGG laser forfacial resurfacing. Lasers Surg Med. 2011;43(4):273–82.

Orringer JS, Kang S, Johnson TM, Karimipour DJ,Hamilton T, Hammerberg C, Voorhees JJ, FisherGJ. Connective tissue remodeling induced by carbondioxide laser resurfacing of photodamaged human skin.Arch Dermatol. 2004;140(11):1326–32.

Ortiz AE, Tremaine AM, Zachary CB. Long-term efficacyof a fractional resurfacing device. Lasers Surg Med.2010;42(2):168–70.

Riggs K, Keller M, Humphreys TR. Ablative laserresurfacing: high-energy pulsed carbon dioxide anderbium:yttrium-aluminum-garnet. Clin Dermatol.2007;25:462–73.

Shah S, Alster TS. Laser treatment of dark skin: an updatedreview. Am J Clin Dermatol. 2010;11(6):389–97.

Sriprachya-anunt S, Marchell NL, Fitzpatrick R, et al.Facial resurfacing in patients with Fitzpatrick SkinType IV. Lasers Surg Med. 2002;30(2):86–92.

Taylor SC, Cook-Bolden F, Rahman Z, Strachan D. Acnevulgaris in skin of color. J AmAcad Dermatol. 2002;46(2 Suppl Understanding):S98–106.

Fractional Ablative and Non-Ablative Lasers for Ethnic Skin 221

Tierney EP, Eisen RF, Hanke CW. Fractionated CO2 laserskin rejuvenation. Dermatol Ther. 2011;24(1):41–53.

Wat H, Wu DC, Chan HH. Fractional resurfacing in theAsian patient: current state of the art. Lasers Surg Med.2017;49(1):45–59.

Xu XG, Luo YJ, Wu Y, Chen JZ, Xu TH, Gao XH, He CD,Geng L, Xiao T, Zhang YQ, Chen HD, Li YH.Immunohistological evaluation of skin responses

after treatment using a fractional ultrapulse carbondioxide laser on back skin. Dermatol Surg. 2011;37(8):1141–9.

Yang YJ, Lee GY. Treatment of striae distensae with non-ablative fractional laser versus ablative CO2 fractionallaser: a randomized controlled trial. Ann Dermatol.2011;23(4):481–9.

222 P.R. Barbosa et al.

Laser for Hair Removal

Patricia Ormiga and Felipe Aguinaga

AbstractLasers for the removal of unwanted hair, usingselective destruction of the hair follicle withoutdamage to adjacent tissues, are a common pro-cedure in the dermatologist’s practice.

The diode laser, neodymium-doped yttrium-aluminum-garnet (Nd:YAG) laser, ruby laser,alexandrite laser, and intense pulsed light aresome of the technologies available today forlong-term hair removal. Proper selection of thewavelength, pulse duration, and fluence is cru-cial to the success and safety of the procedure.

Treatment performed with laser and otherlight sources usually produces a complete tem-porary hair loss, followed by partial permanenthair removal.

The patient’s phototype and hair color mustbe carefully evaluated as well as the presenceof tanning, since the presence of epidermalmelanin increases the risks and decreases theeffectiveness of the procedure. The idealpatient for laser or IPL hair removal is the onewith low skin phototype and dark hair.

There is currently no consensus regardingthe number of treatment sessions and the inter-val between them. Its determination must takeinto consideration the individual characteris-tics of hair growth, the body area, and thetype of light source used.

The most common complications are hyper-or hypopigmentation, which is temporary inmost cases, but there are reports of permanentchanges. In general, laser treatment for hairremoval is considered to be both safe andeffective.

KeywordsEpilation • Intense pulsed light • Laser • Photo-thermolysis • Hair removal

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224

History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224

The Hair Follicle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224

Mechanism of Hair Follicle Destruction . . . . . . . . . . 225

Parameters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226

Lasers and IPL Characteristics . . . . . . . . . . . . . . . . . . . 226

Patient Selection and Preparation . . . . . . . . . . . . . . . . . 227

Conducting Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228

Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229

P. Ormiga (*)Rio de Janeiro, RJ, Brazile-mail: contato@patriciaormiga.com.br

F. AguinagaInstituto de Dermatologia Professor Rubem David Azulay –Santa Casa de Misericórdia do Rio de Janeiro, Rio deJaneiro, RJ, Brazile-mail: felipeaguinaga@gmail.com

# Springer International Publishing AG 2018M.C.A. Issa, B. Tamura (eds.), Lasers, Lights and Other Technologies, Clinical Approaches and Procedures inCosmetic Dermatology 3, https://doi.org/10.1007/978-3-319-16799-2_16

223

Devices for Home Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229

Take Home Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230

Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231

Introduction

The desire to permanently remove unwanted hairis becoming more prevalent everyday. Devicesusing laser technologies and other light sources,such as intense pulsed light (IPL), are widely usedfor this purpose.

The term “hair removal” encompasses two dif-ferent concepts: “temporary hair loss” and “per-manent hair reduction.” “Temporary hair loss”defines a delay in hair growth, which can last forup to 3 months, according to the induction oftelogen phase. “Permanent hair reduction” refersto a significant decrease in the number of terminalhair after treatment administration that remainsstable for a longer period than the full cycle ofhair follicles, which is now defined as4–12 months (Dierickx and Grossman 2006;Klein et al. 2013).

Treatment performed with laser and other lightsources usually produces a complete temporaryhair loss (for up to 3 months), followed by partialpermanent hair removal. Therefore, the expectedresult is an absolute reduction in hair count, whileremaining hair becomes thinner, lighter, andgrows more slowly.

The efficacy in achieving long-term hairremoval, as well as an excellent safety profile,has been demonstrated in the medical literaturefor all treatment systems available for medical use(Gan and Graber 2013).

History

The earliest reports of skin treatments using laserswere made about 50 years ago (Goldman et al.1963). But it was with the advent of the selectivephotothermolysis theory that the concept ofachieving selected targets in the tegument wasestablished (Anderson and Parrish 1983).

The neodymium-doped yttrium-aluminum-garnet (Nd:YAG) laser was the first device devel-oped for laser hair removal. It was approved bythe Food and Drug Administration (FDA) in 1996(Grossman et al. 1996). The ruby (694 nm), alex-andrite (755 nm), diode (800–810 nm), and Nd:YAG (1,064 nm) lasers and IPL (590–1,200 nm),are some of the technologies available today forlong-term hair removal (Ibrahimi et al. 2011).

After the development of lasers with longerwavelength and pulse duration, all skin photo-types can now be handled safely (Vachiramonet al. 2012).

The Hair Follicle

The hair follicle is divided into three main areas:infundibulum, isthmus, and bulb. The germinalmatrix of the hair follicle is located at the base ofthe bulb of the hair, about 2–7 mm below the skinsurface, and it has a high concentration of melaninin comparison with the epidermis. The matrix issituated around the dermal papilla (or follicularpapilla), which plays an important role in deter-mining the thickness, length, and cycle of the hair(Krause and Foitzik 2006 Mar; Campos andPitassi 2012).

Stem cells or totipotent cells are located in the“bulge,” a structure with a great capacity forregeneration located near the insertion of thearrector pili muscles. The bulge is supposed tobe the real target of laser hair removal, accordingto the latest studies.

The hair follicle cycle can be divided into threedistinct phases: anagen, when there is activegrowth; catagen, a regression phase; and telogenwhen the follicle interrupts its growth (Philpottet al. 1990).

During the anagen phase, the majority ofmatrix cells are replicating, and the amount ofpigment present in the bulb is increased. Anagenduration depends on the activity of those cells.

The proportion of hair follicles in each phasevaries in different body areas. Axillary and ingui-nal regions have more follicles in the anagenphase than the limbs (Kolinco 2000). The telogenphase can last a few weeks in the face and a few

224 P. Ormiga and F. Aguinaga

months in the limbs. The complete body hair cycleduration is approximately of 4–10 months. Thereare differences in hair growth between men andwomen, due to hormonal variations (Casey andGoldberg 2008).

There are three main types of hair: lanugo (verythin, identified in the neonatal period); vellus(slightly pigmented, approximately 30 μm diam-eter); and terminal hair (150–300 μm diameter).The hair type produced by each follicle can bechanged according to different stimuli (Rosenfield2005; Ibrahimi et al. 2011).

Mechanism of Hair Follicle Destruction

Light can destroy the hair follicles through threedifferent mechanisms: thermal (local heating),mechanical (wave shocks or violent cavitations),and photochemical (generation of toxic media-tors) (Dierickx 2000). Lasers and IPL promotephotothermal tissue destruction, which is basedon the selective photothermolysis principle,except for Nd:YAG devices equipped with theQ-switched mechanism, which promote photome-chanical destruction.

Described by Anderson and Parrish in 1983,the selective photothermolysis principle postu-lates that there will be selective thermal damageof pigmented structures as long as light’s wave-length is selectively absorbed by a target withsufficient energy and for a duration shorter than,or equal to, its thermal relaxation time (TRT)(Anderson and Parrish 1983; Dierickx andGrossman 2006).

When light is applied to the skin, part of it isreflected, another part spreads, and only a portionis absorbed. Only the amount absorbed isconverted into heat, causing thermal effects onthe treated area.

Light’s wavelength is the factor that most influ-ences its absorption. Each structure of the humanbody has affinity for certain wavelengths. Thisallows selective absorption of light energy andthe treatment of specific targets without any dam-age to adjacent structures. Targets capable ofabsorbing specific wavelengths are called chro-mophores (Boechat 2002).

It is hypothesized that, in order to obtain per-manent hair removal, the target of destruction isthe stem cells of the follicle, located in the “bulge”area. However, the actual chromophore in hairfollicles is the melanin in the matrix, its mostpigmented area.

Because of the distance between the chromo-phore and the real target area, the extended photo-thermolysis theory has been proposed, whichpostulates that the heat generated on the chromo-phore is diffused to the target during the laserpulse (Altshuler et al. 2001).

The electromagnetic spectrum absorbed bymelanin ranges from 350 to 1,200 nm. Thus,ruby, alexandrite, diode, and Nd:Yag lasers andIPL devices, which operate in this range, areable to produce epilation (Casey and Goldberg2008; Ibrahimi et al. 2011; Campos andPitassi 2012).

We know that, within the range of the electro-magnetic spectrum with higher affinity to mela-nin, this affinity decreases as the wavelengthsbecome larger. Thus, lasers with longer wave-lengths have a greater penetration power in thetissue and a low affinity for melanin, with reducedrisk of damage to the skin surface, being able toachieve dermal chromophores as the hair folliclebulb (Boechat 2002; Gan and Graber 2013).

Hair has melanocytes in greater number, size,and having more melanosomes compared to theepidermal melanocytes. Therefore, wavelengthsnear 700 nm are two to six times more absorbedby hair melanin than by the epidermal melanin,which allows the use of laser epilation even ifthere is little contrast between the color of theskin and the hair of the patient (Macedo 2012).

Thermal damage is more selective when pulseduration is close to the thermal relaxation time(TRT) of the target. TRT corresponds to the timerequired for the tissue to be cooled to half thetemperature it has reached after a laser pulse.

If the pulse duration is longer than the TRT, theheat can dissipate beyond the target, before thethermal damage required occurs. If it is shorter, itcan lead to excessive damage. Thus, the pulseduration should be immediately shorter than theTRT, so that the chromophore does not have itsheat dissipated and thermal damage remains

Laser for Hair Removal 225

restricted to the target (Stratigos and Dover 2000;Gan and Graber 2013).

The TRT is directly related to the target dimen-sions. Long pulse lasers (measured in millisec-onds) are closer to the TRT of the hair follicle(10–100 ms) (Anderson and Parrish 1983; VanGermet and Welch 1989; Ross et al. 1999).

There are two basic principles that should beobserved when we evoke the selective photo-thermolysis concept. The first is to use an optimalwavelength to be selectively absorbed by the tar-get tissue. The second is that the pulse should belong enough to produce an effect on the chromo-phore, but fast enough to cause minimal effect onadjacent tissues.

However, all technology that targets dermalstructures hits the epidermis first, which has amelanin “barrier” in their basal layer. Therefore,there is always some attenuation of the energyused, with less tissue penetration and some riskof reaching the surrounding skin. The higher thephototype of the patient, the bigger is the risk, and,therefore, ideal patients for laser and LIP epilationare those of lower phototypes, with thick andpigmented hair (Boechat 2002).

It is important to note that LIP, that uses lowerwavelength and show higher affinity for mela-nin, needs greater contrast between the skin andhair colors, being less suitable for higherphototypes.

To solve the problem of presence of melanin inthe epidermis, the most modern devices use highenergy with cooling protection systems. Thus, thetreatment effectiveness remains high, with lowrisk and less pain for the patients, also allowingtreatment of higher phototype patients (Dierickx2000; Zenzie et al. 2000; Mandt et al. 2005).

Parameters

The amount of energy delivered to the tissue is thefactor that determines its temperature increases.

The energy is the amount of power dispensed bylasers in a given time interval, measured in Joules(J). The device power is measured in watts (W).

Another parameter required to determine theamount of energy delivered to the target is the spot

size, which is measured in millimeters (Nouriet al. 2004).

Fluence is the energy density obtained in eachshot, and this is measured in J/cm2.

Fluence J =cm2� � ¼ energy Jð Þ=area cm2

� �

The pulse duration is the time, in seconds, duringwhich the tissue is exposed to light (Boechat 2002).

Thus, fluence and pulse duration are importantparameters to determine the amount of heatabsorbed. Fluence determines the peak tempera-ture obtained on the target structures, and pulseduration determines the time during which thestructure is exposed to a given temperature (Ganand Graber 2013).

Proper selection of the wavelength, pulse dura-tion, and fluence is crucial to the success and safetyof the procedure (Dawber 2005). To treat thin andlight hair, higher fluence should be used. To treathigh concentration of thick hair or higher phototypes,lower fluence is required (Macedo 2012). A goodmethod to determine the appropriate fluence is toobserve the immediate clinical response, whichshows perifollicular erythema and edema on thetreated area. Higher fluence is associated withincreased effectiveness in hair removal; however, itmay increase adverse effects (Ibrahimi et al. 2011).

Hair diameter can influence the structure’sTRT and, therefore, the pulse duration selection(Dierickx 2000). For thin hair, shorter pulses areused, around 7–10 ms, while for thick hair, pulsesaround 30–40 ms are preferable (Macedo 2012).

The matrix depth influences the wavelength,spot size, and energy choice, while the hair coloris also decisive for appropriate parameters choice(Randall et al. 2006, Table 1).

Lasers and IPL Characteristics

Light emitted by laser has characteristics that dif-ferentiate it from other light sources. It is mono-chromatic, emitting photons with the samewavelength, and coherent, with all photonsgoing in the same direction. It is also collimated,with photons moving in parallel between themand with minimal angular divergence (Boechat

226 P. Ormiga and F. Aguinaga

2002). Diode and alexandrite lasers are consid-ered, in general, the most effective for hairremoval, followed by IPL and Nd:YAG devices(Campos and Pitassi 2012). Recent studies pointthat diode laser is more effective than IPL(Ormiga et al. 2014).

The diode laser (800 nm) can be safely used onI–V skin phototypes (Campos et al. 2000). Thedevices pulse duration varies between 5 and400 ms and their fluences, in general, between10 and 60 J (Dierickx and Grossman 2006).

Latest devices have larger tips, about22 � 35 mm, and a vacuum system that sucksthe skin prior to light emission. The objective isto decrease the discomfort and to optimize thetreatment of large areas. There are also deviceswith 10 � 50 mm tips, with which the treatmentmay be done continuously and scanned. Anotherrecent technology is the combination of radiofrequency energy to the laser optics energy, inorder to achieve higher target temperatures, evenwith the use of lower fluence, providing safety andeffectiveness to the treatment.

Alexandrite laser (755 nm) has shorter pulsedurations than diode laser, showing better resultson thin hair. But most studies show similar resultson hair removal produced by both technologieswhen used on skin phototypes I to IV. This tech-nology should be used preferably in patients oflower phototypes, due to increased possibility ofcomplications in higher phototypes.

The Nd:YAG (1,064 nm) has lower affinity formelanin. For this reason, the laser is consideredthe safer technology for patients of V and VI skinphototypes (Gan and Graber 2013) and alsoshows good results.

IPL has different characteristics because it isgenerated differently. The devices use a flash lamp

controlled by a computer. The light is polychro-matic, emitting various wavelengths. Filtersplaced in front of the lamps provide the wave-length selection. Another LIP characteristic is tobe incoherent, emitted in several directions, beingfocused with reflective surfaces (Boechat 2002;Gan and Graber 2013).

IPL devices work on a range of 650–1,200 nmwavelength, emitting shorter wavelengths that donot penetrate so deeply into the skin, and are moresafer to use in lower phototypes patients, becauseof its increased risk of reaching the epidermalmelanin (Ismail 2012). The IPL pulse duration isgiven in milliseconds. Because of its broad spec-trum, emitting shorter wavelengths, IPL can beused on thin light hair, although with not so inter-esting results as those seen for dark hair (Camposand Pitassi 2012).

Patient Selection and Preparation

Patient selection should include a thorough clini-cal examination, hormonal evaluation, and medi-cation use investigation.

The patient’s phototype must be carefully eval-uated as well as the presence of tanning, since thepresence of epidermal melanin increases the risksand decreases the effectiveness of the procedure(Gan and Graber 2013). Hair color evaluation isalso important, because light hair hardly respondsto therapy. Thus, the ideal patient for laser or IPLhair removal is the one with low skin phototypeand dark hair (Dierickx and Grossman 2006).

Around 80% of women with polycystic ovarysyndrome develop hirsutism, which may havegood response to light treatment, if properlyadministered (McGill et al. 2007).

The presence of herpes virus infections shouldbe investigated, and chemoprophylaxis is requiredfor patients with recurrent episodes. The propen-sity to hypertrophic scars or keloids should also beinvestigated.

Although there is no evidence of risk, patientsshould not be treated during pregnancy. There is noconsensus on the treatment during breastfeeding.

The presence of autoimmune disorders shouldbe investigated, due to the predisposition to

Table 1 Parameters used in treatments

Power (W or J/s) Quantity of energy given per timeunit

“Spot size” (mm) Tip area

Pulse duration (s) Time during which the tissue isexposed to light

Fluence (J/cm2) Energy dispensed through the tiparea

Laser for Hair Removal 227

photosensitivity. Diseases that can triggerKoebner phenomenon, such as vitiligo or psoria-sis, are also contraindications to the procedure.

Patients using medications with gold or photo-sensitizing drugs should not be treated, because ofthe risk of hyperpigmentation (Ibrahimi et al.2011; Gan and Graber 2013).

There is no consensus on the use of oral isotret-inoin and epilation, and although some studies sug-gest their safety, there is a risk of phototoxicity, skinfragility, scarring, and delayed re-epithelialization.It is proposed the interval of 6months to 1 year afterdiscontinuing the medication for treatment initia-tion (Khatri 2004; Cassano et al. 2005; Khatri andGarcia 2006). Topical retinoids may be suspended1 or 2 days before the sessions.

Drugs such as cyclosporine, cortisone, phenyt-oin, and penicillamine, as well as hormonal imbal-ances such as polycystic ovary syndrome ormenopause, can stimulate the growth of newhair, and patients may require maintenance treat-ment regime after completion of conventionaltreatment sessions (Fields and Pitassi 2012).

Patients should avoid sun exposure, in order toensure the security of the procedure.

Any traction method for hair removal must beavoided in the 4 weeks prior to treatment, to ensurethat the chromophore of follicles is present. The hairshould be shaved or removed by depilatory creams,so that its shafts do not become targets in the surfaceof the skin, increasing the risk of burns.

Conducting Treatment

The parameters choice has already been explainedabove. However, it is important to discuss otherissues to be considered during treatment.

More intense pigmented and thicker hair ismore susceptible to treatments. Thus, the cyclehair phases should be considered in determiningthe frequency of treatment sessions, since the aim isto submit the follicle to thermal aggression in itsanagen phase, when it is more pigmented. Further-more, it is important that the hair is not completelyremoved from the follicle through tractionmethods, such as waxing, in order to preservesufficient melanin for the light source action.

There is currently no consensus regarding thenumber of treatment sessions and the intervalbetween them. What is known is that the cyclevaries according to the anatomical location andgender of patients. Likewise, the time required forhair resurgence after treatment sessions alsovaries, with an average of 8 weeks. Thus, theideal interval between sessions remains unclear,and the main authors estimate it to be between4 and 8 weeks.

The ideal number of treatment sessions is alsonot well established. Its determination must takeinto consideration the individual characteristics ofhair growth, the body area, and the type of lightsource to be used. Most authors agree thatrepeated treatments increase the effectiveness ofthe method, recommending three to eight sessionsof treatment to achieve satisfactory results (Caseyand Goldberg 2008). It is estimated that there is anaverage reduction of 20–30% in each treatmentand that patients with lower phototypes and darkhair, the chance of long-term epilation is 80–89%depending on the apparatus used (Dierickx andGrossman 2006).

The use of proper eye protection is critical tothe treatment safety. Each wavelength requiresdifferent types of lens, so different machinesrequire the use of different glasses. Patients, appli-cators, and remaining people in the roommust useprotection. Treatment of the periocular area is notadvised.

At the beginning of the procedure, a test with afew shots in a small area must be performed.Pigmented lesions and tattoos must be avoidedduring treatment.

After the session, ice packs may be used todecrease the occurrence of pain and edema. Ifthere is evidence of excessive inflammation,with burning risk, high-potency topical cortico-steroids may be used to minimize potential sideeffects (Gan and Graber 2013). Perifollicular ery-thema and edema are expected reactions, particu-larly with the laser use. This reaction will be lessintense with the use of LIP, which works withlonger pulse duration (Fields and Pitassi 2012).

It is extremely important to avoid sun exposurefor 6 weeks before and after each treatment ses-sion (Pictures 1, 2, 3, and 4).

228 P. Ormiga and F. Aguinaga

Complications

The most common complications are hyper- orhypopigmentation, which is temporary in mostcases, but there are reports of permanent changes(Ibrahimi et al. 2011). There may also be ery-thema, edema, pain, burns, blistering, and scarring(Lim and Lanigan 2006). The skin phototype andprior sun exposure of the treated area are crucial inthe development of such complications. Protectedareas, such as the armpits and groin, tend to havefewer side effects (Gan and Graber 2013).

Paradoxical hypertrichosis occurs in 0.6–10%of patients treated with LIP or lasers. The exactmechanism by which it occurs is unknown, and itis most common after treatment with IPL andalexandrite lasers. Factors associated with itsdevelopment include the use of insufficientfluence, higher phototypes, hormonal changes,and the use of medications (such as finasteride orcorticosteroids) or hormone supplements. Womenseem to bemost affected and areas such as the faceand neck are more prone to this complication(Desai et al. 2010).

Severe and persistent urticaria can occur, evenin patients without a history of physical urticaria,possibly caused by the use of cryogens or sensi-tivity to specific wavelength (Bernstein 2010).

Ocular complications such as cataract, atrophyand iris adhesions, iritis, uveitis, photophobia,pupil changes, and visual field alterations havebeen described, even in patients who used appro-priate glasses. Wavelengths 400–1,400 nm, fall-ing directly on the eyes, can cause burns on theretina and permanent visual disturbances, makingmandatory the use of eye protection for patientsand applicators (Shullman and Bichler 2009; Ganand Graber 2013).

Acne aggravation, development of lesionssimilar to those of rosacea, early follicles depig-mentation, diffuse erythema, and inflammatoryor pigmentary changes of pre-existing nevi werealso reported as rare side effects (Rasheed2009).

Devices for Home Use

Portable devices for domestic use (home devices)have been developed on a large scale and aregaining popularity because of its low cost andease of use. They use laser and IPL technologies,with very low fluences when compared to themedical devices.

Although approved by the FDA, there are fewcontrolled studies showing its effectiveness andsafety (Thaysen-Petersen et al. 2012).

Picture 1 Axilla before and after 6 monthly sessions of IPL

Laser for Hair Removal 229

Take Home Messages

• Laser hair removal has emerged as a leadingtreatment option for long-term hair reduction.Devices such as diode laser, Nd:YAG laser,and intense pulsed light (IPL) are in constantdevelopment, but there are few comparativestudies between these technologies. Recentstudies point that diode laser might be moreeffective than IPL.

• Proper selection of the wavelength, pulseduration, and fluence is crucial for the successand safety of the procedure. To treat thin andlight hair, higher fluences are required. Totreat high concentration of thick hair orhigher phototypes, lower fluences mightbe used.

• The ideal patient for laser or IPL hair removalis the one with low skin phototype anddark hair.

Picture 2 Axilla before and after 6 monthly sessions of diode laser

Picture 3 Dermoscopic images showing axilla before and after 6 monthly sessions of IPL

230 P. Ormiga and F. Aguinaga

• There is currently no consensus regarding thenumber of treatment sessions and the intervalbetween them.

• Hyper- or hypopigmentation, burns, scarring,and paradoxical hypertrichosis are some of theadverse effects reported.

Cross-References

▶Biophotonics

References

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Anderson RR, Parrish JA. Selective photothermolysis:precise microsurgery by selective absorption of pulsedradiation. Science. 1983;220(4596):524–7.

Bernstein EF. Severe urticaria after laser treatment for hairreduction. Dermatol Surg. 2010;36:147–51.

Boechat A. Laser: princípios, efeitos e aplicações. In:Osório N, Torezan LAR, editors. Laser emdermatologia. São Paulo: Roca; 2002. p. 1–19.

Campos V, Pitassi L. Epilação no rosto e no corpo. In:Mateus A, Palermo E, editors. Cosmiatria e Laser:Prática no consultório médico. São Paulo: GEN;2012. p. 489–503.

Campos VB, Dierickx CC, Farinelli WA, Lin TY,Manuskiatti W, Anderson RR. Hair removal with an

800-nm pulsed diode laser. J Am Acad Dermatol.2000;43(3):442–7.

Casey AS, Goldberg D. Guidelines for hair removal.J Cosmet Laser Ther. 2008;10(1):24–33.

Cassano N, Arpaia N, Vena GA. Diode laser hair removaland isotretinoin therapy. Dermatol Surg. 2005;31(3):380–1.

Dawber RPR. Guidance for the management of hirsutism.Curr Med Res Opin. 2005;21:1227–34.

Desai S, Mahmoud BH, Bhatia AC, HamzaviIH. Paradoxical hypertrichosis after laser therapy:a review. Dermatol Surg. 2010;36:291–8.

Dierickx C. Laser-assisted hair removal: state of the art.Dermatol Ther. 2000;13:80–9.

Dierickx CC, Grossman MC. Epilação com laser. In:Goldberg DJ, editor. Laser e Luz, vol. 2. Rio de Janeiro:Elsevier; 2006. p. 63–79.

Gan SD, Graber EM. Laser hair removal: a review.Dermatol Surg. 2013;39(6):823–38.

Goldman L, Blaney DJ, Kindel JR DJ, Franke EK. Effectof the laser beam on the skin. Preliminary report.J Invest Dermatol. 1963;40:121–2.

Grossman MC, Dierickx C, Farinelli W, Flotte T,Anderson RR. Damage to hair follicle by normal-mode ruby lasers pulses. J Am Acad Dermatol.1996;35:889–94.

Ibrahimi OA, Avram MM, Hanke CW, Kilmer SL, Ander-son RR. Laser hair removal. Dermatol Ther. 2011;24(1):94–107.

Ismail SA. Long-pulsed Nd:YAG laser vs. intense pulsedlight for hair removal in dark skin: a randomized con-trolled trial. Br J Dermatol. 2012;166:317–21.

Khatri KA. Diode laser hair removal in patients undergoingisotretinoin therapy. Dermatol Surg. 2004;30(9):1205–7. discussion 1207.

Picture 4 Dermoscopic images showing axilla before and after 6 monthly sessions of diode laser

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Khatri KA, Garcia V. Light-assisted hair removal inpatients undergoing isotretinoin therapy. DermatolSurg. 2006;32(6):875–7.

Klein A, Steinert S, Baeumler W, Landthaler M, BabilasP. Photoepilation with a diode laser vs. intense pulsedlight: a randomized, intrapatient left-to-right trial. Br JDermatol. 2013;168(6):1287–93.

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Rasheed AI. Uncommonly reported side effects of hairremoval by long pulsed-alexandrite laser. J CosmetDermatol. 2009;8:267–74.

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Shulman S, Bichler I. Ocular complications of laser-assisted eyebrow epilation. Eye (Lond).2009;23:982–3.

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Thaysen-Petersen D, Bjerring P, Dierickx C, Nash J,Town G, Haedersdal M. A systematic review of light-based home-use devices for hair removal and consid-erations on human safety. J Eur Acad DermatolVenereol. 2012;26(5):545–53.

Vachiramon V, Brown T, Mcmchael AJ. Patiente satisfac-tion and complications following laser hair removal inethnic skin. J Drugs Dermatol. 2012;11(2):191–5.

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232 P. Ormiga and F. Aguinaga

Laser on Hair Regrowth

João Roberto Antonio, Carlos Roberto Antonio, andAna Lúcia Ferreira Coutinho

AbstractAlopecia is a common disorder affecting morethan half of the population worldwide. There isan urgent need to investigate alternative treat-ment options, while there are still a few thera-peutics options for different types of alopeciain the market. The photobiomodulation phe-nomenon followed by hair growth was firstdescribed in 1967 by Professor Endre Mester,an Hungarian physician, the pioneer of lasermedicine. For decades, clinical studies havebeen conducted to evaluate the efficacy, mech-anism of action, and risks of using Low-levellaser therapy - LLLT (collimated or non-collimated) in different forms of hair loss as afurther treatment option. This chapter will pre-sent the clinical studies conducted with LLLTon female pattern hair loss (FPHL), male pattern

hair loss (MPHL), alopecia areata (AA), andchemotherapy-induced alopecia (CIA) investi-gated in several databases including PubMed,Google Scholar, Medline, Embase, andCochrane. At the end of this chapter, the authorsconcluded that LLLT may be a promising treat-ment option for patients who do not respond toconventional treatments and who do not want toundergo hair transplantation. This technologyappears to work better for some people thanothers. Factors predicting who will get themost benefit need to be determined. Larger,longer-term placebo-controlled studies areneeded to confirm these findings and reinforcethe efficacy of the LLLT in those patients, gen-erating, therefore, more consistent protocols.

KeywordsLaser • Low-level laser therapy • Low-levellight therapy • Photobiomodulation • Hairloss • Alopecia • Androgenetic alopecia •Female pattern hair loss • Male pattern hairloss • Alopecia areata • Chemotherapy

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234

Historical Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234

Proposed Mechanisms: LLLT onHair Growth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235

LLLT in Chemotherapy-Induced Alopecia(CIA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236

LLLT in Androgenetic Alopecia (AGA) . . . . . . . . . . 237

J.R. Antonio (*)Faculdade Estadual de Medicina, Hospital de Base de SãoJosé do Rio Preto, São Paulo, Brazile-mail: dr.joao@terra.com.br; dr.joao@pelle.com.br

C.R. AntonioFaculdade deMedicina Estadual de São José do Rio Preto –FAMERP, São José do Rio Preto, SP, Brazil

Hospital de Base de São José do Rio Preto,São Paulo, Brazile-mail: carlos@ipele.com.br

A.L. Ferreira CoutinhoInstituto de Dermatologia Professor Rubem David Azulaydo Hospital da Santa Casa da Misericórdia do Rio deJaneiro, Rio de Janeiro, Brazile-mail: anacoutinho_10@hotmail.com

# Springer International Publishing AG 2018M.C.A. Issa, B. Tamura (eds.), Lasers, Lights and Other Technologies, Clinical Approaches and Procedures inCosmetic Dermatology 3, https://doi.org/10.1007/978-3-319-16799-2_17

233

LLLT in Alopecia Areata . . . . . . . . . . . . . . . . . . . . . . . . . . 240

Authors Experience: Case Studies . . . . . . . . . . . . . . . . 241

Take Home Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242

Introduction

The use of laser in dermatology was firstlyassessed in the treatment of benign vasculartumors. However, it gained ground while provingclinical effectiveness and safety in the treatmentof other dermatological conditions such asremoval of pigmented lesions, tattoos, scars, andundesirable hairs and in photoaging treatment.

Laser therapy has become popular over the lastyears. The first report of the use of the laser forhair growth was carried out by Professor EndreMester et al. in 1967, during an experimentalobservation. Investigators reported the hair regrowthin the epilated area exposed to low-potency rubylaser, evaluated to demonstrate the potential car-cinogenic effect on the shaved backs of guineapigs (Mester et al. 1968). This finding triggeredthe interest not only in identifying which laserapparatus could give efficient clinical responseswithout risk but also in verifying which therapeu-tic mechanisms would be involved in thoseresponses.

To understand the mechanism of action of laserin hair regrowth process, mainly in the scalp, lasermedicine experts have developed different lines ofresearch in low-level laser therapy (LLLT) andhair loss disorders with available data to datedemonstrating efficacy.

The LLLT could be distinguished from otherforms of laser therapy using low power and lowdensity. Most low-level laser therapy devicesoperate at wavelength intervals between 600 and1000 nm and use much less power than theamount requested to warm tissue (10 mW/cm,2–5 W/cm2) (Bouzari and Firooz 2006).

Recently, the use of low-level laser therapy(LLLT) has been proposed as an alternativetherapy (mono or in combination) for hair loss tostimulate hair regrowth in alopecia: FPHL,

MPHL, and AA. In the next paragraphs, experi-mental and clinical studies conducted with the useof LLLT in these conditions will be discussed.

Historical Data

In 1996, a team of researchers from KuopioUniversity, Finland, conducted a single-blind pla-cebo-controlled study to assess and compare theeffects produced by three different types of laser/light (He-Ne, As-Ga-Al diode, noncoherent LEDlight) on hair blood flow. The study involved tenhealthy male individuals. Two sessions were held,and the placebo (noncoherent LED light) wascompared to other two laser sources (He-Ne andAs-Ga-Al diode). Measurements were carried outby laser Doppler flowmetry. Results demonstratedthat coherent laser sources were the only lightsources able to produce vasodilation (Pöntinenet al. 1996).

In 2000, a study carried out by researchersfrom Harvard Medical University showed thatvolunteers exposed to ruby laser (694 nm) forhair removal and diode (800 nm), responders ornonresponders, presented some level of hairgrowth, thinner and without pigment, sometimeafter the procedure. The authors concluded thatchanges observed depend on the type of laser andindividual response (Lin et al. 2000).

Gerardo Moreno-Arias et al. (2002) reported aphenomenon called paradoxical hypertrichosis orterminalization or induction of terminal hairgrowth. The clinical finding was described as arare but significant secondary effect present inpatients with hirsutism who undertook intensepulsed light (IPL) treatment during a periodfrom 3 to 6 months. As the authors argue, intensepulsed light would have the property of inducinglatent hair follicle in non-treated areas locatedaround treated areas (Moreno-Arias et al. 2002;Desai et al. 2010).

In recent literature’s review made by SophiaRangwala, paradoxical hypertrichosis rates rangefrom 0.6% to 10% after low-energy laser therapieswith almost all types of laser: XeCL excimer308 nm, helium-neon (He-Ne), and fractional

234 J.R. Antonio et al.

Erbium glass fiber 1550 nm. The event is morefrequent over the face and the neck of volunteerswith darker skin color (prototypes III–IV), darkhair, and/or with coexisting hormone imbalance(Rangwala 2012).

The appearance of pilli bigeminy in four casesafter alexandrite or ruby laser treatments due tosuboptimal fluencies insufficiently low to inducethermolysis, but high enough to stimulatefollicular growth. Although the face and neckseem to be the areas which are most sensitiveto hair growth induction effect, sensitivity andresponse of scalp under these conditions are notrecognized (Ye et al. 1999).

Under some researchers’ perspective, laserphototherapy prolongs the duration of anagenphase, stimulates the anagen reentry in telogenhair follicles, increases the proliferation rates ofthe anagen hair follicles, and prevents the pre-mature catagen development (Chung et al.2004). There are many theories to explain theLLLT’s mechanism of action in hair loss, but ithas not yet been fully elucidated (Karu 1989;Karu and Kolyakov 2005; Hawkins-Evans andAbrahamse 2008a, b; Lubart et al. 1992;Oliveira et al. 2008; Mognato et al. 2004; Karu1987).

Although medical guidelines make specialreference to LLLT clinical benefits in alopecia, itis important to reinforce the need for clinicalstudies of a better quality, randomized with anadequate number of volunteers (Kreisler et al.2003; Kim et al. 2015; Avram and Rogers 2010;Stillman 2010).

Proposed Mechanisms: LLLT on HairGrowth

The LLLT has biomodulating effects on cellsand tissues. These effects activate or inhibitphysiological, biochemical, metabolic processesthrough photophysical or photochemical effectsand promote morpho-differentiation, cellular pro-liferation, tissue neoformation, revascularization,reduction of edema, increased cellular regeneration,microcirculation, and vascular permeability (Karu

1989; Karu and Kolyakov 2005; Hawkins-Evansand Abrahamse 2008a, b).

When laser therapy is used in the visible elec-tromagnetic spectrum, there is an initial photo-biostimulation in mitochondria, which activatesa chain of biological events. When the irradiationis in the infrared spectrum, there is stimulation ofthe plasmatic membrane channels, resulting inchanges in membrane permeability, temperature,and pressure gradient (Lubart et al. 1992; Oliveiraet al. 2008; Mognato et al. 2004; Karu 1987).

Both visible and infrared light can be absorbedby different components of the cellular respiratorychain such as chromophores in cytochrome Coxidase or porphyrins, which results in the pro-duction of reactive oxygen species or superoxideradicals. It has been commented that reactive oxy-gen species have a fundamental role in increasingthe proliferation of keratinocytes (Lubart et al.1992; Oliveira et al. 2008; Mognato et al. 2004;Karu 1987).

According to Mognato et al., the oxidationreaction seems to be associated with stimulationand proliferation, whereas the reduction reactionseems to be associated with inhibition of cellgrowth (Mognato et al. 2004).

Kreisler et al. (2003) emphasized that there is astimulation of photoreceptors in the mitochondrialrespiratory chain. After the laser light has beenabsorbed, photophysical and photochemicaleffects, isolated or combined, stimulate themitochondrial membrane, increasing the mem-brane potential and, consequently, changing themitochondria’s properties. LLLT acts onthe mitochondria and may alter cell metabolismthrough photodissociation of inhibitory nitricoxide (NO) from cytochrome C oxidase (CCO),resulting in an increased production of molecularoxygen and ATP, which stimulates the activity ofDNA and RNA to synthesize regulatory proteinsof the cell cycle, and thus the speed of mitosis canbe increased (Kim et al. 2015; Avram and Rogers2010; Stillman 2010). Moreover, NO is knownto be a potent vasodilator via its effect oncyclic guanine monophosphate production, andit can be speculated that LLLT may cause photo-dissociation of NO not only from CCO but also

Laser on Hair Regrowth 235

from intracellular stores such as nitrosylatedforms of both hemoglobin and myoglobin leadingto vasodilation and increased blood flow whichwas reported in several studies (McElwee 2012;Chung et al. 2012).

According to Stein et al. (2005), laser therapyinduces the phosphorylation of MAPK/ERKprotein kinases in cells, which are known to beassociated with the mechanism of cell prolifera-tion. It is worth noting that the interaction oflaser light with tissues can lead to differentresults (stimulation or inhibition) depending onseveral factors, such as wavelength, dose,power, time, number of irradiations, opticalproperties of tissues, and type of irradiated cell,besides the physiological characteristics of thecells at the time of irradiation.

In fact, the magnitude of the cellular responseto irradiation depends on the physiological state ofthe cell (the amount of nutrients available and theage of the cell culture). Generally, cells in theexponential phase of growth are more photosen-sitive than those in the stationary phase of growth(Avram and Rogers 2010; Stillman 2010;McElwee 2012; Chung et al. 2012; Stein et al.2005; Karu 1988) (See Fig. 1.)

LLLT in Chemotherapy-InducedAlopecia (CIA)

In 2003, a nonclinical study was conductedfocusing on assessing the use of low-level lasertherapy in guinea pigs (rodents) which presentedchemotherapy-induced alopecia (CIA), consider-ing that there was no efficient approach to thistype of alopecia.

HairMax LaserComb#, a low-level laserdevice, was used, whose application had alreadybeen authorized by FDA for androgenetic alope-cia treatment.

Throughout the study, traditional chemothera-peutical agents were used, cyclophosphamide,etoposide, or a combination of cyclophosphamideand doxorubicin, to induce alopecia in young ratswith or without low-level laser therapy (LLLT).As expected, after 7–10 days of chemotherapy,all rats developed complete corporeal alopecia.However, the rats, which had been submitted tolow-level laser therapy, recovered their naturalstate, with hair growth around 5 days earlier thanthose submitted only to chemotherapy withoutLLLT exposure. Hair growth in rats treated withlaser was confirmed by histological study.

ATPENERGY

NO

PROMOTESGROWTH FACTORS

INCREASED BLOODVESSELS

REPAIRS NEURONS

INCREASES COLAGEN

DECREASESINFLAMMATION

PROMOTES HEALING MITOCHONDRIA

GENE UPREGULATION

NITRIC OXIDE Blood vessels

dilata�on

DNA(NUCLEUS)

ADAPTED FROM SAJJAD KHAN 2016ILHT.COM

Fig. 1 Schematic drawing of possible mechanisms of LLLT on hair growth

236 J.R. Antonio et al.

Results showed that low-level laser treatmentaccelerated significantly hair growth after CIA,without affecting chemotherapy efficiency, con-cerning the guinea pig model used for that study(Wikramanayake et al. 2013).

LLLT in Androgenetic Alopecia (AGA)

Androgenetic alopecia (AGA) is one of the mostcommon chronic problems seen by dermatolo-gists worldwide, characterized by progressivehair loss, especially of scalp hair. It has distinc-tive patterns of loss in women versus men, but inboth genders the central scalp is most severelyaffected.

It often begins around puberty and is known toeffect self-esteem and the individual’s quality oflife. In contrast to the high prevalence of AGA,approved therapeutic options are limited. In addi-tion to the scarce pharmacologic treatments, thereare numerous nonprescription products claimedto be effective in restoring hair in androgeneticalopecia.

Low-intensity laser therapy or photobio-modulation or photobiostimulation was approvedby US Food and Drug Administration (FDA) in2007 with a safe approach to the treatment of maleand female androgenetic alopecia. From then on, aseries of devices designed for domestic use (dailyor many times a week) became available on themarket, relatively cheap if compared to medicaltreatment and hair transplant surgery.

Although the mechanism of action of thisdevice is still not clear about androgenetic alope-cia treatments, some controlled clinical studiesshow visible hair growth.

Different types of laser have been studied dur-ing the assessment of hair growth in androgeneticalopecia, including XeCL excimer 308 nm,helium-neon (He-Ne), and fractional Erbiumglass fiber 1550 nm (Blumeyer et al. 2011; Tsuboiet al. 2012; van Zuuren et al. 2012; Zarei et al.2016; Jimenez et al. 2014; Leavitt et al. 2009;Wikramanayake et al. 2009; Avram et al. 2007;Kim et al. 2011; Kobielak et al. 2013; Kandybaand Kobielak 2013; Kandyba et al. 2013;

Kobielak et al. 2003, 2007; Lee et al. 2011) (seeTable 1).

The HairMax LaserComb# (Lexington Int-ernational, Florida), a 3R class laser (safety level),was evaluated in androgenetic alopecia in multi-center, double-blind controlled study (against anon-active device). The clinical trial was per-formed in four centers and assessed 110 menwith male AGA (Norwood-Hamilton: IIa-V,Fitzpatrick: I a IV) aged between 30 and 60 years(Jimenez et al. 2014).

The study subjects were instructed to use thedevice three times a week, during 15 min, over26 weeks. The sites for application were markedwith a circular tattoo, 2.96 cm in diameter, whichwas assessed after haircut. By means of comput-erized countdown, the scalp was evaluated viamacroimage.

The study subjects treated with laser comb(655 nm) showed an increase in density of around19.8 hairs/cm2 in comparison to 7.6 hairs/cm2

presented by the control group (P < 0,0001). Nostatistical improvement was observed in the inves-tigator’s overall evaluation.

In 2014, another group of researchers publisheda double-blind, randomized, controlled, multicenterstudy which had been performed to assess the clin-ical efficacy and safety of the same device inwomen and men with androgenetic alopecia.

A hundred and forty-one female volunteers(n = 141) and a hundred and twenty-eight malevolunteers (n = 128) were randomized to receivethe active device LaserComb or sham device(control) according to the following design: #1with beams 9 X control, #2 with beams 12 Xcontrol, #3 with beams 7 X control, and #4 withbeams 12 X control.

The application all over the scalp wasperformed three times a week throughout26 weeks. Terminal hair density in the targetedarea was assessed at the beginning and in the 16thand 26th weeks of the follow-up.

Both investigators and study subjects remainedblind to the type of device used during the test.The specialist responsible for evaluating the dig-ital pictures taken along the trial also remainedblind to each branch of the study.

Laser on Hair Regrowth 237

At the end of study, the investigators observedan increase statistically significant in terminal hairdensity for subjects treated with active deviceagainst those treated with the sham device(control).

No serious adverse events have been reported.According to the authors, these results suggestthat LLLT might be an efficient option for hairloss regarding both male and female patterns.However, the researchers recognized that the

mechanism by which LLLT convert telogen intoanagen follicles remains unknown.

Avram and Rogers conducted the first indepen-dent blinded study of LLLT and hair growth withseven volunteers and found that on average, therewas a decrease in the number of vellus hairs, anincrease in the number of terminal hairs, and anincrease in shaft diameter. Nevertheless, thesedata were not considered statistically significant(Avram et al. 2007).

Table 1 Literature review about different devices and protocols

Home devices PowerTreatmentregimes Studies Subjects Results

Peerreviewed?

CapillusTM

82 Laser Cap410 mW 30 min

3–4�/weekDouble blindRCT

44F 63.7% increase interminal hair count vssham

No

CapillusTM

202 Laser Cap1010 mW 30 min

3–4�/week

CapillusTM

272 Pro LaserCap

1360 mW 30 min3–4�/week

HairMaxTM

Laser Band 41205 mW 3 min

3�/weekProspectivecohort

28M,7F

Total hair count andhair tensile strengthincreased

Yes (Satino)

HairMaxTM

Laser Band 82410 mW 90 s

3�/weekDouble blindRCT

110M Mean terminal hairdensity increased by~20 hairs/cm2

Yes(Leavitt)

HairMaxTM

Prima7 LaserComb

35 mW 15 min3�/week

Case report 2M No significant changein hair count orthickness

Yes(Rushton)

HairMaxTM

Ultima 9 LaserComb

45 mW 15 min3�/week

RetrospectiveCohort

11M,21F

Global photos –majority w/moderateimprovement

Yes (Munk)

HairMaxTM

Ultima12 Laser Comb

60 mW 8 min3�/week

Double blindRCT

128M,141F

Terminal hair densityincreased by ~15 hairs/cm2

Yes(Jimenez)

iGrowTM HairGrowth System

255 mW 25 minevery otherday

Double blindRCT

41M 35–37% increase interminal hair count

Yes(Lanzafame)

Double blindRCT

42F

iRestoreTM

Hair GrowthSystem

255 mW 25 minevery otherday

Double blindRCT

18M,18F

Pending, study inprogress

N/A

LasercapTM

LCPRO1120 mW 36 min

every otherday

Case series 7F Improvement in hairvolume and shine

N/A

Case series 1M, 2F

NutraStimTM

Laser HairComb

60 mW 8 min3�/week

N/A N/A N/A N/A

TheradormeTM

LH80 PRO400 mW 20 min

2�/weekDouble blindRCT

80M Pending, study inprogress

N/A

Source: Data obtained by consulting suppliers/internet/sales representatives. May 2017

238 J.R. Antonio et al.

The first study involving a fractional Erbiumglass fiber 1550 nm (Mosaic# Lutronic Co., Ltd.,Seoul, South Korea) published is a non-clinicessay carried out in 2011. The investigators eval-uated the effect of the device on hair cycle in aform of alopecia in rats. The radiation was appliedover the shaved skin of C3H/HeN rats using var-ious power and density configurations in differentradiation intervals. Stimulation effects on hair wereobserved due to the level of power employed,density, and radiation interval. Histologic findingsreveal the conversion of hair in telogen phase intoanagen phase. The conversion into anagen hair andthe increase of 5a Wnt, β-catenin were regarded assigns of therapeutic response.

Later, to assess the clinical effects of that samesort of laser, a study was performed involving20 males with AGA (Kim et al. 2011). In thestudy involving humans, 20 male volunteerswere treated in five sessions and in 2-week inter-vals. It was employed with 5 mJ power with a totaldensity of 300 spots/cm2.

According to the investigators, fractional lasercan cause thermal injury or photothermolysis foreach thermal microzone (TMZ), which induces col-lagen regeneration and thermal shock over proteins.Both events lead to the expression of growth fac-tors, including vascular endothelium growth factor(VEGF), which induces neoangiogenesis. Otherpossible mechanisms are cytokine biomodulationand growth factors such as PDGF, KGF, and IGF.

Nowadays, it is known that there is a complexnet of genes involved in the control of hair growthcycle and connected to Wnt and BMP signalingpathways, especiallyWnt7 gene, which cause inad-equate hair growth, if inactivated. Research datahave already proved that, if BMP signaling path-ways are reduced andWnt pathways are increased,a hair growth phase is activated (Kobielak et al.2013; Kandyba and Kobielak 2013; Kandyba et al.2013; Kobielak et al. 2003, 2007).

During the study, incremental improvements inhair density and hair growth rate were observed,which suggested that fractional Erbium glass fiber1550 nm might induce hair growth.

In that same year (2011), the investigatorsevaluated fractional Erbium glass fiber 1550 nmeffect on female pattern alopecia (Lee et al. 2011).

Twenty-eight South Korean volunteers took partinto the study. The volunteers received laser appli-cation with intervals of 15 min, following thesame parameters of the study conducted withmale volunteers. Phototrichograms and globalphotos were taken at the beginning and at theend of the treatment. Changes in density and inthe hair shaft diameter were analyzed. The globalphotos were evaluated by three independent der-matologists using a scale of seven points.Volunteers involved also answered an efficacyself-evaluation questionnaire. All adverse eventswere reported during 5 months of treatment.

After 5 months of study, the results demonstratedan increase in hair density of 157 � 28/cm2

(P < 0.0001) and in shaft thickness of 75 �13 μm (P < 0.001).

According to the global photos, out of theremaining 27 volunteers, 24 (87.5%) showed animprovement in their conditions. Two volunteers(7.4%) reported moderate pruritus after laser appli-cation, which was spontaneously solved 2 h later.

In 2013, a multicenter, double-blind, random-ized, controlled study was performed to evaluatethe efficacy and safety of LLLT in volunteers withandrogenetic alopecia against a sham device, over24 weeks, against sham device (control).

The study involved 40 volunteers with andro-genetic alopecia. One group of volunteers wasexposed to a helmet-like apparatus, which pro-duces radiation in wavelengths of 630, 650, and660 nm, and the other group was exposed to shamdevice (control) during 18 min per day.

A phototrichogram and overall evaluationswere carried out. After 24 weeks, the resultsshowed a significant increase in hair density ingroup of volunteers exposed to the active appara-tus (LLLT) against the other group (sham device).The average diameter of hair shaft also increasedsignificantly in the volunteers submitted to theintervention compared to sham device group.

According to the investigator’s evaluation, asignificant clinical improvement was observed inthe group of volunteers exposed to the activeapparatus. No adverse event was reported. Inthe investigators’ opinion, LLLT was consideredeffective and safe concerning AGA treatment(Kim et al. 2013).

Laser on Hair Regrowth 239

LLLT in Alopecia Areata

Alopecia areata is an autoimmune disease whichis characterized by rapid and complete hair loss inone or many sites in the form of patches, generallylocated on the scalp. Available treatments areemployed with variable success. These includepulsed high doses of oral or intravenous steroids,topical high-potency steroids under occlusion,photochemotherapy, and topical immunotherapy.Efficacy of treatments in patients with alopeciatotalis and alopecia universalis is poor, withlong-term complete regrowth in less than 20% ofpatients (Tosti et al. 2006).

In 1984, Trelles and collaborators investigatedHe-Ne laser action in alopecia areata (Trelles et al.1984), and, from 2002 on, a series of studies wereundertaken to evaluate the role played by differentforms of light/laser as an alternative therapy to thetypes of alopecia (particularly alopecia areata)(Shukla et al. 2010; Touma and Rohrer 2004).

In 2003, a study assessed the effects of polar-ized linear infrared radiation produced by a com-mercial device denominated Super Lizer# involunteers with alopecia areata. Fifteen volunteersover 18 years old diagnosed with alopecia areataand with multiple patches were engaged in thistrial. Results showed that, out of 15 volunteers(46.7%), 7 presented hair growth in the radiatedareas around 1.6 months earlier than those notradiated. Regarding the adverse events, only onepatient complained about heat sensation over theradiated area (Yamazaki et al. 2003).

The most explored laser in the treatment of alo-pecia areata is the XeCL excimer 308 nm, betterestablished by a vast number of studies conductedeven in children, proposing as its mechanism ofaction apoptotic effect over T cells (Gundoganet al. 2004; Raulin et al. 2005; Al-Mutairi 2007,2009; Ohtsuki et al. 2010, 2013; Byun et al. 2015).

In 2006, a study evaluated the efficacy ofsuperpulsed Ga-As, 904 nm diode laser, in thetreatment of alopecia areata. For this purpose,16 volunteers with 34 alopecia areata patchesrefractory to other forms of therapy were selected.In each patient, there was a remaining patch with-out treatment as control lesion. Four sessions wereheld, one per week, with pulsed infrared diode laser

(904 nm), pulse rate of 40/s. Photos were taken ofeach patient before and after the treatment, being11 males (68.75%) and 5 females (31.25%).Concerning the volunteers’ age, there was a rangebetween 4 and 50 years of age with an average of26.6 +/� SD of +/�m 13.8. The disease durationvaried between 12 months and 6 years with anaverage of 13.43 +/� SD of +/� 18.34.

Results showed that hair regrowth wasobserved in 32 areas of alopecia (94%), whereasonly two areas of alopecia did not show anyresponse. On the alopecic patches, consideredcontrol, hair regrowth was not verified. On29 patches (90.6%), terminal hair could be veri-fied. Less pigmented vellus have been observedon three patches (Waiz et al. 2006).

In responders, the effect was earlier detected:24 volunteers(75%) a week after the first session.At the end of the study, the researchers concludedthat pulsed infrared diode laser is an efficienttherapy with a high success rate in volunteerswith alopecia areata (patches) refractory to vari-ous modalities of treatment.

In 2009, a group of researchers from theDepartment of Dermatology of Chung-AngUniversity College of Medicine, Seoul, SK,report the case of a 35-year-old man with severallarge-sized alopecia areata patches on frontalregion of the scalp refractory to differentmethods/drugs (minoxidil topical solution 5%,topical steroids, and intralesional corticosteroidinjections). Non-ablative laser (fractional Erbiumglass fiber 1550 nm) applications were made oncea week, during 24 weeks. A pulse energy of10–15 mJ, with a density of 300MTZ/cm2, wasused in each application. Two applications weremade in each session (Yoo et al. 2009).

The treatment was well tolerated, without anyside effect reported. Firstly, hair growth wasobserved 1 month after the treatment was started.After 3 months, lesions were covered with termi-nal hair, mostly pigmented, in an average of30–40%. Six months after the therapy began,new hair grew over all lesions. No relapse wasreported during a 6-month clinical follow-up.

Regarding the LLLT’s mechanism of action onAA, researchers assumed that one or more factorsamong improved microvascular circulation,

240 J.R. Antonio et al.

reduced inflammation, and increased cell energyin the form of ATP, working together, couldexplain the clinical benefits of LLLT on AA.

In conclusion, a LLLT offers a safe and effec-tive option as monotherapy or in combinationwith other conventional therapy for non-scarringalopecia, such as male and female pattern hairloss, chemotherapy-induced alopecia, and alope-cia areata, with available data to date demonstrat-ing efficacy. We must consider that, regardless ofthese good results, the establishment of more

consistent protocols requires the conduction ofrandomized, double-blind, sham-device-con-trolled trial with an adequate number of volun-teers and longer follow-up.

Authors Experience: Case Studies

Our case studies (Figs. 2, 3, and 4) involving twopatients with androgenetic alopecia using Erbiumglass laser 1550 nm, energy of 8 mJ, density of

Lateral view

Vertex view

a b

Fig. 2 Patient 1: Before (a) and 6 months after (b) 6 sessions, 1 month apart. Erbium glass laser 1550 nm; energy, 8 mJ;density, 9%

a b

Frontal view

Parietal view

Fig. 3 Patient 2: Before (b)and 6 months after (b)6 sessions, 1 month apart.Erbium glass laser1550 nm; energy, 8 mJ;density, 9%

Laser on Hair Regrowth 241

9%, and making 6 applications over the areasaffected by alopecia. One-month interval betweensessions.

Take Home Messages

1. LLL therapy offers a safe therapeutic option asmonotherapy or in combination with otherconventional therapies for non-scarring alope-cia, taking into consideration the data availabledemonstrating efficacy up to date.

2. The interaction of laser light with tissuescan lead to different results (stimulation orinhibition) depending on several factors, wave-length, dose, power, time, number of irradia-tions, optical properties of tissues, and type ofirradiated cell, besides the physiological char-acteristics of the cells at the time of irradiation.

3. There has been a rapid increase in marketavailability of devices each with differing char-acteristics making both physician and patient/consumer navigation difficult.

4. Further investigation is needed to compareefficacy of LLLT devices to be able to addresspatient needs and expectations.

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244 J.R. Antonio et al.

Laser Lipolysis

Paula Amendola Bellotti Schwartz de Azevedo,Bianca Bretas de Macedo Silva, and Leticia Almeida Silva

AbstractStudies concerning laser’s direct action on fatbegan in 1992. Two years later the first study oflaser lipolysis was produced. The method wasapproved by the FDA in October 2006. Laserlipolysis is a minimally invasive procedure forthe treatment of localized fat, improving thefacial and body contour and flaccidity. It con-sists of the application of laser directly on theadipose tissue, based on the principle of selec-tive photothermolysis. This method has theadvantage to be less traumatic; to cause lessbleeding, pain, ecchymosis, and edema; andminimizes side effects and complications. Thepostoperative recovery time is reduced whencompared to conventional liposuction. There isinduction of neocollagenesis, which leads tocutaneous retraction. Indications include the

submental area, arms, abdomen, flanks, innersurface of thighs, knees, and elbows. Patientswith irregularities after previous liposuction orother surgeries are also excellent candidates.For areas with more fibrous tissue, such asmale breast (gynecomastia), flanks, and back,laser lipolysis maybe the only option. Recentarticles described the use of laser lipolysis forthe treatment of lipoma, as conventional sur-gery can result in disfiguring scars whentreating lesions bigger than 10 cm. Other ques-tionable indications are axillary hyperhidrosisand cellulite. There are no specific contraindi-cations. Complications are rare, and when theyoccur they are not specific to the laser.

KeywordsLaser lipolysis • Fat • Localized fat • Bodycontour • Flaccidity • Cutaneous retraction •Cellulite • Liposuction • Neocollagenesis •Submental • Gynecomastia

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246Indications and Contraindications . . . . . . . . . . . . . . . . . . . 247

Preoperative Considerations . . . . . . . . . . . . . . . . . . . . . . . 248

Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249

P.A. Bellotti Schwartz de Azevedo (*)Brazilian Society of Dermatology and Brazilian Society ofDermatology Surgery, Rio de Janeiro, Brazile-mail: bellotti.paula@gmail.com;draleticiaalmeida@gmail.com;laise.almeida@paulabellotti.com.br;atendimento@paulabellotti.com.br;rosangela.caetana@paulabellotti.com.br

B. Bretas de Macedo SilvaBrazilian Society of Dermatology, Rio de Janeiro, Brazile-mail: biancabretas@yahoo.com.br

L. Almeida SilvaBrazilian Society of Laser in Medicine and Surgery, Rio deJaneiro, RJ, Brazile-mail: draleticiaalmeida@gmail.com

# Springer International Publishing AG 2018M.C.A. Issa, B. Tamura (eds.), Lasers, Lights and Other Technologies, Clinical Approaches and Procedures inCosmetic Dermatology 3, https://doi.org/10.1007/978-3-319-16799-2_18

245

Postoperative Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250

Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250

Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250

Take Home Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250

Introduction

In 1992, Apfelberg was the first to describe laser’sdirect action on fat. Two years later, he and col-laborators produced the first study of laser lipoly-sis. However, its benefit was not significantlydemonstrated. This equipment was not approvedby the FDA, and the company HeraeusLasersonics abandoned the technology(Apfelberg et al. 1994).

The first study to demonstrate the effect of laseron fat, as well as on the dermis, vessels, and apo-crine and eccrine glands, was described between2002 and 2003 by Bluggerman, Schavelzon, andGoldman, who introduced the concept of pulsedlaser for laser lipolysis (Apfelberg et al. 1994).

In 2003, Badin founded these findings in onestudy titled “Laser Lipolysis: Flaccidity UnderControl.” The author demonstrated the histologi-cal changes after the thermal laser injury. Theadipocytes’ membrane was torn, vessels werecoagulated, and collagen was reorganized. Thesehistological changes were correlated with the clin-ical observation of reducing adiposity, ecchymo-sis, blood loss, and improvement of flaccidity.Badin concluded that laser lipolysis was less trau-matic because of the cannula’s smaller pitch andthat this type of laser, Nd: YAG, produced a tissuereaction leading to cutaneous retraction (Badinet al. 2002).

In a subsequent study carried out by Goldman,1734 patients were treated, including 313men and1421 women aged 15–78. In this group, less bloodloss and ecchymosis, improvement of postopera-tive comfort, and better effectiveness of fat reduc-tion in denser areas such as in gynecomastia, forexample, were also documented (Kim andGeronemus 2006).

In 2006, a study by Kim and Geronemus usedmagnetic resonance to evaluate the volume of fatreduction after Laser lipolysis. Seventeen percentof patients achieved a reduction of fat volumedocumented by magnetic resonance imaging,and 37% noticed an improvement in only3 months, a quick recovery time and good cuta-neous retraction (Kim and Geronemus 2006).

In this same year, the FDA approved the firstlaser lipolysis equipment, an Nd: YAG laser of6 W (produced by DEKA and distributed byCynosure, Westfort, Massachusetts). Soon after,several equipments with different wavelengthsentered the market (Table 1).

In 2007, Morton et al. detailed a mathematicalmodel that compared an equipment with a 980 nmlaser diode to a 1064 nm Nd: YAG. This studysuggested that regardless of the wavelength, whatreally drove the lipolysis and skin contraction wasthe heating. They have mentioned that the level ofthe internal temperature to achieve a contractionwas from 48 �C to 50 �C (118–1222 �F) (Morton2008).

In 2008, McBean and Katz studied an equip-ment which associated two wavelengths 1064 and1320 nm, respectively, the SmartLipo®. Theobjectives of the study were to assess cutaneoussafety and effectiveness. The effect of cutaneousretraction was documented by photographic doc-umentation and measurement, as well as throughhistological studies and electron microscopy,which revealed study neocollagenesis. This was

Table 1 Equipment available in the market

Commercial nameWavelength(nm)

Lasertype

SmartLipo (Cynosure,Westfort, MA) FDA 2006

1064/1320 Nd:YAG

ProLipo (Sciton, Palo Alto,CA)FDA 2007

1064/1319 Nd:YAG

CoolLipo (CoolTouch,Roseville, CA) FDA 2008

1320 Nd:YAG

LipoLite (Syneron, Yokneam,Israel)FDA 2008

1064 Nd:YAG

SlimLipo (Palomar,Burlington, MA) FDA 2008

924/975 Diode

246 P.A. Bellotti Schwartz de Azevedo et al.

the first study to demonstrate the clinical effects ofcutaneous retraction produced by laser lipolysis,with objective measures proven by electronmicroscopy (Mcbean and Katz 2009).

In the same year, Palomar launched theAspire™ platform (SlimLipo ®) in the market, alaser diode with two selective and safe wave-lengths, respectively, the 924 nm for fatty cellsand 975 nm, with greater selectivity for water inthe connective tissue, promoting cutaneous retrac-tion (Mcbean and Katz 2009).

Today, it became clear that laser lipolysis liq-uefies fat and promotes remodeling of collagenfibers, improving flaccidity. Currently, newresearch aims to standardize the methods thatwill optimize results, safety, and efficacy.

Laser lipolysis is a new technique, a minimallyinvasive procedure for the treatment of localizedfat and laxity, improving facial and body contour.It consists of the application of laser directly onthe adipose tissue, based on the principle of selec-tive photothermolysis. This method has theadvantage to be less traumatic and to cause lessbleeding, reducing the postoperative recoverytime when compared to conventional liposuction.

Since its approval by the FDA in October2006, studies have corroborated for early clinicobservation of the adipose tissue reduction, arapid recovery, and flaccidity improvement.

Goldman has proposed that two properties mustbe considered to determine the effectiveness oflaser lipolysis: wavelength and the energyemployed. According to the theory of selectivephotothermolysis, these chromophores (fat, colla-gen, and blood vessels) preferentially absorb thelaser energy based on the specific absorption coef-ficient, according to the wavelength. Many wave-lengths, including 924, 968, 980, 1064, 1319, 1320,1344, and 1440 nm, have been evaluated by theirinteraction with these chromophores.Many authorssuggest that certain wavelengths are more effectivefor lipolysis (DiBernardo et al. 2009).

Parlette and Kaminer have documented that the924 nm wavelength has a higher selectivity toabsorb fat, but it is not effective to induce cutane-ous retraction, improving laxity. They showedthat 1064 nm wavelength has a good penetration

in the tissue but low absorption by fat. However,its distribution of heating is superior with goodcutaneous retraction effect. Finally, the 1320wavelength has demonstrated great absorptionby fat, but with low penetration in the tissue, soit is safe for treating more fragile skins, such as inthe neck and arm areas (Parlette and Kaminer2008).

The different wavelengths have variableabsorption coefficients for fat, water, and hemo-globin. Fat contains approximately 14% of water,and collagen contains 60–70%; therefore theappropriate selection of the laser allows a prefer-ential target of fat and/or water. When comparinglight absorption by fat and by the dermis, wenoticed that the highest selectivity to melt fathappens when 924 nm laser diode is used. Dueto great absorption of light directly into fat, theheating effect is limited to the fibrous septum offat and to the reticular dermis, preserving theunderlying tissues, with less risks of thermal dam-age. Less trauma to the suction will be necessarydue to great fat liquefaction (Parlette and Kaminer2008).

There are multiple laser systems for lipolysis.Current technologies use small optical fibers1–2 mm thick to transmit the laser directly intothe subcutaneous tissue; the 924 nm has thehighest affinity for fat and less heating of thecollagen. Therefore, it promotes larger liquefac-tion of fat and less tissue retraction (McBean andKatz 2011).

Rupture and liquefaction of the adipose tissue,coagulation of small blood and lymphatic vessels,and collagenesis induction with tissue remodelinghave been reported after laser lipolysis treatment.Other mechanisms of action such as photo-acoustics and photomechanical effect have beenpurported (DiBernardo and Reyes 2009).

Indications and Contraindications

The primary indication of laser lipolysis is thetreatment of localized fat through the liquefactionof the adipose tissue. Any location where there islocalized fat and moderate flaccidity, including

Laser Lipolysis 247

the submental, arms, abdomen, flanks, the innersurface of thighs, knees, and elbows, has an indi-cation to this procedure because they simulta-neously promote cutaneous retraction throughneocollagenesis. It is very well indicated for facecontour (Fig. 1a, b) (McBean and Katz 2011).

Patients with irregularities after liposuction andother surgeries are also excellent candidates. Forareas with more fibrous tissue such as male breast(gynecomastia), flanks, and back, laser lipolysismay be the only option. The small size of thecannula facilitates the treatment in these fibrousareas without the additional trauma (McBean andKatz 2011; Palm and Goldman 2009).

Recent articles described the use of laser lipol-ysis for the treatment of lipoma, considering thatconventional surgeries for lesions bigger than10 cm can result in disfiguring scars. Laser lipol-ysis alone or associated with aspiration by suctionfacilitates the removal of these tumors with abetter aesthetic result (Stebbins et al. 2011).

Other indications described are axillary hyper-hidrosis and cellulite, still with questionableresults. It can also be used in association withother technologies, such as fractional CO2, inthe submental to increase neocollagenesis andcutaneous retraction internally and externally(Parlette and Kaminer 2008).

Careful patient selection is crucial before theprocedure. The ideal candidate for laser lipolysisis a healthy patient with little localized fat. It isimportant to tell the patient that this procedure

does not replace a healthy diet and physical exer-cises (McBean and Katz 2011).

There are no specific contraindications. Patientsover 60 years old with cardiovascular disorders,hypertension, or diabetes should be carefully eval-uated. Additionally, patients with liver disease,previous chemotherapy, and in use of antiretroviralmedicine have risk of lidocaine toxicity (McBeanand Katz 2011).

Preoperative Considerations

During the consultation, complete anamnesesshould be performed, and the real objectivesregarding the procedure must be identified(McBean and Katz 2011).

Drug allergies must be investigated. Patientsshould be informed about drugs that should beavoided before the procedure, such as warfarin,clopidogrel bisulfate, aspirin, or other nonsteroi-dal anti-inflammatories, to avoid bleeding. Drugsthat inhibit the cytochrome P450 liver enzymes,such as selective inhibitors of serotonin and anti-fungal azole agents, decrease the metabolism oflidocaine and should also be avoided (McBeanand Katz 2011).

The laboratorial tests should be done to holdoff some disorders in the liver, kidney, and blood.Some infections, such as HIV and hepatitis, andpregnancy are also contraindication (McBean andKatz 2011).

Fig. 1 (a, b) Before andafter treatment with laserlipolysis

248 P.A. Bellotti Schwartz de Azevedo et al.

During the physical examination, the patientshould be standing and without clothes. With theaim of obtaining better body contour, the patientmay benefit from the treatment of adjacent areas,for example, to treat the abdomen and flanks, evenwhen their initial complaint is limited to the abdo-men (McBean and Katz 2011).

To assess the tonus and the elasticity of the skinon the area to be treated, the physician shouldperform the clamp test, in which the skin is gentlypulled between the forefinger and the thumb andsubsequently released. If the skin instantlyreturns, it indicates good elasticity. If the skinreturns slowly, it indicates poor elasticity. Patientswith excess flaccidity are not good candidates(McBean and Katz 2011).

Previous photographic documentation isimportant and mandatory to identify all irregular-ities, ripples, or previous scars and objectivelyevaluate the postoperative results (McBean andKatz 2011).

A preinformed consent form with guidanceabout the procedure and about postoperativecares should be signed by the patient before theprocedure (Morton 2008).

Technique

Laser lipolysis can be performed under local anes-thesia isolated or in association with intravenoussedation, epidural block, or general anesthesia.The type of anesthesia chosen depends on patienthealth and preference and should be decided withthe doctor. The area to be treated must be markedwith the patient in the orthostatic position. Oncemarked, the patient is taken to the sterile surgicalenvironment (Palm and Goldman 2009).

Local anesthesia is performed through subcu-taneous infiltration of tumescent solution ofheated Klein or other similar solutions combininglidocaine and epinephrine. The total volume of theSC infiltration depends on the surgeon’s prefer-ence and also on the size of the area to be treated.The solution is heated to minimize any discomfortassociated with the difference of temperaturebetween tissue and fluid, in addition to maintain

the basal body temperature. The procedure shouldonly be started after 20–30 min to allow a suitablefluid diffusion and adequate vasoconstriction.Besides promoting analgesia, the tumescent anes-thesia also increases the selectivity and effective-ness of the laser (Klein 1993).

The use of suitable goggles in the operatingtheater for everyone in the team, including thepatient, is a matter of safety (Palm and Goldman2009).

The application of laser on the adipose tissueis performed through an 1.5 mm thick opticalfiber directly on the tissue or inserted within acannula 2–3 mm thick. The optical fiber leadsnot only the therapy light (924, 975, 1064,1320 nm) but also a guiding light of neon-helium (634 nm), which allows the precise loca-tion of the tip of the fiber, so the doctor isconstantly aware of the area of the laser opera-tion (Palm and Goldman 2009).

The application technique happens throughquick, constant, and back and forth movements,as if moving a fan, to avoid overheating of thetreated area, preventing burns and consequentlyscars. The doctor will notice a decrease in tissueresistance to the cannula movement, indicatinglipolysis. This parameter is used as a treatmentendpoint. An infrared thermometer must be usedthroughout the entire treatment to measure theexternal temperature, taking care not to exceed38–40 C (Palm and Goldman 2009).

The resulting content of lipolysis is an oilcontaining broken adipocytes and cellular debris,mixed with the tumescent solution. Aspiration ofthis content is optional and is the doctor’s choice.The aspiration can be done through an externalcannula 2–3 mm thick with negative pressure of0.3–0.5 atm. Very small areas such as the sub-mental, with small volumes, recover well withoutaspiration (Morton 2008).

Regardless of aspiration, a manual drainagemust be performed while the patient is still in theoperating theater, and the cannula’s orifice mustremain open to promote gradual output of theremaining content, which can occur up to 48 hafter procedure (Palm and Goldman 2009;Stebbins et al. 2011).

Laser Lipolysis 249

Postoperative Care

It is recommended that patient uses compressivemeshes placed at the end of the procedure andmaintained for a period of 2–4 weeks. The returnto routine activities occurs after the first 24 h, exceptfor intense physical activities, which can be takenup within 15 days. The manual lymphatic drainageis initiated after 48 h, performed two to three times aweek for 15 days (Palm and Goldman 2009).

Results

Although the initial clinical results can be similarto those obtained in a traditional liposuction, thehistological findings show some differences suchas rapid recovery due to blood vessel coagulationwith peri- and post-procedure bleeding reduction.In addition it promotes neocollagenesis and reor-ganization of collagen in the reticular dermis,explaining the cutaneous retraction. This lasercapacity of producing retraction is very importantfor the treatment of patients with some degree offlaccidity, who may not have indication of a tra-ditional liposuction (DiBernardo and Reyes 2009;Palm and Goldman 2009; Morton et al. 2007;Goldman et al. 2011; Mann et al. 2008).

Complications

Complications are rare, and when they occur, theyare not specific to the laser. Excessive energy orsuperficialization of the laser cannula can promoteburn with unaesthetic scar. Adverse effects such asecchymosis, edema, asymmetries, and temporaryparesthesia are also reported and are similar totraditional liposuction (Katz and McBean 2008).

Conclusion

Laser lipolysis is a minimally invasive safe andeffective procedure. It is a useful tool for bodyand facial contouring treatment. Through this

technique, pain, ecchymosis, and edema arereduced, minimizing complications. In additionit promotes cutaneous retraction, avoiding laxityafter lipolysis, and has a short downtime.

Take Home Messages

• Laser lipolysis is a minimally invasive safe andeffective procedure.

• Any location where there is localized fat andmoderate flaccidity, including the submental,arms, abdomen, flanks, the inner surface ofthighs, knees, and elbows, has an indicationto this.

• Induction of neocollagenesis and short down-time are the two major advantages.

• Complications are rare.

References

Apfelberg DB, Rosenthal S, Hunstad JP, et al. Progressreport on multicenter study of laser-assisted liposuc-tion. Aesthet Plast Surg. 1994;18(3):259–64.

Badin AZ, Moraes LM, Gondek L, et al. Laser lipolysis:flaccidity under control. Aesthet Plast Surg. 2002;26(5):335–9.

DiBernardo BE, Reyes J. Evaluation of skin tighteningafter laser-assisted liposuction. Aesthet SurgJ. 2009;29(5):400–7.

Goldman A, Wollina U, Mundstock EC. Evaluation oftissue tightening by the subdermal Nd:YAG laser-assisted liposuction versus liposuction alone. J CutanAesthet Surg. 2011;4(2):122–8.

Katz BE, McBean JC. Laser-assisted lipolysis: the reporton complications. J Cosmet Laser Ther. 2008;10(4):231–3.

Kim KH, Geronemus RG. Lipolysis using a novel laser1064 nm Nd: YAG Laser. Dermatol Surg. 2006;32(2):241–8.

Klein JA. Tumescent technique for local anesthesiaimproves safety in large-volume liposuction. PlastReconstr Surg. 1993;92(6):1085–98.

Mann MW, Palm MD, Sengelmann RD. New advances inliposuction technology. Semin Cutan Med Surg.2008;27:72–82.

Mcbean JC, Katz B. The pilot study of the efficacy of a1064nm and 1320 nm sequentially firing Nd: YAGlaser device for lipolysis and skin tightening. LasersSurg Med. 2009;41(10):779–84.

McBean JC, Katz BE. Laser lipolysis: an update. J ClinAesthet Derm. 2011;4(7):25–34.

250 P.A. Bellotti Schwartz de Azevedo et al.

Morton MR. Mathematical modeling of laser lipolysis.Biomed Eng Online. 2008;7(1):10.

Morton S, Eymard-Maurin AF, Wassmer B, et al. Histo-logic evaluation of lipolysis laser: pulsed Nd: YAGlaser 1064nm versus CW 980 nm diode laser. AesthetSurg J. 2007;27(3):263–8.

Palm MD, Goldman MP. Laser lipolysis: current practices.Semin Cutam Med Surg. 2009;28:212–9.

Parlette EC, Kaminer ME. Laser-assisted liposuction:here’s the skinny. Semin Cutan Med Surg. 2008;27:259–63.

Stebbins WG, Hanke CW, Peterson J. Novel method ofminimally invasive removal of large lipoma after laserlipolysis with 980nm diode laser. Dermatol Ther.2011;24(1):125–30.

Laser Lipolysis 251

Laser Treatment of Vascular Lesions

Andréia S. Fogaça

AbstractLaser surgery has become the treatment ofchoice for many vascular lesions. The mostcommon indications are vascular anomaliesincluding port-wine stain and hemangiomas,as well as facial erythema and telangiectasias.In this chapter, we are going to approach dif-ferent types of lasers and its indications,results, and side effects.

KeywordsVascular lesions • Oxyhemoglobin •Deoxyhemoglobin • Methemoglobin • Pulseddye laser • KTP laser • Near-infrared radiation

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253

Laser Parameters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255Wavelength . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255Pulse Duration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255Spot Size . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255Surface Cooling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255

Physiological Influences . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256Superficial Vessels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256Skin Temperature, Vascular Dilatation,

and Blood Flow . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256

Vascular Lasers and Light Sources . . . . . . . . . . . . . . . 256Pulsed Dye Laser (PDL: 577, 585, and 595 nm) . . . . 256

Potassium Titanyl Phosphate Laser(KTP: 532 nm) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256

Alexandrite Laser (755 nm) . . . . . . . . . . . . . . . . . . . . . . . . . 257Diode Laser (800–983 nm) . . . . . . . . . . . . . . . . . . . . . . . . . . 257Nd:YAG Laser (1064 nm) . . . . . . . . . . . . . . . . . . . . . . . . . . . 257Intense Pulsed Light (IPL: 500–1200 nm) . . . . . . . . . . 257

Vascular Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257Facial Telangiectasia and Spider Telangiectasia . . . . 257Rosacea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258Poikiloderma of Civatte . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259Venous Lakes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260Infantile Hemangiomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260Port-Wine Stains Birthmarks . . . . . . . . . . . . . . . . . . . . . . . . 260

Pretreatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261

Posttreatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264

My Experience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264

Take Home Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264

Introduction

One of the first indications of lasers in dermatol-ogy was the removal of vascular lesions, using thetheory of selective photothermolysis, introducedby Anderson and Parrish in 1983 (Anderson andParrish 1983). Three components are necessaryfor selective photothermolysis: (1) a laser wave-length with preferential absorption of the target

A.S. Fogaça (*)Dermatology/Medicine, University Santo Amaro(UNISA), São Paulo, São Paulo, Brazile-mail: andreia@andreiafogaca.com.br

# Springer International Publishing AG 2018M.C.A. Issa, B. Tamura (eds.), Lasers, Lights and Other Technologies, Clinical Approaches and Procedures inCosmetic Dermatology 3, https://doi.org/10.1007/978-3-319-16799-2_19

253

chromophore, (2) appropriate pulse durationmatched to the target size, and (3) a fluence thatboth treats the target and minimizes nonspecificthermal-related injury. The classic target chromo-phore for vascular lesions has been oxyhemoglo-bin, which has the greatest absorption peaks at418, 542, and 577 nm. The laser light is absorbedby oxyhemoglobin and converted to heat, whichis transferred to the vessel wall causing coagula-tion and vessel closure. Other hemoglobin specieshave more recently been recognized as appropri-ate targets, depending on the vascular lesion. Theyare deoxyhemoglobin and methemoglobin. In thecase of deoxyhemoglobin, the greatest absorptionpeaks is 755 nm and has been used for refractoryor hypertrophic PWS (port-wine stain), a veno-capillary malformation.

The first lasers to treat vascular lesions wereCO2 and argon lasers. The argon laser at 488 and515 nm enjoyed a high absorption coefficient forhemoglobin (HgB), but the pulse durations (con-tinuous wave) were longer than the thermalrelaxation time of the targeted blood vessels,and in the absence of surface/epidermal cooling,the high absorption by epidermal melaninresulted in a high risk of hypopigmentation andscaring. In 1968, Dr. Leon Goldman e col. dem-onstrated the histopathology of the laser treat-ment of port-wine lesions (Solomon et al.1968). Although Goldman accurately predictedthat vascular lesions could be selectively heated,the pulsed dye laser (PDL) was the first laser, in

1986, to show that this selectivity was effective.Initially it was developed at 577 nm to target theyellow absorption peak of oxyhemoglobin. Cur-rently, PDL lasers shifted to 585 nm and 595 nm,allowing for a depth penetration of approxi-mately 1.16 nm.

In general, vascular laser technologies can bedivided into three spectral ranges (Graphic 1):

1. Green-yellow (GY) light sources, such as PDL(pulsed dye laser/585,595 nm) and KTP(potassium titanyl phosphate laser 532 nm)

2. The diode laser (800 nm) and alexandrite(755 nm) lasers

3. Near-infrared radiation (NIR), lasers with asmaller ratio of melanin to HgB absorption anddeeper penetration (940, 980, and 1064 nm)

In summary, smaller lesions in lighter skin aretreated with GY light sources, and larger lesions indarker skin are treated with NIR lasers.

Intense pulsed light (IPL) devices emit poly-chromatic noncoherent broadband light from420 to 1400 nm with varying pulse durations,can cover all of the HgB peaks, and cannot be“framed” into one of the three aforementionedcategories.

There are alternatives to treat vascular lesions,such as ablatives lasers (CO2) or photodynamictherapy (PDT).

The microanatomy of the vascular lesionshould always be considered.

Graphic 1 Depth ofpenetration of differentlasers

254 A.S. Fogaça

Laser Parameters

Wavelength

In general, the first parameter to be considered iswavelength, and it should be elected to achievethree goals: (1) to absorb the vascular target(O2 saturation of cutaneous blood ranges from50% to 80%), the peaks of oxy-HgB absorptionare 418, 542, and 577 nm with a smaller peak at940 nm (Anderson and Parrish 1981a); (2) toavoid melanin target in darker-skinned patients,it is possible to use Nd:YAG laser 1064 nm (mel-anin absorption is much less than GY light); (3) toachieve desirable depth of penetration.

The lasers used to treat vascular lesions havewavelengths that are well absorbed by hemoglo-bin. However, we should be aware of concurrentabsorption by melanin, which is maximal at shortwavelengths (Anderson and Parrish 1981b). Thismay result in unwanted clinical effects such ashypopigmentation, especially when treating per-sons with dark skin types. As melanin in thenormally pigmented skin is situated in the epider-mis, overheating of the melanosomes may eveninduce epidermal necrosis, eliciting clinical blis-tering or at the long term even scaring.

In addition, penetration depth is also mainlydetermined by wavelength. As a rule, longerwavelengths have less scattering and a larger pen-etration depth. Theoretically, longer wavelengthsmay, therefore, be preferred for deeper and largervascular lesions such as reticular veins, whereasshorter wavelengths may be suited for superficialvascular lesions such as telangiectasias.

Pulse Duration

The ideal pulse duration should be equal to or onlyslightly larger than the thermal relaxation time(time required for the heated tissue to lose abouthalf of its heat). The very short pulses confine heatnot only to the vessels but also to the erythrocytes.Accordingly, thermal confinement is excessive,and localized vessel rupture and intravascularthrombosis are observed in the treated area. Withlonger pulses (6–40 ms), intravascular thrombosis

and spot-sized purpura are mitigated as gentleheating resulted in vessel wall stenosis and throm-bosis of the larger vessels but not the microvesselsthat produce widespread purpura (Table 1).

Spot Size

Larger spots increase the number of photons thatpenetrates deeper into the dermis, compared tosmaller spots. However, with the same fluence, alarger spot will produce more epidermal damageand pain. The rule is larger spots should be accom-panied by smaller fluences than their small spotscounterparts.

Surface Cooling

Epidermal cooling was introduced in the 1990s toprotect the epidermis, minimizing pigmentarychanges and epidermal necrosis. In the treatmentof all vascular lesions, cooling of the skin surfaceis crucial to minimize epidermal damage, to allowhigh radiant exposure, and to minimize discom-fort associated with treatment (Nelson et al. 1995).

In resume, there are three types of surfacecooling:

1. Cryogen spray (nitrogen or tetrafluoroethane),a significant reduction in pain score can beachieved when adequate dynamic cooling isused (on the order of tens of milliseconds).Disadvantages of the spray are the possibilityof pigmentation changes (excessive cooling)and the need for purchasing cryogen canisters.

2. Contact cooling (sapphire windows or copperplate) that is placed on the skin during laser

Table 1 Thermalrelaxation time of vesselswith different diameters

Diameters(μm)

Tr(ms)

10 0.048

20 0.19

50 1.2

100 4.8

200 19.0

300 42.6

Laser Treatment of Vascular Lesions 255

treatment. The main caution is to avoid highcompression of the vascular lesion. Risks ofcontact cooling are fogging and poor contact.

3. Refrigerated air cooling (cooling devices)works well but requires a second hand to holdnear the surface or an accessory that allowsone-hand operation. Air cooling has the advan-tage that the device can be used for differentprocedures and for large areas of the skin.However, caution is mandatory especially inpatients with darker skin types. Post-inflammatory hyperpigmentation due to aircooling has been widely reported (Manuskiattiet al. 2007).

Physiological Influences

Superficial Vessels

Superficial vessels located over the deep vesselswork as a shield reducing the efficacy of thetreatment. Therefore, these vessels should befirstly treated for better results.

Skin Temperature, Vascular Dilatation,and Blood Flow

Low temperature of the skin on the area to betreated requires a slightly higher fluency to reachgood effect (purpuric response). It is alsodescribed that high temperature with increasedblood flow in the target can improve the treatmenteffect. On the other hand, vascular dilatation, suc-tion, pressure, or erythema induced by UVBseems to not have any influence on clinicalresponse (Paul et al. 1983; Aguilar et al. 2012).

Vascular Lasers and Light Sources

Pulsed Dye Laser (PDL: 577, 585,and 595 nm)

Pulsed dye lasers use a rhodamine dye dissolved ina solvent and pumped by a flashlamp. The PDLwas the initial “test” for selective photothermolysis

(SPT). The first PDLs were slow (0.5 Hz or less),equipped with only small diameter spot size(3–5 mm), lacked cooling, and used a 577 nmwavelength near one of the peaks of oxy-HgBabsorption. Over the years from 1981 to 1990, thewavelength was changed to 585 nm. Later coolingdevices were added and the laser wavelength wasagain increased to 595 nm to further enhance epi-dermal/vascular penetration.

Pulsed dye lasers have been proven safe andeffective in the treatment of a variety of vascularlesions, including port-wine stains (Faurschou et al.2011). Dierickx et al. identified the ideal pulse dura-tion for PWS treatment to be 1–10 ms. In practice,treatment often begins at 1.5 ms, though this may beadjusted down to 0.45 ms and up to 6 ms. Parame-ters to consider include 7–10 mm spot size, pulseduration of 0.45–6 ms, and fluence of 5.5–9.5 J/cm2

with appropriate epidermal cooling. Lower energiesare used for larger spot sizes, with shorter pulsedurations. Longer pulse durations are advisable indarker skin types. Treatment should start at lowerenergies, and this can be increased if treatment istolerated well. The fluence is adjusted to achieve thedesired end point. For the PDL, the desired endpoint is immediate purpura. Parameters vary bydevice.

Proper eye protection is essential and surgicallubricant may be placed on eyebrows and eye-lashes to avoid singeing. Although hair oftenregrows, permanent hair loss can occur withPDL treatment, given the close proximity of thefollicles to the surface.

Potassium Titanyl Phosphate Laser(KTP: 532 nm)

The lasers KTP are Nd:YAG with frequency dou-bled to 532 nm. This wavelength (532 nm) has ahigh absorption to oxy-HgB and melanin, there-fore should be avoided in darker skin typesbecause of the high risk of hypopigmentation(Foumier et al. 2002). The KTP laser penetrationis approximately 1 mm, and it is more appropri-ately used to treat telangiectasias. The KTP lasermay be used to treat individual vessels, with theadvantage of no purpura.

256 A.S. Fogaça

There are many devices with this wavelength,all equipped with sapphire contact cooling.

Alexandrite Laser (755 nm)

The alexandrite is long-pulsed near-infrared laser .It was initially used for laser hair removal. Thereis strong absorption for deoxy-HgB, and overallblood absorption of 755 nm is 2� that of the1064 nm Nd-YAG laser. However, melanin ishighly absorbed by 755 nm; for this reason, it isbetter indicated in lighter skin types and darkervessels. There are many alexandrite lasers withlong-pulsed capability. Cryogen spray, contactcooling, and refrigerated air are integrated intothese devices. The alexandrite laser is typicallyused for PDL-resistant lesions, though it may beimplemented as a first-line treatment for hypertro-phic violaceous lesions in adults. The end point isa subtle gray-blue discoloration followed bydeeper purpura. Care must be taken not to overlappulses, as scarring can occur.

Diode Laser (800–983 nm)

Multiple diode lasers are now available, and dif-ferent systems can emit infrared light at a varietyof wavelengths, including 800, 810, 940, and983 nm. Above 900 nm, absorption by melaninis lower than absorption by oxyhemoglobin. Thismakes diode lasers a safer treatment option forpatients with darker skin types than the alexan-drite laser. Like the alexandrite laser, 810 nm isbetter indicated for deeper vascular lesions inrelatively fair-skinned patients (Wall et al. 2007).

Nd:YAG Laser (1064 nm)

The Nd:YAG laser has relatively poor HgBabsorption, therefore this device should be usedat higher fluences. These higher fluences necessi-tate epidermal cooling to achieve epidermal pro-tection. Absorption by melanin at this wavelengthis lower than for any other laser type used forvascular procedures. Nd:YAG laser treatment is

supposed to be especially effective and safe indarker skin types. At 1,064 nm, penetration depthis at its peak at more than 4 mm. This makes theNd:YAG laser a suitable treatment modality fordeeply located veins (Meesters et al. 2013a).Although depth of penetration can be increased,there is a narrow therapeutic window with thesedevices, and caution is advised owing to the risk ofscarring. It is recommended that only experiencedlaser surgeons use these devices.

Intense Pulsed Light (IPL:500–1200 nm)

IPLs rely on xenon flashlamp that emits high-intensity, noncoherent, and polychromatic broad-spectrum light (500–1200 nm), with varying pulsedurations. By appropriate filtering, one can cus-tomize the spectrum for specific disorders. Formost vascular applications, shorter wavelengthranges are applied. IPL devices are commonlyused with the 550 and 570 nm filters to deliverprimarily yellow and red light, with a minor com-ponent of near-infrared light. The use of IPL forvascular lesions have been increased becauseimprovement in power supplies, in cooling, andin filtering is now available, and IPL devices aresafer andmore efficient (Ross 2006; Goldman et al.2005; Goldman and Eckhouse 1996) (Graphic 2).

Vascular Lesions

Facial Telangiectasia and SpiderTelangiectasia

Telangiectasias are small superficial vessels0.1–1.5 mm in diameter that are commonly asso-ciated with sun damage, aging, and/or genetics(Goldman and Bennett 1987). Spider telangiecta-sia represents telangiectasia with a central feedingarteriole. Both can be treated with PDL, KTP, andIPL. Near-infrared lasers, specifically diode andNd:YAG, have been used to treat deeper- orlarger-caliber vessels (Fig. 1a–c). The laser treat-ment is efficient and is the gold standard to treatthese lesions. The KTP laser produce better results

Laser Treatment of Vascular Lesions 257

than PDL laser when used to treat individualvessels, with the advantage of no purpura. Thereis relatively stronger absorption of hemoglobin at532 nm, and care must be taken in patients withdarker skin. Rule of thumb: for discrete, smaller(0.1–0.6 mm) telangiectasias, PDL, KTP laser, orIPL can be applied; for larger vessels (1 mm ormore), Nd:YAG laser or Alexandrite laser is pre-ferred, but care must be taken to apply the smallest

fluence and smallest spot sufficient for vessel clo-sure. The end point for treating vessels is vesselclearance, a transient blue coagulum, or purpura(Table 2).

Vessels around the nasal ala have more risk ofscarring; therefore in this area, cooling is essentialand overlap pulses should be avoided. We useepidermal cooling devices before and after shoot-ing. The advantages of IPL are the relatively largespots sizes, which can minimize the polka doteffect common to PDL and KTP lasers.

Rosacea

Rosacea is a cutaneous vascular disorder associ-ated with follicular inflammation. Patients withrosacea often have associated background facial

Graphic 2 Absorptionspectra of chromophores(melanin, Oxi-Hb andwater) Vs LASER Types

Fig. 1 (a) Telangiectasiabefore treatment, (b)Telangiectasia immediatlyafter treatment with Nd:YAG(Xeo Cutera) (100 J/cm2; 3mm; 30 ms),(c) Telangiectasia after 4weeks-treatment with Nd:YAG (Xeo Cutera) (100 J/cm2; 3 mm; 30 ms)

Table 2 Incidence rate (%)of Infantile Hemangiomasbased on the depth of tissueinvolvement

Infantilehemangiomas Incidence

Superficialhemangiomas

50%

Deephemangiomas

15%

Combinedhemangiomas

35%

258 A.S. Fogaça

erythema. Lasers and IPL are the first choice treat-ment for telangiectasias and facial erythema(Fig. 2). A comprehensive review of the literaturefinds that of the 18 histologic studies on rosacea,14 showed an increase in Demodex mites(Schimidt and Gans 2004). It is hypothesized thatthese mites may play a role in the inflammation ofrosacea. Studies have demonstrated thermaldestruction of these mites after IPL therapy,which may contribute to the therapeutic effects ofIPL (Prieto et al. 2002). Usually two to three ses-sions demonstrated good results; a certain percent-age of patients (20%) do not respond to the IPL andneed to be treated with PDL. PDL provides likeIPL effective and relatively risk-free results.

In our experience, two treatments per year is thebest method to control rosacea. Aminolevulinicacid-photodynamic therapy (ALA-PDT) or methylaminolevulinate-photodynamic therapy (MAL-PDT) has also been reported to be resistant torosacea (Baglieri and Scuderi 2011).

Poikiloderma of Civatte

Poikiloderma of Civatte presents in chronicallysun-exposed areas, most commonly on the neck,chest, and lateral cheeks, with red-brown

discoloration and associated telangiectasias. Inour experience, the best results are achieved withIPL. Multiple sessions are necessary, and somecases are resistant to treatment. Several studiesdemonstrated that patients presenting typicalchanges of poikiloderma on the neck were treatedwith IPL at various settings every 4 weeks untildesired improvement occurred. A 50–75%improvement in the extent of telangiectasia andhyperpigmentation comprising poikiloderma wasobserved in an average of 2.8 treatments. Incidenceof hypopigmentation was 5%. Approximately 75%improvement occurs after one treatment. Sideeffects include transitory erythema from 24 to72 h. Purpura occurs only 10% of the time andresolution occurs within 3–5 days (Weiss et al.2000; Goldman and Weiss 2001). We advise ourpatients that “footprints” can be seen, it representsthe shape of the contact crystal, and it is a normaltransitory response. PDL has also beenimplemented to treat the vascular component ofpoikiloderma of Civatte with good results. Largerspot sizes and low fluences are advised for PDL tolimit potential side effects like hypopigmentationor “polka dot”. Fractional lasers have been studiedto treat poikiloderma and showed to reduce theredness and hyperpigmentation (Behroozan et al.2006; Tierney and Hanke 2009).

Fig. 2 Rosacea before andafter treatment withLimelight (IPL) – 4sessions/program A (19J,20J, 21J, 21J)

Laser Treatment of Vascular Lesions 259

Venous Lakes

Venous lakes are red-blue nodules, usually seen asa single lesion, typically occur on the lip, and canbe treated successfully by PDL, KTP, or Nd:YAGlasers and/or IPLs. For superficial lesions, KTPand PDL are helpful. For deeper lesions diode,alexandrite, and Nd:YAG lasers are more effec-tive. Often one treatment session will reduce thelesion by 80% in volume, and occasionally thelesions will disappear after one treatment (Fig. 3).Surface cooling is necessary to avoid epidermalinjury. Any device with contact cooling should beheld against the skin surface with only gentlepressure to avoid vessel collapse.

Infantile Hemangiomas

Infantile hemangiomas constitute the most com-mon vascular tumors of early infancy. The esti-mated incidence of IHs ranges from 1% to 2.6% inhealthy infants in the immediate newborn periodto about 4–10% of infants by 1 year of age. Afemale predominance has been described rangingfrom 2:1 to 9:1 (Esterly 1996). Histopathologi-cally, these lesions are composed of benign pro-liferations of plump endothelial cells with a

unique vascular phenotype. Glutaminase transfer-ase 1 staining of these lesions is positive anddemonstrates small, scanty capillaries, a featurethat persists throughout the natural progression ofIH and can help confirm the diagnosis (North et al.2000). Studies of the natural history of IHs revealthat complete resolution occurs in 50% of childrenby age 5 years and 70% by age 7 years, withcontinued improvement in the remaining childrenuntil 10–12 years of age (Bivings 1954; Garzonand Frieden 2000). IHs tend to be classified basedon the depth of tissue involvement (Table 2)(Chiller et al. 2002). Many studies demonstratedthat PDL lasers are more effective and safe thanKTP lasers and Nd:YAG (Leonard-Bee et al. n.d.;Raulin and Greve 2001). According to our expe-rience, the best results are achieved with the fol-lowing parameter: fluence 5–9 J/cm2, spot size7–10 mm, and pulse duration 0.45–1.5 ms. Alex-andrite laser or Nd:YAG can be used to comple-ment the results in the treatment of deeper lesions.Ablative fractional lasers are also being exploredfor their role in treating fibro-fatty residual frominvoluted hemangiomas and scars secondary toprevious surgical excision. The alternatives totreat the IHs are imiquimod 5% cream or topicaltimolol maleate 0.5% gel (Jiang et al. 2011; Popeand Chakkittakandiyil 2010) (Fig. 4).

Port-Wine Stains Birthmarks

Port-wine stains are congenital, though in rarecase they may be acquired. PWS are found inapproximately 0.3% of newborns. They tend tooccur on the head and neck, although they mayappear anywhere on the body. PWS persistthroughout life and many thicken with time.Early treatment may improve the responsiveness,decrease the number of treatments, and reduce thelikelihood of permanent adverse sequelae (Reyesand Geronemous 1990; Chapas et al. 2007;Chapas and Geronemus 2005). PDL remains thegold standard of treatment for most PWS,although newer-generation IPL (narrow IPL) andKTP lasers have evolved as reasonable options.Anesthesia is an important concern whenperforming laser surgery in the pediatric

Fig. 3 Venous Lakes before and after treatment with Nd:YAG (Xeo Cutera), (90 J/cm2; 5 mm; 30 ms)

260 A.S. Fogaça

population. While older children may tolerate thelaser procedure using topical anesthetics only,infants and young children may require generalanesthesia. Cooling the skin is crucial to minimizedamage in surrounding tissue and to reduce therisk of postoperative complications such as swell-ing, scarring, and post-inflammatory pigmentarychanges (specially in darker-skinned patients).

The PDL remains the most studied device inPWS treatment. Over the years, different parame-ters have been used to treat PWS, with signifi-cantly good results. The fluence is adjusted toachieve the desired end point. For PDL, thedesired end point is immediate purpura. A conflu-ent gray color signifies that the fluence is too high.The most commonly applied pulse duration is1.5 ms. However, for lighter PWS, 0.45 ms hasbeen advocated. Treatment intervals are normallyabout 3–6 weeks apart. A recent study showedthat more frequent treatments might be preferable(Minkis et al. 2009; Chapas and Geronemus2009). In general, improvement and clearancewere gradual and require five to ten treatments.

The alexandrite laser is typically used forPDL-resistant lesions, though it may beimplemented as a first-line treatment for hypertro-phic violaceous lesions in adults. Care must be

taken not to overlap pulses as scarring can occur.Note that the range of appropriate fluences foralexandrite laser use is quite broad. Nd:YAGlaser and IPL can also be used for PWS. Photody-namic therapy (PDT) has been utilized success-fully to treat PWS, primarily in China. The use ofsystemically administered hematoporphyrin pho-tosensitizers results in prolonged photosensitivity(weeks), which limits its use. Alternative photo-sensitizers, such as benzoporphyrin derivativemonoacid ring A and mono-L-aspartyl chlorine6 (Npe6), have shorter periods of photosensitiv-ity and maybe a good option (Eppley and Sadove1994).

Laser treatment according to the vascularlesions is summarized in Table 3 part 1 and 2.

Pretreatment

• Clean the skin gently.• Topical anesthesia should be avoided

(blanching of the skin caused by anesthesiacan decrease the results of the treatment). Insome cases, it can be necessary taking intoaccount the patient’s age, extent of lesions,and preference.

Fig. 4 InfantileHemangioma before andafter treatment (Timololmaleate 0,5 % gel; 2 times aday; 7 days)

Laser Treatment of Vascular Lesions 261

Table

3Correlatio

nbetweenvascular

lesion

sandlasertreatm

ents

Diagn

ostic

Clin

ical

characteristics

Laser

Param

eters

End

point

Intervalof

treatm

ent

Tratm

entexp

ectatio

nsCom

ments

Facial

telang

iectasia

0.1–1mm

diam

eter;

Red-purple;

Macules

orlin

ear

papu

les

KTP

7–16

J/cm

2,3

–7mm,

10–3

0ms

Vesselb

lanching

orclosure

4–6weeks

1–2treatm

entsare

indicated;

vesselsarou

ndnasalalaaremoreresistant

andcann

otdisapp

ear;new

telang

iectasiascanappear

Hereditary

hemorrhagic

telang

iectasias,lupu

serythematosus,systemic

sclerosis(CREST

synd

rome),rosacea,

hyperstrog

enicstate,

basalcellcarcino

ma

PDL

5–8J/cm

2,

10–1

2mm,

0.45–6

ms

IPL

24–4

0J/cm

2,

10–3

0ms

(550–5

70nm

)

Nd:YAG

90–115

J/cm

2,

3–5mm,2

0–30

ms

Spider

telang

iectasia

Red-purplepapu

les

PDL

5–8J/cm

2,7

–10mm,

1–5ms

Vesselb

lanching

orclosure

4–6weeks

1–2treatm

entsare

indicated

Hyp

erestrog

enicstate,

pregnancy

Nd-YAG

90–1

00J/cm

2,

3–5mm,2

0–30

ms

Rosacea

Facialerythem

a;telang

iectasias

IPL

24–4

5J/cm

2,

10–2

0ms

(550–5

70nm

)

Hom

ogeneous

erythema

4weeks

After

3–6treatm

ents,a

clearanceof

50–8

0%is

usually

achieved.

Re-treatm

ento

nceor

twice

ayear

Hyp

erestrog

enicstate,

tabagism

,dietary

habits,

sunexpo

sure,stress

Nd-YAG

(Genesis)

13–1

5J/cm

2,

6,00

0–10

,000

shots

Venou

slake

2–10

mm

diam

eter;

Blue-pu

rplepapu

les

KTP

7J/cm

2,4

mm,14ms

Vesselb

lanching

orpu

rpura

4–6weeks

1–2treatm

entsare

indicated

Associatedto

photo

damage

Nd-YAG

90–110

J/cm

2,

5–7mm,2

0–30

ms

Nd-YAG

100–

150J/cm

2,

3–7mm,2

0–30

ms

262 A.S. Fogaça

Poikiloderm

aof

Civatte

Telangiectasias;

Hyp

erpigm

entatio

n;Hyp

opigmentatio

n;Skinatroph

y

IPL

17–2

4J/cm

2,

20–3

0ms

(550–5

70nm

)

Hom

ogeneous

erythema

4–6weeks

After

3–6treatm

ents,a

clearanceof

50–8

0%is

usually

achieved

Associatedto

photo

damage

PDL

5–7J/cm

2,7

–10mm,

0.45–2

ms

Purpu

ra

Port-Wine

Stain

Pink-red-pu

rple-blue

macules

orpapu

les;

Present

atbirth

PDL

6–8J/cm

2,1

0mm,

1.5ms

Purpu

ra4–12

weeks

Gradu

allesion

discoloration(10%

per

treatm

ent)

Glaucom

a,SturgeWeber

synd

rome,Klip

pel-

Trenaun

ay,G

LUT

1negativ

e

Infantile

hemangiom

aPink-redmacules;

Firstfewweeks

oflife

PDL

6–8J/cm

2,7–1

0mm,

0.45–1

.5ms

Purpu

ra2–8weeks

Slowgrow

thrate

Caremustb

etakenwhen

lesion

isnear

ocular

glob

eGLUT1po

sitiv

e

Pyo

genic

granulom

a0.5–2cm

diam

eter;

Red-purplepapu

les

PDL

6.5–9J/cm

2,

7–12

mm,0

.45–3ms

Subtlegray-blue

discoloration

followed

bydeeperpurpura

3–4weeks

1–3treatm

entsare

indicated

Eletrosurgery

and

excision

arethemost

indicatedtreatm

ent

Nd-YAG

100–

150J/cm

2,

3–7mm,2

0–30

ms

Laser Treatment of Vascular Lesions 263

• Intralesional lidocaine or nerve blocks may berequired to treat deeper lesions such as venousmalformations.

• Systemic anesthesia should be considered forchildren when treating hemangioma.

• Proper eye protection is essential.

Posttreatment

• Surface cooling is very important to stop theheating and minimize side effects (scaring,pigmentary changes).

• Physical sunscreen is recommended aftertreatment.

My Experience

In my experience, the success of vascular lesionstreatment, with safety and efficacy, is related tosurface cooling just before and after each session.Proper cooling is essential to protect the epidermisand minimize side effects (scaring).

I am therefore summing up the key points:

• Do not treat tanned skin• Use longer pulse durations and/or lower

fluences for darker skin.• To treat port-wine stains, my first choice is

pulsed dye laser.• For hypertrophic lesions or PDL-resistant

PWS treatment, we can use alexandrite laser.• For venous lake, Nd:YAG is a good choice.

One to two sessions will reduce 80–100% ofthe lesion.

• The use of 1064 nm long-pulse Nd:YAG laserrequires fluences over ten times of that usedwith 532 and 595 nm lasers since the absorp-tion of Hb and HbO2 at 1,064 nm is tentimes less.

• My best results for treatment of rosacea includetwo to three IPL sessions per year.

• To avoid the polka dot effect in the treatment ofvessels around the nasal ala, my best choiceis IPL.

Conclusion

The laser treatment of vascular lesions was thefirst to use selective phototermolisys and nowa-days is one of the most important treatments usingthis theory. The treatment is safe and efficient formost of vascular lesions. The parameters selectionguarantees the treatment success (wavelength,spot size, pulse duration, surface cooling). Newpossibilities come up with technological advancesand the increase of medical knowledge.

Take Home Messages

• Pulsed dye laser remains the gold standardtreatment for port-wine stains.

• Early laser treatment improves port-wine stainresponse.

• The end point for treating vessels is vesselclearance, a transient blue coagulum, orpurpura.

• Lasers and IPL are the first-choice treatmentfor telangiectasias and facial erythema.

• Multiple sessions are necessary to treatpoikiloderma of Civatte, and some cases areresistant to treatment.

• Alexandrite laser or Nd:YAG can be used tocomplement the results in the treatment ofdeeper lesions.

• It is indicated to use longer pulse durations andlower fluences for darker skin.

• Do not treat tanned skin.

References

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266 A.S. Fogaça

Laser for Onychomycosis

Claudia Maria Duarte de Sá Guimarães,Taissa Vieira Machado Vila, and Sergio Bittencourt-Sampaio

AbstractOnychomycosis is a common fungal infectionthat affects the nail plate or the nail bed and isresponsible for approximately 50% of thepathologies affecting the nails (GhannoumMicrobiology 157:3232–42, 2011). Its treat-ment remains a challenge, even though pro-gress has occurred with the introductionof new antifungal drugs in the 1990s, sincemany cases linger for decades without aclinical cure (Sigurgeirsson J Europ AcadDermatol Venerol 24:679–684, 2010). Mostcases are caused by dermatophyte fungi; how-ever, in recent years there has been a progres-sive increase of records of onychomycosiscaused by nondermatophyte fungi (yeast andfilamentous fungi) that do not respond to anti-fungal agents (Ranawaka et al. DermatolOnline Journal 18(1):7, (2012); Hwang et al.Ann. Dermatol 24(2):175–180, 2012). Photo-biomodulation and photoinactivation studies

indicate that lasers in the range of theinfrared electromagnetic spectrum (870, 930,1,064 nm), when applied with biochemicalenergy, are able to improve the microcircula-tion, to stimulate the metabolism of cells, andto inhibit the fungal and bacterial multiplica-tion through the action in the wall of the micro-organisms, by altering the electric chargesand favoring the formation of ROS (singletoxygen radicals, free radicals). This techniquecan be associated with the application in thenails of the fractional CO2 laser so that ina drug delivery system it can be associatedwith antifungal and/or antibacterial agentsin order to act synergistically and thus reducethe number of sessions of sub-millisecond1,064 nm laser.

KeywordsOnychomycosis •Antifungal •Dermatophyte •Nondermatophyte • Biofilm • Photo-biomodulation • Nd:YAG laser • CO2 laser •Drug delivery

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268

Basic Concepts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268

Etiology and Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . 269Biofilms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270Biofilms in Dermatology . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271Biofilms in Onychomycosis . . . . . . . . . . . . . . . . . . . . . . . . . 271

C.M. Duarte de Sá Guimarães (*)Rio de Janeiro, Brazile-mail: doctorsa@uol.com.br

T.V.M. VilaLaboratory of Cell Biology of Fungi, Carlos Chagas FilhoInstitute of Biophysics, Federal University of Rio deJaneiro, Janeiro, Brazil

S. Bittencourt-SampaioDepartment of Histology and Embryology, UFRJ, SouzaMarques School of Medicine, Rio de Janeiro, RJ, Brazile-mail: sergiorpbs@globo.com

# Springer International Publishing AG 2018M.C.A. Issa, B. Tamura (eds.), Lasers, Lights and Other Technologies, Clinical Approaches and Procedures inCosmetic Dermatology 3, https://doi.org/10.1007/978-3-319-16799-2_20

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Biofilms of Candida spp. . . . . . . . . . . . . . . . . . . . . . . . . . . . 273Biofilms of Fusarium spp. . . . . . . . . . . . . . . . . . . . . . . . . . . 273

Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274

Clinical Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274Clinical Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274Prognostic Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275

Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276Topical and Systemic Treatment . . . . . . . . . . . . . . . . . . . . . 276Treatment with Light and Laser . . . . . . . . . . . . . . . . . . . . . 277The 1,064 nm Nd:YAG Laser . . . . . . . . . . . . . . . . . . . . . . . 279The 10,600 nm CO2 Laser . . . . . . . . . . . . . . . . . . . . . . . . . . . 280

Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281

Take Home Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281

Introduction

Onychomycosis is a common fungal infectionthat affects the nail plate or the nail bed and isresponsible for approximately 50% of the pathol-ogies affecting the nails (Ghannoum et al. 2000).Its treatment remains a challenge, even thoughprogress has occurred with the introductionof new antifungal drugs in the 1990s, asmany cases linger for decades without clinicalcure (Sigurgeirsson 2010). It is estimated thatthe rate of clinical cure with oral medicationsreaches slightly over 50% of the cases, inthe most optimistic statistics, while topical treat-ments do not reach 20% of cure rates (Scheret al. 2007).

Onychomycosis can complicate other footproblems in elderly persons, affect social inter-actions, impair employment in which there isdirect contact with the public, and serve as areservoir for potentially aggressive fungi inimmunosuppressed individuals. Some factorsare considered as predisposing factors, such asadvanced age, diabetes, hyperhidrosis, immuno-compromised individuals (tumors of hematologicorigin, HIV/AIDS), alteration of peripheral circu-lation, and nail trauma (tight shoes, athletes, etc.),tinea pedis, and trauma from manicure or pedi-cure, in addition to family history (probablybecause of transmission) and nail psoriasis(Fig. 1) (Pariser et al. 2013).

Basic Concepts

The nails are keratinized plates of hardened consis-tency located on the distal ends of the fingers andtoes. The first signs of the structure that will lead tothe nails appear near the end of the first trimester offetal life. The epidermis of the extremities of thefingers begins to proliferate and grow in the shapeof a curved line toward the dermis. Next, the pro-liferative plate is divided into segments forming thenail groove. Cells in the deepest part of this groovegive rise to the nail matrix, where the upper cellsare keratinized and form the plate or body of thenail. As the mitoses in the matrix continue, the nailplate is displaced along the dorsal surface of thefinger. This process in the hands precedes the onein the feet. Thus, approximately at the 32nd week,the fingernails reach the ends of the fingers, while,in the feet, this only happens at approximately the36th week of intrauterine life.

The proximal part of the nail is called the root,where the nail matrix is located, which continues inthe exposed part named body. Matrix cells becomekeratinized and, unlike the other parts of the body,do not come off; on the contrary, they becomecompact and move in the linear path of the nailplate, where they remain included. In the matrix,Merkel cells and melanocytes are also found. Thedermis of that proximal part presents short papillae.The matrix is firmly attached to the dermis, so that,when the nail is extracted, the entire matrix cannotbe removed. The root is covered with a smallskinfold (proximal nail fold), which covers asmall portion of the body of the nail, thus consti-tuting the eponychium, formed by soft keratin.

Fig. 1 (a) Diabetes. (b) Diabetes – 1 year after five ses-sions of Nd-YAG laser

268 C.M. Duarte de Sá Guimarães et al.

Underlying the body of the nail, the epidermisdiffers from other anatomical regions by pre-senting only the Malpighian layer without cellscontaining keratohyalin granules, existing in theskin throughout the body. In this case, the nailplate performs the function of the cornea layer.The proximal portion of the nail bed has epidermisthat is very thick, generating an opalescent imageknown as lunula, most evidenced in the thumband which may appear in other fingers (Montagnaand Parakkal 1974). The cells responsible for theproduction and the growth of the nail (nail matrix)are located there. On a layer of prismatic (basal)cells, 6–10 layers of polyhedral cells and 3–12layers of flat cells can be found. It is assumedthat the white discoloration is derived from thisthick condition, which does not allow the indirectviewing of the blood inside the capillaries (Bloom1977; Weiss 1977; Montagna and Parakkal 1974;Snell 1985); however, the lunula does not alwayscoincide with the location of the matrix (Monta-gna and Parakkal 1974).

The nail plate contains a type of keratin that isvery high in sulfurous amino acids (hard keratin),which explains its structural stability and chem-ical resistance. In this region, the cells have athick cell membrane and are firmly attached toeach other, with a large amount of thick andbirefringent tonofibrils, measuring from 60 to80 A, in their interior, and surrounded by denseamorphous material (Wiess 1977). On the sur-face of the nail plate, there are very evidentlongitudinal grooves in the elderly, but they arerarely present in the young population (Monta-gna and Parakkal 1974). Despite being thick andcompact, the nail, as well as hair, is more perme-able to water than the stratum corneum of theskin in general.

Underlying the body of the nail (nail bed), thedermis rests on the periosteum of the phalanx. Inthis segment, the dermal papillae form longitudi-nal and parallel ridges, which accompany the lon-gitudinal axis of the nail. The vascularization isintense, which gives the pink opaque colorobserved through the nail plate. The side edgesare involved by skinfolds, the lateral nail folds,separated from the bed where the body of the nailrests. The location that establishes the continuity

of the epidermis of the finger with the distal end ofthe nail bed is named hyponychium, from wherethe free edge of the nail emerges.

Fingernails grow from 0.5 to 1.2 mm per week,while toenails show a slower evolution (Snell1985). Several conditions can interfere in thisgrowth: circadian rhythms (the growth is greaterduring the day than during the night and greater insummer than in winter), age group (greatlyreduced growth after the seventh decade), hor-monal factors (which speeds up during pregnancy,slowdown with hypothyroidism, etc.), nutritionalconditions, and traumatic conditions.

Etiology and Epidemiology

Most cases of onychomycosis are caused by der-matophyte fungi, which are microorganisms foundin soil (geophilic), animals (zoophilic), or humans(anthropophilic). The anthropophilic species areTrichophyton,Microsporum, and Epidermophyton.Dermatophytes are able to invade keratinized tis-sues (cornea layer, hair, and nails) and therefore arecalled keratinophilic microorganisms. Nonder-matophyte fungi are not keratolytic, which iswhy they are found in the intercellular cement orfixed in the keratin previously destroyed by thedermatophytes, by trauma, or by other nail disease(Pariser et al. 2013; Hwang et al. 2012). Filamen-tous nondermatophyte fungi are most common intropical regions (e.g., Fusarium and Aspergillus),as well as yeasts (especially Candida spp.). Non-dermatophyte fungi have presented increasingincidence and are considered more difficult to betreated, because they often do not respond toantifungal agents (Fig. 2) (Ranawaka et al. 2012;Hwang et al. 2012).

A large-scale American study isolated derma-tophyte fungi in 59% of the cases and non-dermatophyte fungi and yeasts in approximately20% of the cases. The Trichophyton rubrum andTrichophyton mentagrophytes are among the mostfrequently encountered dermatophytes, while theTrichophyton tonsurans,Microsporum canis, andEpidermophyton floccosum represented 0.8% ofthe dermatophytes. Among the isolated non-dermatophytes, the Acremonium, the Fusarium,

Laser for Onychomycosis 269

and the Scopulariopsis spp. deserve to be high-light with 29.5%, 34.1%, and 20% of frequency,respectively. Among the yeasts, Candida para-psilosis represented 66.7% and Candida albicans16.7% of the cultures (Ghannoum et al. 2000). Astudy carried out in Rio de Janeiro in 2001 eval-uated 2,271 patients and diagnosed 400 patients,being these diagnoses in 264 fingernails and136 toenails, through direct mycological exami-nation and culture; this study indicated the pres-ence of dermatophyte fungi in 46.5% of the casesof onychomycosis in toenails, Candida in 49% ofthe fingernails of women, and 4.5% of emergingfungi (nondermatophytes and other microorgan-isms). Among the nondermatophyte fungi capableof causing onychomycosis, the Scopulariopsisbrevicaulis, the Fusarium spp., the Acremoniumspp., the Aspergillus spp., the Scytalidium spp.,and the Onychocola canadensis were identified(Araujo et al. 2003). A study performed in SriLanka recorded onychomycosis by nonder-matophyte fungi in 45.8%, Candida spp. in34.1%, and dermatophytes in 20% of the cases.This variation of pathogens was attributed to thecontact with soil, the habit of walking barefoot,the frequent immersion of the hands in water, andthe moist and warm climate. The most encoun-tered nondermatophyte fungi were Aspergillusniger, Aspergillus flavus, and Fusarium spp.Onychomycosis was accompanied by paronychiain 76% of the cases. Nondermatophyte fungiaccounted for 22% of the onychomycoses inIndia, 35.5% in Malaysia, 51.6% in Thailand,and 68% in Pakistan (Ranawaka et al. 2012).

The Fusarium spp. have been highlighted asplant pathogens and can occasionally infect ani-mals and humans. They can be found in soil,underground, and aerial parts of plants, organicsubstrates, and water, where they are part of thestructure of biofilms. Among humans, they causesuperficial infections (such as keratitis andonychomycosis), local invasive disease, or dis-seminated infections, the latter affecting severeimmunocompromised patients (with deep andprolonged neutropenia and/or severe Tcell immu-nodeficiency) and patients with hematologic dis-eases, mainly patients with acute leukemia.Furthermore, they can cause allergic sinusitis inimmunocompetent individuals and mycotoxicosisin humans and animals from the intake of foodcontaminated by the toxin produced by thesefungi. Among the 50 known species, 12 are capableof causing infection, and preexisting onycho-mycosis can be the source of the disseminatedfusariosis (Nucci et al. 2007).

Biofilms

Since the seventeenth century, biofilms have beendescribed in multiple systems. Most bacteria pref-erentially grow, as biofilms, in all self-sustainingaquatic ecosystems, and these sessile bacterialcells differ deeply from their planktonic counter-parts (cells in suspension) (Costerton et al. 1995).The definitions of biofilm have evolved over theyears, in parallel to the advances of the biologyarea and research studies on the subject. The def-inition used today was proposed by Donlan andCosterton (2002), and it describes biofilm as amicrobial community in which the cells areconnected to a substrate, or to each other, embed-ded in a matrix of extracellular polymeric sub-stances (produced by themselves) and exhibit analtered phenotype regarding the rate of growthand transcription of genes (Fig. 3) (Donlan andCosterton 2002).

In fungi, the ability to colonize surfaces and toform biofilms was initially demonstrated for Can-dida albicans and Saccharomyces cerevisiae, inthe 1990s and early 2000s (Hawser and Douglas1994; Reynolds and Fink 2001).

Fig. 2 (a) Onychomycosis by Fusarium. (b)Onychomycosis by Fusarium after treatment by Nd:YAGlaser and CO2 fractional laser plus topical amphotericin B

270 C.M. Duarte de Sá Guimarães et al.

However, the growing awareness on theimportance of fungal biofilms can be seen in theincrease in the number of publications describingthe formation of biofilms by other species of Can-dida spp. (Bizerra et al. 2008; Lattif et al. 2010;Silva et al. 2011) as well as other yeasts that causeopportunistic infections and pneumonia inhumans, such as Malassezia pachydermatis(Cannizzo et al. 2007), Rhodotorula sp. (Nuneset al. 2013), Trichosporon asahii (Di Bonaventuraet al. 2006), Blastoschizomyces (D’Antonio et al.2004) Pneumocystis spp. (Cushion et al. 2009),and Cryptococcus neoformans (Martinez andCasadevall 2007). Moreover, the ability to formbiofilms has also been demonstrated in severalfilamentous fungi, including Aspergillus fumigatus(Mowat et al. 2009) and Fusarium spp. (Imamuraet al. 2008); in fungi that cause endemic mycoses,such as Histoplasma capsulatum (Pitangui et al.2012), Paracoccidioides brasiliensis (Sardi et al.

2014), and Coccidioides immitis (Davis et al.2002); and in zygomycetes, such as Mucorales(Singh et al. 2011).

Biofilms in Dermatology

Despite the participation of biofilms in nail infec-tions still being an open discussion, their involve-ment in other dermatological infections, includingacne, miliaria, atopic dermatitis, and wounds, isquite accepted, especially related to bacterialbiofilms (Vlassova et al. 2011).

Biofilms in Onychomycosis

During the course of the nail infection, the forma-tion of a thick biomass can be observed, withfungal elements embedded in an extracellular

Fig. 3 (a) Biofilms. (b) Biofilms

Laser for Onychomycosis 271

matrix (Burkhart et al. 2002). Several factors,including the firm adhesion of the fungi to thenail plate, the presence of persister cells, and thedifficulty of eradicating the infection, suggest thatbiofilms are an important factor in the pathogen-esis of onychomycoses (Nusbaum et al. 2012).Complementing this hypothesis, the ability toform biofilms was demonstrated in vitro for theprimary causative agent of onychomycosis, thedermatophyte Trichophyton sp. (Costa-Orlandiet al. 2014). A model for biofilm formation inhuman nail fragments has recently beenestablished usingCandida albicans and Fusariumoxysporum (Vila et al. 2014) and may help toelucidate the involvement of biofilms in the path-ogenesis of onychomycoses and to validate theantibiofilm activity of new molecules and newtreatments (Fig. 4).

Antifungal Resistance Associatedwith BiofilmsAccording to the definition of a biofilm, the cellsthat make up its structure have altered phenotypeand differ from the planktonic cells in the expres-sion of genes, in the rate of growth, and, mainly, inthe susceptibility to antifungal agents. The increaseof antifungal resistance in the cells ofCandida spp.grown as biofilms, in relation to their planktonicforms, is the most medically relevant behavioralchange (Ramage et al. 2002).Multiplemechanismshave been suggested to explain the increased anti-fungal resistance of the biofilm, including cell den-sity, alteration of drug targets, expression of drugefflux pumps, extracellular matrix, and presence ofpersistent cells (Kuhn et al. 2002a; Lattif et al.2011; Mukherjee and Chandra 2004; Perumalet al. 2007; Ramage et al. 2002, 2012).

Role of the Extracellular Matrixof the Biofilm in ResistanceIn most biofilms, the population of microorgan-isms corresponds to 10% of the total mass, and theextracellular matrix (ECM) corresponds to 90%.The matrix consists of a cluster of differentbiopolymers responsible for keeping the cellsadhered to the surface and the cohesion ofthe biofilm, for restraining the cells, and for keep-ing them close, this way allowing cell-cell

communication and diffusion of signaling mole-cules (Flemming and Wingender 2010).

The ECM, by definition, provides protection tocells against environmental factors, such as theimmunity of the host and the antifungal agents(Seneviratne et al. 2008). One of the describedkey components of the ECM of C. albicans is aβ-1,3-glucan responsible for abducting azoles,echinocandins, pyrimidines, and polyenes (Nettet al. 2010a, b; Vediyappan et al. 2010), behavingas a “drug sponge” and contributing to theincreased resistance of biofilms of C. albicans(Nett et al. 2010a, b). The latest study publishedon the subject suggests that, in addition to theβ-1,3-glucan, a polysaccharide complex formedby mannan-glucan (which is, in fact, the polysac-charide in greater abundance in the ECM ofbiofilms of C. albicans) is also capable of bindingto fluconazole (and possibly to other drugs) andcontributes to the resistance (Zarnowski et al.2014). In this work, it is emphasized that, possi-bly, most polysaccharides of the ECM must act asdrug sequestrants and contribute to the resistanceof the biofilm to antifungal agents.

In addition to the polysaccharides, the extra-cellular DNA present in the ECM of biofilms ofC. albicans also appears to have a role in theresistance to non-azole agents, as the addition ofDNase increases the antibiofilm activity of poly-enic agents and echinocandins, but not the activityof azoles (Martins et al. 2009, 2012).

Even though the resistance mechanisms asso-ciated with the lower susceptibility of biofilms toantifungals available are not fully elucidated,

Fig. 4 Dermatophytoma

272 C.M. Duarte de Sá Guimarães et al.

several studies show that biofilms of C. albicans,C. parapsilosis, and C. tropicalis are resistant totreatments with different commercially availableantifungals, among them fluconazole, nystatin,terbinafine, amphotericin B, voriconazole, andravuconazole (Ferreira et al. 2009; Kuhn et al.2002b). Moreover, in vitro studies with biofilmsof Fusarium spp. also highlight its lower suscep-tibility to the commercial antifungal agentsamphotericin B, voriconazole, itraconazole, andfluconazole (Mukherjee et al. 2012; Zhang et al.2012).

Biofilms of Candida spp.

The in vitro development of biofilm of Candidaspp. (in abiotic surfaces) can be didacticallydescribed in four sequential steps: (1) adherence,initial phase, in which the yeast in suspension andthose circulating (planktonic cells) adhere to thesurface; (2) intermediate phase, concerning thedevelopment of biofilm; (3) maturation phase, inwhich the polymer matrix completely soaks alllayers of cells adhered to the surface in a three-dimensional structure; (4) dispersion, in which themost superficial cells leave the biofilm and colo-nize areas surrounding the surface (Chandra et al.2001; Ramage et al. 2005; Seneviratne et al.2008). At the end of the development, the biofilmconsists of a dense network of cells in the form ofyeasts, hyphae, and pseudohyphae soaked bypolymeric extracellular matrix and with waterchannels between the cells, which facilitate thediffusion of nutrients from the environmentthrough the biomass to the lower layers andwhich also allow the elimination of waste(Chandra et al. 2001; Ramage et al. 2001, 2005).

Biofilms of Candida spp., formed in in vivomodels, seem to follow the same sequence offormation (Andes et al. 2004); however, the mat-uration occurs more rapidly and the final thicknessis greater in these biofilms than those grown inin vitro systems.

The final architecture of the biofilm is variableand depends, in part, on the substrate on which it isformed and the growing conditions, such as culturemedium used (in vitro), concentration and types of

sugars, presence of serum proteins, pH, and tem-perature (Kumamoto 2002; Seneviratne et al.2008).

Biofilms of Fusarium spp.

Species of the genus Fusarium are soil sapro-phytic and important pathogens of plants andhumans. The clinical form of the fusariosisdepends on the immune status of the host. Inimmunocompetent individuals, keratitis andonychomycoses are the most common infections.In immunocompromised individuals, the dissem-inated fusariosis is the second most common fila-mentous fungal infection, and it particularlyaffects patients treated with high-dose corticoste-roids and with severe neutropenia, with mortalityrate of up to 100% (Nucci and Anaissie 2007).The Fusarium spp. is an important causative agentof microbial keratitis, and the biofilm formationhas been suggested as a contributing factor inrecent outbreaks, mainly associated with the useof contact lenses (Mukherjee et al. 2012). TheFusarium spp. is also commonly isolated as acausative agent in onychomycoses (de Araújoet al. 2003; Morales-Cardona et al. 2014). Innails, fungal cells form thick fungal biomasses,with fungal elements embedded in an extracellularmatrix (Burkhart et al. 2002); this behavior sug-gests the participation of biofilms in the pathogen-esis of onychomycosis (Nusbaum et al. 2012). Inthe northern hemisphere, onychomycosis causedby dermatophytes, especially T. mentagrophytesand T. rubrum, are more prevalent (Ghannoumet al. 2000). However, in warmer and humidcountries such as Brazil, the incidence of non-dermatophytic filamentous fungi (such as Fusar-ium spp.) and yeasts (such as Candida spp.) ascausative agents of these infections is very signif-icant (de Araújo et al. 2003; Morales-Cardonaet al. 2014). These data are extremely relevantsince, while most dermatophytes are sensitive tothe terbinafine and azoles commonly used in thetreatment of onychomycoses (ketoconazole, clo-trimazole, and fluconazole), Fusarium spp. isoften resistant to the available antifungals(Bueno et al. 2010; Ortoneda et al. 2004).

Laser for Onychomycosis 273

Diagnosis

The diagnosis of onychomycosis involvesresearching the involvement of the nail unit (nailplate, nail bed, and periungual tissues). Dermato-phytes affect toenails more than fingernails, wherethe infections by Candida spp. are more frequent.The physical examination should be careful inorder to register all the nail units involved and toobserve the clinical signs of onychomycosis:onycholysis, material under the nail plate, sub-ungual hyperkeratosis, change of color (white oryellow, brown), and intensity of the destruction ofthe nail plate (Fig. 5) (Pariser et al. 2013).

Clinical Evaluation

The clinic evaluation begins by gathering infor-mation such as age, sex, presence of vasculardiseases, diabetes, hypertension, number ofinfected nails, duration of infection, history ofprevious treatment, type of onychomycosis, per-centage of nail involvement, thickness of the nail,presence of dermatophytoma, involvement of thematrix, and exclusively lateral involvement(Ghannoum et al. 2000; Scher et al. 2007). InBrazil, there is also the need to include the familyhistory of onychomycosis and the habit of remov-ing the cuticles by manicures, which facilitates theinvolvement of the nails with mixed infections(bacterial and fungal). The examination of areasof intertrigo assists in the identification and treat-ment of fungal reservoirs. Individuals with a fam-ily history of diabetes, metabolic syndrome,peripheral circulatory problems, or immunodefi-ciency should be treated by a multidisciplinaryteam. Young individuals from 20 to 30 yearswith chronic infection that is difficult to treatshould be investigated for family onychomycosis,because of the contamination of the nails in theinfancy, the use of bathrooms with contaminatedrelatives and/or locker rooms, and fungi resistantto traditional treatment.

The identification of the clinical presentation isimportant for the choice of appropriate therapeuticapproach for each case (Scher et al. 2007). Thewhite-yellow or orange-brown spots may be

caused by fungi that do not respond to the medi-cation used, as in the case of nondermatophytefungi. The brown spots are common in the fifthtoe and should be differentiated from nail mela-noma (although these two pathologies may occurat the same time). Patients with chroniconychomycosis should be examined for signsthat indicate active infection, even if the cultureis negative.

1. Change of more than 10% of the nail platecompatible with infection caused by dermato-phytes by dermatoscopy

2. Presence of white, yellow, orange, or brownspots of plates on the nail

3. Lateral onycholysis with debris4. Lateral hyperkeratosis on the nail plate or bed

(Fig. 6) (Ortiz et al. 2014)

The following are some fungi that can causemelanonychia: Scytalidium, Scopulariopsis,Aspergillus, Fusarium, Trichophyton rubrum, Tri-chophyton mentagrophytes, Trichophytonsoudanense, Candida albicans, Candidatropicalis, Curvularia, etc. (Finch et al. 2012).

Differential Diagnosis

Irritant contact Enamels, acrylics, or artificial nails

Nail trauma Athletes, contusions

Psoriasis Secondary infection by fungus

Lichen planus

Neoplasms Subungual

Bacterialinfection

Gram-positive bacteria

Clinical Classification

Distal and lateral subungual onychomycosis –mixed infection by Candida and bacteria,dermatophytes

Proximal subungual onychomycosis – affects thebase of the nail and can be caused by the genusFusarium spp.

274 C.M. Duarte de Sá Guimarães et al.

White superficial onychomycosis –T. mentagrophytes

Endonyx onychomycosis – dermatophytesTotal onychomycosis – dermatophytes and mixed

infections with nondermatophyte fungi(Pariser et al. 2013; Hwang et al. 2012; Carneyet al. 2011)

Prognostic Factors

Onychomycoses are under the influence of factorsthat make the prognosis grim. They act in theworsening of the nail infection. Their characteris-tics are:

Host – impaired peripheral circulation, diabetes,and immunosuppression (Figs. 7 and 8)

Nails – hyperkeratosis greater than 2 mm, lateraldisease, dermatophytoma (biofilm), involve-ment of more than 50% of the nail plate, slow

growth of the nails, total dystrophiconychomycosis, involvement of the matrix,and serious onycholysis

Microorganism – filamentous nondermatophytefungi, yeasts, and mixed infections (Carneyet al. 2011)

Clinically, it is not possible to identify or dif-ferentiate onychomycosis caused by dermato-phytes, filamentous nondermatophytes, or yeasts(Ranawaka et al. 2012). The collection of samplesis carried out with sterile instruments, with curet-tage after cutting part of the free edge of the nail,with curettage of the nail plate when white super-ficial onychomycosis is suspected, or with sam-ples of the nail and the nail bed when theinvolvement is closer to the matrix. The materialis collected after cleaning the nail with alcohol,stored and transported in sterile collector. Part ofthis material will be used for the direct

Fig. 5 (a) Traumatic onychodystrophy, negative culture,athletic runner. (b) Traumatic onychodystrophy, 7 monthsafter first session of Nd:YAG laser. (c) Traumatic

onychodystrophy 1 year and 4 months after first sessionof Nd:YAG laser

Laser for Onychomycosis 275

examination and another part for the culture inSabouraud agar medium. The direct examination,although nonspecific, aids in the differential diag-nosis from other diseases, such as psoriasis orlichen planus, although secondary bacterialand/or fungal infections may occur in relation tothe other inflammatory pathologies. It is importantto inform the laboratory when there is the need toresearch a nondermatophytic fungus and/or bac-teria so that the material can be grown in suitablemedium.

The culture is a method considered as goldstandard for the diagnosis of onychomycosis in3–4 weeks, although it can show a false negativein 15% of the cases (Pariser et al. 2013; Liu et al.2000). The isolation of a nondermatophyte fungusor yeast can be considered as environmental con-tamination or from the local microbiota. The rec-ommendation of the diagnosis of these pathogensis based on the lack of growth of the dermatophytefungus in the culture and the growth of five colo-nies of the same microorganism in two consecu-tive samples (Araujo et al. 2003; Ranawaka et al.2012).

The examination through the technology ofnucleic acid amplification (PCR) has offered theopportunity to improve the quality and speed ofdiagnosis of dermatophytes by up to 4 h. It iden-tifies species and subspecies of dermatophytesand sets them apart from nondermatophytes andCandida spp., and it does not require viablemicroorganisms for the test (Liu et al. 2000).

Treatment

Topical and Systemic Treatment

The treatment of onychomycoses faces severaldifficulties, among them the need for long-termmonitoring, the side effects of systemic medica-tions, and the difficulty of taking the medication tothe target area to be treated (Vural et al. 2008). Thetraditional therapeutics of onychomycoses con-sists of palliative care, chemical or mechanicaldebridement (Chiacchio et al. 2004), and use ofsystemic or topical medications. The definition of“complete healing” by the US regulatory agency

Fig. 6 (a) Dystrophic onychomycosis. (b) Dystrophic onychomycosis – after seven sessions of Nd:YAG laser. (c)Dermatoscopy – before treatment. (d) Dermatoscopy – after treatment

276 C.M. Duarte de Sá Guimarães et al.

Food and Drug Administration (FDA), for evalu-ation of clinical results, are the negative results ofthe direct examination and culture, as well ascompletely normal appearance of the nail (Pariseret al. 2013).

The choice of treatment depends on the clinicalpresentation, the severity of the disease, and thecost and time of treatment. The systemic drugsused – terbinafine, itraconazole, and fluconazole –are associated with significant adverse effects,which hinder the prescription for patients withhepatic and/or renal problems. The topical medi-cations are safer but are ineffective. In clinicalpractice, patients with long-term infections orchronic onychomycosis with serious changes ofthe nail plate, nail bed, and matrix can beobserved. The study of Pariser et al. (2013)indicates that the cure rate with ciclopirox topical8% for 48 weeks is 5.5–8.5%. Therefore it is notrecommended as monotherapy. The cure rateswith therapeutic treatment with systemic medica-tions range from 14% to 54%, according tothe used medication, the dose, and theadministration time.

Treatment with Light and Laser

The application of lights in tissues and organismscan have both stimulatory and inhibitoryresponses according to the parameters used.Some terms are used to determine these effects,such as biostimulation, low-level laser (or light)therapy (LLLT), low-intensity laser therapy,low-power laser therapy, cold laser, soft laser,

Fig. 7 Occlusion of right popliteal artery

Fig. 8 (a) Mixed infection – Trichophyton sp. and Pseu-domonas sp. – treatment with Nd:YAG laser plus topicalgaramycin and isoconazole. (b)Mixed infection – 3monthsof treatment. (c) Mixed infection – 2 years after treatment

Laser for Onychomycosis 277

photobiostimulation, and photobiomodulation.The most used term is the low-level laser therapy(LLLT), a term that is often mentioned in theMedical Subject Heading (MeSH) in the con-trolled vocabulary thesaurus of the NationalLibrary of Medicine. The conference of theNorth American Association for Light Therapyand the World Association for Laser Therapy inSeptember 2014 determined in consensus that theterm that better designates it is photo-biomodulation, proposed to be included in theMeSH Section at the National Library of Medi-cine (Anders et al. 2015).

The photodamage of the ultraviolet light inbacteria and fungi without the use of a photo-sensitizing agent was demonstrated in the begin-ning of the decade of 1903 with lamps thatradiated a wavelength between 226 and 328 nm(UVC + UVB). The germicidal activity againstprokaryotic and eukaryotic pathogens wasobserved in 2002; however, its use was aban-doned because of the photocarcinogenic effect inhuman cells (Bornstein et al. 2009a). Since then,other wavelengths in the near-infrared range(NIR) of the electromagnetic spectrum havebeen studied in order to identify the photo-inactivation of pathogens, both with the use oflight and photosensitizing agent, and with theuse of laser (Vural et al. 2008; Kosarevet al. 2010).

The studies of lights and lasers with antimicro-bial objective have walked parallel paths in theareas such as physical-chemical, microbiology,and clinic. Although studies on the electromag-netic spectrum are unraveling the behavior ofcertain wavelengths and some tests with the useof the laser in the culture of T. rubrum and bacteriaindicate the photoinhibition of certain microor-ganisms, there is still a lack of in vitro studiesthat mimic clinical conditions and clinical studieswith broader sampling. One of the difficulties isthe wide variety of clinical presentations ofonychomycoses and the combinations of mixedinfections that form biofilms (Meral et al. 2003;Vural et al. 2008; Knappe et al. 2004; Pasquini2003; Landsman et al. 2010).

Interaction of the Laser with the SkinThe extent and the intensity of the action of thelaser on the skin depend on the structure of thetissue determined by its water content and bloodcirculation that influences the absorption, scatter-ing, reflection, thermal conductivity, heat capac-ity, and density, which in turn are influenced bythe parameters of the laser beam (energy intensityand wavelength). Depending on the duration ofthe irradiation of the laser in the tissues, there aredifferent energy densities that will lead to threetypes of interaction: photochemical effects(10s–1000s; 10�3–1 W/cm2), photothermaleffects (1 ms–100 s;1–106 W/cm2), and photoion-ization and photomechanical effects(10 ps–100 ns; 108–1012 W/cm2). The photo-thermal and photochemical effects are obtainedusing less energy and with pulses greater thanthose used for the photoionization and photome-chanical effects. These physical parameters areimportant to classify the type of laser equipmentavailable and their purposes. In this way, the sametype of wavelength may be indicated for differentclinical conditions according to the energy of theequipment and its ability to generate short or longpulses (Knappe et al. 2004).

The increase in temperature and its distributionin the place exposed to laser radiation depend onthe energy absorbed by the tissue and its thermalproperties. According to the temperatureachieved, different effects will happen. When thetemperature reaches 45 �C, there is no irreversibletissue damage. Temperatures between 50 and45 �C generate alterations of enzymes andedema. Temperature above 60 �C for a few sec-onds generates denaturing coagulation of the tis-sue proteins, and the temperature between 90 and100 �C causes the vaporization of the plasma cell(as with the CO2 laser) (Knappe et al. 2004).Currently, there are studies on the effects of laserswhose wavelength of the electromagnetic spec-trum lies on the near-infrared range (NIR). Lasersin this range between 700 and 1,400 nm have incommon the ability to penetrate deeply into thedermis with virtually no dispersion of the lightbeams. A study performed with the diode laser

278 C.M. Duarte de Sá Guimarães et al.

system of 870 nm and 930 nm indicates the in vitrophotoinactivation in physiological temperaturesof Staphylococcus aureus, Escherichia coli, Can-dida albicans, and Trichophyton rubrum byreducing the membrane potential and increasingthe generation of reactive oxygen species (ROS)without harmful effects to human cells.

A clinical study with laser diode of 870 nm and930 nm performed by Landsman et al. (2010),based on previous studies of Bornstein, obtainedimprovement in cases of onychomycosis in 63%of the cases accompanied during 180 daysthrough the growth of 3 mm of treated nails andculture examined by periodic acid-Schiff beingnegative in 30% of the cases (Landsman et al.2010; Bornstein 2009; Bornstein et al. 2009).The exposures were done with two applicationswith duration of 2 min and accompanied with themeasurement of the temperature with infraredthermometer.

The 1,064 nm Nd:YAG Laser

The 1,064 nmNd:YAG laser has been used for theremodeling of collagen (Dang et al. 2005; Kohet al. 2010; Dayan et al. 2003a, b; Schmults et al.2004; Tan et al. 2004), treatment of pseudo-folliculitis barbae (Ross et al. 2002), pyogenicgranuloma, stimulation of angiogenesis(Kipshidze et al. 2001), and as antibacterial andantifungal agent as noted in photobiomodulationperformed with visible light and near-IR (Guffeyet al. 2014).

A new in vitro model was created to study theeffectiveness of the Nd:Yag laser through the irra-diation of nails previously sterilized and subse-quently contaminated by biofilms of Candidaalbicans and Fusarium oxysporum. The evalua-tion of the colonies in electron microscopyshowed 50% inhibition of the biofilm of Candidaalbicans and 100% of the biofilm of Fusariumoxysporum, even with the presence of holes inthe wall of the latter microorganism and emptyingof contents, which would indicate injury of thewall of the fungus. The tests indicated reduction

of viability of the colonies of Candida albicansand Fusarium oxysporum studied (Vila et al.2014).

The Nd:YAG laser is used in cases in which thesystemic medication is contraindicated, such aswhen the growth of the nail is slow (because ofcirculatory problems, diabetes, trauma, etc.). The1,064 nm Nd:YAG laser belongs to a range of theelectromagnetic spectrum that is characterized bythe ability to penetrate deeply into the skin withlittle dissipation and dispersion, and it has hemo-globin and water as known target chromophoresand little affinity for melanin. In this way, it ispossible to use safely in high phototypes (IV, V,VI). (Dayan et al. 2003b) indicates that the Nd:YAG laser stimulates the formation of collagenfibers and improves microcirculation (Bornstein2009; Dayan et al. 2003a, b). The 1,064 nm Nd:YAG laser facilitates the revascularization of theextremities through a nonthermal effect. Clini-cally, there is a stimulus for the growth of thenail and improvement of its structure and vascu-larization, which is why it is used in cases of slowgrowth of the nails or onychoschizia.

When there is the presence ofdermatophytomas (adherent fungal abscesses pro-tected by biofilms and refractory to oral antifungaltherapy), the chemical and/or surgical debride-ment is recommended. It can be done with theuse of urea at 40% or trimming of the nail withCO2 laser.

The sub-millisecond Nd:YAG laser can beused in the treatment of the nails. According tothe equipment, it can be used with a 5 or 6 mmspot, which allows a good dispersion of the laserin the treated area with reduced Gaussian curve(which concentrates the energy in the center of thespot), forming a top hat, with less joules anddeeper penetration than the smaller spots.

Although clinical studies use a small sampling,the treatment with the Nd:YAG laser can be analternative that can be used alone or in combina-tion with other treatments (Sá Guimarães 2014).Currently, some neodymium-doped yttrium alu-minum garnet (Nd-YAG) laser devices have beenapproved for temporary whitening of the nails:

Laser for Onychomycosis 279

Pinpointe Footlaser (Nuvolase), GenesisPlus(Cutera), Q-Clear (Light Age), CoolTouchVARIA (CoolTouch), and Joule ClearSense(Sciton) (Ortiz et al. 2014; Kimura et al. 2012;Hochman et al. 2011). The Joule ClearSense tip(Sciton equipment) emits a 6 mm spot, withproficiency ranging from 5 to 6 j/cm2, with pulseduration of 0.3 ms, 4.0 Hz, and with real-timetemperature control, measured through the infra-red thermometer built into this handpiece.

The application is done in concentric circlesrepeated until reaching the temperature between42 and 44 �C. Three initial sessions are performedwith an interval of a week, and then there is themonitoring until the total growth of the treatednails with intervals ranging from 1 to 3 monthsaccording to the intensity of the nail involvementand clinical improvement (Fig. 9).

The prevention of recurrences can be donewith the application of antifungal powder withmiconazole 2% on the feet and shoes at the longterm (Warshaw et al. 2005). This measure treatsand prevents tinea pedis in mocassin, usuallycaused by T. rubrum or T. mentagrophytes(interdigitalis).

The 10,600 nm CO2 Laser

The CO2 laser has water as its main chromophore.In the continuous mode, it is used in parallelpoints (with 3 or 4 W, in a continuous mode withthe control of the cutting perpendicular to thepedal) in order to cut the plate with the preserva-tion of the nail bed. The cutting of the hyperker-atotic nail facilitates the collection of material forculture and surgical debridement.

The experimental use of fractional CO2 laser asa way of drug delivery was described byHaedersdal et al. (2010). In this experiment,methyl 5-aminolevulinate (MAL) was used,which is a precursor of porphyrin as drug test. Itwas observed a significant absorption in the depthof the skin with the creation of intradermal chan-nels created by the 3 mm laser and increasedconcentration of porphyrin in the hair folliclesbecause of the diffusion of MAL in the area tested(Haedersdal et al. 2010).

The fractional CO2 laser can be used in thetreatment of onychomycosis caused by Fusariumspp. with application (12 W, 1,000 μm of spacing,700 μs of pulse duration, and five stacks,

Fig. 9 Nd:YAG application and equipment

280 C.M. Duarte de Sá Guimarães et al.

Smartxide, Deka laser) in the entire length of thenail plate and eponychium followed by the appli-cation of cream with tetracycline and topicalamphotericin B (occlusive dressing at night)(Lurati et al. 2011) followed by morning brushingwith hydrogen peroxide 10 vol (Garcez et al.2010) until the total growth of the nail. The appli-cation of amphotericin B produces a brown pig-mentation on the sick part of the nail where thereis debris of dehydrated appearance. This colora-tion serves as an auxiliary chromophore for theapplication of Nd:YAG laser causing a higherconcentration of heat in these areas.

Conclusions

Anders et al. (2015) suggest that the term photo-biomodulation therapy would be “a form of lighttherapy which uses non-ionizing forms of lightsources, including lasers, LEDs, and broadbandlight, in visible light and infrared. It is a nonthermalprocess that involves endogenous chromophoresthat promote photophysical and photochemicalevents in multiple biological scales.” This therapyis applied to reduce pain, inflammation, andimmune modulation, and it promotes woundhealing and tissue regeneration (Anders et al.2015). Meral et al. (2003), Ortiz et al. (2014), Vilaet al. (2014), and Vural et al. (2008) found that thelights and lasers used in photobiomodulation areable to inhibit bacterial and fungal growth.Research studies are just beginning, and they cer-tainly will bring new solutions to the infectionscaused by biofilms from different sources.

Take Home Messages

• Rate of clinical cure with oral medicationsreaches slightly over 50% of the cases, whiletopical treatments do not reach 20% of curerates.

• Nondermatophyte fungi have presentedincreasing incidence and are considered moredifficult to be treated.

• Form biofilms was demonstrated in vitro forthe primary causative agent of onychomycosis.

• Nd:YAG laser stimulates the formation of col-lagen fibers, improves microcirculation, and isantibacterial and antifungal agent.

• Fractional CO2 laser can be used for drugdelivery.

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Lasers for Aesthetic and FunctionalVaginal Rejuvenation

André Vinícius de Assis Florentino, Thales Lage Bicalho Bretas,and Maria Claudia Almeida Issa

AbstractVaginal rejuvenation has been popped uprecently due to the increase in life expectancyand the search for a better quality of life.Nowadays, women live one-third of theirlives after menopause, demanding effortsto keep their sexual life up to their bodyand mind’s health. Advances in laser therapyhave made this possible, reversing vulvo-vaginal atrophy and its symptoms, known asgenitourinary syndrome of menopause, includ-ing vaginal dryness, dyspareunia, decrease insexual arousal and orgasm, stress urinaryincontinence, and vaginal bleeding. Carbondioxide laser (CO2) and the erbium laser (Er:YAG) are the most common lasers used forfemale rejuvenation. They promote neo-collagenesis and neovascularization in the con-nective tissue of the vaginal wall, as well as

recover the mucosal epithelium, restoringlubrication and elasticity of vaginal walls.

KeywordsCO2 laser • Erbium laser • Er:YAG • Genito-urinary syndrome of menopause • Intimatelaser • Menopause • Radiofrequency • Urinaryincontinence • Vaginal laxity • Vaginal rejuve-nation • Vulvovaginal atrophy

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286

History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287

Mechanisms of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287

Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289

Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289

Orientations Prior to Treatment . . . . . . . . . . . . . . . . . . 290

Procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290

Treatment Protocols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291

Posttreatment – What Is Recommended orExpected . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291

Vaginal Laser Rejuvenation – LiteratureReview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291

Authors Experience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295

Take Home Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295

A.V. de Assis Florentino (*)Department of Gynecology, Faculdade de CiênciasMédicas de Campina Grande, Campina Grande, PB, Brazil

Brazilian Federation of Gynecology and Obstetrics,São Paulo, SP, Brazile-mail: f.andrevinicius@gmail.com

T. Lage Bicalho BretasUniversidade Federal Fluminense, Niterói, RJ, Brazile-mail: thalesbretas@gmail.com

M.C.A. IssaDepartment of Clinical Medicine – Dermatology,Fluminense Federal University, Niterói, RJ, Brazile-mail: dr.mariaissa@gmail.com

# Springer International Publishing AG 2018M.C.A. Issa, B. Tamura (eds.), Lasers, Lights and Other Technologies, Clinical Approaches and Procedures inCosmetic Dermatology 3, https://doi.org/10.1007/978-3-319-16799-2_40

285

Introduction

Vaginal rejuvenation is commonly defined as acombination of minimally invasive proceduresthat stimulate regeneration of female lower genitaltract, aiming to regain aesthetic and functionalfeatures lost with the aging process in menopausalwomen. It is also indicated to treat vagina relaxa-tion in young women.

Vagina relaxation, for example, is one of thebiggest responsibilities for sexual dissatisfaction.It represents the loss of the optimum structuralarchitecture of the vagina, generally associatedwith natural aging and specially affected by child-birth, whether vaginal or not. Multiple pregnan-cies increase the alteration of these structures,making vaginal muscles relaxed with poor tone,strength, control, and support. The vaginal canalbecomes wider and stretched, and sexual gratifi-cation consequently diminishes, since it has beenattributed to frictional forces generated duringintercourses. Therefore, many women, especiallyafter menopause, seek for vaginal treatments toregain their sexual health and well-being (Sturdeeet al. 2010).

As we know, menopause is the cessation ofmenstruation for more than 1 year, reflectingthe depletion of ovarian function. As the lifeexpectancy of women has increased, nowadays,approximately one-third of a woman’s life is post-menopausal (NAMS 2013). The progressive ces-sation of estrogen circulating levels leads tometabolic and tissue changes, more evident inthe genital tract due to its particular sensitivity tovariations in sexual hormone levels. Togetherwith menopause, the vaginal epithelium starts toget thinner and vaginal walls become less elasticwith loss of rugations, looking more pale, dry,and friable at the specular exam, often bleedingafter minimal trauma. The entire vaginal canalbecomes shorter and narrower. The vulvar area,particularly the clitoris, becomes atrophic andmore vulnerable (Mehta and Bachmann 2008).These alterations lead to a constellation of symp-toms grouped as genitourinary syndrome of men-opause (GSM).

The GSM is a new term in substitution tovulvovaginal atrophy as agreed by the North

American Menopause Society and the Interna-tional Society for the Study of Women’s SexualHealth (Portman et al., 2014). This syndromeis characterized by a combination of symptomssuch as vaginal pain during sex intercourse(dyspareunia), itching, urinary incontinence, dys-uria, and the main complaint of aging women:vaginal dryness, an early symptom. The GSMaffects around 20–45% of women (Santoro andKomi 2009) and reflects directly in the generalquality of life, mostly causing a profound negativeimpact in the sexual field.

Vaginal health can be objectively assessedby the vaginal health index score (VHIS). TheVHIS evaluates the appearance of vaginal mucosa(elasticity, pH, vaginal discharge, mucosal integ-rity, and moisture). Each parameter is graded from1 to 5; the higher the score, the better the vaginalhealth. If the total score is smaller than 15, thevagina is considered atrophic (Bachmann et al.,1992) – see Table 1.

There are several treatment options tominimize GSM symptoms, including non-hormonal products for mild cases, local vaginalhormone therapy for persistent symptoms, andsystemic hormonal replacement therapy (HRT)as a broader approach for severe symptoms(Sturdee et al. 2010).

The nonhormonal therapy is mostly based onthe use of vaginal lubricants and moisturizes in aregular basis, providing only temporary reliefprior to intercourse. Lubricants have been demon-strated to decrease vaginal irritation during sexualactivity but do not provide a long-term solution(Bygdeman and Swahn 1996).

Low-dose local estrogen therapies can beuseful for women with GSM symptoms withoutsystemic climacteric complaints, in the absence ofcontraindications, such as personal history ofeither endometrial or breast cancer. The majordisadvantage of this approach is the recurrenceof symptoms once it has been suspended, gener-ating a dependency relation among women.

The systemic HRT relieves not only thevaginal symptoms but also general complaintslike hot flushes, mood lability, and sleep distur-bances. It is not indicated for exclusive GSM,since it has more contraindications and side

286 A.V. de Assis Florentino et al.

effects than the local HRT, like the increased riskof thrombosis and breast/endometrial cancer(Santoro and Komi 2009).

In this context, the vaginal laser (an acronymfor “light amplification by stimulated emissionof radiation”) therapy appears as a feasible optionfor women desiring nonhormonal therapy with alonger efficacy compared to the topic local ther-apy. The laser device is a coherent, collimated, andmonochromatic source of light, which is absorbedby tissue according to its light absorbance coeffi-cient. Considering vaginal indications, the mostused kind of lasers are the fractional carbon diox-ide (CO2) and Erbium-doped yttrium aluminumgarnet (Er:YAG) lasers, both of them targetingthe water of the tissue through different wave-lengths: 10,600 nm for the CO2 and 2940 nm forthe Er:YAG lasers (Vizintin et al. 2012).

History

The concept of stimulated light was conceived byAlbert Einstein back in 1905, in a phenomenoncalled the photoelectric effect. The first laser wasconstructed in 1960, a chromium-ruby device.The first carbon dioxide (CO2) laser was built in1964 by Patel and his team.

Laser is considered one of the most versatiletherapeutic instruments in several medical fields.In dermatology, fractional lasers like Er:YAG andCO2 lasers have been used mainly for

resurfacing, rejuvenation, and scar improvement,with significant effects in the connective tissue,stimulating tissue remodeling, with similar effectsbeing reproducible within the vaginal epithelium(Sasaki et al. 2009).

Gynecologists have been using lasers success-fully to treat vaginal and cervical pathologiesover the past five decades (Kaplan et al. 1973).In this last decade, a wave of publications involv-ing vaginal rejuvenation has caught attention ofthe scientific community worldwide. The mecha-nism of action involves neocollagenesis and res-toration of the trabecular architecture of thevaginal wall, regaining the appearance observedin premenopausal women.

The CO2 and the Er:YAG lasers are amongthe most studied and spoken technologies aimingvaginal rejuvenation. More recently, radio-frequency has also gained some strength intreating this area, with prominent findings,specially using a transcutaneous temperature-controlled radiofrequency for vulvovaginal reju-venation (Vanaman et al. 2016).

Mechanisms of Action

The medical use of Laser technology is basedon the interaction between the light emittedand tissue chromophores, including hemoglobin,melanin, connective tissue, and water (Alexiades-Armenakas et al. 2008), which depends on the

Table 1 Vaginal health index score (VHIS)

1 2 3 4 5

Elasticity None Poor Fair Good Excellent

Vaginaldischarge(fluidvolume)

None Scant amount,vault notentirelycovered

Superficialamount, vaultentirelycovered

Moderate amount of dryness(small areas of dryness oncotton tip applicator)

Normal amount(fully saturates oncotton tipapplicator)

pH >6.0 5.6–6.0 5.1–5.5 4.7–5.0 <4.7

MusosalIntegrity

Petechiaenotedbeforecontact

Bleeds withlight contact

Bleeds withscraping

Not friable – thin epithelium Normal

Moisture None,surfaceinflamed

None, surfacenot inflamed

Minimal Moderate Normal

Adapted from Bachmann et al. (1992)

Lasers for Aesthetic and Functional Vaginal Rejuvenation 287

different absorption of light in the electromagneticspectrum.

The vaginal wall is composed of four layers:squamous epithelium, lamina propria, muscularlayer, and the adventitia. Like the epidermis,the squamous epithelium has basal and supra-basal layers, and differentiates to form acornified envelope comprised of a flattenedlayer of specialized cells. Electron microscopyshows lipid lamella, but they do not form animpermeable intercellular lipid envelope asthey do in the epidermis, making vaginal wallpermeable to water and soluble proteins. Alsounlike epidermis, the vaginal epithelium usu-ally is not keratinized and stores glycogen. Thesynthesis of glycogen is diminished by estrogencessation after menopause, as well as the epi-thelial thickness already mentioned (Andersonet al. 2014).

The CO2 laser is a fractional, ablative laser thatemits light at the wavelength of 10,600 nm, whichis strongly absorbed by tissue’s water (Fisher1992), promoting microthermal ablation of theepithelium (the so-called microthermal zones –MTZ), with preservation of healthy tissue islandsbetween the ablated area. This ablation inducesthe body to repair and promote re-epithelization ofthe vaginal tissue, restoring the flora, the thick-ness, and lubrication. It also causes an importantheating deep in the dermis surrounding the ablatedtissue, which, in turn, promotes neocollagenesisand reorganization of the elastic and collagenfibers of the connective tissue, restoring thehealthy architecture of the vagina. FractionalCO2 laser, differently from local therapies, canact in deep layers stimulating collagen synthesis(Gaspar et al. 2011).

The Er:YAG laser is a fractional, nonablativelaser that emits light at the wavelength of2940 nm, which is also absorbed by tissue’swater, with 15 times more affinity than the CO2,with less recovery downtime but also less colla-gen production, since its rays reach smallerdepths. It induces photothermal heating of thevaginal wall without ablating its surface, whichboosts neocollagenesis and remodeling of theconnecting tissue and also stimulates regrowth ofthe epithelium, but with comparatively less

thermal injury and less mucosa swelling than theCO2 laser (Gaviria and Lanz 2012).

The Er:YAG 2940 nm Smooth Mode is amodified Erbium 2940 nm in which laser energyis delivered onto the mucosa tissue in a fastsequence of low-fluence laser pulses inside anoverall super-long pulse of several hundred milli-seconds. The delivered laser energy thus resultsin an overall nonablative buildup of heat andcreates a temperature increase within the mucoustissue. With this Er:YAG laser (IntimaLase™,Fotona®), human tissue can get nonablativelyheated to a depth of 100 microns, which is justwhat is required for a depth-controlled thermaltreatment of vaginal mucosa tissue (Vizintinet al. 2012).

However, through diverse ways, Er:YAG andCO2 lasers share some similarities in their mech-anism of action, since both target the waterresulting in tissue heating. This mechanisminvolves a controlled heat-shock response thatstimulates the production of a small family ofproteins called the heat-shock proteins. Heat-shock proteins 43, 47, and 70 (a protein subtypeas chaperone of collagen, which is overexpressedafter laser irradiation) appear to play an importantrole, stimulating the production of many growthfactors. Among these factors are: transforminggrowth factor-A (stimulates matrix proteins syn-thesis such as collagen), basic fibroblast growthfactor (stimulates angiogenic activity with endo-thelial cell migration and proliferation), epidermalgrowth factor (stimulates re-epithelization), plate-let-derived growth factor (stimulates fibroblaststo produce extracellular matrix components), andvascular endothelial growth factor (regulatesvasculogenesis and angiogenesis). Therefore, thelaser stimuli activate fibroblasts to producenew collagen, other components of the extracel-lular matrix (proteoglycans, glycosaminoglycans,etc.), and new vessels, with specific effects onepithelial tissue (Prignano et al. 2009). Suchbody response of recovery results in a thickerepithelium, neocollagenesis, reorganization ofthe trabecular architecture of the collagen, neo-vascularization with recovery of the papillary dis-position of the subepithelial connective tissue,and regain in production of mucopolysaccharides

288 A.V. de Assis Florentino et al.

by the extracellular matrix (Salvatore et al. 2015).These alterations lead to reestablishment of thevaginal health, with return of lubrication, amelio-rate in epithelial pallor, reverse of vaginal laxity,return of vaginal pH and microbiota, improve-ment in elasticity of the vaginal wall, and eleva-tion of sexual arousal and satisfaction for boththe woman and her partner.

In our practice, we often use the CO2 LaserFemilift™ from Alma Lasers for vaginal rejuve-nation, which has a special sterile, disposable,and individual cover for each patient. Thisfacility makes the procedure more hygienic andallows the operator to perform multiple laser ses-sions subsequently, without the long wait for ster-ilization (Fig. 1). The Er:YAG laser we oftenuse is either from Fotona (IntimaLase™ andIncontiLase™) or from LMG (Solon Femina™),and both of them have a laser speculum thatavoids the contact between the laser device andthe vagina, but needs to be sterilized beforethe next patient. The former, IntimaLase® andIncontiLase®, emit, respectively, a circumferen-tial and an angular laser beam, to reach either thewhole vaginal wall or selectively the anterior wall(for urinary incontinence) – Fig. 2.

Indications

The vaginal laser is indicated to women between20 and 80 years old with one of the follow-ing symptoms (Salvatore et al. 2014; Zerbinati

et al. 2015; Gambacciani and Levancini, 2015;Vizintin et al. 2015; Perino et al. 2016;Gambacciani et al. 2015):

• Hypotrophy and/or vaginal atrophy• Mild to moderate urinary incontinence• Sexual dysfunction such as dyspareunia, dry-

ness, low vaginal sensitivity, and vagina wallbleeding during intercourse

• Postpartum and lactation (temporary estrogen-reduced levels)

• Vagina relaxation/laxity• Posttreatment for gynecological cancers

(breast and endometrial), to improve vaginalsymptoms of the lack of estrogen

Contraindications

• Pregnancy• Bacterial or fungal vaginal infection – laser

treatment can be performed only 30 days aftervaginal infection treatment

• HPV infection• Active herpes viral infection - laser treatment

can be performed without active infection andduring prophylaxis treatment

• Gynecological oncology pathologies• Previous surgical orthesis implant for urinary

incontinence, like transvaginal mesh/sling• Impaired immune system or chronic corticoid

therapies

Fig. 1 CO2 vaginal laser –Femilift from Alma Lasers,with its disposable coverand its marks signaling the1 cm distance of each shot,circumferentially

Lasers for Aesthetic and Functional Vaginal Rejuvenation 289

• Scleroderma, lichen sclerosus, vitiligo, orpsoriasis

• Uncontrolled diabetes• Anticoagulant therapy• Patients who have used isotretinoin in the

last 12 months (Salvatore et al. 2014; Zerbinatiet al. 2015; Gambacciani and Levancini 2015;Vizintin et al. 2015; Perino et al. 2016;Gambacciani et al. 2015)

Orientations Prior to Treatment

Prior to the treatment, patients should fill thepretreatment questioner and sign the InformedConsent Form. It is highly recommended thatthe physician take a detailed patient medicalhistory, including previous treatment modalities,to examine the gynecology condition for treat-ment suitability with the vaginal laser (Salvatoreet al. 2014; Zerbinati et al. 2015; Gambaccianiand Levancini 2015; Vizintin et al. 2015; Perinoet al. 2016; Gambacciani et al. 2015).

It is also important to determine why the patientis seeking treatment and to understand herexpectations. It is advisable to warn the patientthat there may be very mild discomfort associ-ated with the treatment.

Patients shall perform a pregnancy test atleast 1 day before the session, and show arecent cervical screening test result (best ifwithin less than 30 days).

Patients with personal history of previousgenital herpes simplex infection should undergothe prophylaxis protocol, which is valacyclovir500 mg every 12 h for 7 days, starting 24 h priorto the laser session. Acyclovir or fancyclovir canalso be used (Beeson and Rachel 2002).

Procedure

1. The patient should be in lithotomy position.2. Insert a disposable or sterile vaginal speculum

to look for active lesions, signs of infection, oralterations of either the vaginal fluid or themucosa. If the normal aspect is observed, drythe pathway with sterile gauze to avoid burningfrom water absorption.

3. After taking out the speculum, carefully intro-duce the laser device completely, until you feeltouching the cervix or the patient complains ofpain. Some lubricant oil, like mineral oil, mightbe used in the introit if it is too dry, avoiding thelaser window. Usually, the laser probes aremarked circumferentially and have a sign thatrepresents the vaginal depth, between 7 and13 cm. They also have a security distancefrom the tip to the laser window, which pre-vents the patient from cervix irradiation.

4. Some devices have a 360� laser-beam deliverysystem, enabling 360� irradiation of the vagi-nal canal, whereas others carry a limited laserwindow, which needs to be clockwise rotatedsystematically to reach the totality of vaginal

A. The 90° scanning scope

B. The 360 ° scanning scope

C. Special Vaginal speculum for the scanning scopes

A

B

C

Fig. 2 Er:YAG vaginal laser: Fotona accessories neededfor application of the laser beam to the vaginal mucosa,consisting of, from the bottom to the top, a sterile laserspeculum, a circular 360� (IntimaLase), and an angular 90�

(IncontiLase) adapter. (a) The 90� scanning scope. (b) The360� scanning scope. (c) Special vaginal speculum for thescanning scopes

290 A.V. de Assis Florentino et al.

wall circumference. These last devices are alsoassigned to make rotation easy and patterned,so the doctor is sure to perform the 360�

irradiation.5. After the first circumferential deep shot, pull

back the device as marked (1 cm), makingsubsequent shots until the whole marked areais outside the vagina. Patients usually reportsome heating sensation when the laser win-dow is coming closer to vaginal introit. Thisis when you shall fully insert it again andperform a new pass, starting from the deepto the introit.

6. The number of subsequent passes and lasersessions are also described by the manufac-turer’s protocol, depending on the patient’scomplaints and the results achieved by eachsession (Salvatore et al. 2014; Zerbinati et al.2015; Gambacciani and Levancini 2015;Vizintin et al. 2015; Perino et al. 2016;Gambacciani et al. 2015).

Treatment Protocols

Each laser device has its own protocols, with theright fluency and power indicated for the patient’sneeds. Nevertheless, one rule is always true: thehigher the power, the bigger is the depth and themagnificence of the thermal injury provoked.

If the main objective is tightening, for example,higher energies are required. The doctor mustperform three consecutive passes, throughout thewhole vagina wall, circumferentially, in each lasersession, with a total of three sessions spaced by aperiod of 30 days for the best outcomes.

The same protocol with high energy is alsoapplied to urinary incontinence treatment. How-ever, in these cases, at least two passes shouldbe applied focusing on the anterior wall of thevagina (using a clock as a reference, the laserwindow must be focused between 10:00 and02:00 o’clock), and one circumferential pass.

When vaginal dryness and atrophy are themain complaints of the patient, lower energy isindicated. One or two circumferential passes areenough for each session. Three sessions are nec-essary for better results.

Posttreatment – What IsRecommended or Expected

• No sexual intercourse for 3–7 days• No tampons for 3 days• No healing cream is needed• Some translucent or blood discharge might

occur within the following 3–7 days after theprocedure

• Be available for patients’ contact. Ask themto notify you in case of any bleeding, fever,or other unusual side effects (Salvatoreet al. 2014; Zerbinati et al. 2015; Gambaccianiand Levancini, 2015; Vizintin et al. 2015;Perino et al. 2016; Gambacciani et al. 2015)

Vaginal Laser Rejuvenation –Literature Review

Over the last few years, much has been studiedabout the use of lasers for vaginal aging. In a12-week treatment with fractional CO2 laserfor GSM, this treatment has been proved to beefficacious, feasible, and safe to ameliorate theGSM symptoms (Salvatore et al. 2014). In 2015,researches have revealed restoration on vaginalmucosa by the remodeling and neosynthesis ofcollagen in the lamina propria (Zerbinati et al.2015). In the same year, Gambacciani andcolleagues showed that vaginal erbium laser(VEL) induced subjective improvement in dry-ness, dyspareunia, and the overall VHIS in65 postmenopausal women (PMW) after threemonthly sessions. Twenty-one of them who alsohad mild-moderate stress urinary incontinencereported improvement, which was measured bytheir score at the International Consultation onIncontinence Questionnaire – Urinary Inconti-nence Short Form (ICIQ-UI SF) (Gambaccianiand Levancini 2015). Also in 2015, anothergroup demonstrated the improvement in vaginallaxity, stress urinary incontinence, and GSMsymptoms after Er:YAG laser treatment (Vizintinet al. 2015).

In 2016, a study involving 30 postmenopausalwomen complaining about GSM and overactivebladder (OAB) symptoms showed that, after three

Lasers for Aesthetic and Functional Vaginal Rejuvenation 291

Fig. 3 Case 1: Before (left)and after (right) three CO2

Femilift™ laser sessions,showing improvement invaginal thickness andrugations. Courtesy ofDr. Ana Lucia Sayeg

Fig. 4 Case 2: Before(left), immediately after(middle), and 30 days after(right) CO2 laser. In themiddle figure, note themicrothermal zones (MTZ)provoked in the mucosa,representing epitheliumvaporization. After healing(right), see theimprovement in palor andrugations of the vagina wall.Courtesy of Dr. AndreVinicius

292 A.V. de Assis Florentino et al.

sessions of CO2 vaginal laser, there was signifi-cant improvement on OAB symptoms, such asreduction in the number of micturition and ofurge episodes (Perino et al. 2016). In the sameyear, 70 women with GSM and vestibulodyniawere studied by Murina and colleagues. Patientsunderwent three sessions of treatment with micro-ablative fractional CO2 laser, applied on the vulvaand vestibular surface, resulting in statically sig-nificant improvement in dyspareunia and painscores (Murina et al. 2016). The benefits of CO2

laser treatment on the vaginal flora were alsodocumented: there was restoration of the post-menopausal vaginal flora equilibrium, with thepredominance of Lactobacillus, and the low pH,protecting women from vaginal infections(Athanasiou et al. 2016).

In 2017, a study presented 1-year results withfractional CO2 laser for genitourinary syndrome ofmenopause. It emphasized the advantages of posi-tive effects duration and the low risk of adverse

events, concluding that CO2 laser therapy was safeand effective for GSM (Sokol and Karram 2016).

Authors Experience

In our practice, we experienced different technol-ogies, but most of our results were performed withthe CO2 Laser Femilift™, from Alma Lasers.These results are shown in the case reports below.

In case 1 (Fig. 3), a 62-year-old postmeno-pausal woman was submitted to three monthlysessions of CO2 Femilift™ laser, with the follow-ing parameters: 100 mJ per pixel, long-pulse,Power: high, three circumferential (360�) passesper section.

Case 2 (Fig. 4) shows the specular exam of a44-year-old woman with premature menopauseand a family history of breast cancer. The figureon the left shows the vagina walls before thelaser session: note the palor, the dryness, and

Fig. 5 Case 3: (a) Before,(b) after 1 CO2 lasersession, and (c) after twolaser sessions. Observe thegain in vaginal wall rugaeand loss of palor. Courtesyof Dr. Andre Vinicius

Lasers for Aesthetic and Functional Vaginal Rejuvenation 293

the absence of rugations. Three circumferen-tial passes of the CO2 Femilift™ laser wereperformed, with the parameters: Energy: 75 mJper pixel, long-pulse, Power: medium. The mid-dle figure shows the vagina wall immediately after

the three laser passes: note the microthermal zones(MTZ) ablated in the mucosa, representing epi-thelium vaporization. After healing (right), see theimprovement in pallor and rugations, 1 monthafter the first laser session.

Fig. 6 Case 4: 47-year-old woman before (left pictures)and after (right pictures) three Er:YAG Femina™ monthlysessions. a–c show, respectively, the right, the left, and

both vagina walls, before the laser treatment. d–f, on theright side, show the same vagina walls 30 days after the lastlaser session. Courtesy of Dr. Andre Vinicius

294 A.V. de Assis Florentino et al.

In case 3, we show the specular exam of a58-year-old postmenopausal woman, with vaginaldryness and dyspareunia (Fig. 5a–c). In Fig. 5a,vaginal wall before any treatment: observe the pal-lor, the lack of rugae, and dryness. In Fig. 5b, vag-inal wall after the first session of CO2 laser, startingto present rugae and increased mucous secretion. InFig. 5c, observe the vaginal wall 15 days after thesecond session of CO2, with the healing areas(in white), significant increase in vaginal rugae,and improvement in pallor and in lubrication. Thelaser used was the Femilift™ with the parameters:Energy: 100 mJ per pixel, long-pulse, Power: high,three circumferential passes per section.

Case 4 (Fig. 6) illustrates a 57-year-old post-menopausal woman’s specular exam, showing, inFig. 6a–c, the right, the left, and both vagina walls,respectively, before the Er:YAG 2940 Femina™laser treatment. On the right, in Fig. 6d–f, we cansee the same walls 30 days after one laser session,with the 360� scope in multiple micropulse mode,1.7 J delivered per shot, 3 multishots, 3 passesper session.

Conclusion

According to the literature review and our experi-ence, laser treatment is a new and effective toolfor vaginal rejuvenation. It is able to improvesymptoms such as vaginal dryness, itching, uri-nary incontinence, dysuria, as well as vaginal painduring sex intercourse.

Take Home Messages

1. Almost half of menopaused women experi-ment some symptoms of the genitourinary syn-drome of menopause (GSM), includingvaginal dryness, dyspareunia, urinary inconti-nence, and loss of sexual pleasure.

2. The GSM is due to the ovarian failure andconsequent lack of estrogen, which repositionis not always a comfort and feasible option forthe patient.

3. The vaginal lasers were developed to stimu-late, via deep tissue heating, the regrowth of

epithelium, and dermis structures, with reorga-nization of collagen and elastin fibers, regain inmucosal thickness and irrigation, and recoveryof vaginal wall elasticity and lubrication, withconsequent increase in sexual pleasure.

4. The CO2 and the Er:YAG lasers are the moststudied and proven to be efficient technologies.Radiofrequency has also been used with prom-ising results.

5. The candidate to the treatment must perform aPap smear at least 30 days to the first lasersession, as well as a nonpregnancy status war-ranty at the days of the laser sessions.

6. There cannot be any sign of active infection orneoplasia at the sessions, making the specularexam an essential tool before the laser procedure.

7. Herpes simplex previous infections require aprophylaxis treatment, starting 24 h prior to thelaser session, and kept for 7 days (untilre-epithelization).

8. Patients are oriented to refrain from sexual inter-course from 3–5 days after the laser. No healingcream is needed. Tampons are not recommended!

9. The treatment consists of three monthly lasersessions, with a maintenance protocol ofannual single sessions.

References

Alexiades-Armenakas MR, Dover JS, Arndt KA. Thespectrum of laser skin resurfacing: nonablative, frac-tional, and ablative laser resurfacing. J Am AcadDermatol. 2008;58:719–37.

Anderson DJ, Marathe J, Pudney J. The structure of thehuman vaginal stratum corneum and its role in immunedefense. Am J Reprod Immunol. 2014;71:618–23.

Athanasiou S, Pitsouni E, Antonopoulou S, et al. The effect ofmicroablative fractional CO2 laser on vaginal flora ofpostmenopausal women. Climacteric. 2016;19(5):512–8.https://doi.org/10.1080/13697137.2016.1212006.

Bachmann GA, Notelovitz M, Kelly SJ, et al. Long-termnonhormonal treatment of vaginal dryness. Clin PractSex. 1992;8:3–8.

Beeson WH, Rachel JD. Valacyclovir prophylaxis for herpessimplex virus infection or infection recurrence followinglaser skin resurfacing. Dermatol Surg. 2002;28(4):331–6.

BygdemanM, SwahnM. Replens versus dienoestrol creamin the symptomatic treatment of vaginal atrophy inpostmenopausal women. Maturitas. 1996;23:259–63.

Fisher JC. Photons, physiatrics, and physicians. A practicalguide to understanding laser light interaction with

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living tissue, part 1. J Clin Laser Med Surg. 1992;10(6):419–26.

Gambacciani M, Levancini M. Short-term effect of vaginalerbium laser on the genitourinary syndrome of meno-pause. Minerva Ginecol. 2015;67(2):97–102.

Gambacciani M, Levancini M, Cervigni M. Vaginalerbium laser: the second-generation thermotherapy forthe genitourinary syndrome of menopause. Climac-teric. 2015;18:757–63.

Gaspar A, Addamo G, Brandi H. Vaginal fractional CO2laser: a minimally invasive option for vaginal rejuve-nation. Am J Cosmet Surg. 2011;28:156–62.

Gaviria JE, Lanz JA. Laser vaginal tightening (LVT) –evaluation of a novel noninvasive laser treatment forvaginal relaxation syndrome. J Laser Health Acad.2012;2012(1):59–66.

Kaplan I, Goldman J, Ger R. The treatment of erosions ofthe uterino cervix by means of the CO2 laser. ObstetGynecol. 1973;41(5):795–6.

Mehta A, Bachmann G. Vulvovaginal complaints. ClinObstet Gynecol. 2008;51(3):549–55.

Murina F, Karram M, Salvatore S, Felice R. FractionalCO2 laser treatment of the vestibule for patients withvestibulodynia and genitourinary syndrome of meno-pause: a pilot study. J Sex Med. 2016;13:1915.

NAMS. Management of symptomatic vulvovaginalatrophy: 2013 position statement of the North Amer-ican Menopause Society. Menopause. 2013;20(9):888–902.

Perino A, et al. Is vaginal fractional CO2 laser treatmenteffective in improving overactive bladder symptoms inpost menopausal women? Preliminary results. Eur RevMed Pharmacol Sci. 2016;20(12):2491–7.

Portman DJ, Gass ML, Vulvovaginal Terminology Con-sensus Conference Panel. Genitourinary syndrome ofmenopause: new terminology for vulvovaginal atrophyfrom the International Society for the Study ofWomen’s Sexual Health and the North American Men-opause Society. Climacteric. 2014;17:557–63.

Prignano F, Campolmi P, Bonan P, et al. Fractional CO2 laser:a novel therapeutic device upon photobiomodulation oftissue remodelling and cytokine pathway of tissue repair.Dermatol Ther. 2009;22(Suppl 1):S8–S15.

Salvatore S, Nappi RE, Zerbinati N, et al. A 12-weektreatment with fractional Co2 laser for vulvovaginalatrophy: a pilot study. Climacteric. 2014;17:363–9.

Salvatore S, Maggiore ULR, Athanasiou S, Origoni M,Candiani M, et al. Histological study on the effectsofmicroablative fractional CO2 laser on atrophic vaginaltissue: an ex vivo study. Menopause. 2015;22(8):845–9.

Santoro N, Komi J. Prevalence and impact of vaginalsymptoms among postmenopausal women. J SexMed. 2009;6:2133–42.

Sasaki GH, Travis HM, Tucker B. Fractional CO2 laserresurfacing of photoaged facial and non-facial skin:histologic and clinical results and side effects. J CosmetLaser Ther. 2009;11:190–201.

Sokol ER, Karram MM. An assessment of the safetyand efficacy of a fractional CO2 laser system forthe treatment of vulvovaginal atrophy. Menopause.2016;23:1102–7.

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Vanaman M, Bolton J, Placik O, Fabi SG. Emerging trendsin nonsurgical female genital rejuvenation. DermatolSurg. 2016;42(9):1019–29.

Vizintin Z, Rivera M, Fistonić I, Saraçoğlu F, Guimares P,et al. Novel minimally invasive VSP Er:YAG lasertreatments in gynecology. J Laser Health Acad.2012;2012(1):46–58.

Vizintin Z, LukacM, Kazic M, Tettamanti M. Erbium laserin gynecology. Climacteric. 2015;18(Suppl 1):4–8.

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296 A.V. de Assis Florentino et al.

Laser Safety

João Paulo Junqueira Magalhães Afonso andMeire Brasil Parada

AbstractThis chapter will describe the laser securityaspects from the classification of laser’s riskuntil the preventive measures. The main riskssuch as eye risks, skin risks, teeth risks, plumerisks, fire risks, and electrical risks will bediscussed, and preventive measures since pro-tective equipment until behavioral aspects willalso be addressed.

KeywordsLaser • Safety • Hazards • Risk • Preventive •Eye risk • Skin risk • Teeth Risk • Plume Risk •Fire Risk • Electrical Risk • Home-use devices

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297

Preventive Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298

Hazards Area . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300Beam Hazards: Related to Direct or Reflected

Impact of the Laser Beam to Tissue . . . . . . . . . . . . . 300Non-beam Hazards: Secondary Hazards Not

Related to Beam Directly . . . . . . . . . . . . . . . . . . . . . . . . 303

Home-Use Intense Pulsed Light (Ipl) and LaserDevices Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306

Home-Use Devices Desirable Characteristics . . . . . . . 306

Take Home Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307

Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308

Introduction

The International Electrotechnical Commission(IEC) is a global organization that prepares andpublishes international standards for all electrical,electronic, and related technologies. The IEC doc-ument 60825-1 is the primary standard that out-lines the safety of laser products (Smalley 2011).

The IEC published some documents that rep-resent international benchmarks of laser safety.These documents are 60601, 60825, and 60825-Part 8. The national regulatory agencies usuallycombine these international recommendationswith national legislation to produce local lasersafety guidance and/or regulation.

Classification is based on calculations and deter-mined by the Accessible Emission Limit (AEL) alsoincorporating viewing conditions as follows:

• Class 1 lasers products that are very low riskand “safe under reasonably foreseeable use,”including the use of optical instruments (eyeloupes or binoculars) for direct intrabeamviewing. There is risk of glare, dazzling, andreduction in color vision due to afterimages:– Examples: laser printers and compact disk

players

J.P. Junqueira Magalhães Afonso • M. Brasil Parada (*)Universidade Federal de São Paulo, São Paulo, Brazile-mail: drjoaopaulodermato@yahoo.com.br;mbparada@uol.com.br

# Springer International Publishing AG 2018M.C.A. Issa, B. Tamura (eds.), Lasers, Lights and Other Technologies, Clinical Approaches and Procedures inCosmetic Dermatology 3, https://doi.org/10.1007/978-3-319-16799-2_21

297

• Class 1 M lasers have wavelengths between302.5 nm and 400 nm and are safe except whenused with optical aids (e.g., microscopes,loupes, binoculars):– Safe under reasonably foreseeable condi-

tions of operation (unaided eye) but maybe hazardous if the user employs opticswithin the beam

– Examples: optical fiber communicationsystems

• Class 2 lasers have visible wavelengths(400–700 nm) safe if viewed for less than0.25 s (safe for momentary exposures but haz-ardous if deliberately staring into the beam).Do not permit human access to exposure levelsbeyond the Class 2 AEL for wavelengthsbetween 400 nm and 700 nm. Any emissionsoutside this wavelength region must be belowthe Class 1 AEL:– Emitting visible laser beams.– Not inherently safe for the eyes, but protec-

tion by natural aversion responses, such asblink reflex, is usually adequate.

– Example: amusement laser guns, laserpointers, and barcode scanners.

• Class 2 M lasers have wavelengths between400 nm and 700 nm and are potentially haz-ardous when viewed with an optical instru-ment. Any emissions outside this wavelengthregion must be below the Class 1 M AEL:– Emitting visible laser beams– Eye protection normally by aversion

responses including blink reflex but maybe more hazardous if the user employsoptics within the beam

– Example: level and orientation instrumentsfor civil engineering applications

• Class 3R lasers are marginally unsafe forintrabeam viewing of beams and are poten-tially hazardous, but the risk is lower thanthat of Class 3B lasers because the accessibleemission limit is within five times the Class2 AEL for wavelengths between 400 nm and700 nm and within five times the Class 1 AELfor wavelengths outside this region:– Direct intrabeam viewing is potentially haz-

ardous, but the risk is lower than Class 3Blasers.

– Fewer manufacturing requirements andcontrol measures for the user than forClass 3B lasers.

– Example: laser pointers and alignmentlasers.

• Class 3B lasers are normally hazardous underdirect beam viewing conditions but are nor-mally safe when viewing diffuse reflections.May produce minor skin injuries or even posea risk of igniting flammable materials:– Output power of continuous wave not

exceeding 0.5 W– Examples: lasers for physiotherapy

treatments• Class 4 lasers are hazardous under both

intrabeam and diffuse reflection viewing con-ditions. They may cause also skin injuries andare potential fire hazards:– High-power output devices– Output power of continuous wave exceed-

ing 0.5 W– Capable of producing hazardous reflections– May cause eye and skin injuries– Could constitute a fire hazard– Requires extreme caution in using– Examples: laser projection displays, laser sur-

gery devices, and laser metal-cutting devices

Most of the lasers used in medicine are Class3 or 4, which means that risks are greater in everyapplication.

Well-stablished routines that consider theserisks can prevent mistakes such as describedbelow.

Preventive Measures

The preventive measures are always the gold stan-dard choice on laser safety.

The control measures are engineering nature,administrative nature, procedural nature, and pro-tective equipment.

These measures are listed and described below:

1. Engineering measures manufactures safety mea-sures built into the systems to prevent accidentalemission of laser radiation. Some examples are

298 J.P. Junqueira Magalhães Afonso and M. Brasil Parada

guarded foot switch, key lock, housing inter-locks, audible and visible emission indicators,beam stops, aperture covers or shutters, standbymode, foot + hand operative switches, and con-tact switches and sensors.

2. Administrative measures are continuous mon-itoring of the safety program by responsiblephysician, compliance with the laser securitymeasures and laser safety officer or committee;formal audits; written policies (safety setupchecklists, procedure log sheets), procedures,and documentation tools; mandatory educationand training programs; and a reporting mecha-nism for complications.

3. Procedural measures are perioperative activitiesor work practices adopted by all the laser per-sonnel in order to prevent complications. Thisincludes controlled access to laser room, prepar-ing a laser-safe operative site (nonflammable

antiseptics and prep solutions, nonreflectivematerial, fire-retardant drapes, avoid oxygensource near laser application, bowel prepara-tion in the case of perineal and perianal laserapplication), controlling of electrical hazards,eliminating smoke from the surgical siteintraoperatively, setting up, checking and test-ing the laser system and accessory equipmentbefore usage (test the laser beam firing in atongue blade before the first use of the day),and assisting the physician and the patientbefore, during, and after the laser application.

4. Protective equipment: window barriers, mirrorcoverage, signs on room access door, labels,protective eyewear (Figs. 1, 2, and 3), teeth pro-tection (Fig. 3), fire extinguishers, nonflammabledrapes, anodized instruments, skin protection,masks, and smoke evacuation systemswithfilters(Smalley 2011; Smalley and Goldman 1998).

Fig. 1 Eyes protection

Laser Safety 299

Hazards Area

It is extremely advisable that signs posted visi-bly indicate the area where there are laser haz-ards. In some countries it is a legal obligation.These signs will alert the staff and patients aboutthe area where laser security measures are nec-essary, such as control access and wearingsafety glasses. It is also advisable that in eachentryway to this area, there are always availableprotective goggles during laser operation in caseof emergency entry in this area.

The doors must always be closed but neverlocked during laser use.

Beam Hazards: Related to Direct orReflected Impact of the Laser Beamto Tissue

Eye RisksThe human eye has as the only defense systemthe “blink reflex.” This reflex takes one-fourthof a second to be effective. As the lasers work inmilli-, nano-, and picoseconds scale, it is notpossible to the “blink reflex” to protect againstthe lasers. Furthermore, some lasers do notwork with wavelengths of bright visible light,such as infrared ones, which does not elicit thereflex.

Even with eyelids closed, some lasers cancause damage to the eyes that makes us emphasizeeven more the importance of eye protection.

The eye lens is capable to focus light in a verysmall point in retina that makes the coherent lightof lasers even more dangerous (Dudelzak andGoldberg 2011).

As known even a laser pointer with anoutput greater than 5 mW can induce perma-nent eye injury. So many professional laserdevices and home-use devices are able tocause eye damage.

Some laser variables are related to intensity ofeye injury.

Fig. 3 Teeth protection

Fig. 2 Intraocular protection (eyeshield)

300 J.P. Junqueira Magalhães Afonso and M. Brasil Parada

Laser variables are:

1. Wavelength

Lasers operating with wavelengths of ultraviolet(200–400 nm), mid-infrared (1400–3000 nm), andfar-infrared (3000–10,600 nm) are absorbed by theanterior ocular segment inflicting damage on thelens and cornea.

Visible light lasers (400–760 nm) and near-infrared ones (760–1400 nm) are absorbed in theposterior ocular segment by the retina and vascu-lar choroid.

Wavelengths above 700 nm and below400 nm may cause photochemical damage forthe cornea and lens cataract, and above 1400 nmcan cause corneal burn.

Blind spots and glaucoma due to damage toretina vessels and pigmented iris are also possible.

The chromophores of the eyes are the same ofdaily use in dermatology such as water, melanin,and hemoglobin.

The lasers such as CO2 (10,600 nm), Nd-YAG(1320 and 1064 nm), alexandrite (755 nm), Diodo(810 nm), Er-YAG (2940 nm), and Q-switchedones (alexandrite, ruby, and Nd-YAG) can causedamage to multiple structures of the eye throughmechanisms of photochemical, photothermal, andphotoacoustic damage.

2. The pulse duration

The pulse duration of almost all lasers used indermatology is smaller than the blink reflex elicittime (0.25 s), which makes almost all pulse dura-tions of risk.

The shorter the pulse duration, the fasterthe delivery of the energy defined in theparameters.

3. The energy/fluence

The higher the energy defined in the parame-ters, the greater the risk of eye damage.

4. The beam diameter

The beam diameter can influence more or lessaccording to the wavelength and the position ofincidence on the eye.

The damage is also modified by eye variables.The eye variables are:

1. The location of damage in the eye (foveal onesare worst).

2. The iris color (dark-skinned ones are worst).3. If the pupil is dilated (night lesions or lesions in

the dark can be more dangerous than indaylight).

4. The state of refraction of the eye at the momentof injury (if the focus is before or after theretina, the damage can be less or more intense)(Barkana and Belkin 2000).

After being damaged by a laser, the primaryeye injury can evolve with secondary eye injuriesthat are caused by shock wave, heat, and release ofvarious noxious agents by the directly injuredneurons (Lee et al. 2011).

If the damage occurs, the treatment options arefew. Corticosteroids are the main choice, but anec-dotal case reports used antioxidant vitamins andvasodilator drugs. There are drugs under develop-ment that intend to block secondary injury. Thesedrugs are called neuroprotective compounds.Some reports also suggest the use of growth fac-tors (Lin et al. 2011; Jewsbury andMorgan 2012).

Sometimes surgery may be necessary for thetreatment.

Because of the above exposed, the eye protec-tion is one of the most important topics in lasertraining, laser use, and laser security.

The eye protection may be thought for thepatient, for the physician, and for the support per-sonnel. The goggles are the main component in eyeprotection, and the goggles for protection againstlaser wavelengths are specially designed for that.

These patient goggles may be of heatproofstainless steel with smooth polished concave sur-face and anodized convex surface without anytransparency (external or topical usage). The

Laser Safety 301

staff goggles are generally of other material suchas coated glass or polymeric material withselected transparency. The selected transparencyis chosen according to the laser that will be used,because they can have a central rejected wave-length or a band of wavelengths. Another charac-teristic of these goggles is the optical density(OD) that is the log of attenuation of the lighttransmitted through the lens. So lens with anODof 4 allow 1/104 of the laser energy to pene-trate. These goggles also may have side shieldsand no front surface reflection.

All goggles may have permanent labels indi-cating wavelengths and optical density, sideshields, adequate visible light transmission, andproper fit and be comfortable.

When the goggles are cracked, scratched,discolored, or with any other damage to lens,frame, or straps, they may be replaced.

Abrasive cleaning methods and alcohol-basedcleaning solutions can degrade the optical coatingon the lenses and decrease the optical density,resulting in eye injury.

As the eye injury may be caused also byreflected laser and not only by direct light emis-sion, all jewelry should be removed, glass ofwindows and mirrors should be covered, and allinstruments should be anodized, roughened, orebonized with fluoropolymeric coating. Thereflection is not related to instrument color asblack can be as reflective as silver.

Chlorhexidine should not be used to disinfecteye contact goggles because this substance maycause keratitis and corneal opacification.

According to national regulations, doorwarning signs may be placed outside the laseroperation rooms to alert visitors about risks.

Some technologies to transform lasers ineye-safe machines have been suggested suchas the use of efficient wide-angle forward scat-tering diffusers that would change the coherentnature of lasers and intense pulses lights (IPLs)in noncoherent. This is theoretically justifiedbecause the biological effect of lasers and IPLsoccurs after the light of these sources isscattered in the skin before acting in its finaltarget (the chromophores). So the coherent

nature of these light sources is not essential forthe efficiency of the treatment. However, thistechnology is not applicable for all types oflasers and still must be further developed(Slatkine and Elman 2003).

It is important to remember that goggles pro-tection is also necessary to protect the eyes fromsplatter of biological material that can occur afterlaser impact in the tissue.

Skin RisksSkin risks are related to inappropriate selection ofpatients, energy, pulse duration, or any other lasercontrollable parameter or inadvertent firing of thelaser.

To avoid skin risks, the continuous educationand training programs are essential once the incor-rect use of one laser variable may cause greatdamage to the skin.

Understanding the physics, the laser-tissueinteraction, the laser parameters, and variables,knowing the characteristics of that specificmachine that will be used in that treatmentand the patient skin, and tailoring theses vari-ables according to each case are the best ways toprevent accidental damage to the skin.

Cooling is also a good way to prevent laserdamage in some cases. Depigmenting skin prior tolaser therapy with topical hydroquinone 4 weeksbefore is a method to diminish some risks.

The skin damages can result in temporary orpermanent lesions such as erythema, edema,crusting, blistering, scarring, atrophy, or hyper- orhypopigmentation (Dudelzak and Goldberg 2011).

Table 1 shows which damage each kind ofradiation can cause in the skin and eyes.

Teeth RisksDental enamel is vulnerable to ultraviolet andinfrared light. When using laser near the mouth,the patient should be alerted to maintain closedmouth, and some protection may be used as moist-ened gauze and protective mouthpiece (Fader andRatner 2000).

Possible teeth damage is charring, cracking,flaking, and craters.

302 J.P. Junqueira Magalhães Afonso and M. Brasil Parada

Non-beamHazards: Secondary HazardsNot Related to Beam Directly

Fire HazardThe combustible materials above are of risk ofignition when exposed to certain lasers:

– Gauze– Towels– Drapes– Dry sponges– Plastics– Rubber– Tape removers– Skin degreases and skin preparation solutions– Foam devices– Respiratory devices (face masks, nasal

cannulae)– Methane gas (perianal area)– Makeup, hair spray, alcohol-based mousse or

gels, nail polish– Oil-based eye ointments– Products with alcohol– Solutions with iodophors– Hair-bearing areas

Some of this kind of risk materials can beprepared with saline solution prior to the

procedure to reduce risk of ignition. Other mate-rials may be avoided in the laser room.

When using CO2 laser on tissue, it is importantto notice that generally a carbonized tissue layer isbuilt up during application. This layer blocks laserpenetration and continuously heats. If notremoved this carbon layer can heat to tempera-tures over 1000 �C making possible to fire igni-tion, burns, and extensive tissue damage (Faderand Ratner 2000).

Hair and cotton can be ignited by lasers in anenriched oxygen atmosphere or when not soakedwith saline solution.

A fire extinguisher for standard electrical equip-ment and a water container must be available toany emergency when working with fire hazard.

The O2-enriched atmosphere is the most com-mon cause of fire in laser use (Sheinbein and Loeb2010). The fire ignition can occur even out of lasertreatment field (remote fire) as reported in litera-ture (Waldorf et al. 1996) (Fig. 4).

Electrical HazardThe laser devices are high-voltage, high-currentinstruments, and there is great risk of circuity fireand electrocution. Only trained personnel mayoperate these devices.

Correct installation and grounding are veryimportant in preventing electrical hazard.

Table 1 Tissue changes caused by different radiations

Wavelengthrange Spectrum Eyes Skin

200–280 nm UVC Photokeratitis (inflammation of the cornea,equivalent to sunburn)

Erythema, burns, and skin cancer

280–315 nm UVB Photokeratitis (inflammation of the cornea,equivalent to sunburn)

Tanning, burns, and skin cancer

315–400 nm UVA Photochemical cataract (clouding of theeye lens)

Photoaging, tanning, and skin cancer

400–780 nm Visible Photochemical damage to the retina,retinal burn

Burns, photosensitivity reactions, andincreasing pigmentation

780–1400 nm InfraredA

Cataract, retinal burn Burns

1400–3000 nm InfraredB

Aqueous flare (protein in the aqueoushumor), cataract, corneal burn

Burns

3000–10,000 nm InfraredC

Corneal burn Burns

Adapted from Mattos (2012)

Laser Safety 303

Fig. 4 Security measures to prevent surgical fires

304 J.P. Junqueira Magalhães Afonso and M. Brasil Parada

The clamps, connecting cords, power cords,fuses, circuit breakers, and plugs integrity maybe checked before use (Dudelzak and Goldberg2011).

Plume HazardPlume and smoke are frequently produced duringlaser usage, and the mutagenic and carcinogeniccapacity of these subproducts is alreadyrecognized.

The disease transmission of plume and smokehas also been described and should be of concernof healthcare professionals and support staff(Sawchuk et al. 1989).

Red blood cells, cellular clumps, bacteria, HIV,and HPV DNA have been recovered of laserplume. Carbon particles, benzene, formaldehyde,acrolein, and over 41 toxic gases have been pro-ved to be liberated by tissue after laser thermaldisruption of cells (Andre et al. 1990; Ulmer2008).

A laser surgeon infected in nasal anterior naresand another one with laryngeal papillomatosisafter treating anogenital papillomatosis werereported in literature (Hallmo and Naess 1991).

The carbon and toxic compounds such as form-aldehyde and benzene that exist in the plume andcan cause (Ulmer 2008):

– Asthma– Anemia– Anxiety– Bronchiolitis– Carcinoma– Cardiovascular dysfunction– Colic– Congestive interstitial pneumonia– Dermatitis– Dizziness– Emphysema– Eye irritation– Headache– Hepatitis

– HIV– Hypoxia– Lacrimation– Leukemia– Light-headedness– Nasopharyngeal lesions– Nausea or vomiting– Sneezing– Throat irritation– Weakness

The common surgical masks are not able to filterthe very small particles produced during laser appli-cation. The laser masks are made of synthetic fiberselectrostatically charged and should be replacedperiodically because the smoke eliminates theirpolarity after a period of usage. However, masksare not considered the first-line protective devices,once their chance to fail after 20 min of usage ishigh. Thefit andwearing technique also interferes inmasks efficiency.

Smoke aspiration and elimination is extremelynecessary in the site and room of laser applicationand is the first-line protective device (Bigony2007). The device should employ a triple-filtersystem. The high-efficiency particulate air filterthat removes particles larger than 0.3 μm is notsufficient; an ultralow particular air filter, whichis capable of removing particular matter up to0.1 μm in size, is necessary and a charcoal filterto remove toxic chemicals within the smoke.

Some aspects to be evaluated before choosingthe smoke aspirator are:

• Cost and operating expenses• Effectiveness• Filter and canister design• Filter monitoring• Fluid removal capabilities• Foot pedal activation versus automatic

activation• Noise production• Single use versus reusable• Size

Laser Safety 305

The distance between laser-treated site and thesuction tip recommended is 1 cm, and the effec-tiveness drops from 99% to 50% when this dis-tance is changed from 1 to 2 cm.

After laser use the room atmosphere may take20 mins to return to normal concentration ofparticles.

Q- switched lasers present a particular chal-lenge because they generate high-speed tissuefragments and particles that may escape captureby the smoke evacuation device. Some specificsafety measures have been recommended in thesesituations such as splatter shields or collectingcones, treatment through a transparent membrane,appropriate eye protection, gloves, gowns, andlaser surgical masks.

Some laser surgeons cover lesions with opticalclear biological dressings and shoot through them,sacrificing 5–10% of energy drop for a clean andelegant protective barrier.

The recent application of lasers in treatment offungal infections like onychomycosis turned onthe alert to the possibility of viable fungi in smoke(Karsai and Däschlein 2012).

More intriguing is the suggestion by someauthors that plume can spread viable malignantcells like melanoma cells to other sites (Lewinet al. 2011).

The American Academy of Dermatology rec-ommends the use of face masks, eye protectors,gloves, gowns, caps, and shoe covers (Dover et al.1999).

After the surgery one may remember that thesmoke may have contaminated the covered anduncovered body surfaces. So washing hands andother body parts is advisable.

Smalley PJ and Goldman MP 1998 wrote: Ofall safety hazards, complacency is by far themost dangerous. Accidents happen when weadopt the attitude: “I have been using lasers foryears; we’ve never had a problem and it won’thappen here.”

This attitude makes that the surgeon and thestaff relax on preventive measures opening theway for mistakes and accidents.

Home-Use Intense Pulsed Light (Ipl)and Laser Devices Safety

The home-use epilation devices use the sameprinciple of selective photothermolysis of profes-sional devices. Although some differences areimportant in home-use devices compared to pro-fessional ones:

– Low energy– Few energy settings– Fixed pulse duration– Single fixed filter– Small treatment areas– Parallel skin cooling not possible– Cover fewer skin tones

These differences should alert the manufac-tures and healthcare providers to not carry theclinical experience and knowledge of publishedstudies about professional devices to the home-use ones (Town et al. 2012).

However, it is reasonable to expect similar sideeffects but with different incidences betweenthese two kinds of devices.

The most common adverse effects reported insome studied devices were erythema, edema,pain, pigmentary changes, skin abrasion, follicu-litis, skin irritation, pruritus, stinging, tingling,skin dryness, and blistering.

Although these adverse effects were not toofrequent, the studies selected the subjects withinclusion and exclusion criteria in order to dimin-ish risks. From the moment the devices are avail-able to general population with no control of“inclusion and exclusion criteria,” it is expectedthat the incidence of adverse effects will be higherin real-life daily use.

Home-Use Devices DesirableCharacteristics

– Eye safe– Easy to use without training

306 J.P. Junqueira Magalhães Afonso and M. Brasil Parada

– Clinically effective (causes follicular biologi-cal damage without causing epidermal or ocu-lar damage)

– Cost-effective in mass production

The manufactures developed different technolo-gies to achieve these characteristics such as con-tact switches or sensors, auto-standby, andlow-energy preset, and then they claim in somecountries to reclassify of these devices as Class Ilaser category not requiring the use of safetyglasses. The reclassification is under evaluationand not approved yet (Thaysen-Petersen et al.2012).

Many of them do not inform the claimedfluence, pulse duration, wavelength, and homoge-neity or spectral output (in case of IPLs) thatcomplicates safety evaluation.

Some studied home-use devices showed risksof skin and eye damage regardless of safety mech-anisms adopted by manufactures. Moreover,patients can misclassify their skin tones and canapply on tanned skin, and the safety mechanismscan fail. All these variables may be consideredwhen classifying home-use devices safety (Townand Ash 2010).

The regulatory standards are not well definedon many countries, and some important measuresregarding users education should be adopted as:

– Comprehensive education materials (e.g., usermanuals)

– Consumer care support (e.g., telephonehelpline support)

– Detailed instructions for use– DVDs– In-store trained sales consultants– Physician-directed use of home-use devices– Web-based tutorials

Once the home-use devices will be used asappliances, safety measures include those as elec-trical safety, assembling, maintenance, disposal,labeling, and categorization of consumer risk(as children).

Other issues may be considered when usinghome-use devices by nonprofessional users suchas:

– Treating areas with melanocytic nevi.– Treating areas with tattoos.– Treating individuals with polycystic ovarian

syndrome or ovarian hyperandrogenism.– Treating pregnant woman.– Treating tanned skin.– Treating still healing skin.– Treating individuals using photosensitizers or

phototoxic drugs (specially in IPL devices).– Treating face and eyebrows.– Treating with suboptimal energy may induce

paradoxical hair growth on home-use devicesthat typically work with lower energies com-pared to professional ones.

Take Home Messages

• The lasers used in medicine can be generallyhigh-risk devices.

• Preventive measures will be effective if allinvolved staffs follow security routines thattake the risks into account.

• The intrabeam most dangerous risk is the eyerisk that may lead to complete blindness.

• The non-beam hazards are diverse and mostreported is related to plume.

• The home-use devices are not free of risks, andconsumers should be aware of the risks.

Cross-References

▶CO2 Laser for Other Indications▶CO2 Laser for Scars▶CO2 Laser for Stretch Marks▶CO2 Laser for Photorejuvenation▶Erbium Laser for Photorejuvenation▶Erbium Laser for Scars and Striae Distensae▶ Fractional Ablative and Non-Ablative Lasersfor Ethnic Skin

Laser Safety 307

▶ Intense Pulsed Light for Photorejuvenation▶ Intense Pulsed Light for Rosacea and OtherIndications

▶Lasers for Aesthetic and Functional VaginalRejuvenation

▶Laser on Hair Regrowth▶Laser for Hair Removal▶Laser Lipolysis▶Laser for Onychomycosis▶Laser Treatment of Vascular Lesions▶Light-Emitting Diode for Acne, Scars, andPhotodamaged Skin

▶My Personal Experience with Laser▶Non-ablative Fractional Lasers for Scars▶Non-ablative Lasers for Photorejuvenation▶Non-ablative Lasers for Stretch Marks▶ Photodynamic Therapy for Acne▶ Photodynamic Therapy for Photodamaged Skin▶Q-Switched Lasers for Melasma, Dark CirclesEyes, and Photorejuvenation

▶Transepidermal Drug Delivery with AblativeMethods (Lasers and Radiofrequency)

References

Andre P, Orth G, Evenou P, Guillaume JC, Avril MF. Riskof papillomavirus infection in carbon dioxide lasertreatment of genital lesions. J Am Acad Dermatol.1990;22(1):131–2.

Barkana Y, BelkinM. Laser eye injuries. Surv Ophthalmol.2000;44(6):459–78.

Bigony L. Risks associated with exposure to surgicalsmoke plume: a review of the literature. AORNJ. 2007;86(6):1013–20.quiz 1021–4

Dover JS, Arndt KA, Dinehart SM, Fitzpatrick RE,Gonzalez E. Guidelines of care for laser surgery. Amer-ican academy of dermatology. Guidelines/outcomescommittee. J Am Acad Dermatol. 1999 Sep;41(3 Pt1):484–95.

Dudelzak J, Goldberg DJ. Laser safety. Curr ProblDermatol. 2011;42:35–9.

Fader DJ, Ratner D. Principles of CO2/erbium laser safety.Dermatol Surg. 2000;26(3):235–9.

Hallmo P, Naess O. Laryngeal papillomatosis with humanpapillomavirus DNA contracted by a laser surgeon. EurArch Otorhinolaryngol. 1991;248(7):425–7.

Jewsbury H, Morgan F. Uveitis and iris photoablationsecondary to intense pulsed light therapy. Can JOphthalmol. 2012;47(4):e13–4.

Karsai S, Däschlein G. “Smoking guns”: hazards generatedby laser and electrocautery smoke. J Dtsch DermatolGes. 2012;10(9):633–6.

Lee WW, Murdock J, Albini TA, O’brien TP, LevineML. Ocular damage secondary to intense pulse lighttherapy to the face. Ophthal Plast Reconstr Surg.2011;27(4):263–5.

Lewin JM, Brauer JA, Ostad A. Surgical smoke and thedermatologist. J Am Acad Dermatol. 2011;65(3):636–41.

Lin CC, Tseng PC, Chen CC, Woung LC, Liou SW. Iritisand pupillary distortion after periorbital cosmetic alex-andrite laser. Graefes Arch Clin Exp Ophthalmol.2011;249(5):783–5.

Mattos R. Conceitos de Biossegurança: Laser/Dermatologia. In: Kadunc B, Palermo E, Addor F,Metsavaht L, Rabello L, Mattos R, Martins S, editors.Tratado de cirurgia dermatológica, cosmiatria e laser:da Sociedade Brasileira de Dermatologia. 1st ed. Rio deJaneiro: Elsevier; 2012. p. 895–9.

Sawchuk WS, Weber PJ, Lowy DR, DzubowLM. Infectious papillomavirus in the vapor of wartstreated with carbon dioxide laser or electrocoagulation:detection and protection. J Am Acad Dermatol.1989;21(1):41–9.

Sheinbein DS, Loeb RG. Laser surgery and fire hazards inear, nose, and throat surgeries. Anesthesiol Clin.2010;28(3):485–96.

Slatkine M, Elman M. Conversion of aesthetic lasers andintense pulsed light sources into inherently eye-safeunits. J Cosmet Laser Ther. 2003;5(3–4):175–81.

Smalley PJ. Laser safety: risks, hazards, and control mea-sures. Laser Ther. 2011;20(2):95–106.

Smalley PJ, Goldman MP. Laser safety: regulations, stan-dards and practice guidelines. In: Goldman MP,Fitzpatrick RE, editors. Cutaneous laser surgery: theart and science of selective photothermolysis. 2nded. St. Louis: Mosby Inc; 1998. p. 459–72.

Thaysen-Petersen D, Bjerring P, Dierickx C, Nash JF,Town G, Haedersdal M. A systematic review of light-based home-use devices for hair removal and consid-erations on human safety. J Eur Acad DermatolVenereol. 2012;26(5):545–53.

Town G, Ash C. Are home-use intense pulsed light (IPL)devices safe? Lasers Med Sci. 2010;25(6):773–80.

Town G, Ash C, Dierickx C, Fritz K, Bjerring P,Haedersdal M. Guidelines on the safety of light-basedhome-use hair removal devices from the Europeansociety for laser dermatology. J Eur Acad DermatolVenereol. 2012;26(7):799–811.

Ulmer BC. The hazards of surgical smoke. AORNJ. 2008;87(4):721–34.quiz 735–8

Waldorf HA, Kauvar NB, Geronemus RG, LeffelDJ. Remote fire with the pulsed dye laser: risk andprevention. J Am Acad Dermatol. 1996;34(3):503–6.

308 J.P. Junqueira Magalhães Afonso and M. Brasil Parada

My Personal Experience with Laser

Neal Varughese and David J. Goldberg

AbstractDuring the last 30 years, I have witnessed first-hand the advances and innovations in laser andenergy-based technology. The pioneering workof Anderson and Parrish in 1983 was instrumen-tal in powering this evolution. Anderson andParrish lead the industry to develop energy-based systems that were more precise, thusallowing clinicians to target specific chromo-phores with minimal adjacent tissue damageand thereby decreasing the risk of complications.In 1985 upon completion of my dermatologictraining, there were limited devices available,and their application was limited to a specificclientele. Fast forward to 2015, the array ofdevices that are now accessible to the everydayconsumer is nothing short of miraculous. Thesingle most effective treatment modality for con-ditions such as photodamage, acne scars,melasma, and stretch marks is difficult to define.The following chapter outlines my approach totreating these conditions based on my own clin-ical practice and research.

KeywordsAcne scars • Melasma • Photorejuvenation •Stretch marks • Laser dermatology • Cosmeticdermatology •Radiofrequency • Intense pulsedlight • Light emitting diode

ContentsPhotorejuvenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309

Melasma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310

Acne Scars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311

Stretch Marks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312

Photorejuvenation

Photorejuvenation encompasses treatments thataddress the quality, tone, and texture of the skinand uneven pigmentation associated withphotodamage. Initially, the only lasers availablewere ablative laser devices (CO2 and Er:YAG),which were effective, but had the disadvantage ofrequiring a high level of operator skill in additionto increased side effects and downtime forpatients. In line with new technological develop-ments, there has been a revolution in non-ablativemodalities that address photorejuvenation leadingto epidermal improvement and dermal collagenremodeling. These modalities include vascularlasers, mid-infrared lasers, intense pulsed light

N. VarugheseSkin Laser and Surgery Specialists of New York and NewJersey, New York, NY, USA

D.J. Goldberg (*)Skin Laser and Surgery Specialists of New York and NewJersey, New York, NY, USA

Department of Dermatology, Icahn Mount Sinai School ofMedicine, New York, NY, USAe-mail: drdavidgoldberg@skinandlasers.com

# Springer International Publishing AG 2018M.C.A. Issa, B. Tamura (eds.), Lasers, Lights and Other Technologies, Clinical Approaches and Procedures inCosmetic Dermatology 3, https://doi.org/10.1007/978-3-319-16799-2_39

309

systems, radiofrequency devices, and light-emitting diode (LED) techniques. Epidermallesions that remain after treatment are amenableto multiple treatment modalities. In such cases, theQ-switched lasers, such as 532 (KTP) and 694 nm(ruby) wavelength, are appropriate.

I treat many of my patients with intense pulsedlight (IPL) (Fig. 1a, b). IPL encompasses wave-lengths from 400 to 1,200 nm which permits thesimultaneous treatment of broken capillaries andmottled pigmentation by targeting the chromo-phores of hemoglobin and melanin (Raulin et al.2003). Often, the clinical results and patient satis-faction tend to be more impressive when I com-bine IPL treatments with adjunctive LEDtreatments. Various LED wavelengths have beenshown to improve wound healing and promotehuman tissue growth. With the application ofthese techniques, caution needs to be taken inpatients with a history of photosensitivity or whotake medications that can increase the risk ofphotosensitivity.

The new IPL devices are very safe; however,scarring and hyperpigmentation still remain a risk.The clinical pearl, especially with darker skin types,is to employ a bleaching cream prior to performingtreatment. In treating patients with dark skin types,the use of longer wavelengths or higher cutoff filtersas well as longer-pulse durations and lower fluenceis recommended. Otherwise, treatment with amid-infrared laser (1,064–1,450 nm) is an option,as postoperative complications including scarringand postinflammatory hyperpigmentation are

minimal when conservative parameters are used(Goldberg 2000).

Additionally, I use more conservative parame-ters when another device (i.e., KTP, QS ruby) isused in conjunction with IPL.

The ideal patient is 35–55 with mild to moder-ate photodamage. Although early indications arethat results may last for several years, patientswho are young may not appreciate the subtleimprovement they are receiving fromnon-ablative resurfacing.Moreover, older patientswith severe photodamage and deep wrinkles mayrequire more aggressive surgical and laser cos-metic treatment.

Melasma

Melasma presents a unique challenge to the der-matologic surgeon. Current therapies include top-ical therapies with bleaching creams, oralmedications, chemical peels, and light-based ther-apies. Although several lasers have demonstratedsome potential, they are complicated by transientimprovement or rapid recurrence of melasma(Pooja et al. 2012).

The devices that have shown the most consis-tent results include IPL, Q-switched and picosec-ond Nd:YAG lasers, and non-ablative fractionallasers (Fig. 2a, b).

Fractional lasers can be applied to achieve partialpigment improvement but only produce temporaryresolution (Goldberg et al. 2008). Low-fluence,

Fig. 1 (a, b) Pre- and post-IPL treatment

310 N. Varughese and D.J. Goldberg

long-pulse-duration, high-filter IPL tends to havemore lasting results in the treatment of melasma,as the cutoff filter permits the use of longer wave-lengths to target deeper melanin. I combine eachtreatment with LED lights, which have been shownto significantly reduce melanin production andtyrosinase expression.

The effects of postinflammatory hyperpig-mentation are mitigated with hydroquinone appli-cation 4–8 weeks prior to laser treatment andthereafter as a maintenance therapy.

Acne Scars

Acne scarring is another difficult dermatologicalcondition to treat. We have found that deep seatedscars respond well to ablative lasers. For patients

unable to tolerate ablative lasers, non-ablative laserand radiofrequency devices are devices that offersignificant improvement in acne scars and skin tex-ture (Fig. 3a, b).

When it comes to treating acne scars in darkerskin types, radiofrequency devices play an impor-tant role in my practice. Postinflammatoryhyperpigmentation (PIH) may be a complicationof fractional laser treatments that persistsfor months, especially in skin types IV–VI (Ong2012; Hu et al. 2009). To avoid this complication,I utilize a fractional bipolar RF device whichgenerates fractional deep dermal heating to induceskin injury. This subsequently elicits a woundhealing response, thereby stimulating theremodeling of dermal collagen. Although the clin-ical improvements may be more modest ascompared to fractional resurfacing, this approach

Fig. 2 (a, b) Pre- and post-melasma treatment

Fig. 3 (a, b) Pre- and post-acne scar treatment

My Personal Experience with Laser 311

involves extremely rapid recovery and lessrisk for PIH (Rongsaard and Rummaneethorn2014).

Stretch Marks

Early in my career, topical retinoids were the goldstandard in treating stretch marks. However,lasers have shown much efficacy in treating bothearly and advanced stretch marks.

In the early stages of stretch marks, changes aremore inflammatory in nature, and thus they appearpigmented purple to red. Although there are mul-tiple treatments available for red stretch marks, Iprefer the long-pulsed 532 nm KTP and 595 nmpulsed dye lasers in lighter skin types and1,064 nm Nd:YAG in darker skin types. Con-versely, older stretch marks are hypopigmentedand atrophic. We have found that the excimerlaser is a wonderful option to restore pigmentation(Goldberg et al. 2003). It is important to remem-ber that stretch marks are “dermal scars,” andtherefore IPL, fractional photothermolysis, andradiofrequency devices are several options toimprove the texture of stretch marks in all skintypes.

Conclusion

Laser dermatology continues to evolve at a star-tling pace. My 30 years of clinical practice haveled to me specific treatment regimens for the

myriad of conditions previously outlined.Although a variety of treatment options currentlyexist, the definitive treatment for each conditionremains elusive. In my own clinical practice, Ihave found that the best patient outcomes oftenoccur when energy-based devices are combinedwith topical or adjunctive therapies.

References

Goldberg DJ. Full-face nonablative dermal remodelingwith a 1,320 nm Nd: YAG laser. Dermatol Surg.2000;26(10):915–8.

Goldberg DJ, Sarradet D, Hussain M. 308-nm excimerlaser treatment of mature hypopigmented striae.Dermatol Surg. 2003;29(6):596–9.

Goldberg DJ, Berlin AL, Phelps R. Histologic and ultra-structural analysis of melasma after fractionalresurfacing. Lasers Surg Med. 2008;40:134–8.

Hu S, et al. Fractional resurfacing for the treatment ofatrophic facial acne scars in Asian skin. DermatolSurg. 2009;35(5):826–32.

Ong MWS, Bashir SJ. Fractional laser resurfacing for acnescars: a review. Br J Dermatol. 2012;166(6):1160–9.

Pooja A, Rashmi S, Garg VK, Latika A. Lasers for treat-ment of melasma and post-inflammatory hyperpig-mentation. J Cutan Aesthet Surg. 2012;5(2):93–103.

Raulin C, Greve B, Grema H. IPL technology: a review.Lasers Surg Med. 2003;32(2):78–87.

Rongsaard N, Rummaneethorn P. Comparison of a frac-tional bipolar radiofrequency device and a fractionalerbium-doped glass 1,550-nm device for the treatmentof atrophic acne scars: a randomized split-face clinicalstudy. Dermatol Surg. 2014;40(1):14–21.

312 N. Varughese and D.J. Goldberg

Part II

Photodynamic Therapy

Daylight Photodynamic Therapy andIts Relation to Photodamaged Skin

Beni Moreinas Grinblat

AbstractPhotodynamic therapy (PDT) with artificialred or blue light is an option for treating actinickeratosis and field cancerization. In this chap-ter, we present a new option of photodynamictherapy, with natural daylight as the lightsource. The method, called as daylight-PDT,is a safe, effective, and almost painful treat-ment for thin actinic keratosis and an option forpatients with multiple lesions.

KeywordsDaylight photodynamic therapy • Actinic ker-atosis • Photodynamic therapy • Red light •Blue light • Photodamaged •Photorejuvenation

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315

Daylight Photodynamic Therapy . . . . . . . . . . . . . . . . . . 316Pre-procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316Protocol of Procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316Post-Procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316

Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317

Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317

DL-PDT x Photorejuvenation . . . . . . . . . . . . . . . . . . . . . 318

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318

Take Home Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319

Introduction

Daylight photodynamic therapy (DL-PDT) is anoption for treatment of thin actinic keratosis. Itwas developed by Wiegell in 2006 (Wiegell et al.2008) and since that several studies werepublished around the world. The principles ofDL-PDT are similar to the conventional PDT,with activation of photosensitizers resulting inthe formation of reactive oxygen species and celldeath. Most of the studies of DL-PDT wereperformed using aminolevulinate cream (MAL)as photosensitizer. MAL is a prodrug that isconverted to protoporphyrin (PpIX) insidethe cell.

Protoporphyrin is activated by visible light,and in DL-PDT the visible light of the naturalsunlight spectrum makes the activation.

DL-PDT is indicated for treating thin actinickeratosis (grades I and II, according to Olsen(Olsen et al. 1991)), mainly in patients with mul-tiple lesions on the scalp and/or face.

Besides treating AKs, DL-PDT seems toimprove other aspects of photodamage, such asfine wrinkles and pigmentation.B.M. Grinblat (*)

Department of Dermatology, Hospital das Clínicas daFaculdade de Medicina da Universidade de São Paulo, SãoPaulo, Brazile-mail: bgrinblat@gmail.com

# Springer International Publishing AG 2018M.C.A. Issa, B. Tamura (eds.), Lasers, Lights and Other Technologies, Clinical Approaches and Procedures inCosmetic Dermatology 3, https://doi.org/10.1007/978-3-319-16799-2_22

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Daylight Photodynamic Therapy

Pre-procedure

There is no specific preparation before treatmentwith PDT. Patients should keep using dailysunscreens.

Protocol of Procedure

Several studies and internationals consensus(Morton et al. 2015; Gilaberte et al. 2015; Grinblatet al. 2015a) established the protocol of daylight-PDT (Fig. 1).

1. The first step is the skin preparation. The objec-tive is to remove scales and crusts and roughenthe surface of the skin to enhance the MALpenetration. The curettage of the field is themost used method, but there are other optionsas slightly abrasive pads and micro-dermabrasion. Microneedling and ablativelasers might be used but with caution, usingsmooth parameters.

2. An organic sunscreen must be applied in thewhole area before or after the skin preparation.The sunscreen (SPF � 30) must be used toblock the ultraviolet radiation and, hence, pre-vent sunburn during the 2 h of daylightexposure.

3. In order to block only UVand not visible lightneeded to activate PpIX, a chemical sunscreenmust be used. Sunscreens containing physical

filters such as zinc oxide or titanium dioxidemust not be used, because they reflect somevisible light and thus may reduce the activationof PpIX by daylight.

4. Fifteen minutes after the skin preparation/sun-screen application, the photosensitizer shouldbe applied. Applying a thin layer in the wholearea and a thicker one over the AKs isrecommended. As mentioned before, themajority of the published studies wereperformed with MAL as the photosensitizerand it is not a recommended occlusion. Usu-ally, 1–2gr of MAL cream is sufficient to treatthe whole face.

5. Up to 30 min after the MAL application, thepatient has to be exposed to daylight, for120 min. He must stay outdoors but can stayunder a shadow. In Brazil, the procedure can beperformed in the whole year, even in the winter(Grinblat et al. 2016). It is recommended toavoid treatment in very cloudy days and, obvi-ously, if it is raining.

6. After the illumination (2 h of daylight expo-sure), the MAL is removed, and the patient hasto avoid the sun exposure for the rest of the day.

Post-Procedure

The erythema after treatment is usually mild andtopical steroids are not recommended in routine.Patients should keep using daily sunscreens, andthe use of moisturizers is indicated.

Chemical sunscreen

Skin preparation

Application of MAL

2 hours of Daylightexposure

Removal of MAL

Skin preparation

Chemical sunscreen

Application of MAL

2 hours of Daylightexposure

Removal of MAL

OR

Fig. 1 Protocol of DL-PDT with MAL

316 B.M. Grinblat

Side Effects

DL-PDT is usually not painful, and the erythemaafter treatment is usually mild. Blistering andcrusting are very rare.

Discussion

Several studies were published about DL-PDT indifferent countries, and they showed similarresults when DL-PDT was compared to conven-tional MAL-PDT, when treating thin AKs. Themain advantages of DL-PDT are:

1. The possibility of treating large areas (face andscalp)

2. There is no equipment involved in thetreatment

3. DL-PDT is almost painless

During conventional photodynamic therapy,the pain can be intense. Pain occurs when thereis a great amount of PpIX into the cells and inDL-PDT that does not happen. During the treat-ment with DL-PDT, there is a continuous activa-tion of few amounts of porphyrin; there is noaccumulation of PpIX into the cells.

In an Australian study (Rubel et al. 2014),DL-PDT was compared to conventional PDTand the clinical results were similar. But, most ofthe patients considered DL-PDT much less pain-ful and most of them preferred DL-PDT.

Australian study showed similar results whenDL-PDTwas performed in sunny or cloudy days,and a Brazilian study (Grinblat et al. 2015b)showed good results even if DL-PDT wasperformed during winter. The Latin-Americanconsensus (Grinblat et al. 2015a) recommends2 h of daylight exposure under comfortabletemperatures.

For most of the authors, one single treatment ofDL-PDT is sufficient, but sometimes another ses-sion is indicated and the authors recommend3-month interval till the second treatment. In ourexperience, patients with intense photodamageneed more than one session.

Daylight-PDT is usually indicated for patientswith multiple thin AK (types I and II). Treating thewhole area, DL-PDT can be considered as a “fieldcancerization treatment.”

In 2016, Philipp-Dormston and colleaguespublished a study about DL-PDT for “fieldcancerization” (Philipp-Dormston et al. 2016).They defined “field cancerization” as an areawith photodamage and AK. For those authors,

Fig. 2 Before and after onesession of MAL- DLPDT

Daylight Photodynamic Therapy and Its Relation to Photodamaged Skin 317

DL-PDT is effective and could prevent theappearance of new AK lesions in aphotodamaged skin.

We observe reduction of the number of AKlesions and improvement of the photodamagedskin (skin texture and pigmentation) in ourpatients after treatment with only one MAL-DL-PDTwith 2 h of daylight exposure (Figs. 2 and 3).

DL-PDT x Photorejuvenation

Besides treating multiple AKs, DL-PDT seems toimprove other aspects of photodamage.

Kohl and colleagues published a study aboutphotodynamic rejuvenation. The authorsobserved improvement of hyperpigmentation,fine wrinkles, and skin tightness after conven-tional PDT, with IPL, blue light, and red light(Kohl et al. 2010). Issa and colleagues showedskin remodeling induced by conventional PDT,with increase expression of metalloproteinase9 in the dermis and also of collagen type I (Issaet al. 2009). In 2010, the same group showed anincrease of collagen and reduction of elastic fibersafter conventional MAL-PDT (Issa et al. 2010).

In 2015, a group of experts published thatbesides the clearance and prevention of AK,

most studies after conventional PDT showedimprovement of skin texture (tactile roughness),pale skin, wrinkles, mottled pigmentation, facialerythema, and elastosis (Philipp-Dormston et al.2016).

There is no data in the literature about photo-rejuvenation with daylight-PDT, but in our expe-rience patients treated with DL-PDT showedimprovement of skin texture. As mentioned,there are several published studies about skinrejuvenation after conventional PDT, and in ourexperience, we can observe improvement of finewrinkles with DL-PDT, although lower than theone observed after conventional PDT. Accordingto some authors (Philipp-Dormston et al. 2016),daylight photodynamic therapy could be a com-plementary and convenient treatment option toalready existing rejuvenation procedures forpatients with actinic field damage.

Conclusion

DL-PDT is safe, effective, almost painless and canbe considered a first-line option in the treatment ofmultiple and thin AKs. Besides the excellent curerate of AK lesions, an improvement in the texture,pigmentation, and fine wrinkles can be observed.

Fig. 3 Before and after onesession of MAL- DLPDT

318 B.M. Grinblat

Take Home Messages

• DL-PDT is an option for treatment of thin AK.• DL-PDT maintains the efficacy of conven-

tional PDT for AK treatment.• DL-PDT is almost painless. Erythema and

edema are very discreet comparing toconventional PDT.

• The use of a chemical sunscreen isrecommended before the application of thephotosensitizer.

• DL-PDT seems to improve signs ofphotodamage.

References

Gilaberte Y, Aguilar M, Almagro M, Correia O, Guillén C,Harto A, Pérez-García B, Pérez-Pérez L, Redondo P,Sánchez-Carpintero I, Serra-Guillén C, ValladaresLM. Spanish-Portuguese consensus statement on useof daylight-mediated photodynamic therapy withmethyl aminolevulinate in the treatment of actinic ker-atosis. Actas Dermosifiliogr. 2015;106(8):623–31.

Grinblat B, Galimberti G, Chouela E, Sanclemente G,Lopez M, Alcala D, Torezan L, Pantoja G. Daylight-mediated photodynamic therapy for actinic damage inLatin America: consensus recommendations. Photo-dermatol Photoimmunol Photomed. 2016;32(2):81–7.

Grinblat BM, Festa Neto C, Sanches Jr JA, Szeimies RM,Oliveira AP, Torezan LA. Daylight photodynamic ther-apy for actinic keratoses in São Paulo, Brazil. Photo-dermatol Photoimmunol Photomed. 2015b;31:54–6.

Grinblat BM, Galimberti G, Pantoja G, Sanclemente G,Lopez M, Alcala D, Torezan L, Kerob D, Pascual T,Chouela E. Feasibility of daylight-mediated photody-namic therapy for actinic keratosis throughout the yearin Central and South America: a meteorological study.Int J Dermatol. 2016;55(9):e488–93.

Issa MC, Piñeiro-Maceira J, Farias RE, Pureza M, RaggioLuiz R, Manela-Azulay M. Immunohistochemical

expression of matrix metalloproteinases in photo-damaged skin by photodynamic therapy. Br JDermatol. 2009;161(3):647–53.

Issa MC, Piñeiro-Maceira J, Vieira MT, Olej B, Mandarim-de-Lacerda CA, Luiz RR, Manela-Azulay M. Photo-rejuvenation with topical methyl aminolevulinate andred light: a randomized, prospective, clinical, histo-pathologic, and morphometric study. Dermatol Surg.2010;36(1):39–48.

Kohl E, Torezan LA, Landthaler M, SzeimiesRM. Aesthetic effects of topical photodynamic therapy.J Eur Acad Dermatol Venereol. 2010;24(11):1261–9.

Morton CA, Wulf HC, Szeimies RM, Gilaberte Y, Basset-Seguin N, Sotiriou E, Piaserico S, Hunger RE,Baharlou S, Sidoroff A, Braathen LR. Practicalapproach to the use of daylight photodynamic therapywith topical methyl aminolevulinate for actinic kerato-sis: a European consensus. J Eur Acad DermatolVenereol. 2015;29(9):1718–23.

Olsen EA, Abernethy ML, Kulp-Shorten C, Callen JP,Glazer SD, Huntley A, McCray M, Monroe AB,Tschen E, Wolf Jr JE. A double-blind, vehicle-con-trolled study evaluating masoprocol cream in the treat-ment of actinic keratoses on the head and neck. J AmAcad Dermatol. 1991;24:738–43.

Philipp-Dormston WG, Sanclemente G, Torezan L, TrettiClementoni M, Le Pillouer-Prost A, Cartier H,Szeimies RM, Bjerring P. Daylight photodynamic ther-apy with MAL cream for large-scale photodamagedskin based on the concept of 'actinic field damage':recommendations of an international expert group. JEur Acad Dermatol Venereol. 2016;30(1):8–15.

Rubel DM, Spelman L, Murrell DF, See JA, Hewitt D,Foley P, Bosc C, Kerob D, Kerrouche N, Wulf HC,Shumack S. Daylight PDT with MAL cream as a con-venient, similarly effective, nearly painless alternativeto conventional PDT in actinic keratosis treatment: arandomised controlled trial. Br J Dermatol.2014;171:1164–71.

Wiegell SR, Haedersdal M, Philipsen PA, Eriksen P, EnkCD, Wulf HC. Continuous activation of PpIX by day-light is as effective as and less painful than conven-tional photodynamic therapy for actinic keratoses; arandomized, controlled, single-blinded study. Br JDermatol. 2008;158:740–6.

Daylight Photodynamic Therapy and Its Relation to Photodamaged Skin 319

Actinic Cheilitis: Efficacy and CosmeticResults

Marco Antônio de Oliveira

AbstractActinic cheilitis (AC) is a common diseasecaused by long-term solar exposure and is con-sidered a premalignant lesion of the lips. AChas potential to develop into squamous cellcarcinoma (SCC) and metastasis. SCC of thelip arising from AC is more prone to metastasisthan cutaneous form with rates of the formervarying between 3% and 20% and is the mostcommon malignancy of the oral cavity. ACaffects especially pale-skinned individualswith poorly pigmented lower lips. The overallsurvival rate in 5 years is less than 75%. Treat-ments are difficult because surgical treatmentcan have significant adverse effects, whereasless invasive procedures may not be as effi-cient. A high degree of clinical suspicionshould be maintained, given the malignantnature of the condition. We emphasize theneed for regular follow-up, rigorous clinicalexam, and accurate pathologic analysis. Thechapter will discuss the efficacy of therapywith photodynamic therapy (PDT) usingmethyl aminolevulinate and 5-aminolevulinicacid, application times, skin preparation tech-niques, pain, cosmetic outcome, and patientsatisfaction.

KeywordsActinic cheilitis • Solar cheilitis • Photody-namic therapy • 5-Aminolevulinic acid •Methyl aminolevulinate • Cosmetic outcome •Lip cancer • Squamous cell carcinoma

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321

Photodynamic Therapy: . . . . . . . . . . . . . . . . . . . . . . . . . . . 323PDT Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . 323PDT Indications and Contraindication . . . . . . . . . . . . . . 324PDT: Use and Doses: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324PDT: Side Effects and their Management . . . . . . . . . . . 325

Authors’ Experience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326

Take Home Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326

Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326

Introduction

An understanding of the nature of actinic cheilitiscan be achieved by studying and reflecting oncomments about it by three dermatologists,namely, Dubreuilh in1896, Freudenthal in 1926,and Sutton Jr. in 1896 (Heaphy and Ackerman2000). Actinic cheilitis is a very frequent diseaseof the lips (Dufresne and Curlin 1997). This omi-nous precursor of cancer occurs specially onlower lip due to chronic sunlight exposure and

M.A. de Oliveira (*)A. C. Camargo Cancer Center, São Paulo, Brazile-mail: m.oliveira@jkdermatologia.com.br; dr.mao@uol.com.br

# Springer International Publishing AG 2018M.C.A. Issa, B. Tamura (eds.), Lasers, Lights and Other Technologies, Clinical Approaches and Procedures inCosmetic Dermatology 3, https://doi.org/10.1007/978-3-319-16799-2_23

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outdoor activities of people such as fishermen,farmers, beachworkers, golfers, and surfers(Dufresne and Curlin 1997; Martins-Filho et al.2011; Lucena et al. 2012; Ribeiro et al. 2014).

Basic ConceptsActinic cheilitis, or solar cheilosis, attracts a

number of clinical definitions from malignantlesions to relative mild descriptions of thesun-damaged lips. This occurrence is sunlightdose dependent (Table 1) and is cumulative overa 5–20-year exposure to ultraviolet radiation,immune status (organ transplantation), age,genetic predisposition (xeroderma pigmentosum,porphyria cutanea tarda, oculocutaneous albi-nism), drugs (voriconazole), geographic latitude(countries close to equator), and use of lip protec-tion (lipstick, lip sunscreen) (Rogers and Bekic1997; Savage et al. 2010; Lucena et al. 2012;Jadotte and Schwartz 2012a). Other factors liketobacco, alcohol, poor oral hygiene, and chronicscarring in discoid lupus erythematous areinvolved (Table 1) (Jadotte and Schwartz 2012a).

As with actinic keratosis, the exact transition rateto most common lip cancer, the squamous cell car-cinoma (SCC), is unknown, but the relative risk isfelt to be 2.5 times higher. SCC is, however, themost frequent oral cavity cancer and head and neckmalignant tumor, with an incidence in the UnitedStates of 1.8 per 100.000 (Ulrich et al. 2007). SCC isconsidered a disease of low aggression and favor-able prognosis because it tends to progress slowly.Estimated occurrence of SCC is 89% on the lower

lip, 3% on the upper lip, and 8% at the oral com-missures (Picascia and Robinson 1987).

When diagnosed early it has a cure rate of80–90% and a mortality rate between 10% and15%. Metastases tend to occur in between 3% and20%; of these cases the mean survival for 5 yearsdecreases to25%(Kwonetal. 2011;Limetal.2014).

As already noted, AC occurs more often on thelower lip. Two forms exist, acute which is lesscommon in the elderly which occurs after pro-longed sunlight exposure. Edema and rednessare characteristic of the mildest forms. Severecongestion, fissuring, and ulceration typify themost severe form. At times vesicles may appearon the vermilion edge. These vesicles rupturecausing superficial erosions and vary from daysto weeks to heal (Nico et al. 2007).

The chronic form of AC usually manifestsitself as slight scaling involving the whole areaof the lower lip up to the commissures and ispresent in all seasons of the year. The scaling isnot always uniform and some areas may displaymore intensive hyperkeratosis than others(Picascia and Robinson 1987; Nico et al. 2007).Leukoplakia, scale plaque with a sandpapery feelon palpation with a gloved finger, is a commonpresentation (Jadotte and Schwartz 2012a).

White-gray or brown changes may appear. Thevermilion edges lose their usual plasticity whichcan be assessed by the appearance of markedfolds. These wrinkles are parallel to one anotherand are perpendicular to the long axis of the lip(Picascia and Robinson 1987; Nico et al. 2007).

The differential diagnosis (Table 2) of CAcovers a spectrum of neoplastic, inflammatory,eczematoid, and photosensitive disorders, alongwith a few rare but important diseases (Picasciaand Robinson 1987; Jadotte and Schwartz 2012b).

Evaluation of ultraviolet ray-induced lesions ofthe lower lip can be difficult, as often clinicalaspects do not correspond to the severity of themicroscopic epithelial alterations. When clinicalsigns are present in well-demarcated area of thelip, it is supposed that the most severe histologicalchanges occur at this point.

However, AC frequently presents as diffuseand poorly demarcated alterations along the

Table 1 Relationship between the various risk factors inactinic cheilitis

Major risk factors:

Genetic predisposition

Skin pigmentation

UV radiation history

Minor risk factors:

Smoking

Alcoholism

Organ transplantation

Lupus discoid

Chronic scars

Poor oral hygiene

322 M.A. de Oliveira

vermilion, and choosing an area for incisionalbiopsy in these cases may be challenging (Nicoet al. 2007). The carcinomatous transformationgenerally is characterized by induration, infiltra-tion, or ulcers in actinic area (Samimi 2016).Sometimes two or more biopsies are required.

Currently, reflectance confocal microscopyseems to be a promising diagnostic tool for actiniccheilitis as it allows noninvasive evaluation in realtime and in vivo (Ulrich et al. 2011).

Treatment of actinic cheilitis provides relief ofsymptoms, improves the cosmetic appearance,but, more importantly, prevents the developmentof squamous cell carcinoma (Picascia andRobinson 1987).

Surgical scalpel vermilionectomy offers the mostdefinitive treatment to date for actinic cheilitis,followed by carbon dioxide laser (Nelson et al.2007). There are various options to treat actiniccheilitis; however, these options very often havedisabling side effects (Sotiriou et al. 2008).

Treatments have been used for the treatment ofactinic cheilitis, as shown in Table 3 (Robinson1989; Dufresne et al. 2008; Lima Gda et al. 2010;Shah et al. 2010; Ulrich et al. 2011; Jadotte andSchwartz 2012b; Barrado Solís et al. 2015).

The treatment options for actinic cheilitis arediverse and each modality has both distinct advan-tages and disadvantages. Each treatment can besafely performed in an outpatient setting, although

each therapy option comes with different potentialadverse effects. Some of them requires operatorexpertise to perform. Apart of therapeutic option,actinic cheilitis can potentially recur. There areeffective methods well established for actiniccheilitis treatment. Each modality has its owninherent risks, benefits, and anticipated sequelae.To determine the treatment of choice, age,comorbidities, mental health, previous carcino-mas, and immunosuppression should be consid-ered. About the area, single or multiples lesions,localization, extension, induration, as well asulcerated lesions should be considered. Isolatedand well-defined lesions can be treated withdestructive methods such as cryosurgery, derm-abrasion, electrodesiccation and curettage, andlasers, while extensive areas can be fully treatedwith field treatment as diclofenac, 5-fluoracil,imiquimod, lasers, dermabrasion, ingenolmebutate, photodynamic therapy, surgery, or tri-chloroacetic acid peel as presented in Table 3.

The photodynamic therapy can be used inlocalized lesions or in all entire lip.

Photodynamic Therapy:

PDT Mechanism of Action

Photodynamic therapy has been introduced as atherapeutic modality for epithelial skin tumorsrevealing a high efficacy rate and satisfactory out-comes in cutaneous actinic keratosis, superficial

Table 2 Differential diagnosis of actinic cheilitis

Squamous cell carcinoma

Amelanotic melanoma

Discoid lupus erythematous

Oral lichen planus

Metastatic cancer

Plasma cell cheilitis

Cheilitis glandularis

Angular cheilitis

Granulomatous cheilitis

Eczematous cheilitis

Nutritional cheilosis

Actinic prurigo cheilitis

Factitious cheilitis

Necrotizing sialometaplasia

Sweet syndrome

Table 3 Cheilitis actinic treatments

3% diclofenac gel

5% 5-fluoracil cream

5% imiquimod cream

Carbon dioxide laser

Cryosurgery

Dermabrasion

Electrodesiccation and curettage

Er-YAG laser

Ingenol mebutate gel

Surgery (scalpel excision, vermilionectomy, MohsMicrographic Surgery)

Trichloroacetic acid peel

Actinic Cheilitis: Efficacy and Cosmetic Results 323

basal cell carcinoma, and Bowen’s disease.Regarding actinic cheilitis, photodynamic therapyis considered a relative new off-label therapeuticoption (Rossi et al. 2008).

The advantages of PDT are its high efficacyand tolerability coupled with excellent cosmeticoutcomes (Morton et al. 2008; Sotiriou et al.2011). As the lip is a cosmetically sensitive site,treatments for actinic cheilitis must consider cos-metic outcomes (Morton et al. 2008; Sotiriou et al.2011; Calzavara-Pinton et al. 2013).

Despite these facts, PDT for actinic cheilitis isnot very common: there are only a few case seriesand studies that report the applicability and efficacyof this treatment modality for actinic cheilitis. Inmost of them, treatment outcome was assessedonly by clinical evaluation (Sotiriou et al. 2010).

PDT Indications and Contraindication

Off-label clinical indications for PDT in actiniccheilitis are generally poor and based on individ-ual case reports or small cases series, and the fewrandomized clinical trials performed enrolledsmall number of patients with short follow-up.

All authors agreed that cosmetic outcome wasexcellent, and the tolerability was acceptable inthe majority of patients (Calzavara-Pinton et al.2013). In one study the cosmetic results wererated by the investigators as excellent in 81.8%of cases (Sotiriou et al. 2010).

If the cosmetic outcome only is considered,PDT offers positive cosmetic outcomes observedby the investigators when compared with conven-tional treatments.

Ulceration, nodularity, atrophy, nodularity,bleeding, blurred demarcation, and friability(especially when prolonged) indicate malignancy(Jadotte and Schwartz 2012a; Yazdani Abyanehet al. 2015). In these cases, biopsy is mandatoryand PDT should be avoided until histopathologi-cal elucidation.

All of the studies are descriptive serieswithout control arms. A bias toward reporting andpublishing series with positive findings should alsobe considered. Furthermore, various treatment

parameters were used and lengths of follow-upranged widely. Clinical responses were assessedsubjectively by nonblinded investigators; a histolog-ical confirmations of cure were established in onlyhalf of the subjects (Yazdani Abyaneh et al. 2015).

Furthermore results are generally based onvisual assessments without controlled parameters,such as histopathology and/or noninvasive imag-ing procedures (Calzavara-Pinton et al. 2013).

These factors led to a wide range in clinicalresponse and histological cure rates. There is aneed for randomized controlled trials with long-term follow-ups to evaluate the clinical and histo-logical response of actinic cheilitis to PDT. Morestudies are also needed to determine the optimalnumber of treatment sessions and techniques(Yazdani Abyaneh et al. 2015).

PDT: Use and Doses:

PDT is a noninvasive and precisely directedtreatment. Patients are prepared for PDT firstwith gentle removal of scale and crust from thelips (Fig. 1). The procedure involves the topicalapplication of photosensitizing agents mostoften 20% 5-aminolevulinic acid (ALA) or16% methyl 5-aminolevulinate cream (MAL)on the lip (Fig. 2). The area is occluded(Figs. 3 and 4) after preestablished time of 3 h,and visible light irradiation (usually red or blue)is applied with subsequent promotion of reac-tive oxygen species, which in turn produceslocal tissue destruction (Barrado Solís et al.2015; Choi et al. 2015).

Daylight PDT (DA-PDT) is a novel modalityin which the activation of the topical photosensi-tizer is induced by the exposure to natural daylightwithout requiring preliminary occlusion. In twostudies enrolling 12 patients, the use of DA-PDTshowed benefits decreasing the pain level (Leviet al. 2013; Fai et al. 2015).

There is no specific data that explains exactlyabout cosmetic outcome of the lip treated withphotodynamic therapy. In our experience weobserved overall lip rejuvenation with a youngerappearance (Figs. 5 and 6), uniform color, best

324 M.A. de Oliveira

delimitated vermilion transition, soft and thinnerepithelium, and less flaking.

PDT: Side Effects and theirManagement

The pain and burning sensation during the irradi-ation is always present in different levels. Edema,

erythema, blistering, hemorrhagic crusting, itchi-ness, erosions, paresthesias, scaling, andmild dry-ness can occur. These reactions resolved5–14 days after the treatment and cold dry helpsin pain control (Sotiriou et al. 2010; YazdaniAbyaneh et al. 2015). After PDT treatment occurs,selective destruction of unhealthy tissue, increaselocal immune response and advantages of short-term treatment as minimal erythema, reducedscaring risk and renewal skin epithelium(Alexiades-Armenakas 2007; Kodama et al.2007; Sotiriou et al. 2008; Rossi et al. 2008;Castaño et al. 2009).

Conventional PDT for actinic cheilitis has beenreported in a number of publications with clinicaland histological cure rates ranging between 47%and 100%. This wide variability in efficacy canpartly be explained by different study designsincluding differences in biological endpoints,light sources, and follow-up periods (Levi et al.2013; Kim et al. 2013). Despite of observationalclinical results, it is important to keep in mind thesignificantly higher histological recurrence rates

Fig. 1 Actinic cheilitis in lower lip

Fig. 2 MAL application in lower lip

Fig. 3 MAL occlusion in lower lip with adhesive tape

Fig. 4 Dressing light protection for 03 hours

Fig. 5 Lower lip before photodynamic therapy

Actinic Cheilitis: Efficacy and Cosmetic Results 325

(Sotiriou et al. 2010). Inadequate uptake of thephotosensitizer owing to dilution by saliva andrapid regeneration of mucosa epithelium com-pared with the skin may result in a lower efficacyof the treatment. PDToffers a promising treatmentoption supported by excellent cosmetic outcomeposttreatment with the need for further study (Kimet al. 2013; Yazdani Abyaneh et al. 2015).

Authors’ Experience

The author always performs lip biopsy before allactinic cheilitis treatment. It is possible to treatisolated lesion as well as all entire lip. When thephotodynamic therapy is the treatment of choice,there is careful curettage of crusts and scales fromthe lip; a 1 mm thick layer of 20% methyl5-aminolevulinate cream is applied over the entirelip. Cotton roll is placed in the gingival transitionand the lip is covered by an occlusive bandage for3 h. After the removal of the cream, lesions areirradiated with 37 J/cm2 of red light (635 nm). Twotreatment sessions are conducted 1 week apart.

Conclusion

Cheilitis actinic is a chronic premalignant condi-tion affecting the lip. Untreated lesions maybecome squamous cell carcinoma, and treatmentoptions can be ablative, surgical and topicalmodalities. Photodynamic therapy is focal andalso a field-directed treatment for actinic cheilitis.The cosmetic outcome and results suggest thatphotodynamic therapy may offer comparablerate response. The pain and high cost sometimes

turns the method unfeasible. However, increasingthe efficacy of PDT through optimization of treat-ment parameters is still necessary.

Take Home Messages

• As with actinic keratosis, the exact transitionrate to squamous cell carcinoma relative risk isfelt to be 2.5 times higher

• Treatment of actinic cheilitis should providerelief of symptoms, improve the cosmeticappearance, but, more importantly, preventthe development of SCC.

• As the lip is a cosmetically sensitive site, treat-ments such as PDT for actinic cheilitis mustconsider cosmetic outcomes.

• PDT is advantageous in that it has transient andmild to moderate cosmetic adverse effects andminimizes patient discomfort.

Cross-References

▶Daylight Photodynamic Therapy and Its Rela-tion to Photodamaged Skin

▶ Photodynamic Therapy for Photodamaged Skin▶Transepidermal Drug Delivery and Photody-namic Therapy

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Photodynamic Therapyfor Photodamaged Skin

Ana Carolina Junqueira Ferolla and Maria Claudia Almeida Issa

AbstractPhotodynamic therapy (PDT) is a well-established therapeutic modality for non-melanoma skin cancer (NMSC). It is based ona photochemical reaction, which causesdestruction of the target tissue associated withan inflammatory response. In the last years,PDT has been indicated for some dermatosisin cosmetic dermatology, such as acne, seba-ceous hyperplasia, rosacea, and photoaging.Although PDT’s mechanism of action in thesedermatoses is not totally clear, some histolog-ical studies had shown dermis remodelinginduced by PDT in photodamaged skin. Inthis chapter, we are going to discuss aboutphotoaging and PDT treatment, comparing lit-erature review and authors’ experience.

KeywordsPhotodynamic therapy • Photosensitizer •Nonmelanoma skin cancer •Actinic keratosis •Basal cell carcinoma • Bowen disease •

Photodamaged skin • Collagen fibers • Elasticfibers • Skin remodeling • Dermis • Aging •Photoaging • Photorejuvenation •Rejuvenation

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329

Photoaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330Concept . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330Clinical and Histopathologic Aspects . . . . . . . . . . . . . . . 331Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331

Photodynamic Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331Concept and Mechanism of Action . . . . . . . . . . . . . . . . . . 331Light Sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332Photosensitizers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332Procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334

Photodynamic Therapy forPhotorejuvenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334

Possible Mechanisms Involved . . . . . . . . . . . . . . . . . . . . . . 334Clinical Reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335Protocol of Treatment (PDT � Photorejuvenation)

and Author’s Experience . . . . . . . . . . . . . . . . . . . . . . . . . 337

Take Home Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339

Introduction

Aging is a complex and multifactor process thatoccurs in all individuals, influenced by environ-mental, hormonal, and genetic elements, resultingin functional and aesthetical skin changes. Photo-aging is clinically manifested by wrinkles,

A.C.J. Ferolla (*)Medical Ambulatory of Specialties, Barradas, São Paulo,Brazile-mail: dracaroljferolla@ig.com.br

M.C.A. IssaDepartment of Clinical Medicine – Dermatology,Fluminense Federal University, Niterói, RJ, Brazile-mail: dr.mariaissa@gmail.com;maria@mariaissa.com.br

# Springer International Publishing AG 2018M.C.A. Issa, B. Tamura (eds.), Lasers, Lights and Other Technologies, Clinical Approaches and Procedures inCosmetic Dermatology 3, https://doi.org/10.1007/978-3-319-16799-2_24

329

roughness, dryness, sagging, pigmentary spots,telangiectasias, and, in some cases, premalignantand malignant lesions (Ferolla 2007; Issa 2008;Gilchrest 1989).

PDT is based on a photochemical reaction,which causes destruction of the target tissue asso-ciated with an inflammatory response. For thisreaction, a photosensitizer agent in the target tissueis necessary, a source of light and oxygen. It isapproved for NMSC treatment, including actinickeratosis (AK), basal cell carcinoma (BCC), andBowen disease (squamous cell carcinoma – SCC insitu) (Issa and Patricia-Azulay 2010; Kalka et al.2000; Szeimies et al. 1996a; Casas et al. 2001;Nestor et al. 2006). The two main photosensitizersare aminolevulinic acid (ALA) and methylaminolevulinate (MAL), which were approved tobe used with light-emitting diode (LED) that emitsvisible light. PDTwith ALA-blue light is very wellindicated for superficial lesions, mainly AK. PDTwith MAL-red light is recommended for deeplesion treatment because of MAL’s lipophilicityand deeper penetration of the red light in the skin(Hurlimann et al. 1994; Szeimies et al. 1994,1996b, 2002a, 2005; Fink-Puches et al. 1998;Salim et al. 2003; Lee and Kloser 2013; Babilaset al. 2005).

The global improvement of the skin aroundAK lesions after PDT called attention to a newpossibility for photoaging treatment. Many clini-cal studies had reported improvement in texture,pigmentation, wrinkles, and laxity in the field ofcancerization treated with PDT (Nestor et al.2006; Hurlimann et al. 1994; Szeimies et al.1994, 1996b, 2002a, 2005; Fink-Puches et al.1998; Salim et al. 2003; Lee and Kloser 2013;Babilas et al. 2005; Bruscino and Rossi 2010;Park et al. 2010; Issa et al. 2010; Shamban 2009;Bjerring et al. 2009; Almeida Issa and Piñeiro-Maceira 2009). However, only in the last years,some histological and immunohistochemicalstudies described some factors involved in themechanism of skin rejuvenation induced by PDT(Issa et al. 2010; Almeida Issa and Piñeiro-Maceira 2009; Szeimes et al. 2012).

Some other off-label indications include acne,rosacea, sebaceous hyperplasia, vulgar warts, pso-riasis, granuloma annulare, necrobiosis lipoidica,

and mycosis fungoides (Morton et al. 2013; Alsterand Tanzi 2003; Calvazara-Pinton et al. 2010;Bissonnette et al. 2002; Szeimies et al. 2002b;Gold and Goldman 2004a).

Photoaging

Concept

Aging is a continuous process that affects the skinfunction and its appearance. The chronologicalaging affects all organs similarly, but environmen-tal (extrinsic) and inherited (intrinsic) processesoverlap to produce skin aging. There are evi-dences that the inherent and extrinsic aging pro-cesses have, at least in part, biological,biochemical, and molecular common mecha-nisms. Chronic sun exposure has been identifiedas one of the main environmental injuries. Otherenvironmental aggressions, such as smoking,wind, and chemical agent exposure, are alsoinvolved (Issa 2008).

Pathogenesis

The UVB radiation (290–300 nm) is responsiblefor sunburn, while the UVA (320–400 nm), whichpenetrates more deeply in the skin, promotes col-lagen and elastic fiber damage. Both UVA andUVB are involved in the pathogenesis of skincancer and photoaging. The UV radiation causesgenetic and molecular changes in the cells of theepidermis, leading to cell atypia (Ferolla 2007;Issa 2008; Gilchrest 1989).

The response to UV radiation involves com-plex paths, which start in the cell surface receptorsthat activate transcription factors, AP-1, andNF-kappaB. These factors regulate synthesis ofcytokines and interleukins (IL-1, IL-6, IL-8,TNF-alpha) and metalloproteinases, such asMMP-1, MMP-9, MMP-3, and MMP-10. Thesecytokines and interleukins stimulate an inflamma-tory process, and on the other hand, they mediatesome antioxidant enzymes, balancing the damage.MMP-1 is increased in photodamaged skin and is

330 A.C.J. Ferolla and M.C.A. Issa

responsible for breaking collagen types I and IIIinto high molecular fragments of collagen, whichchange the extracellular matrix, inhibiting synthe-sis of new collagen. MMP-9 breaks these frag-ments into smaller fractions of collagen,modifying the relationship between the fibroblastsand the extracellular matrix, allowing neo-collagenesis (Kang et al. 2001; Chung et al.2001; Naderi-Hachtroudi et al. 2002; Doughertyet al. 1998; Fisher et al. 2002).

Clinical and Histopathologic Aspects

The clinical findings about photodamaged skininclude wrinkles, roughness, dryness, pigmenta-tion, telangiectasias, and, in some cases, prema-lignant lesions (actinic keratosis) and malignantlesions (BCC and SCC). In the epidermis, cellularatypia is observed, as well as loss of polarity ofkeratinocytes and reduced number of Langerhanscells. In the dermis, eosinophilic material(elastosis solar) is observed, as well as thick andcurly elastic fibers and thin and flat collagen fibers(Ferolla 2007; Issa 2008; Gilchrest 1989; Kalkaet al. 2000).

Treatment

Photoaging treatment includes topical medica-ments and cosmeceuticals, oral nutraceuticals,and cosmetic procedures. Chemical peelings,microneedling, transepidermal drug delivery,lasers, botulinum toxin, and fillers are the mostimportant procedures in aesthetic dermatology(discussed in another chapter). If premalignantand malignant lesions are present, a differentapproach is necessary.

The benefits of PDT for photodamaged skinwere realized during the field of cancerizationtreatment, when the improvement of texture, pig-mentation, and wrinkles was observed. PDT’sprotocol for photodamaged skin varies a lot inliterature with different numbers of sessions,using ALA or MAL and different sources oflight (blue and red light-emitting diode (LED),intense pulsed light (IPL), and laser) (Issa 2008;

Palm and Goldman 2011; Sanclemente et al.2012; Bjerring et al. 2002; Karrer et al. 1999a;Dover et al. 2005; Alster et al. 2005; Alexiades-Armenakias and Gernemus 2003; Gold et al.2006; Togsverd-Bo et al. 2012; Ruiz-Rodriguezet al. 2002).

Photodynamic Therapy

Concept and Mechanism of Action

Photodynamic therapy is based on a chemicalreaction activated by light, in the presence of aphotosensitizer in the target tissue, light, andoxygen. ALA and MAL are the most importantphotosensitizers used ▶Daylight PhotodynamicTherapy and Its Relation to Photodamaged Skin.In fact, they are prodrugs, absorbed by the targetcell and then transformed into protoporphyrin IX(Pp IX), inside the cytoplasm and mitochondria(Ferolla 2007; Issa 2008; Gilchrest 1989; Issaand Patricia-Azulay 2010; Kalka et al. 2000;Szeimies et al. 1996a; Casas et al. 2001). Differ-ent sources of light can be used, but LED withred or blue light (Fig. 1) is the most importantsource for premalignant and malignant lesiontreatment. The selective destruction of target tis-sue occurs through a chemical reaction, wherethe photosensitizer agent in the tissue absorbs thelight, becoming excited and then transferring theenergy to the oxygen. That sequence of chemicalreactions promotes reactive oxygen species(ROS) production, especially the singlet oxygen,which is cytotoxic to malignant cells (Ferolla2007; Issa 2008; Casas et al. 2001; Hurlimannet al. 1994; Szeimies et al. 1996b, 2005; Palmand Goldman 2011; Sanclemente et al. 2012;Bjerring et al. 2002; Karrer et al. 1999a; Doveret al. 2005; Alster et al. 2005; Alexiades-Armenakias and Gernemus 2003; Gold et al.2006; Togsverd-Bo et al. 2012; Ruiz-Rodriguezet al. 2002). PDT causes an inflammatoryresponse, activating nuclear factors that controlthe expression of many cytokine and interleukingenes (IL-1, IL-2, IL-6, IL-10, α-factorof tumoral necrosis – TNF-α) (Ferolla 2007;Issa 2008).

Photodynamic Therapy for Photodamaged Skin 331

Light Sources

Light-Emitting Diode (LED): Visible LightPpIX exhibits maximum light absorption (theSoret peak) at 405 nm (blue light) and a weakerabsorption band at 635 nm (red light). Blue light isbetter absorbed, but it penetrates more superfi-cially, around 1–2 mm. Red light penetratesaround 4 mm, and it is considered the best choicefor deeper lesions (carcinoma) treatment. Bothblue and red light can be used for AK lesionsand for photoaging treatment (Issa 2008; Naderi-Hachtroudi et al. 2002; Palm and Goldman 2011;Sanclemente et al. 2012).

Other Light SourcesLaser or IPL can be used for PDT treatment, butthey are expensive devices without advantagescomparing to LED for AK lesion treatment. Forthis reason, they are better indicated for photo-rejuvenation and acne treatment, as they can actdirectly in vessels, pigments, and collagen(Bjerring et al. 2002; Karrer et al. 1999a; Doveret al. 2005; Alster et al. 2005; Alexiades-Armenakias and Gernemus 2003; Gold et al.2006; Togsverd-Bo et al. 2012; Ruiz-Rodriguezet al. 2002).

Photosensitizers

Aminolevulinic Acid (ALA)In the USA, ALA was approved by the FDA in1999 associated with blue light for AK treatment.It is available as a stick, called Levulan Kerastick(DUSA Pharmaceuticals) (Fig. 2), in a solutionwith 20% of ALA and 48% of ethanol. This stickhas two glass bottles inside. One of them containspowder of ALA and the other contains ethanol(solvent). The bottles should be broken with aslight manual pressure in the tube, which isshaken to mix the powder and the solvent. Aftermixing, ALA is ready to be used through anapplicator in one of the stick’s extremities.

The incubation time of ALA on the skin variesin literature, but at least 3 h are necessary forNMSC treatment. When ALA is used for photo-rejuvenation, 1 or 2 h are enough, but usuallymore than one session is necessary (Ferolla 2007).

Methyl Aminolevulinate (MAL)MAL is a methyl ester derivative of ALA. It islipophilic and therefore has a better permeabilitythrough the cell membrane. It is wellrecommended for NMSC treatment, not only forAK lesions but also for carcinomas (BCC andBowen disease). For NMSC, an incubation time

Fig. 1 Source of lights

332 A.C.J. Ferolla and M.C.A. Issa

of 3 h is necessary. Otherwise, when MAL is usedfor skin rejuvenation, 1 or 2 h are enough (Issa2008; Issa et al. 2010). Different from ALA,MALhas its distribution all over the world, includingBrazil. Its commercial name isMetvix (Galderma)(Fig. 2), and it is available in a tube containing 2 gof a lipophilic cream. In many countries it isapproved for AK and BCC. In the USA, it isapproved for AK, and in Brazil and some othercountries, it is approved for AK, BCC, and Bowendisease. The cure rate of MAL-PDT for AKranges from 70% to 100%, up to 95% for super-ficial basal cell carcinomas, and 70–93% forBowen disease (Issa 2008; Issa and Patricia-Azulay 2010; Hurlimann et al. 1994; Szeimieset al. 2005; Fink-Puches et al. 1998; Salim et al.2003).

Procedure

PDT’s protocol is well established for NMSCtreatment. Photosensitizer’s incubation time is3 h with an occlusive dressing (Fig. 3).ALA-blue light is approved for AK treatment,and MAL-red light is approved for AK, BCC,and Bowen disease. One session is recommendedfor AK lesions, and two sessions with 1-weekinterval are indicated for BCC and Bowen dis-ease. The protocol for rejuvenation varies a lot inliterature, regarding skin preparation, photosensi-tizer incubation time, source of light, and numberof sessions (Ferolla 2007; Issa 2008).

In the standard protocol for NMSC, a slightcurettage should be done over the lesion to pre-pare the skin before applying the photosensitizer.

Fig. 3 Steps of procedure: (1) cleaning the skin; (2) applying the photosensitizer; (3) oclusion with plastic film; (4) lightprotection during incubation time

Fig. 2 Photosensitizers

Photodynamic Therapy for Photodamaged Skin 333

Recently, in order to increase the photosensitizerpenetration, some other methods, as ablativelasers and microneedling, have been evaluated.This technique is called transepidermal drugdelivery (TED). TED + PDT is an option forphotoaging treatment (discussed in another chap-ter ▶ “Transepidermal Drug Delivery and Photo-dynamic Therapy”) (Kassuga et al. 2012; Torezanet al. 2013).

MAL is ready to be applied 10 mm around thelesion. ALA should be prepared when it is to beused, as explained before. An occlusive dressingis maintained during the photosensitizer’s incuba-tion time to increase the penetration and to avoidambient light exposure before 3 h. The excessivedrug is removed with a physiologic solutionbefore illumination. The time of light exposuredepends on the LED to be used. After session,patients should be advised to avoid sun exposurefor 48 h and to use sunscreen after this period.Cold compress and moisturizing cream can beused. Analgesics can be prescribed, but steroidsshould be avoided (Issa 2008).

Side Effects

Side effects of topical PDT are limited to the areatreated, and it includes pain and burning sensa-tion, during the illumination up to 24–48 h aftertreatment. Erythema, edema, and crusts occur inthe first week (Issa 2008; Issa and Patricia-Azulay2010; Kalka et al. 2000; Szeimies et al. 1996a;

Casas et al. 2001; Nestor et al. 2006) (Fig. 4). Theskin peels after 3 days, but is completely recov-ered after 7–10 days. On extra-facial region, ittakes more time to start peeling and to recover.Erythema can be present after 2–4 weeks on theface and up to 3 months on extra-facial region.Dyschromia is very rare, but if it occurs it istemporary. Herpes simplex can occur after 2 or3 days, and antiviral prophylaxis is recommendedfor patients with past history of herpes. Bacterialinfection is rare, and antibiotic prophylaxis is notnecessary. Sterile pustules are described after acnetreatment (Ferolla 2007; Issa 2008).

Photodynamic Therapyfor Photorejuvenation

Possible Mechanisms Involved

The effects of light on the skin involve complexmechanisms. The balance between the dermaldamage and induction of repair seems to definethe final effect. Photoaging is mediated by directabsorption of UV radiation and by photochemicalreactions mediated by ROS. They play an impor-tant role in the pathogenesis of aging and alsoparticipate in mechanism of action of PDT (Issa2008).

Recently, it has been reported that PDTcanmod-ulate the expression of interleukins (IL-1, IL-2, IL-6,IL-10) in tumors and in normal tissue; some of themare also produced after UV radiation. These

Fig. 4 (1) Erythema just after procedure; (2) scales and dryness after 48 h; (3) completely recovery after 8 days

334 A.C.J. Ferolla and M.C.A. Issa

interleukins activate an inflammatory response,causing injury to the tissue, but at the same timethey stimulate antioxidant response, limiting thedamage and allowing dermis repair (Brenneisenet al. 2002; Karrer et al. 2003; Kolh et al. 2010).

Some authors reported an increase of MMP 1and 3 and a reduction of collagen type I in anin vitro study in which culture of fibroblastsfrom normal and scleroderma skin was submittedto PDT (ALA and red light). The result suggestsan anti-sclerotic effect of the PDT on the skin(Kolh et al. 2010). This effect is undesirable forskin rejuvenation and motivates new studies toevaluate possible mechanism involved in PDTfor skin rejuvenation.

Issa et al. (2008) studied the effects ofMAL-red light (two sessions) in patients withphotodamaged skin. They evaluated MMPs(1, 3, 7, 9, 12), MMP inhibitors (TIMP 1, TIMP2), and collagen types I and III. They reported anincrease of MMP-9 in the first 3 months, followedby an increase of collagen type I after 6 months,which was statistically significant, measured bymorphometry (Issa et al. 2010; Almeida Issa andPiñeiro-Maceira 2009). Authors concluded thatMMP-9 degraded the broken collagen (degradedby UV radiation) and changed the extracellularmatrix, allowing fibroblasts to synthesize newcollagen type I. These histological findings cor-roborate clinical improvement in texture, wrin-kles, pigmentation, and firmness, noticed after3 months of treatment, with progressive improve-ment up to 6 months.

Clinical Reports

Ruiz-Rodriguez et al. (2002) treated 17 patientswith different degrees of photoaging with AKlesions (a total of 38 lesions) with two sessionsof PDT with ALA, with 1-month interval. ALA’sincubation time was 4 h. IPL was used as lightsource. A total of 33 AK lesions had a completeresolution within 3 months. The technique waswell tolerated, and an excellent global improve-ment was achieved in all patients.

Gold et al. (2006) evaluated ten patients withsevere photoaging with AK. The protocol for PDT

was application of 20% ALA solution on the face,with an incubation time of 30 min. The lightsource was IPL. Patients were submitted to threesessions of treatment with 1-month interval. AKcure rate was 85%, and 90% of the patients had aglobal improvement (texture, pigmentation, andfacial erythema).

Alster et al. (2005) compared ALA-IPL andIPL isolated for photoaging treatment andreported a better clinical result, without increasingside effects with ALA-IPL. Marmur et al. (2005)reported clinical improvement with an increase ofcollagen type I in photodamaged skin afterALA-IPL.

Touma and Gilrescht (2003) compared differ-ent time of light exposures and reported improve-ment in photoaging even with a short period ofillumination. In another study, Touma et al. (2004)evaluated the use of 40% urea before PDT withALA-blue light, but no significant clinical effectswere observed.

Alexiades-Armenakias et al. (2003) reportedthe use of vascular laser 585 nm, after 3–18 h ofALA incubation time in 35 patients withAK. They evaluated 2.561 AK lesions on theface, scalp, and extremities. The cure rate was99.9% after 10 days, 98.4% after 2 months, and90.1% after 4 months on the face and scalp. Thelesions located on the extremities had a poorresponse with complete resolution of 49.1% after2 months. Authors concluded that when using notpurpuric parameters of PDL for PDT, it is possibleto reach good cure rate with minimum discomfort,low downtime, and excellent aesthetical results.

Palm et al. (2011) treated 18 patients withphotoaging, using MAL-PDT, comparing bluelight with the red light. There was no staticallysignificant difference between them.

Sanclemente et al. (2012) studied histopatho-logical findings after PDT treatment withMAL-red light and reported an increase of colla-gen and elastic tissue, although not statisticallysignificant.

Ferolla et al. (2007) demonstrated the globalclinical improvement of skin (pigmentation, finewrinkles, sagging, AK lesions) after three ses-sions of ALA-red light (Fig. 5). The incubationtime was 2 h, followed by the red light

Photodynamic Therapy for Photodamaged Skin 335

illumination for 20 min. Histological studiesshowed improvement in collagen fibers organiza-tion (Fig. 6a, b).

Issa et al. (2008) evaluated the therapeuticresponse of PDT for photodamaged skin in14 women with and without AK. Two sessionsof MAL-red light were done with 30 days ofinterval. MAL incubation time was 2 h underocclusion. The light source was a LED (Aktilite– Photocure) with a dose of 37 mJ/cm2. Clinicalresults included texture, pigmentation, and wrin-kle improvement observed after 3 and 6 months of

follow-up (Fig. 7). After 6 months, reduction ofskin sagging was more evident (Fig. 8). Sideeffects included edema, erythema, and crusts.Authors also evaluated histological and morpho-metric changes in those patients mentioned aboveand observed a statistically significant increase ofcollagen and elastic fibers mainly 6 months aftertreatment (Figs. 9 and 10).

Le Pillouer-Prost and Cartier (2016) reportedthat PDT is an effective method for photoagingtreatment, improving fine wrinkles, skin rough-ness, and laxity. They consider patients with past

Fig. 6 (a) Beforetreatment: collagen fibersdisorganized (picrosiriuswith polarized light � 340).(b) After treatment:collagen fibers betterorganized (picrosirius withpolarized light � 340)

Fig. 5 Before and 21 daysafter two sessions ofALA-PDT- red light

336 A.C.J. Ferolla and M.C.A. Issa

history of significant sun exposure and with mul-tiple AK lesions as the best indication for PDTphotorejuvenation.

Protocol of Treatment (PDT �Photorejuvenation) and Author’sExperience

1. Advise patients regarding the benefits and thelimits of the technique.

2. Take pictures for further comparison.3. Prophylaxis with aciclovir, if patient has past

history of herpes.4. Remove makeup, and then apply alcoholic

chlorhexidine to clean the skin.5. Do a slight curettage of AK lesions.6. Apply ALA or MAL on the area to be treated.

When using MAL, a thin layer of the creamshould be applied throughout the area and it isalso recommended to put a thicker layer onthe top AK lesions.

7. Occlusive dressing with plastic film and alu-minum paper can be done or not. ALA orMAL incubation time ranges from 1 to 3 h.

8. If AK is visible, it is better to do occlusion for3 h with one session or for 1 or 2 h within twoor three sessions (3–4 weeks of interval).

9. LED is better than IPL for AK lesions for alonger follow-up.

10. Remove the dressing and the excessive photo-sensitizer agent, before starting light exposure.

11. Time of light exposure depends on the lampused. Usually it is programmed to deliver lightdose and turn off automatically. If IPL or laser isused, protocols are going to vary according tothe device based on its irradiance and fluence.

12. Analgesic before light exposure and during24 h, if incubation time is 3 h.

13. Avoid sun exposure for 48 h. After thisperiod, patients are advised to use sunscreen.

14. The use of moisturizing cream and cold com-presses with thermal water is indicated. Cor-ticoid should be avoided, but can be used ifnecessary.

Take Home Messages

1. The light effects on the skin involve complexmechanisms. The balance between dermaldamage and induction of repair seems to definethe final effect.

2. Photoaging is mediated by direct absorptionof UV radiation and by photochemical

Fig. 7 Before and 6 months after treatment (two sessions of MAL-PDT) with red light (dose: 37J/cm2). MAL incubationtime of 2 h

Photodynamic Therapy for Photodamaged Skin 337

reactions mediated by ROS. They play animportant role in the etiopathogeny of pho-toaging and participate in the mechanism ofaction of PDT.

3. PDT protocols for photodamaged skin arereported with ALA or MAL and with differentsources of light: IPL, laser, and LED.

4. Protocols vary in literature: different incuba-tion times of ALA or MAL (30 min to 3 h),with or without occlusive dressing, number of

sessions (average of 2–3), and interval betweenthe sessions (2–4 weeks).

5. Clinically, a global improvement of skin isobserved, with the improvement of texture,actinic keratosis, pigmentation, wrinkles, andsagging.

6. Histologically, there is an improvement in theorganization of elastic and collagen fibers, witha statistically significant increase of thosefibers at morphometry.

Fig. 8 Before and6 months after treatment(two sessions ofMAL-PDT) with red light(dose: 37J/cm2). MALincubation time of 2 h

338 A.C.J. Ferolla and M.C.A. Issa

7. A possible mechanism of action related tophotorejuvenation involves the increase ofMMP-9 after PDT treatment, which modifiesthe extracellular matrix, inducing dermisremodeling with neocollagenesis.

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Photodynamic Therapy for Acne

Ann-Marie Wennberg Larkö

AbstractAcne is a common disease that affects a largepart of the young population. Common treat-ments for moderate acne include the use oforal antibiotics. However, there is anincreased risk of antibiotic resistance. Fur-thermore, the environmental effects of thesedrugs may be severe. Hence there is an alter-native for treatment of moderate acne. Pho-todynamic therapy (PDT) seems to have agood effect. However, treatment parametersneed to be elaborated upon as possibly thechoice of photosensitizer in the future. Painis a cumbersome side effect but may be con-trolled by easy measures.

KeywordsAcne • Antibiotics • Photodynamic therapy •Bacterial resistance • Environmental hazards

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343

Relevant Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344

Photodynamic Therapy (PDT) . . . . . . . . . . . . . . . . . . . . 344

Mechanism of Action in Acne . . . . . . . . . . . . . . . . . . . . . 344

Light Sources for PDT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345

Clinical Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345

Adverse Effects of PDT . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346

Other Photosensitizers Than ALA . . . . . . . . . . . . . . . . 346

Place in Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347

Take Home Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347

Introduction

Acne is a common skin disorder affecting mainlyadolescents but also adults. Comedones becomeinflamed and sometimes cystic acne appears.Acne leads to severe suffering at a sensitive age.Patients with acne have a higher unemploymentrate compared to the person with a healthy skin(Cunliffe 1986).

There is no generally accepted grading systemfor acne. However, in clinical practice this is lessof a problem.

Moderate to severe acne is often treated withsystemic antibiotic, especially tetracyclines. Thismay lead to bacterial resistance and have impacton environmental issues as tetracyclines do notdegrade easily in nature. There seems to be anassociation between bacterial resistance and poortreatment results (Thiboutot 2011).A.-M. Wennberg Larkö (*)

Department of Dermatology and Venereology, Institute ofClinical Sciences, Sahlgrenska Academy, University ofGothenburg, Gothenburg, Swedene-mail: ann-marie.wennberg@gu.se; ann-marie.wennberg@vgregion.se

# Springer International Publishing AG 2018M.C.A. Issa, B. Tamura (eds.), Lasers, Lights and Other Technologies, Clinical Approaches and Procedures inCosmetic Dermatology 3, https://doi.org/10.1007/978-3-319-16799-2_25

343

Relevant Etiology

The pilosebaceous unit is the target organ. Thesecretion of sebum is increased, and P. acnes pro-duces lipase that degrades triglycerides to glyceroland fatty acids which have inflammatory proper-ties. P. acnes also excretes porphyrins which arelight sensitive. Hence, visible light and photody-namic therapy can induce a photochemical reac-tion and less P. acnes (Hongcharu et al. 2000).However, this has been debated (Guffey andWilborn 2006).

Photodynamic Therapy (PDT)

The basic principle is that a photosensitizer isconcentrating in rapidly proliferating cells. Thesensitizer is then converted to light-sensitive por-phyrins. When exposed to light, a photochemicalreaction occurs together with oxygen via energytransfer producing singlet oxygen. Hence, freeradicals are formed and cell death occurs(Dougherty et al. 1978).

The most common photosensitizer used isdelta-aminolevulinic acid (ALA). Several otherderivatives are also used or tried (Song et al.2014). See below.

ALA and its derivatives are mainly used fortreating skin cancer or its precursors, actinic ker-atosis, superficial basal cell carcinoma, and squa-mous cell skin cancer in situ. Clinical results aregood for thin lesions, but thicker tumors areharder to treat, e.g., nodular basal cell carcinomas(Sandberg et al. 2008).

The methyl ester of ALA (MAL) is probablymost often used today. MAL is deesterified toALA. MAL is more lipophilic than ALA andsuggested to be more selective. However, it isquestionable if there is a significant difference intransdermal penetration between ALA andMAL. Recently, a new formulation was intro-duced, BF-200. It may be more effective thanALA in tumor treatment (Neittaanmaki-Perttuet al. 2014).

The rate-limiting steps in heme formation areALA synthetase and ferrochelatase. Exogenousapplication of ALA bypasses the first rate-

limiting enzyme. Accordingly, accumulation ofprotoporphyrin IX (PpIX) takes place asferrochelatase probably is downregulated. Thisprocess occurs in sebocytes. It seems that theintracellular target is the mitochondria (Penget al. 1992). The process is oxygen dependentand oxygen depletion leads to less tissue dam-age (Ericson et al. 2003).

Mechanism of Action in Acne

P. acnes itself produces small amounts of porphy-rins (Romiti et al. 2000). This can be seen asfluorescence when irradiating a skin areawith UVA.

Irradiation with blue or red light leads to exci-tation of the endogenously produced porphyrinsand formation of singlet oxygen. This results inbacterial death.

Applying ALA or its derivatives leads to for-mation of PpIX and accumulation in sebocytes.Again, singlet oxygen is formed in the presence ofoxygen and the sebocytes are affected. In somestudies sebum production has decreased, and inother studies this has not been found (Hongcharuet al. 2000; Horfelt et al. 2007).

More than 15 years ago, PDT treatment of acnewas discussed (Hongcharu et al. 2000). Theyreported good effects of PDT for acne and showeda decreased sebum excretion due to damagedsebaceous glands. Others have not found areduced sebum excretion (Horfelt et al. 2007;Pollock et al. 2004). Mouse studies have alsoindicated that ALA is taken up by sebaceousglands preferentially (Divaris et al. 1990).

Red light has a better tissue penetration thanblue light or UV. Red light has been suggested tohave anti-inflammatory properties on acne as well(Na and Suh 2007).

Blue light seems to be the most effective wave-length in photoactivating P. acnes. It seems thatblue light alone may be beneficial against acne(Morton et al. 2005). Red and blue light mightalso be combined (Papageorgiou et al. 2000).

Jeong et al. have demonstrated that topicalALA-PDT for acne can induce apoptosis ofsebocytes (Jeong et al. 2011).

344 A.-M. Wennberg Larkö

Kosaka et al. demonstrated that focused dam-age of sebaceous glands may be achieved withALA-PDT (Kosaka et al. 2011).

Light Sources for PDT

Both lasers and noncoherent light sources may beused (Zheng et al. 2014). The advantage ofnoncoherent light sources is that they are cheapand simple. However, LED light sources havebecome more common in everyday life andextremely cheap as pointers, LED lightning athome, headlights for cars etc. Unfortunately,LED light sources for treatment are rather expen-sive for various reasons. One can argue in favor ofbroadband light sources but also against. Oneadvantage is that a bigger part of the absorptionspectrum is used, one disadvantage that they pro-duce more heat.

Lasers produce coherent, monochromatic lightwhich exactly can match the absorption spectrumof porphyrins. The irradiated area is usually smallwhich is a disadvantage. Also, the special proper-ties of laser radiation, e.g., coherency, are notnecessary.

Exposure to different wavelengths has beenclaimed to have a beneficial effect (Sadick2009). The effect of sunlight is probably due tobacterial destruction as well as immunosuppres-sion by its effect on Langerhans cells. It is prob-ably mainly the UVA portion that is active. UVBhas a poorer penetration in tissue and does notmatch the absorption band of porphyrins.

Visible light alone has proved to have an effecton acne (Sigurdsson et al. 1997).

Clinical Results

Several authors have reported good results afterALA-PDT for acne (Hongcharu et al. 2000;Horfelt et al. 2007).

Recently, a new LED device was introducedwith green and red light (Dong et al. 2015). Theoverall effectiveness rate was 90% in 46 patientswith moderate to severe acne. They argue thatpulsed light sources may be less effective as

there is not sufficient oxygen. Using shorter wave-lengths may decrease pain.

Ying et al. recently published good results afterPDT treatment of acne. They used 5% ALA in21 patients with severe acne and a LED lightsource emitting at 633 nm. Total effectivenessrate was 85%.

Japanese studies have demonstrated a goodeffect of PDT on acne, but broadband lightsources may cause more pain (Asayama-Kosakaet al. 2014).

Recently Das and Reynolds have discussedadvances in acne pathogenesis and implicationsfor therapy (Das 2014). They discuss differentwavelengths and different light sources. Infraredlasers may minimize the sebaceous glands oraffect lipids (Das and Reynolds 2014).

Both visible light and ALA have been provento have an effect on acne. Pinto et al. compared theefficacy of red light alone and MAL-PDT for mildand moderate acne. MAL-PDT had a quickeraction and a higher response rate than red lightalone (Pinto et al. 2013).

Mei X et al. compared ALA-IPL-PDT photo-dynamic therapy with IPL in a recent study. ALA-IPL-PDT was shown to be superior both in termsof global lesion count and inflammatory andnon-inflammatory lesion count (Mei et al. 2013).

Acne treatment by MAL-PDT with red lightversus IPL has also been compared. Patientsresponded earlier to red light, but both therapeuticregimens were effective (Hong et al. 2013).

Haedersdal, Togsverd-Bo, and Wulf in 2008studied different light sources in a review. Theyconcluded that many therapeutic regimens may beactive but that results are better for MAL-PDTthan optical therapies (Haedersdal et al. 2008).

On the other hand, Hörfelt et al. a year later foundthat single low-dose red light is as efficacious asMAL-PDT for treating acne (Horfelt et al. 2009).

Zheng et al. recently made a review of photody-namic therapy in acne (Zheng et al. 2014). Theystudied 14 randomized clinical trials involving492 patients. They concluded that several photosen-sitizers may be used. ProbablyALA plus red light isthe optimal choice but further studies are warranted.

Linkner et al. evaluated the efficacy ofALA-PDT and microdermabrasion for acne

Photodynamic Therapy for Acne 345

scarring. They found a good effect (Linkner et al.2014). First, microdermabrasion was carried out,then PDT. Side effects were small.

A combination of ALA-PDT and ablative frac-tional Er:YAG laser has also been tried in severeacne (Yin et al. 2014). They evaluated the efficacyof combining ALA-PADT and fractional Er:YAGlaser for scarring lesions in severe acne. Initiallypatients were treated with ALA-PDT four times at10-day intervals. Then they got laser treatmentfive times at 4-week intervals. Scarring was sig-nificantly reduced.

Liu et al. (Liu et al. 2014) demonstrated goodeffect on acne with PDT, intense pulsed light(IPL), and blue-red light-emitting diode (LED)treatment of moderate to severe acne (Liu et al.2014). One hundred fifty patients were enrolled.PDT gave faster clearance but was associated withmore pain than IPL.

Interestingly, ALA-PDT seems to have anantibacterial effect (Li et al. 2013). ALA-PDTmay be able to use in antibiotic resistance toreduce the biofilm.

A typical case is resented in Fig. 1a, b, beforeand after two PDT treatment sessions.

Adverse Effects of PDT

Short-term side effects include erythema and pain.This is often experienced as stinging and burning.The pain sensation is often individual but thelarger the area treated, the worse is the pain

(Grapengiesser et al. 2002). Men also seem tohave more pain. Sometimes blisters occur.

The pain mechanism is not fully understood.Pain control is often achieved by a fan or coldwater.Paoli et al. have used nerve blockswith good results(Paoli et al. 2008). MAL-PDT may be less painfulthan ALA-PDT (Wiegell and Wulf 2006).

Long-term side effects have not been observedso far, but a certain carcinogenic effect cannot beexcluded although there is no convincing evi-dence (Ibbotson 2011).

Other Photosensitizers Than ALA

Other derivatives than ALA are also used. Arecent study demonstrated a good effect ofchlorophyll-a as the photosensitizer (Song et al.2014). Also, side effects were minimal. Absorp-tion peaks for chlorophyll are 430 and 662 nm.Hence, in this study blue and red light were usedto match the absorption peaks of chlorophyll.Even sebum production decreased. Incubationtime is significantly shorter with chlorophyll com-pared to ALA and MAL.

Indole-3-acetic acid (IAA) using green lighthas also been used, and the effect is good andthe procedure relatively painless. Twenty-fivepatients were enrolled in the study. IAA was left15 min under occlusion and green light was givenfor 15 min. Sebum excretion was also reduced(Jang et al. 2011).

Fig. 1 (a) Before PDT. (b) Four weeks after two sessions of PDT

346 A.-M. Wennberg Larkö

Also, indocyanine green has been used withfavorable results (Jang et al. 2011). Thirty-fourpatients were engaged. Half of the face was treatedwith indocyanine green with 805 nm radiation andthe other half with indole-3-acetic acid and greenlight (520 nm). Few side effects occurred.

Place in Therapy

Acne may be treated in several ways. For mild tomoderate acne, topical preparations may suffice.For more severe acne, antibiotics are often advo-cated. Unfortunately, bacterial resistance hasbecome a major problem as well as environmentalissues.

Hence, there is a need for treatment alternativesto antibiotics. PDT may be such an alternative.Most data are collected concerning ALA-PDTandMAL-PDT but new photosensitizers seem toemerge as an alternative. More studies are neededto elucidate proper dosage regimens and properlight delivery. PDT may well be used more fre-quently for acne in the future.

Take Home Messages

• P. acnes itself produces small amounts of por-phyrins. Irradiation with blue or red light leadsto excitation of the endogenously producedporphyrins and formation of singlet oxygen,resulting in bacterial death.

• PDT promotes focused damage of sebaceousglands, decreasing sebum excretion.

• Red light has a better tissue penetration than bluelight or UV. Red light has been suggested to haveanti-inflammatory properties on acne as well.

• Blue light seems to be the most effective wave-length in photoactivating P. acnes. It seemsthat blue light alone may be beneficial againstacne. Red and blue light might also becombined.

• Photodynamic therapy seems to be effectiveagainst moderate acne and may prove to bean alternative to oral antibiotics in the treat-ment of acne.

References

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Cunliffe WJ. Acne and unemployment. Br J Dermatol.1986;115(3):386.

Das S, Reynolds RV. Recent advances in acne pathogene-sis: implications for therapy. Am J Clin Dermatol.2014;15(6):479–88.

Divaris DX, Kennedy JC, Pottier RH. Phototoxic damageto sebaceous glands and hair follicles of mice aftersystemic administration of 5-aminolevulinic acid cor-relates with localized protoporphyrin IX fluorescence.Am J Pathol. 1990;136(4):891–7.

Dong Y et al. A new LED device used for photodynamictherapy in treatment of moderate to severe acnevulgaris. Photodiagnosis Photodyn Ther. 2016;13:188–95. doi: 10.1016/j.pdpdt.2015.06.007. Epub2015 Jun 23.

Dougherty TJ, et al. Photoradiation therapy for the treat-ment of malignant tumors. Cancer Res. 1978;38(8):2628–35.

Ericson MB, et al. Fluorescence contrast and thresholdlimit: implications for photodynamic diagnosis ofbasal cell carcinoma. J Photochem PhotobiolB. 2003;69(2):121–7.

Grapengiesser S, et al. Pain caused by photodynamic ther-apy of skin cancer. Clin Exp Dermatol. 2002;27(6):493–7.

Guffey JS, Wilborn J. In vitro bactericidal effects of405-nm and 470-nm blue light. Photomed Laser Surg.2006;24(6):684–8.

Haedersdal M, Togsverd-Bo K, Wulf HC. Evidence-basedreview of lasers, light sources and photodynamic ther-apy in the treatment of acne vulgaris. J Eur AcadDermatol Venereol. 2008;22(3):267–78.

Hong JS, et al. Acne treatment by methyl aminolevulinatephotodynamic therapy with red light vs. intense pulsedlight. Int J Dermatol. 2013;52(5):614–9.

Hongcharu W, et al. Topical ALA-photodynamic therapyfor the treatment of acne vulgaris. J Invest Dermatol.2000;115(2):183–92.

Horfelt C, et al. Photodynamic therapy for acne vulgaris: apilot study of the dose-response and mechanism ofaction. Acta Derm Venereol. 2007;87(4):325–9.

Horfelt C, et al. Single low-dose red light is as efficaciousas methyl-aminolevulinate – photodynamic therapy fortreatment of acne: clinical assessment and fluorescencemonitoring. Acta Derm Venereol. 2009;89(4):372–8.

Ibbotson SH. Adverse effects of topical photodynamictherapy. Photodermatol Photoimmunol Photomed.2011;27(3):116–30.

Jang MS, et al. A comparative split-face study of photody-namic therapy with indocyanine green and indole-3-acetic acid for the treatment of acne vulgaris. Br JDermatol. 2011;165(5):1095–100.

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Jeong E, et al. Topical ALA-photodynamic therapy foracne can induce apoptosis of sebocytes and down-regulate their TLR-2 and TLR-4 expression. AnnDermatol. 2011;23(1):23–32.

Kosaka S, et al. Targeting of sebaceous glands by delta-aminolevulinic acid-based photodynamic therapy: anin vivo study. Lasers Surg Med. 2011;43(5):376–81.

Li X, et al. Effects of 5-aminolevulinic acid-mediatedphotodynamic therapy on antibiotic-resistant staphylo-coccal biofilm: an in vitro study. J Surg Res. 2013;184(2):1013–21.

Linkner RV, et al. Evaluating the efficacy of photodynamictherapy with 20% aminolevulinic acid and microder-mabrasion as a combination treatment regimen for acnescarring: a split-face, randomized, double-blind pilotstudy. J Clin Aesth Dermatol. 2014;7(5):32–5.

Liu LH, et al. Randomized trial of three phototherapymethods for the treatment of acne vulgaris in Chinesepatients. Photodermatol Photoimmunol Photomed.2014;30(5):246–53.

Mei X, Shi W, Piao Y. Effectiveness of photodynamictherapy with topical 5-aminolevulinic acid and intensepulsed light in Chinese acne vulgaris patients.Photodermatol Photoimmunol Photomed. 2013;29(2):90–6.

Morton CA, et al. An open study to determine the efficacyof blue light in the treatment of mild to moderate acne. JDermatolog Treat. 2005;16(4):219–23.

Na JI, Suh DH. Red light phototherapy alone is effectivefor acne vulgaris: randomized, single-blinded clinicaltrial. Dermatol Surg. 2007;33(10):1228–33. discussion1233.

Neittaanmaki-Perttu N, et al. Daylight photodynamic ther-apy for actinic keratoses: a randomized double-blindednonsponsored prospective study comparing5-aminolaevulinic acid nanoemulsion (BF-200) withmethyl-5-aminolaevulinate. Br J Dermatol. 2014;171(5):1172–80.

Paoli J, et al. Nerve blocks provide effective pain reliefduring topical photodynamic therapy for extensivefacial actinic keratoses. Clin Exp Dermatol. 2008;33(5):559–64.

Papageorgiou P, Katsambas A, Chu A. Phototherapy withblue (415 nm) and red (660 nm) light in the treatment ofacne vulgaris. Br J Dermatol. 2000;142(5):973–8.

Peng Q, et al. Distribution and photosensitizing efficiencyof porphyrins induced by application of exogenous5-aminolevulinic acid in mice bearing mammary carci-noma. Int J Cancer. 1992;52(3):433–43.

Pinto C, et al. Efficacy of red light alone and methyl-aminolaevulinate-photodynamic therapy for the treat-ment of mild and moderate facial acne. Indian JDermatol Venereol Leprol. 2013;79(1):77–82.

Pollock B, et al. Topical aminolaevulinic acid-photodynamic therapy for the treatment of acnevulgaris: a study of clinical efficacy and mechanismof action. Br J Dermatol. 2004;151(3):616–22.

Romiti R, et al. High-performance liquid chromatographyanalysis of porphyrins in Propionibacterium acnes.Arch Dermatol Res. 2000;292(6):320–2.

Sadick N. A study to determine the effect of combinationblue (415 nm) and near-infrared (830 nm) light-emitting diode (LED) therapy for moderate acnevulgaris. J Cosmet Laser Ther. 2009;11(2):125–8.

Sandberg C, et al. Bioavailability of aminolaevulinic acidand methylaminolaevulinate in basal cell carcinomas: aperfusion study using microdialysis in vivo. Br JDermatol. 2008;159(5):1170–6.

Sigurdsson V, Knulst AC, vanWeelden H. Phototherapy ofacne vulgaris with visible light. Dermatology.1997;194(3):256–60.

Song BH, et al. Photodynamic therapy using chlorophyll-ain the treatment of acne vulgaris: a randomized, single-blind, split-face study. J Am Acad Dermatol. 2014;71(4):764–71.

Thiboutot D. Dermatologists do not yet fully understandthe clinical significance of antibiotic use and bacterialresistance in patients with acne: comment on “Antibi-otics, acne, and Staphylococcus aureus colonization.Arch Dermatol. 2011;147(8):921–2.

Wiegell SR, Wulf HC. Photodynamic therapy of acnevulgaris using 5-aminolevulinic acid versus methylaminolevulinate. J Am Acad Dermatol. 2006;54(4):647–51.

Yin R, et al. Combination ALA-PDT and ablative frac-tional Er:YAG laser (2,940 nm) on the treatment ofsevere acne. Lasers Surg Med. 2014;46(3):165–72.

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348 A.-M. Wennberg Larkö

New Substances and EquipmentDeveloped in Brazil: PhotodynamicTherapy

Cristina Kurachi, Kleber Thiago de Oliveira, andVanderlei Salvador Bagnato

AbstractPhotodynamic therapy (PDT) is an attractivetechnique to treat cutaneous lesions, especiallybasal cell carcinoma (BCC). The developmentof topical photosensitization PDT was a greatadvance to enhance its clinical dissemination,even though there is still limitation for a wide-spread use, especially in emerging economycountries, due to a high cost of the availabledrugs. In Brazil, as in worldwide, the maincancer type is BCC, and the present publichealthcare services fail to provide an efficienttreatment. Surgical resection is the electedtreatment, and the available surgical facilitiesare not sufficient, resulting in long waiting list.For patients living far from themedical centers,the waiting between diagnosis and treatmentcan be of several months, besides long distancetravels. Our strategy to overcome this realityand assist to promote the establishment of PDTcenters in the Brazilian territory is to bringtogether the scientific expertise developed inacademia and the technology sector. The Bra-zilian program is funded by the Brazilian

Development Bank (BNDES), coordinated bythe University of São Paulo, and has the part-nership with MMOptics and PDT Pharmacompanies. We present our strategies, the Bra-zilian PDT device and compounds, and thepartial results of this multicenter clinical trial.

KeywordsPhotodynamic therapy • ALA • MAL • Basalcell carcinoma • Brazilian technology

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349

Brazilian Program and Strategies . . . . . . . . . . . . . . . . . 351

ALA and MAL Production . . . . . . . . . . . . . . . . . . . . . . . . 351

PDT Device Development . . . . . . . . . . . . . . . . . . . . . . . . . . 354

Overall Partial Results of the MulticenterStudy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355

Non-oncological Protocols . . . . . . . . . . . . . . . . . . . . . . . . . 356

Final Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 356

Take Home Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 356

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357

Introduction

Photodynamic therapy (PDT) has been presentedas an attractive therapeutic technique for basal cellcarcinoma and potentially malignant cutaneousdisorders (Lehmann 2007; Morton et al. 2008;Soini et al. 2015; Zouboulis et al. 2015).

C. Kurachi (*) • V.S. BagnatoSão Carlos Institute of Physics, University of São Paulo,São Paulo, SP, Brazile-mail: cristina@ifsc.usp.br; vander@ifsc.usp.br

K.T. de OliveiraDepartment of Chemistry, Federal University of SaoCarlos, São Carlos, SP, Brazile-mail: kleber.oliveira@ufscar.br

# Springer International Publishing AG 2018M.C.A. Issa, B. Tamura (eds.), Lasers, Lights and Other Technologies, Clinical Approaches and Procedures inCosmetic Dermatology 3, https://doi.org/10.1007/978-3-319-16799-2_26

349

Dermatology is the medical area with the majorPDT indications including local treatment ofinfected and inflammatory lesions, acne vulgaris,benign lesions, and facial resurfacing (Ma et al.2015; Sakamoto et al. 2012; Issa et al. 2010; Huet al. 2015; Monfrecola et al. 2004), especiallydue to its selective effect and cosmetic results. Themain PDT protocols in dermatology use the topi-cal application of 5-aminolevulinic acid hydro-chloride (ALA) or their ester derivatives such asmethyl 5-aminolevulinate hydrochloride (MAL)or prodrugs that improve the production of theendogenous photosensitizer protoporphyrin IX(PpIX), resulting in a superficial therapeuticresponse, without the overall skin photosensitivityside effect of the systemic administration.

Following the worldwide trend, Brazil alsopresents the nonmelanoma skin cancer as themost common cancer type. According to the Bra-zilian National Cancer Institute (INCA), around182,130 new nonmelanoma skin cancer caseswould be diagnosed in 2014. Brazil is the biggestcountry in South America, considering its conti-nental area and population that is presently ofaround 206 million people. Any health policy inBrazil for a widespread and efficient diagnosisand treatment procedures is complex, especiallyfor those pathologies that require higher-complexity facility and specialized personnel.The number of hospital beds for each 1,000 peo-ple was of 2.26, being the rate of public beds ofonly 0.8 in the last publication of 2012 (Resourcesindicatives, Brazilian Ministry of Health). Duringthe years between 2005 and 2012, the Brazilianpublic health system cut approximately 42,000 ofhospital beds, and until 2014, additional 7,000beds were lost.

This situation goes in the wrong direction if itis considered the increasing population and alsothe increasing needs for health care. Consideringthe current numbers of new cases of nonmela-noma skin cancer and the available beds, if allpatients require the hospitalization for the surgicalremoval of the lesions, the waiting list for thetreatment procedure will never close. As a conse-quence of this reality, a late diagnosis and longwaiting period for cancer treatment are observed.In some regions, this waiting can be of years.

Photodynamic therapy can constitute the firsttreatment option for non-infiltrative basal cell car-cinoma (BCC) lesions. For this, early diagnosis isessential, as well as a small interval between diag-nosis and treatment. Topical ALA/MAL-PDT hasbeen already approved for BCC in several coun-tries, including Brazil, and constitutes a highlyattractive therapy for public health policies espe-cially because it is an ambulatory procedure and,compared to the surgical resection, with reducedcosts. Those are relevant features when consider-ing public health. Metvix™ (Galderma, Switzer-land) is approved by the Brazilian HealthSurveillance Agency (ANVISA) as a PDT drug.A widespread use of MAL-PDT in Brazil is stillprevented by the involved costs, being mainlypresent in private practice.

Our group in Brazil began to work with PDTin 1999, combining experimental studies, instru-mentation, and clinical research. Since then, sev-eral protocols and devices have been tested incell culture, animal models, and clinical trials forcancer, premalignant lesions, and infectious dis-eases (Melo et al. 2004; Bagnato et al. 2005;Souza et al. 2005, 2007, 2009a, b; Ferreira et al.2006, 2007; Inada et al. 2012; Takahama et al.2013; Silva et al. 2013; Andrade et al. 2014).Based on our experience and achieved results,we believe that topical PDT for BCC may con-tribute to decrease the waiting time for skin can-cer treatment, improve patient satisfaction, andreduce treatment costs. Another factor that mustbe pointed out is that great majority of thepatients has to travel long distances to get cancertreatment, in some cases even thousands ofkm. Bringing the skin cancer treatment to lowclinical settings reduces the costs of medical careand of patient transportation and decreases thelong waiting times.

The only feasible way to achieve a wide anddiffuse PDT application in the Brazilian territoryis to reduce the costs and improve the educationand training of the medical teams on the photody-namic concepts, especially on indications andclinical protocol.

Based on these aspects, a Brazilian program forPDT of superficial BCC was established. For this,we have adopted a model combining public and

350 C. Kurachi et al.

private sector interests using the needs as theopportunity for study, technological development,and commercial activity.

Brazilian Program and Strategies

The Brazilian program for PDT of superficialBCC has been financed by the Brazilian Develop-ment Bank (BNDES) and started on 2011. Thisprogram is coordinated by São Carlos Institute ofPhysics, University of São Paulo, and has the twoBrazilian partner private companies; one isMMOptics responsible for the device, and theother is PDT Pharma that produces the ALA andMAL compounds.

The main aims of this multicenter clinical trialwere (1) evaluation of the PDT response using theBrazilian device and drugs, (2) establishment ofPDT centers in different regions, and (3) dissemi-nation of PDT for medical doctors. Within thesethree main aims, other specific objectives wereset, as to compare the feasibility and the tumorcontrol efficacy of the PDT between an experi-enced and non-experienced center and to evaluatethe PDT response depending on tumor site andskin phototypes, among others.

Our strategy for a higher success potential wasto set a multidisciplinary team involving differentexpertise and experience necessary for the projectexecution: medical doctors, physicists, chemists,pharmacists, nurses, and engineers. Since thebeginning, the collaboration with the AmaralCarvalho Cancer Hospital was essential for theclinical trial. Dr. Ana Gabriela Salvio, dermatolo-gist, is the responsible medical doctor for theproject, and the multicenter trial is approved bythe Brazilian Ethics Committee on HumanResearch (CONEP, Comissão Nacional de Éticaem Pesquisa) and institutional local InternalReview Boards.

Presently 70 PDT units were installed in20 Brazilian federal states, 9 centers in LatinAmerica, and 1 in Europe (Scotland). The estab-lishment of each PDT unit included the training ofthe local team on the clinical protocol and thedevice use. Basic concepts on PDT mechanisms,light-tissue interactions, andALA-protoporphyrin

biosynthetic metabolism are discussed. The clini-cal protocol, indications, potential side effects andrisks, and PDT equipment hands-on practice arealso addressed during the training. The treatmentof two patients with non-infiltrative BCC lesionsis performed, so the medical team can observe anddiscuss all the procedure steps together with thespecialized personnel of our group. The training isfinished with the discussion of any questions leftor other comments, and the local team receivessupport educational materials containing thehandout of the clinical protocol. An open commu-nication is stimulated to a frequent discussion onpatient indication and follow-up. A 3-monthreport is asked to be sent to the principalinvestigator.

In this Brazilian program for the multicenterclinical trial, only BCC lesions up to 20 mm indiameter and 2 mm in depth are included, andthe resumed MAL-PDT protocol is presentedat Fig. 1. It is interesting to note that theestablished protocol uses a fluorescence-guidedtreatment, which has shown to allow an opti-mized result.

ALA and MAL Production

As mentioned before, 5-aminolevulinic acidhydrochloride (ALA) and their ester derivativessuch as methyl 5-aminolevulinate hydrochloride(MAL) have occupied a special position in PDTtreatments, not because they are photosensitizers,but because they are well-known direct biosyn-thetic precursors of protoporphyrin IX in cellswhich is the real photosensitizer with ALA deriv-atives. Basically, when ALA or their ester deriva-tives are used as topical cream formulations, aprotoporphyrin IX accumulation is observedafter 1–2 h, thus allowing the use of local PDTtreatments by red light (630 nm) (Kennedy et al.1990). The biosynthetic mechanism of productionand accumulation of protoporphyrin IX is cur-rently well established wherein the excess ofALA inside the cells can also promote an inhibi-tion of some steps for heme production, thusresulting in a protoporphyrin IX localized accu-mulation (Fig. 2) (Kennedy et al. 1990).

New Substances and Equipment Developed in Brazil: Photodynamic Therapy 351

This alternative method was introduced in theliterature in 1990 by Kennedy and coworkers(Kennedy et al. 1990), and an outstandingincrease in PDT indications has been developedsince this discovery. It is important to highlightthat this treatment allowed the possibility to per-form many local treatments with only localizedphotosensitivity instead of the overall skin andocular photosensitivity caused by systemicadministrations. Many scientists consider thelocal photosensitivity as one of the main advan-tages of this technique; however, the most impor-tant is the safety of the treatments. Systemic drugsmay cause side effects, since complex issues areinvolved. A number of protocols should be con-sidered before a new systemic drug is designatedas an approved medicine, in which not only theeffects of drug have to be studied but also theeffect of metabolites, the population variability,and many other factors.

Definitively, ALA-PDT has the potential to actagainst many bacterial, fungal, precancer lesions,BCC, condyloma by human papillomavirus virus(HPV), and cervical intraepithelial neoplasia, aswell as a fluorescent marker in cancer diagnosis(Tetard et al. 2014; Gold and Goldman 2004;Fotinos et al. 2006).

Another growing field for applications ofALA-PDT is the dermatology. In fact, PDT is

essentially a technique for causing cellular dam-age. Therefore, the use of ALA in dermatology iswell established since many inflammatory pro-cesses can be treated, thus selectively eliminatingthe abnormal cells and also killing pathogenmicroorganisms present in dermal infections.

Over the last 25 years, the ALA-PDT protocolshave definitively proven to be useful for manytreatments; therefore, the main question we haveis: Why is ALA-PDT not a routine treatment inhospitals and clinics?

This is a highly complex question to addresssince many factors are involved. Economically,ALA therapies may involve millions of US dol-lars, which correspond to a large market. On theother hand, for many years, big pharmaceuticalcompanies have systematically worked to developsystemic drugs and have spent millions of USD onresearch involving anticancer drugs (chemothera-peutical), and someone has to pay the bill. How-ever, it is most important to convince the edge ofthe pyramid (the doctors) that PDT treatmentspresent several advantages and can contribute toimprove health around the world. As the pharma-cist is directly responsible for promoting freemedicine into the pharmacy, for example, vita-mins and energy supplements, the doctors arealso pivotal for the diffusion and success ofPDT, and they should be the first ones convinced

Fig. 1 Schematic chart of the resumed clinical protocol investigated in the Brazilian program

352 C. Kurachi et al.

that PDT is in fact effective. However, once, againit is not an easy assignment and involves manyissues.

Fortunately, the diffusion of PDT treatmentshas grown around the word, and Brazil has figuredout very useful contributions in this field. A suc-cessful example is the work developed by Opticsand Photonics Research Center (CEPOF) locatedat the University of São Paulo in São Carlos Cityand also by two Brazilian associated companies,namely, PDT Pharma and MMOptics. TheMMOptics started many years ago manufacturingoptical devices, and PDT Pharma is the youngestinitiative in Latin America working with the

synthesis of photosensitizers and photomedicines(Fig. 3). Both companies are currently committedto establish protocols and commercial solutionsinvolving mutually the photomedicine cream andthe light device.

One of themain challenges for both companies isto turn this technology attractive considering PDTcosts, and it has meant a number of investment andwork. The PDT Pharma was born as a spin-offcompany due to the need of a provider whichcould allow the offering of ALA and their deriva-tives with a feasible price and considering the LatinAmerica economical reality. The first challenge wasto establish a facility to synthesize ALA and their

O

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Mitochondria

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ALA-dehydrataseALA

NH

H2N

HO O OHO

4 x

PBG deaminase

HNNH

NH HN

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4 NH3

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inhibition

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Fig. 2 Biosynthesis of heme group

New Substances and Equipment Developed in Brazil: Photodynamic Therapy 353

derivatives fulfilling all the pharmaceutical require-ments, from the active pharmaceutical ingredient(API) production until the formulation of a newcream, both respecting all the patent issues and theinternational protected marked. Since then, almost7 years were spent, and according to informationfrom the PDT Pharma company, in the beginning of2017, a full solution will be technically available forthe market.

The PDT Pharma example is very useful toillustrate the discussion established before wherewe mentioned the difficulty to make the PDT treat-ments more popular and accessible for the peopledue to the bureaucracy and also economical barriers.Obviously, as scientists we also completely under-stand all the market issues and the business marketsize which some systemic drugs can mean, and theobjectives of the PDT team/companies are by far tofight against it. In this case it is important to mentionthat both companies are devoted to make the PDTcloser to the people that need health assistance, thusallowing alternative solutions especially for publichealth consumers.

PDT Device Development

To the best of our knowledge, the LINCE(MMOptics, São Carlos, Brazil) was the first com-mercial system available for PDTwith a widefield

fluorescence visor and illumination probe com-bined in the same device (Fig. 4). The develop-ment of this device was performed by our group atthe University of São Paulo and MMOpticsfinanced by the Brazilian Funding Authority forStudies and Projects (FINEP, Financiadora deEstudos e Projetos), a government federal organi-zation of the Ministry of Science, Technology andInnovation.

The main technical characteristics of the PDTsystem are presented at Table 1. LINCE is a por-table device that has two probes, one for fluores-cence visualization and another for the PDTillumination. Both probes have LED-based lightsources, and optical components to provide a uni-form illumination area. The system contains aphotodetector in the front panel for the irradiancechecking and an electronic visor and push bot-toms for the irradiance and illumination timeselection.

One of the main limitations of the use of ALAor MAL as a topical prodrug is the variability ofproduction of protoporphyrin IX (PpIX) as aresult of the surface and metabolic differences ofthe tumor lesions. As a consequence, the resultedPpIX production may be highly heterogenous,resulting in an overall ineffective PDT response.There is no way to predict the adequate PpIXconcentration and distribution within the tumor,but the monitoring of the tissue fluorescence can

Fig. 3 One of thelaboratories of PDTPharma – with thepermission of the company

354 C. Kurachi et al.

be used to indirectly detect the presence of thePpIX. The skin autofluorescence shows a higheremission at the green spectrum, the cancer lesionshows a decreased autofluorescence, and the PpIXemits a red fluorescence. The possibility to qual-itatively assess the production of PpIX is a greatadvantage for the medical doctor to evaluate if thisPDTstep has been adequately taken place. If thereis no PpIX production after the cream incubationtime or if it is heterogenous, the resulted photody-namic response will be poor. In this case, themedical doctor should reevaluate the lesion prep-aration or even the further illumination.

Another relevant clinical information that canbe obtained using the widefield fluorescenceimaging is the analysis of the resulted photo-bleaching after the completion of the illuminationexposure (Fig. 1, steps 6 and 8). This is a qualita-tive evaluation of the induced photodynamic

reaction since there is a direct correlation betweenthe PpIX photobleaching and the production ofthe singlet oxygen. The PpIX photobleaching canbe assessed by the decreased red fluorescencewhen compared to the before illumination redemission.

Overall Partial Resultsof the Multicenter Study

From the beginning of the PDTapplications in thispresent multicenter clinical trial in March 2011until June 2015, around 4,000 BCC lesions weretreated using the proposed protocol. This databaseis constantly updated with the partial reports fromthe PDT units. Partial results have been alreadypublished (Ramirez et al. 2014; Blanco et al.2015; Buzzá et al. 2016), but the main results

Table 1 Main specifications and technical features of LINCE (2011)

Equipment

Input voltage 100–240 V/50–60 Hz

Electric classification (EN 60601-1) Class II, type B

Operating mode: treatment probe Continuous

Operating mode: evidencer probe (fluorescence) Intermittent (on, 15 min) or (off, 2 h)

Treatment LED spot diameter (20 � 2) mm

Fluorescence LED spot diameter (20 � 2) mm

Treatment LED wavelength (630 � 10) nm

Fluorescence LED wavelength (400 � 10) nm

Treatment LED irradiance levels 50, 75, 125, and 150 mW/cm2 � 20%

Fluorescence LED irradiance Maximum at 40 mW/cm2 � 20%

Protection goggles 1 (evidencer), 2 (treatment)

Fig. 4 LINCE PDTdevice. The portable dualsystem combines the use ofa widefield fluorescencevisor and the illuminationtreatment probe

New Substances and Equipment Developed in Brazil: Photodynamic Therapy 355

evaluated until now demonstrate that the investi-gated MAL-PDT protocol is effective for over85% of the treated lesions (complete tumorresponse in a punch biopsy at 30 days after treat-ment). One important feature was observed whenconsidering the complete response rate; when thePDT was performed by an experienced dermatol-ogist, the rates could reach 95%, but for the onesthat had no previous experience, the achievedrates were lower. Our hypothesis, based on theanalysis of the treated cases, is that the experi-enced doctors are more restricted on theMAL-PDT indication, since they already knowwhich lesions will respond better. This fact pointsout the relevance on the training as well as on acloser follow-up of the medical team, especially todiscuss the lesion selection.

There was only one report of an unexpectedside effect where one patient with a lesion at thenose showed a moderate/severe inflammatorycondition after the first PDT session, which wascontrolled with a topical corticosteroid cream, butprevented the second session at the seventh day.

On the PDT center at the Amaral Carvalho Hos-pital, a double-bind study comparing the treatmentefficacy of ALA-PDT, MAL-PDT, and surgery hasbeen performed in 600 patients. The clinical stepswere completed; the results are under analysis andwill be presented in a scientific paper.

Non-oncological Protocols

In order to evaluate the efficacy of the photo-diagnosis and PDT for the treatment of potentiallymalignant lesions, but also to develop protocolsfor local microorganism inactivation in infectedlesions, other research and instrumentation devel-opment was also performed. Examples of targetedpotentially malignant lesions are condylomaacuminatum by human papillomavirus (HPV) inwomen (Inada et al. 2012) and actinic cheilitis(Takahama et al. 2013), and ongoing clinical trialsare for cervical intraepithelial neoplasia (CIN),actinic keratosis, and field cancerization.

Considering photodynamic therapy for infec-tious diseases, our group and collaborators have

been investigating and determining protocols foronychomycosis (Silva et al. 2013), denture stoma-titis (Mima et al. 2011), pythiosis (Pires et al.2012, 2014), pharyngitis, and infected cutaneousulcers.

Final Considerations

Photodynamic therapy has been showing effec-tive results for the local treatment of cancer andinfected lesions. Even though, PDT presents sev-eral advantages when compared to surgical resec-tion for the treatment of superficial BCC, itswidespread use has been prevented due to limita-tions mainly considering the involved costs of theillumination equipment and photomedicine com-pound. In Brazil, through a national programfunded by BNDES (Brazilian DevelopmentBank), scientists, clinicians, and technologicalcompanies could work together to establish amulticenter clinical study. The achieved resultsshowed that the PDT protocols have similarresponse when compared to literature presentedwith foreign drug and devices. Analyzing theresults and comparing the established centers, itwas possible to infer the relevance of the trainingof the medical team, as well as a closer monitoringof the non-experienced teams. The proper indica-tion of the MAL-PDT was the main factor con-tributing to the higher complete response rates,which was mostly observed at the centers withindicated previous experience with PDT. Thisprogram resulted in the implementation of70 PDT centers, including the ones in low settingclinical facilities.

Take Home Messages

– The Brazilian program to implement PDT cen-ters, using national technology, is presented.

– A clinical MAL-PDT protocol was tested in70 centers for the treatment of superficial BCC.

– The illumination device has a dual platform, awidefield fluorescence visor and an illumina-tion probe, both LED-based light sources.

356 C. Kurachi et al.

– Tumor complete response was of 90% in expe-rienced teams and around 65% for the teamswithout any previous experience on PDT. Theuncorrected indication of some lesions was themain factor attributed to this lower response.

Acknowledgments The authors greatly acknowledge thefinancial support provided by BNDES and FINEP; thepartnership with MMOptics and PDT Pharma; the institu-tional support of the University of São Paulo, FederalUniversity of São Carlos, and Amaral Carvalho Hospital;and our Brazilian team of researchers and graduate studentsthat were intensively committed to make this program real:Ana Gabriela Salvio, Natalia Mayumi Inada, Lilian TanMoriyama, José Dirceu Vollet-Filho, Clovis Grecco, DoraPatricia Ramirez, Kate Cristina Blanco, Hilde Harb Buzzá,Cintia Teles Andrade, Layla Pires, Ana Paula Silva, MirianStringasci, Daniel Bonini, Ana Elisa Serafim Jorge,Mariana Torres Carvalho, and Sebastião Pratavieira. Spe-cial thanks also for the technicians of the partner compa-nies, Luiz Antonio de Oliveira, Anderson Zanchin, andRodrigo Costa e Silva.

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Part III

Ablative and Non-ablativeRadiofrequency

Non-ablative Radiofrequencyfor Facial Rejuvenation

Célia Luiza Petersen Vitello Kalil, Clarissa Prieto Herman Reinehr,and Celso Alberto Reis Esteves Jr.

AbstractOver the last decades, non- or minimally inva-sive skin rejuvenation techniques have showncontinuous and growing demand. Althoughsurgical procedures are the “gold standard”for facial and body skin sagging treatment,many patients choose procedures with lowerdowntime, even if it means more subtle results,because they don’t want to be away from theirwork and social activities. In order to fulfill thisneed, a range of non-ablative devices wasintroduced, such as lasers, devices using lightsources – as intense pulsed light (IPL) – andradiofrequency. This chapters discuss radio-frequency, an extremely valuable therapeuticfor rejuvenation, as it allows patients to keeprealizing their activities and also provides “nat-ural” results.

KeywordsRadiofrequency • Rejuvenation • Collagen •Skin aging •Non-ablative devices • Skin laxity

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362

Radiofrequency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362Types of Radiofrequency Delivery

(Monopolar/Multipolar (Bipolar and Tripolar)/Fractional) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363

Histopathological Changes . . . . . . . . . . . . . . . . . . . . . . . . . . 366Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367Other Indications: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367

Patient Selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367

Benefits of the Procedure (Pros and Cons) . . . . . . 368

Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368Monopolar RF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368Multipolar RF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368Fractional RF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368Contraindication to Radio in the Eyelid Region . . . . 368

Pre-procedure Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368

Application Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369

Expected Results, Number of Sessions, andSession Intervals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 370

Immediate Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 370Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371

Clinical Cases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371

Combined Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371

Take Home Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371

Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 372

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 372

C.L. Petersen Vitello Kalil (*)Department of Dermatology, Santa Casa de Misericórdiade Porto Alegre Hospital, Porto Alegre, Brazil

Brazilian Society of Dermatology, Porto Alegre, Brazile-mail: celia@celiakalil.com.br; clinica@celiakalil.com.br

C. Prieto Herman Reinehr • C.A.R. Esteves Jr.Brazilian Society of Dermatology, Porto Alegre, Brazile-mail: cla.reinehr@gmail.com; celsoj@ig.com.br

# Springer International Publishing AG 2018M.C.A. Issa, B. Tamura (eds.), Lasers, Lights and Other Technologies, Clinical Approaches and Procedures inCosmetic Dermatology 3, https://doi.org/10.1007/978-3-319-16799-2_27

361

Introduction

Over the last decades, non- or minimally invasiveskin rejuvenation techniques have shown contin-uous and growing demand (Mulholland 2011).Although surgical procedures are the “gold stan-dard” for facial and body skin sagging treatment,many patients choose procedures with lowerdowntime, even if it means more subtle results,because they don’t want to be away from theirwork and social activities (Mulholland 2011;Bogle and Dover 2009; Brightman et al. 2009;DeHoratius and Dover 2007; Afrooz et al. 2014;Elsaie 2009; Sadick et al. 2009). In order to fulfillthis need, a range of non-ablative devices wasintroduced, such as lasers, devices using lightsources – as intense pulsed light (IPL) – andradiofrequency (Mulholland 2011; Alexiades-Armenakas et al. 2008).

The use of radiofrequency as a treatment ofperiorbital rhytides and sagging was described in2003 by Fitzpatrick et al. with more than 80% ofthe treated patients showing improvement after amonopolar radiofrequency session (Fitzpatricket al. 2003).

Further studies have evaluated its use in thetreatment of sagging neck skin, improvement oflower third face contour, management of atrophicacne scars, and treatment of body laxity and cel-lulite (Brightman et al. 2009).

Radiofrequency

The devices used for laxity treatment work pro-ducing heat in enough amount to warm up thedermis (DeHoratius and Dover 2007; Hodgkinson2009). Beyond radiofrequency, ultrasonic wavesand infrared radiation devices also act throughdermal heating (DeHoratius and Dover 2007).

Radiofrequency is a form of electromagneticenergy in which electrons move in an electric fieldand change its polarity up to six million times persecond. The alternating electric current generatedfluctuates between 3 kHz and 300 MHz (Bogleand Dover 2009; Osório and Torezan 2009).When trying to move into the tissue, the resistance

to the rotational movement of electrons generateshigh-frequency oscillation in the water moleculesof the dermis (Goldberg et al. 2008). This energyoscillation is eventually transformed into thermalenergy (Ohm’s law) (Mulholland 2011;Hodgkinson 2009; Osório and Torezan 2009).The resistance to the passage of electrons dependson the tissue’s characteristics, such as its temper-ature and the concentration of water (Abrahamand Mashkevich 2007).

The formula that represents the total energyfollows:

Energy Jð Þ ¼ I2 � R� T

I = currentR = tissue impedanceT = time of application

The principle that guides the process is calledreverse thermal gradient: protective epidermalcooling occurs and dermal heating as well (Gold-berg 2004). The epidermal cooling is appliedbefore, during, and after the application of theradiofrequency handpiece (Goldberg 2004). Thisprotection of the epidermis results in lower risk ofinfection, scarring, and pigmentary changes whencompared to ablative procedures.

The heating of dermal collagen between 50 and70 �C (Celsius degrees) results in the rupture ofhydrogen bonds and in changes in the conforma-tion of collagen fibers, which lose their three-dimensional structure and assume an amorphousform, causing it to contract by 30% and thickeningthe fiber (immediate tissue retraction)(Hodgkinson 2009; Bogle et al. 2007). The colla-gen contraction is a time- and temperature-dependent process, every 5� of temperature reduc-tion, a 10 min increment is required to obtain thesame amount of retraction (the Arrhenius equa-tion) (Brightman et al. 2009). In monopolar radio-frequency, the dermis heating is expected to reacharound 65–75 �C, and the epidermis must bemaintained at a temperature below 40 � C. If der-mal heat produced is suboptimal, it will notimprove sagging and rhytides. In the event of an

362 C.L. Petersen Vitello Kalil et al.

excessive heat production, atrophy, scars, ero-sions, and skin discoloration may occur (Royode la Torre et al. 2011) (Fig. 1).

After that begins the subepidermal inflamma-tory reaction process resulting in neocollagenesisand a gradual improvement seen in 6–12 weeks(late effect) (Steiner and Addor 2014).

Moreover, the heat delivered to the deepertissues stimulates adipose tissue capillary bloodflow and accelerates lipid metabolism (Hodgkinson2009).

Types of Radiofrequency Delivery(Monopolar/Multipolar (Bipolarand Tripolar)/Fractional)

Monopolar RadiofrequencyFirst generation of radiofrequency. Volumetricheating (three dimensional) of the dermis andsubcutaneous occurs in a short period of time.Maximum depth reached is 20 mm, and it dependson the size and geometry of the handpiece (Steinerand Addor 2014). The type of handpiece used andthe amount of energy delivered through it are themain determinants of depth reached (Hodgkinson2009; Alster and Lupton 2007). Handpieces withlarger contact areas on the treated surface obtaindeepest dermal heating (Goldberg et al. 2008).

There is only one active electrode in contactwith the skin surface to be treated (dipole in thedevice handpiece) in this type of radiofrequency,and the current flows from this electrode toward aneutral or return electrode placed in a distantlocation, usually in the back (Hodgkinson 2009).Most of the heat is produced in the area locatedbelow the active electrode (Steiner and Addor2014) (Fig. 2).

Thermage CPT System (ThermaCool®)1. Radiofrequency generator: alternating current

(AC) 6.78 MHz, maximum flow 225 J/cm2,with a display through which current, energy,number of sections, duration of treatment, andimpedance can be monitored. At the displaythe energy can be selected according to the areato be treated (Hodgkinson 2009; Abraham andMashkevich 2007).

2. Pulsed cryogen within the treatmenthandpiece: cooling system before, during, andafter the application of radiofrequency (Gold-berg 2004).

3. Cable connected to disposable treatmenthandpiece containing treatment electrodeinside: single use, with duration limited bythe number of shots (200, 400, or 600) andtime (“one handpiece, one patient, one treat-ment”) (Hodgkinson 2009; Abraham andMashkevich 2007).

4. Microprocessor: located on the handpiecewhich controls pressure, current flow, andskin temperature in contact with the handpiece(Abraham and Mashkevich 2007).

There are 0.25 cm2 handpieces used to treatthe upper eyelid and fine wrinkles and 3.0 cm2

handpieces used to lower eyelid, periorbitalwrinkles, and bottom of the eyebrow region. Inaddition there is the DC handpiece body and aspecific body handpiece for cellulite treatment(Hodgkinson 2009).

A complete cycle of radiofrequency emissionsranges from 1.5 to 1.9 s (Steiner and Addor 2014).

The treatment is performed in the clinic with noneed of topical anesthetic since it is slightly painfuland also because heat intensity evaluation by the

Collagen triple helix molecule Collagen denatured fibers

HEAT

Fig. 1 Representation of the immediate effect of dermal heating on the collagen fibers

Non-ablative Radiofrequency for Facial Rejuvenation 363

patient is necessary to reduce the risk of possiblecomplications. The postoperative does not requirespecific care and one session gives good results(Steiner and Addor 2014) (Figs. 3, 4, and 5).

Multipolar Radiofrequency

BipolarIn this type of radiofrequency, there are two activeelectrodes in contact with the area to be treated,located at a fixed distance, and the current flows

only in the space between them (closed powercircuit) (Sadick 2007). This type of radio-frequency shows a more superficial dermalheating and reaches a maximum depthof 2–4 mm, and this maximum depth is half thedistance between electrodes. More sessions arenecessary to achieve similar results to thoseobtained with monopolar radiofrequency (Steinerand Addor 2014). Among the RF devices that usebipolar energy, we quote Aluma™/Lumenis®,Santa Clara, and Accent® and Accent XT®,Alma Lasers.

Fig. 2 Representation ofaffected depth of the tissueby monopolar and bipolarradiofrequencies,respectively

Fig. 3 Patient 1 –ThermaCool. One session –treatment for contouringand facial saggingimprovement (before andafter 8 months)

364 C.L. Petersen Vitello Kalil et al.

TripolarIt is the third generation of radiofrequency, whichhas three active electrodes that deliver energy andenhance the flow. Although smaller, the energyreleased is more concentrated when compared tothe mono- or bipolar radiofrequency (Steiner andAddor 2014). This technique allows homoge-neous heating of the dermis and hypodermis,reaching 20 mm deep with the use of lower

power, approximately 50 W (Steiner and Addor2014). An example of this technology is found inthe device Apollo TriPollar®, Pollogen LTDA.

Fractional RadiofrequencyFractional radiofrequency consists of minimallyinvasive technique of bipolar radiofrequencywherein the heat generated by an electromagneticcurrent results in cellular evaporation in the

Fig. 4 Patient 2 –ThermaCool. One sessionfor abdominal contourimprovement (before andafter)

Fig. 5 Patient 3 –ThermaCool. One session,0, 25 cm tip, eyelids andperiorbital treatment,improvement of the sideand upper eyelid sagging

Non-ablative Radiofrequency for Facial Rejuvenation 365

epidermis (Reddy and Hantash 2009). Electro-magnetic waves cause oscillations of the watermolecules and produce thermal energy in the der-mis. This controlled volumetric heating of thedermis will finally stimulate the neocollagenesis.The device comprises electrodes or microneedlesarranged in pairs. The technique combinesnon-ablative coagulative effect on dermis withareas of controlled ablation in less than 5% ofthe treated epidermis (Taub and Garretson 2011).This RF mode allows intermediate areas of treatedskin with untreated areas that function as a cellreservoir and accelerate the healing. Fractionalradiofrequency can be used in facial rejuvenationand treatment of acne scars (Steiner and Addor2014; Taub and Garretson 2011).

PlasmaNewest type of radiofrequency uses the state ofmatter called plasma. Plasma pulses are createdwhen very high radiofrequency energy passesthrough inert nitrogen and oxygen gas and gener-ates ionized gas. The handpiece directs this formedenergy to the treated surface. The operating princi-ple is the same as other types of radiofrequencywith dermal heating and stimulating neo-collagenesis (Rivera 2008; Spandau et al. 2014).

Histopathological Changes

According to what was reported by Zelickson et al.and Meshkinpour et al., denaturation of collagenfibers and mRNA expression of collagen I areobserved after the radiofrequency. The increase in

collagen III occurs at a higher intensity than that oftype I collagen, with a peak between the sixth andtenth weeks post procedure (Meshkinpour et al.2005; Zelickson et al. 2004). Javate et al. demon-strated an intact epidermis with increased thick-ness and amount of collagen fibers in thesuperficial and deep dermis post-radiofrequencynon-ablative biopsies (Javate et al. 2011).

In 2011, El-Domyati et al. observed that aftersix biweekly interval monopolar radiofrequencysessions, skin biopsies showed epidermal hyper-plasia that continued to increase 3 months after theend of the treatment, increase of granulosa layer,and increase in the epidermal organization degree.Besides that, the study showed elastosis reductionin the papillary dermis and increase in the amountof collagens I and III, 3 months after treatment thatwere statistically relevant (El-Domyati et al. 2011).

Study with non-ablative lasers (Pulsed DyeLaser and Nd:YAG) observed similar effects instimulating collagen production and in the eleva-tion of crucial enzymes for dermal proteinsremodeling of the extracellular matrix (MMPs)(Orringer et al. 2005).

Table with the main radiofrequency non-ablativedevices

Radiofrequency devices/manufacturer

Radiofrequency(RF) technology

Thermage™/Thermage Monopolar RF

Aluma™/Lumenis®, SantaClara

Bipolar RF and vacuum

Accent®, Accent®

XL/Alma LasersUnipolar and bipolar RF

Apollo TriPollar®/PollogenLTDA

Tripolar RF

Polaris ReFirme™/Syneron Bipolar RF and diodelaser

ReFirme™/SyneronMedical

Bipolar RF and opticalenergy

Reaction™/Viora Multipolar RF andvacuum

PowerShape™/EunsungGlobal Corp.

Multipolar/bipolar RFand vacuum

Apollo®/Pollogen LTDA Bipolar RF

Venus Freeze®/VenusConcept

Multipolar RF

Triniti E-max®/SyneronCandela

Bipolar RF + diode laser

Key features of the types of radiofrequency

Monopolar

Multipolar

Bipolar Tripolar

1 activeelectrode

2 active electrodes 3 activeselectrodes

Depth20 mm

Depth 2–4 mm Up to 20 mm

Deeper More superficial,multiple passages,greater number ofsessions

Deeper; energy ismore concentratedthan monopolarradiofrequency

366 C.L. Petersen Vitello Kalil et al.

Indications

As a result, in general, facial contour (jaw) andsagging are improved.

The technique can be used in the treatment ofmoderate submental shrinkage and sagging in theneck region.

The middle third of the face may also benefit,with attenuation of the nasolabial groove andreduction of sagging of the treated area (Sukaland Geronemus 2008).

Other Indications:

Treatment of body cellulite – associated with bipolarradiofrequency vacuum (VelaShape® – Syneron Candela )(Brightman et al. 2009)

Waist circumference reduction – bipolar radiofrequencyassociated with vacuum (VelaShape® – SyneronCandela) (FDA approved in 2007) (Brightman et al.2009)

Treatment of atrophic acne scars – all types ofradiofrequency may be used (monopolar, multipolar, andfractionated) (Taub and Garretson 2011; Rivera 2008)

Body treatment: laxity in the upper limbs, abdomen, andbuttocks (Hodgkinson 2009) (FDA approved inDecember 2005)

Treatment of active acne – report with Thermage®

(Dierickx 2004)

Radiofrequency in drug delivery (Subramony 2013;Gratieri et al. 2013)

The radiofrequency may be used as an adjunctin the treatment of gynoid lipodystrophy (Osório

and Torezan 2009; Site Thermage). Goldberget al. evaluated the efficacy of monopolar radio-frequency treatment of cellulite in the thigh in sixsessions with biweekly intervals in 30 patientsshowing a circumference reduction of the thighsand improvement in cellulite degree, with nochanges in lipid metabolism (Goldberg et al.2008).

Patient Selection

The ideal patient for radiofrequency facialrejuvenation should be between 30 and 60years old, presenting with mild to moderateskin sagging and facial rhytides, and shouldhave realistic treatment expectations (Abrahamand Mashkevich 2007; Goldberg 2004). Pa-tients who underwent face lift surgery who pre-sent recurrent mild laxity 2–3 years after theprocedure are, in general, good candidates forradiofrequency (Hodgkinson 2009; Abrahamand Mashkevich 2007).

Patients presenting sagging after weight lossand abdominal sagging after pregnancy also ben-efit for body radiofrequency.

The correct patient selection is a major deter-minant of the response level to treatment (Suhet al. 2013). Patients with advanced age, who areobese, and with marked sagging will present mildresults (Abraham and Mashkevich 2007). How-ever, explained the limitations, if the patient doesnot wish to be submitted to more invasive pro-cedures, radiofrequency is an interesting option(Goldberg 2004).

The correct selection of patients is a majordeterminant of the level of response to treatment(Suh et al. 2013). Patients with advanced age,obese, and with marked sagging will haveless satisfactory results (Abraham andMashkevich 2007). However, if the patientdoes not wish to be subjected to more invasiveprocedures and even after the limitations havebeen explained still wants to be subjected toradiofrequency, it is possible to do it (Goldberg2004).

Table with the main radiofrequency ablative devices

Radiofrequency devices/manufacturer

Radiofrequency(RF) technology

Scarlet RF™/Viol Co., LTDA Fractional bipolar RF

HF Fraxx®/Loktal Fractional RF withmicroneedles

Matrix RF®/Syneron Fractional bipolar RF

Renesis®/Primaeva Medical,Inc.

Fractional bipolar RF

ePrime®/Syneron Candela Fractional bipolar RF

Duet RF PowerShape®/Eunsung Global Corp

Fractional andthermal RF

Non-ablative Radiofrequency for Facial Rejuvenation 367

Benefits of the Procedure (Prosand Cons)

If we compare radiofrequency, a non-ablativetechnique, with ablative and surgical procedures,the procedure allows faster recovery and lowerrisk of complications. The results, however, aremore discrete (Goldberg 2004). Another benefitregards the possibility to realize the procedure inall skin types, since radiofrequency operatingmechanism differs from lasers and there is noabsorption or scattering by the tissue melanin(Abraham and Mashkevich 2007). Moreover, itcan be used on hairy areas without risks, becauseit does not damage the follicle.

Contraindications

Monopolar RF

Absolutes (Abraham and Mashkevich 2007)

Patients with cardiac pacemaker or defibrillator

Patients with other implantable electronic devices

Skin pathologies on the application area

Infection at the application site

Presence of permanent fillers in the area to be treated,especially polymethyl methacrylate (PMMA)

Relatives

Smoking

Autoimmune disease

Previous radiotherapy at the application site

Pregnancy

Chronic use of corticosteroids or nonsteroidalinflammatory

Other conditions that can impair healing

It is not recommended to use monopolar radio-frequency on areas with metal plates or on tattoos(Abraham and Mashkevich 2007).

Multipolar RF

Absolutes

Patients with cardiac pacemaker or defibrillator

Patients with other implantable electronic devices

(continued)

Skin pathologies on the application area

Infection at the application site

Presence of permanent fillers in the area to be treated,especially polymethyl methacrylate (PMMA)

Inelastic scars

The use of photosensitizing medication

Systemic neoplasm

Venous thrombosis in use of anticoagulants

Fractional RF

Absolutes

Patients with cardiac pacemaker or defibrillator

Patients with other implantable electronic devices

Skin pathologies on the application area

Infection at the application site

Presence of permanent fillers in the area to be treated,especially polymethyl methacrylate (PMMA)

Silicone prothesis in the area to be treated

Use of copper IUD (in the case of treatment in thelower abdomen)

Dental abscess if applied in the area of the face

Active rosacea

Contraindication to Radio in the EyelidRegion

Patients who underwent prior cornea surgery can’tbe submitted to radiofrequency in the eyelidregion because of the need to use intrapalpebralprotector that could injure the cornea (Steiner andAddor 2014).

Pre-procedure Care

The pre-procedure standardized photographsare essential. There are systems that allow,in addition to the standardization of photo-graphs, the examination of variations in pig-mentation and in epidermal thickness and thenumber and depth of rhytides, enabling theassessment of therapeutic response (Suh et al.2013).

368 C.L. Petersen Vitello Kalil et al.

Application Techniques

For monopolar and multipolar radiofrequency,the following precautions should always befollowed:

1. Fulfillment of consent form with the necessaryexplanations, expected results, and side effectsand possible complications. The term shouldbe applied by a dermatologist and all thepatient’s questions must be clarified. Makesure the patient does not have any of thecontraindications to the procedure.

2. Before the procedure, it is necessary to removeall metals that are in contact with the patient’sskin (jewelry, costume jewelry, watches).

3. Clean the area of the skin that the application ofradiofrequency will be held, remove makeupand perform antisepsis of the skin with isopro-pyl alcohol (Steiner and Addor 2014).

After, formonopolar radiofrequency, pro-ceed to the following steps:

4. Position the dispersive plate on the back of thepatient.

5. Apply the temporary marking grid, accompa-nying the individual handpiece, on the area tobe treated.

6. If the procedure is performed in the eyelid area,it is essential to use intrapalpebral protectorthat should be of plastic material to preventits heating. This measure seeks to protect theeye globe from heat, from the electric field, andfrom mechanical damage.

7. Apply generous amount of specific fluid tomonopolar radiofrequency, provided by theequipment company, over the area to be treatedto occur correct docking of the handpiece onthe skin. The handpiece should remaincompletely in contact with the skin at the timeof application (Steiner and Addor 2014).

After completing the steps above, treatment isstarted. The equipment automatically calculatesthe impedance of the patient (Hodgkinson 2009).The energy levels are adjusted as the treated areachanges according to the tolerance of the patient(Jacob and Kaminer 2008).

It is recommended that, when defining the areato be treated, the area adjacent to the one pre-senting sagging and loss of shape will also betreated so as to assist in support of dermal process(Jacob and Kaminer 2008).

Since its introduction, algorithms’ applicationhas been modified. Today are proposed treatmentprotocols with lower energy and greater numberof passages, as opposed to what was initiallydescribed (individual passages with high energy),with better results (Bogle et al. 2007).

Current techniques allow less discomfort to thepatient and more meaningful and homogeneousresults (Sukal and Geronemus 2008).

By making the procedure without requiringanesthesia there is the possibility tolerable ofinteraction with the patient during the procedureas to the degree of warming sense. This fact madeit possible to avoid overheating the epidermis andits complications (Sasaki et al. 2007).

During the execution of the procedure, thepatient will refer feeling warmth in the treated area.Ideal heat is the one reported by the patient as“warm” and it is not intolerable (Hodgkinson 2009).

There are three techniques described for theapplication of monopolar RF:

1. Two simple passages2. A scaled passage3. A superimposed passage: recommended use in

the Thermage CPT® device (Thermage, Inc.,Hayward, California)

In the technique described as two simple pas-sages, a row of passages is realized following thesquares marked by the temporary grid, and then asecond passage is performed on the marked cir-cles in a staggered grid manner, alternating rows(Abraham and Mashkevich 2007). Following thecompletion of two passages, we proceed to thevectors’ application, which consists of additionalpassages following the direction in which theelevation of the skin is desired (lifting effect)(Abraham and Mashkech 2007).

The technique with multiple passages (staking),maintaining the tissue heated, shows more efficientresults, since the heating of the dermis diminishes

Non-ablative Radiofrequency for Facial Rejuvenation 369

the tissue’s resistance to the electrical current pas-sage (Hodgkinson 2009). In the multiple passagetechnique, the energy required is reduced at eachsubsequent passage at the same location. Further-more, the technique allows freedom to the operator,who can perform higher number of passages in areasthat are more lax than in less affected areas (Jacoband Kaminer 2008).

The study of Dover et al. compared the singlepassage technique with the multiple one in 5,700patients. In the group undergoing single passage,54% of patients had improvement in skin laxityafter 6 months. On the other hand, in the multiplepassage group, improvement was observed in84% of patients, which also reported less painduring the procedure and greater satisfactionwith the results (Dover and Zelickson 2007).

The number of shots ranges from 400 to800 for facial treatment session and from 1,000to 1,200 on body section. On the face, manypractitioners choose to perform one side andthen the other. A session is performed in about1 h. One may proceed to treatment of the entiresurface or only a localized area, such as the man-dibular region and the forehead (Jacob andKaminer 2008). The expected effects of the ses-sion are erythema and immediate contraction ofthe treated surface, being able to also have localedema (Hodgkinson 2009).

The multipolar radiofrequency differs fromthe monopolar for not having marking grid anddispersive plate. Glycerin fluid is used on theapplication area of the skin, and there are specifichandpieces for each region (the face, lower eyelid,and body). It is important to use an external infra-red thermometer to monitor the temperature of theepidermis, which should not exceed 40 �C, toavoid burns (Steiner and Addor 2014).

Expected Results, Number of Sessions,and Session Intervals

The result can take up to 6 months to be noticed,since it is dependent of neocollagenesis and der-mal remodeling, starting on average between 2and 3 months (Abraham and Mashkevich 2007).

Some patients also referred improvement of skincolor and texture with smoothed scars (Abrahamand Mashkevich 2007). Moreover, the results arehighly variable, and even the application withsuitable technique, some patients with show betterresults than others. The photographic recordpre- and post-standardized procedure is essen-tial in the evaluation of these patients (Steinerand Addor 2014).

In monopolar radiofrequency with one session,the results are obtained depending on timedescribed above. In individual cases, two tothree sessions with 6–12-month intervals betweenthem are required.

In order to study the effect of subsequent sessionsof monopolar radiofrequency, the study of Suh et al.evaluated eight patients who underwent monopolarradiofrequency sessionswithThermageCPT®appa-ratus for facial rejuvenation over a period of 7 years.The patients had an average of four sessions, withintervals between them ranging 4–45 months. Dur-ing this period, there was no worsening in theassessment by the Glogau scale in eight patients,and seven patients reported satisfaction with treat-ment outcomes. Randomized studies with largernumbers of patients are needed to confirm the find-ings (Suh et al. 2013).

Regarding multipolar RF, a larger number ofsessions, most often five to six sessions every10–15 days, are required (Steiner and Addor 2014).

Therapeutic response is also dependent on thearea being treated. The middle and lower third ofthe face respond faster than the neck because theyhave higher amounts of subcutaneous fat (Bogleet al. 2007).

Immediate Effects

Soon after the procedure, local edema can beobserved, which is responsible for the “lifting”effect immediately observed. Mild erythema alsooccurs and remains for a few minutes after theprocedure and resolves spontaneously (AbrahamandMashkevich 2007). Erythema and mild swell-ing the endpoints are expected immediately afterthe procedure (Sadick 2007).

370 C.L. Petersen Vitello Kalil et al.

Adverse Effects

Edema May persist for up to1 weekAcneiform eruption

Linear surface crusts

Hypersensitivity of theneck

In general up to 2–3 weeksafter the procedure

Moderate erythema

Burns overlying skin Bad-quality technique,high energy application

Nodosities in the cervicalregion (Site Thermage)

Disappear in 1–2 weeks

Irregularities of jaw andtemporal contour(Hodgkinson 2009)

Monopolarradiofrequency, occur witholder equipment

Mild to moderate pain(Site Thermage)

During the procedure,disappears shortly after

Temporary paresthesia Perineural edema insensitive nerves,disappears in weeks(Abraham andMashkevich 2007)

According to the manufacturer ThermaCoolSystem® (Thermage, Inc., Hayward, Califor-nia), 99.8% of monopolar radiofrequencynon-ablative procedures performed show noadverse effects (Abraham and Mashkevich2007). Mild erythema and edema generally dis-appear in less than 24 h (Sukal and Geronemus2008).

The day after the procedure, the patient canresume the skin care, as well as treatments previ-ously used (Hodgkinson 2009).

Regarding the fractional RF, hypopigmentationcan occur if the fluence used is too high andalso postinflammatory hyperpigmentation in pre-disposed patients (Mulholland 2011).

Clinical Cases

Picture 3: Patient 1 – ThermaCool. One session– treatment for contouring and facial saggingimprovement ((before and after 8 months)

Picture 4: Patient 2 – ThermaCool. One sessionfor abdominal contour improvement (beforeand after)

Picture 5: Patient 3 – ThermaCool. One session,0, 25 cm tip, eyelids and periorbital treatment,improvement of the side and upper eyelid sagging

Combined Treatments

Supplementation with other treatments such asIPL, fillers, botulinum toxin, chemical peels, andmicrodermabrasion is beneficial and should beindividualized according to the needsof each patient (Abraham and Mashkevich 2007).

Some devices combine optical energy to elec-trical energy, in general the association of radio-frequency with laser (Laser Diode – Polaris WRsystem) or light source (LIP – Aurora®, SR, Syn-eron) and allow the treatment of vascular injuriesand pigmented hair removal and treatment ofrhytides’ addition and sagging (Lanigan 2008).The combination of the two types of energy hasa synergistic effect, allowing the use of lowerdoses of both, with less risk of adverse effects(Sadick 2007). In combined systems, in whichthe optimal energy used is lower than that usuallyrequired, there is the possibility of use in patientswith higher phototypes with less risk of adverseeffects (Alster and Lupton 2007).

We also found in the market devices for treat-ment of gynoid lipodystrophy linking bipolar RFvacuum and ultrasound (Syneron CandelaVelaShape®) (Brightman et al. 2009).

Take Home Messages

– Radiofrequency is extremely valuable in thetherapeutic arsenal for rejuvenation as it allowsthe patients to keep realizing their activitiesand also provides “natural” results.

FDA-approved uses for: Monopolar RF – ThermaCoolSystem (Thermage, Inc., Hayward, California): (Abra-ham and Mashkevich 2007)

Treatment of periorbital skin sagging (FDA approved2002)

Treatment of periorbital rhytides (FDA approved 2002)

Treatment of perioral rhytides (FDA approved 2002)

Treatment of facial rhytides (FDA approved 2004)

Treatment of generally rhytides (FDA approved 2005)

Non-ablative Radiofrequency for Facial Rejuvenation 371

– The correct knowledge of the technique andthe proper selection of patients are extremelyimportant to the treatment success, since it isdependent on these variants for the best results.

– Radiofrequency can be combined to othersrejuvenation techniques with synergisticeffects.

Cross-References

▶ Intense Pulsed Light for Photorejuvenation▶Non-ablative Lasers for Photorejuvenation

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Non-ablative Radiofrequency for Facial Rejuvenation 373

Non-ablative Radiofrequencyfor Cellulite (Gynoid Lipodystrophy)and Laxity

Bruna Souza Felix Bravo, Carolina Martinez Torrado, andMaria Claudia Almeida Issa

AbstractCellulite, also known as gynoid lipodystrophy,is a multifactor disorder of the dermis, epider-mis, and subcutaneous cellular tissue(Goldman et al. Pathophysiology of cellulite.New York: Taylor & Francis; 2006). In mostcases, this alteration occurs in postpubertalwomen with a prevalence of 80–90%(Goldman and Hexsel. Cellulite: pathophysiol-ogy and treatment. 2nd ed. Florida: EditorialInforma, Healthcare; 2010; Emanuele. ClinDermatol 31(6):725–30, 2013). Clinically, cel-lulite presents irregularity of the skin surfacewith depressions, lumps, and nodules associ-ated with laxity. Usually, cellulite is located inthe abdomen, buttocks, and lower limbs, but itcan also occur on the arms and the back. His-tologically, cellulite is caused by subcutaneousherniated fat within the fibrous connective tis-sue (Rossi and Vergnanini. JEADV 14:251–62, 2000; Khan et al. J Am AcadDermatol. 62(3):361–70, 2010; De Peña and

Hernández-Pérez. Rev Cent Dermatol Pascua3:132–5, 2005). An increase in the thickness ofthe subcutaneous cellular tissue is alsoobserved. Although cellulite is still consideredas an unclear etiological condition, there aremany hypotheses trying to explain this disorder.Treatments can be invasive and noninvasive.Invasive methods include subcision and meso-therapy, as well as liposuction when patientsalso want to remove excessive localized fat.Noninvasive treatments include topical treat-ments, controlled diets, cryolipolysis, focusedultrasound, endermology, laser, andnon-ablative radiofrequency. In this chapter weare going to discuss the treatment withnon-ablative radiofrequency. Radiofrequency(RF) contracts collagen and stimulates neo-collagenesis by thermal heat, promoting thick-ening of the dermis, avoiding fat herniation. Itcan also promote improvement in local circula-tion due to the vasodilatation and lymphaticdrainage. Clinically it improves the laxity andthe irregularity of the skin surface (Coringratoet al. Radiofrecuencia ablativa en dermatologíaquirúrgica: Una revisión, Rev. dermatologíaargentina, vol. XIV, Julio–Septiembre 2008,Número 3; Brightman et al. Lasers Surg Med41:791–8, 2009).

B.S.F. Bravo • C.M. TorradoInstituto de Dermatologia Prof. Rubem David Azulay –Santa Casa da Misericórdia do Rio de Janeiro, Rio deJaneiro, RJ, Brazile-mail: brunabravo@globo.com;carolinamartinezt@hotmail.com

M.C.A. Issa (*)Department of Clinical Medicine – Dermatology,Fluminense Federal University, Niterói, RJ, Brazile-mail: dr.mariaissa@gmail.com; maria@mariaissa.com.br

# Springer International Publishing AG 2018M.C.A. Issa, B. Tamura (eds.), Lasers, Lights and Other Technologies, Clinical Approaches and Procedures inCosmetic Dermatology 3, https://doi.org/10.1007/978-3-319-16799-2_28

375

KeywordsCellulite • Gynoid lipodystrophy • Noninva-sive radiofrequency • Neocollagenesis • Lax-ity • Fat herniation • Dermis thickness

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376

Cellulite (Gynoid Lipodystrophy) . . . . . . . . . . . . . . . . . 376Concept and History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376Clinical Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377Predisposed Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378Clinical Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378Cellulite Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380

Radiofrequency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380Radiofrequency Frequency . . . . . . . . . . . . . . . . . . . . . . . . . . 381Radiofrequency Waves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381Radiofrequency Power . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 382Penetration Depth and Radiofrequency Energy

Distribution Between Electrodes . . . . . . . . . . . . . . . . 382

Cellulite and Radiofrequency: ClinicalStudies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385

Take Home Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 386

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387

Introduction

The skin is the most external organ and itsappearance contributes to the patient’s personal-ity. Skin diseases and cosmetic problems signif-icantly affect the self-esteem. The psychologicaleffects of the cellulite (gynoid lipodystrophy) arefrequently more serious than the physical alter-ation observed in this dermatosis. It can affectinterpersonal relationships in a social, affective,and sexual way. It can affect normal daily activ-ities, such as going to the beach, practicingsports, or using certain type of clothing. In thelast years, the idea of having an ideal sculptingbody changed the concept of cellulite from acosmetic problem to a disease. Nowadays,women look for all types of treatments with thehope of reducing cellulite or making it disappear(Goldman and Hexsel 2010; Goldman et al.2006). Different mechanisms are involved incellulite’s pathogenesis, and many different

treatments are developed with aim to fightagainst each mechanism. There is no ideal treat-ment, but there are many therapeutic alternativesto reduce the physical appearance of this condi-tion. Recently, noninvasive devices such as non-ablative radiofrequency (RF) and the combina-tion of RF with other technologies have gainedstrength and have been very successful. The mostused RFs for cellulite are the unipolar, bipolar,and the combination of RF with infrared light,vacuum, and mechanical massage.

Cellulite (Gynoid Lipodystrophy)

Concept and History

Cellulite, also known as gynoid lipodystrophy,nodular liposclerosis, adiposis edematosa, dermo-paniculosis deformans, edematous fibroscleroticpanniculopathy, panniculosis, and cellulite hypo-dermosis, is a multifactor disorder of the dermis,epidermis, and subcutaneous cellular tissue(Goldman et al. 2006). In most cases, this alter-ation occurs in postpubertal women with a preva-lence of 80–90% (Goldman and Hexsel 2010).

Alquier and Paviot described cellulite for thefirst time in 1920 (Rossi and Vergnanini 2000).They described a non-inflammatory complex cel-lular dystrophy of the mesenchymal tissue causedby a water metabolism disorder, which producesthe saturation of the adjacent tissues by interstitialfluid (Rossi and Vergnanini 2000). In the samedecade, Laguese described cellulite as changes inthe subcutaneous tissue characterized by theincreased fatty tissue and interstitial edema(Goldman et al. 2006; Laguese 1929). In 1958,Merlem defined cellulite as an angiopathy, and in1978, Benazzy and Curri suggested the term “scle-rotic-fibrous-edematous panniculopathy” (Goldmanet al. 2006). In 1978 Nüremberg and Müller (1978)found differences in the structure of the skin andthe subcutaneous tissue of men and women thatwould partially explain the prevalence of cellulitein women (Nürnberger and Müller 1978). Cur-rently, the terms cellulite and gynoid lipodystrophyare the most used terms in medical literature.

376 B.S.F. Bravo et al.

Clinical Manifestations

Usually, cellulite is located in the abdomen,buttocks, and lower limbs, but it can also belocated on the arms and the back. Cellulite iscaused by subcutaneous herniated fat within thefibrous connective tissue, with a typical dimpledappearance (with alternated depressions withlumps) or orange skin appearance (due to swell-ing of the flat surfaces and dilation of the follic-ular openings) (Rossi and Vergnanini 2000;Khan et al. 2010; De Peña and Hernández-Pérez 2005). The majority of the injuries havean oval shape, where the axis of the injuries isparallel to the tension lines of the skin (Goldmanand Hexsel 2010). Cellulite is more evident withlaxity, therefore getting worse with aging. Dur-ing palpation, pinching the skin in a cellulitearea, we can feel an increasing in the thicknessof the subcutaneous cellular tissue and inits consistency and a decreasing in its mobilityby adhesion (De Peña and Hernández-Pérez2005).

In general, cellulite is an asymptomatic alter-ation; however, painful nodules can accompany itin the severe stages, suggesting an inflammation indermis and adipose subcutaneous underlying tissue(Goldman and Hexsel 2010; Emanuele 2013).

Cellulite is different from obesity; obesity ischaracterized by hypertrophy and hyperplasia ofthe adipose tissue that is not necessarily limited tothe abdomen or the lower limbs(Rossi andVergnanini 2000). The presence of celluliteshould not be confused with obesity, even thoughadipogenesis aggravates this condition (Emanuele2013).

Etiopathogenesis

The etiopathogenesis of cellulite has been widelydiscussed in the last decades. Although cellulite isstill considered as an unclear etiological condi-tion, there are many hypotheses with respect toits origin, such as vascular changes and edema,architectural difference of the skin related togender, inflammatory alterations, and hormonalvariations.

Vascular Changes and EdemaThe first document about the pathophysiology ofcellulite reported the increasing in the glycosami-noglycan amount in the dermis and extracellularmatrix and on the capillary dermal vessels of theskin in the cellulite area. This could explain theamount of water retained in the skin, attracted byglycosaminoglycans. Based on these findings,edema in cellulite was related to the changes inthe composition of the extracellular matrix(Emanuele 2013). Some degree of damage in theskin vasculature with an alteration in the pre-capillary arteriole sphincters was also reported.Other findings, such as the presence of new cap-illary formations, telangiectasia, microthrombi,and micro-hemorrhages, related cellulite to achronic venous insufficiency (Rossi andVergnanini 2000). These contribute to capillarypermeability and excessive retention of fluids inthe dermis, as well as in the fat layer, between theadipocytes and the lobular septa, increasing theinterstitial pressure due to the hydrophilic proper-ties of glycosaminoglycan.

Vascular alterations, edema, and decreasedvenous return cause hypoxia of the tissue whichleads to the thickening of the fibrous septa in thesuperficial adipose tissue and deep dermis, whichcauses the padded aspect of cellulite (Curri andBombardelli 1994).

Architectural Difference of the SkinRelated to GenderThis theory was described by Nüremberg andMüller in 1978 when they reported cellulite as afat herniation called “papillae adiposae.” In thiscondition, fat penetrates from the subcutaneoustissue through the interior surface of a weak der-mis in the dermo-epidermal interface, which isconsidered a characteristic of female anatomy(Nürnberger and Müller 1978). This alterationhas been confirmed through ultrasound, spectros-copy, and magnetic resonance imaging (MRI)(Bravo et al. 2013). It has been observed that theherniation of the tissue is typical in womenbecause the fibrous septa are different in this gen-der than in men. In men, septa are distributed in anintersecting way forming small polygons that gen-erate a type of cell that does not move forward

Non-ablative Radiofrequency for Cellulite (Gynoid Lipodystrophy) and Laxity 377

facially toward the dermis and are not placedperpendicularly as what occurs in women. Thisparticularity helps to understand why cellulite canoccur both in skinny and in obese women(Nürnberger and Müller 1978).

Querleux et al. (2002) reveal the three mainorientations of the septa, which are parallel, per-pendicular, and angular (approximately 45�).They describe that women with cellulite have ahigher percentage of perpendicular septa thanwomen or men without cellulite.

Inflammatory AlterationsInflammatory alterations were cited as one of themain pathophysiology factors of cellulite.Kligman concluded that cellulite is a blurredappearance of swollen chronic cells (Nürnbergerand Müller 1978); also there is evidence of lym-phocyte and macrophage infiltration in the fibroussepta, resulting in adipocytes and cutaneous atro-phy (Nürnberger and Müller 1978; Bravo et al.2013). This hypothesis would explain why somepatients with cellulite have pain and sensitivity tocompression. Other authors do not considerinflammation as part of this process (Piérardet al. 2000).

Hormonal VariationsOther authors suggest that cellulite is a connectivetissue abnormality that results from estrogenactivity over fibroblasts to produce matrix meta-lloproteases which damage the connective tissue,degrading collagen fibers in the trabeculae insideadipose tissue (Bravo et al. 2013).

The physical manifestations of cellulite are dueto the destruction of the normal architecture of thecollagen trabeculae that keep the adipose tissueconfined in only two layers: superficial and deeplayers of fat (Pugliese 2007). Therefore, the cor-relation between cellulite and hormones is justi-fied by its appearance after puberty, worseningduring pregnancy and with estrogen treatments,as well as in obesity, in which estrogen level isincreased.

On diet with excessive fat and carbohydrate, ahyperinsulinemia is produced, increasing lipo-genesis and inhibiting the lipolysis, generating

fat accumulation. It has also been described thatprolactin increases water retention in the adiposetissue generating edema (Isidori 1983).

Other hormones involved are the thyroid hor-mones that increase lipolysis and reduce the activ-ity of phosphodiesterase and decrease antilipolyticreceptor activity. Patients with hypothyroidismhave more cellulite due to a reduction of lipolysis(Rosenbaum et al. 1998).

Predisposed Factors

Cellulite occurs in all races, although whitewomen tend to show more cellulite than Asianor black women (Draelos 2001). It is said thatLatin women have more cellulite in the hips andgluteus, while Anglo-Saxon and Nordic womenhave more cellulite in the abdomen, influenced bytheir biotype.

Diet, as mentioned previously, is also an influ-ential factor. Diets based on high level of carbo-hydrates, fats, and salt promote cellulite. Tightclothes and high-heel shoes make the venousreturn difficult, alternating the pumping mecha-nisms and thus increasing cellulite (Goldman et al.2006).

Smoking is considered a predisposed factor asit can modify skin’s microcirculation and canincrease elastic fiber and collagen fiber degrada-tion (Morita 2007). Some contraceptives and betablockers may make cellulite worse.

There is another series of circumstances thatcan aggravate cellulite such as obesity, localizedfat accumulation, and laxity.

Cellulite can be aggravated or begin after sur-geries, mainly liposuction, that cause subcutane-ous fibrosis or atrophy (Goldman et al. 2006).

Clinical Evaluation

The patient must be questioned about trauma his-tory, liposuction or injections in the affected area,chronic diseases, pregnancies, surgeries, familyhistory, type of usual diet, and consumption oforal contraceptives or hormones (Goldman andHexsel 2010).

378 B.S.F. Bravo et al.

The physical exam must be conducted with thepatient standing and with relaxed muscles. Cellu-lite is observed better with a pinching test, whichconsists of taking a piece of the skin between thethumb and the index finger along the natural ver-tical fold of the skin until forming a skinfold. Thepalpation must be conducted to assess the elastic-ity of the skin and the subcutaneous tissue. Thevenous or lymphatic insufficiency and the degreeof obesity or overweight of the patient must beassessed using the body mass index (BMI). Laxityand other aggravating conditions should be eval-uated (Goldman and Hexsel 2010; Bertin et al.2001).

Cellulite Classification

The clinical classification of cellulite is a keyelement before starting any specific medical treat-ment, regarding the mechanism of action, numberof sessions, and session interval.

Clinical StagesGrade I: the patient is asymptomatic and there are

no clinical alterations (Goldman and Hexsel2010; Rossi and Vergnanini 2000).

Grade II: cellulite is evident only after compres-sion or muscle contraction, paleness, decreaseof temperature, and decrease of elasticity.

Grade III: the mattress appearance of the skinand/or orange skin is evident while resting,fine granulation of palpable sensation in deeplevels, pain during palpation, decrease of elas-ticity, paleness, and decrease of temperature.

Grade IV: has the same characteristic as the thirddegree with more palpable, visible, and painfulnodules, adhered to deep levels and wavyappearance of the surface of the skin.

Clinical DescriptionLimited or hard cellulite: the skin has a verypronounced thickness and is more prominent insuperficial tissues (Goldman et al. 2006; Rossiand Vergnanini 2000; De Peña and Hernández-Pérez 2005). Normally, hard or limited celluliteoccurs in young women who practice exercises.Since this cellulite is hard, it is limited and

occupies less space. The aspect of cellulite iscompact and firm and does not change accordingto the position. It is usually associated with stretchmarks. When a piece of the infiltrated skin issqueezed between the fingers, a roughness similarto the skin of orange with dilated follicular poreswill appear on the surface. When rotating a pieceof skin between the fingers, small nodules of hardconsistency can be seen. Also, there is an impos-sibility to slide the superficial layer of the skinover a deeper layer. It has a good response to thetreatment.

Soft or diffuse cellulite: the tissue is notattached to a deeper layer; it’s the most frequent.It usually occurs in women who do not practiceexercise. It is associated with muscular hypoto-nia and laxity. The diagnosis is generally madethrough visual inspection. It is characterized bya modification of the anatomy, provoking adeformation of the pelvic area. Usually, it ispresent in women over 40. The skin can have athickness of 5–8 cm. When standing, the paddedappearance can be observed, and the skin shakeswith movements and changes in position. Whentouching, the soft tissue can be felt as well as thepresence of small and hard nodules. Withrespect to mobility, the superficial and deeplayers of the skin can slide easier. It can beaccompanied by circulatory complications suchas varicose veins, ecchymosis, telangiectasias,heavy sensation, fatigue, feet numbness, andnight pains, as well as orthostatic hypotensiondue to blood ectasia in peripheral zones. It isnormal to find soft and hard lipodystrophyassociation.

Edematous cellulite: is the most severe andleast frequent, usually accompanied by obesity.In this classification the positive Godet sign isobserved. In this sign, a pressure on the tissuewith the finger will produce a depression on theskin surface, lasting some minutes to disappear.The infiltration is harder compared to the previousone; this characteristic is due to the compositionof the interstitial fluid that is viscous and with highmolecule weight proteins, with lymphedemaappearance. It also associates vascular symptoms.The patient experiences a heavy and painfulsensation.

Non-ablative Radiofrequency for Cellulite (Gynoid Lipodystrophy) and Laxity 379

Treatments

The demand for therapeutic options to improvethis alteration is very high, and in the past years,the offer of therapeutic alternatives has increased.Among them are invasive treatments such as:

• Liposuction: removing localized fat, not indi-cated to cellulite (Draelos 2001).

• Subcision is a surgical technique that does notrequire incisions and leave no scars. Throughthis technique, fibrous septa are cut and thedepressions are reduced.

• Carboxitherapy increases vascular tone andproduces active microcirculatory vasodilata-tion due to the action of CO2 on arteriolesmooth muscle cells (Goldman and Hexsel2010).

• Mesotherapy comprises injections composedby some active substances. These substanceshave lipolytic action (Goldman and Hexsel2010).

Noninvasive treatments are the following:

• Topical treatments: which work mainly in fourobjectives: increasing microvascular flow,reducing lipogenesis and promoting lipolysis,restoring the normal structure of the dermis andthe subcutaneous tissue, and preventing ordestroying the formation of free radicals(Goldman et al. 2006)

• Oxygen therapy: promotes superficial lipolysis• Controlled diets: to avoid overweight• Cryolipolysis approved by the FDA to elimi-

nate localized fat, producing a crystallizationof the fats in adipose cells at above freezingtemperatures, leading to an apoptosis of adi-pose cells and an inflammatory process thatresults in the reduction of the fat layer in2–4 months

• Focused ultrasound: produces heating of theadipocytes, generating coagulative necrosisand death of the cells in the adipose tissue

• Endermology: consists of motorized rollerswith vacuum suction between them to lift theskin and reach deeper structures, producing

stimulation of the metabolism and vasculariza-tion with lymphatic drainage (Goldman andHexsel 2010)

• Laser• Ablative and non-ablative radiofrequency

In this chapter we will discuss in detail thetreatment of cellulite with non-ablativeradiofrequency.

Radiofrequency

Radiofrequency (RF) is a form of electromagneticenergy (Shapiro et al. 2012). Its frequency rangesfrom 3 kHZ to 300 GHz (Lapidoth and Halachmi2015). When applied to skin tissue, rapidly oscil-lating electromagnetic fields cause movement ofcharged particles within the tissue resulting in heatgeneration proportional to the tissue’s electricalresistance (Shapiro et al. 2012). The idea of usingheat to cauterize comes from Egyptian era.Nevertheless, only in the nineteenth century, adevice using a galvanic current was built. Lee deForest (http://www.newworldencyclopedia.org/entry/Lee_De_Forest) was an American inventorand engineer who created the thermionic valve orvacuum tube that allowed RF amplification(Kotcher Fuller 2005). William Bovie, in 1920(O’Connor et al. 1996), developed the electrocau-tery for electrosurgery, which could cut, coagu-late, cauterize, and fulgurate tissues. In 1939, thehyfrecator was introduced in the market. It is adevice that uses low frequencies and high AC(alternating current) electrical voltage. Thisdevice is used for tissue destruction and for bleed-ing control (Lapidoth and Halachmi 2015).

RF is currently used in medicine in severaltreatments with different spectrum variations,including aesthetic medicine where it is consid-ered a simple, effective, and minimally invasivemethod (Lapidoth and Halachmi 2015). RF isused in aesthetic medicine with applications forablative and non-ablative applications (Lapidothand Halachmi 2015).

The tissue effects achievable using RF energydepend on the applied energy density; the

380 B.S.F. Bravo et al.

following are several RF-induced thermalchanges of tissue that are commonly used in med-icine (Lapidoth and Halachmi 2015):

• Ablation of tissue: this effect is used for cuttingor removing tissue and is based on thermalevaporation of tissue.

• Coagulation: this provides hemostasis for con-trolling bleeding. Coagulation may be appliedto soft tissue as well, to induce necrosis.

• Collagen contraction: high temperaturesinduce immediate transformation in the ter-tiary structure of proteins. For noninvasivecosmetic procedure, this effect is producedwith lower temperatures to avoid skinnecrosis.

• Tissue hyperthermia: it is to use subnecrotictemperatures to stimulate natural physiologicalprocesses in attempts to modify skin appear-ance and to reduce subcutaneous fat; an exam-ple of this is ThermaCool.

The first device based on non-ablative RF wasapproved by FDA (Food and Drug Administra-tion) in 2002. It is a monopolar device calledThermaCool (Thermage, Hayward, CA). It wasdeveloped to treat photodamaged skin on the face,reducing wrinkles and improving laxity (Lolis andGoldberg 2012; Alexiades-Armenakas et al.2008).

Non-ablative RF does not absorb or disperseepidermal melanin; therefore, it can be used in allskin phototypes, without risk for epidermis injury.RF contracts collagen fibers and stimulates neo-collagenesis by thermal energy, improving laxityand wrinkles. For cellulite treatment, synthesis ofnew collagen by fibroblasts promotes dermisthickening, improving the clinical aspect of cellu-lite (Coringrato et al. 2008; Brightman et al.2009).

Radiofrequency Frequency

The frequency of electrical current characterizeshow many times per second an electrical currentchanges its direction and is reported in hertz.

This change in direction is associated with achange of voltage polarity. Frequencies inthe range of 200 kHz to 6 MHz are the mostcommon in medicine (Lapidoth and Halachmi2015).

Radiofrequency Waves

The energy generated by RF can spread in a tridi-mensional way in the area treated with a con-trolled depth. The depth of the RF depends onthe RF electrode configuration, the device param-eters, and the tissue to be treated (Alan and Drover2010).

The electric conductivity in RF is variableaccording to the tissue. Tissues with few amountof water have less electric conductivity. There-fore, good results can be reached when RF isused to treat tissues with high water concentration,as sweat or sebaceous glands (Alan and Drover2010).

The RF energy can be delivered in continuouswave (CW) mode, burst mode, and pulsed mode.For gradual treatment of large areas, the CWmodeis most useful as it allows a slow increase intemperature in bulk tissue as in cellulite or skintightening (Lapidoth and Halachmi 2015). Theburst mode delivers RF energy with repetitivepulses of RF energy, and it is used, for example,in blood coagulation (Lapidoth and Halachmi2015). Pulsed mode is optimal when the goal isto heat a small tissue volume while limiting heatconduction to the surrounding tissue and is effec-tive for fractional skin ablation (Lapidoth andHalachmi 2015).

In RF the impedance matching systems are acombination of several capacitors and inductors(Lapidoth and Halachmi 2015). The challenge inthese devices is that they must distinguish thedifferent impedances of different parts of thehuman body (Lapidoth and Halachmi 2015). Theimpedance matching system must compensate forthese differences (Lapidoth and Halachmi 2015).An impedance matching system may be variable(Thermage) or broadband (Accent) (Lapidoth andHalachmi 2015).

Non-ablative Radiofrequency for Cellulite (Gynoid Lipodystrophy) and Laxity 381

Radiofrequency Power

The most important characteristics of RF energyare its peak and average power. Peak power isimportant to estimate the thermal effect produced,while average power affects the speed at whichthe heating is induced (Lapidoth and Halachmi2015).

High-power density applied to a large skinsurface may create only gentle warming, butwhen applied through a needle electrode, thesmall power is applied over a small contactpoint, leading to high-power density (Lapidothand Halachmi 2015).

Penetration Depth and RadiofrequencyEnergy Distribution BetweenElectrodes

Penetration depth is a parameter broadly used inlaser dermatology to mean the distance below theskin, which is heated. In RF current decreases at adistance from the electrode due to the divergenceof current lines (Lapidoth and Halachmi 2015).The depth of penetration can be affected by alter-ing the topology of the skin and optimizing the

electrode system and can be affected by the ana-tomical structure of treated area (Lapidoth andHalachmi 2015).

Types of RadiofrequenciesThe energy used for RF is calculated with thefollowing formula (Table 1):

Energy Jð Þ ¼ I2 � z� t, I ¼ current,

z ¼ impedance, t ¼ time secondsð Þ:

Monopolar RadiofrequencyThe first monopolar RF (MRF) device wasapproved by the Food and Drug Administrationfor the improvement of periorbital rhytides in2002, followed by full-face wrinkles in 2004, aswell as the temporary improvement in the appear-ance of cellulite when vibration was added to thedelivery system (Carruthers et al. 2014). Sincethen, the monopolar radiofrequency is an impor-tant part of the treatment of cellulite (Carrutherset al. 2014).

The MRF devices release energy using a local-ized dipole in the tip and another in contact withthe patient’s skin, acting as a ground or returnelectrode. The electrode is designed to disperse

Table 1 RF properties and its indications

Types ofRF Properties Mechanism/indication

Monopolar Capacitive couplingActive tip + return electrodeHeat depth depends on size and geometry of the tipHeat decreases as distance increase from the electrodeDepth: 3–6 mm

Tissue ablationCoagulationSubnecrotic heating (collagenremodelingLaxity/cellulitisWrinkles

Unipolar No eletric currentEletromagnetic field is produced by RF (high rotating frequencyof water molecules)Penetration depth: up to 20 mm

Body countourCellulits

Bipolar Two active electrode in the tipLow penetration depth: 3 mm

Promotes fibers contraction:collagen remodelingCellulitsLaxitywrinkles

Tripolar Combines the effects of monopolar and bipolar in one applicatorHeats superficial and deep skinVery low power, safer

LaxityCellulits

382 B.S.F. Bravo et al.

energy uniformly through the skin by a processcalled capacitive coupling that creates a zone ofhigher temperature to controlled depth of3–6 mm.

The tissue exposed to an electric field promotesresistance to the RFwaves, generating heat, whichmodifies micro- and macromolecular structure ofthe tissue (Alan and Drover 2010). The electro-magnetic energy (RF) is transformed into thermalenergy (Fig. 1). The heat promotes collagen dena-turation and collagen fiber contraction, stimulatesnew fibers of collagen synthesis, and increasedfibroblast activity, improving laxity and wrinkles.On the other hand, monopolar RF can also be usedin electrosurgery because of its ablative potential(Bravo et al. 2013; Carruthers et al. 2014). Theamount of newly produced collagen seems to bedependent on the intensity of heating of connec-tive tissue and time that the tissue is heated(Carruthers et al. 2014). Depending on the MRFsystem used, energy can be delivered in a“stamped” mode, a continuously gliding move-ment, or internally along the dermal–hypodermalinterface through a fiber or electrode (Carrutherset al. 2014).

The heat generated by RF current near theactive electrode does not depend on the size,shape, or position of the return electrode whenthe return electrode is much larger in size thanthe active electrode and is located at a distancewhich is much greater than the size of the activeelectrode (Lapidoth and Halachmi 2015). Heatingdecreases dramatically as distance increases fromthe electrode (Lapidoth and Halachmi 2015).Monopolar devices have a more deeply penetrat-ing effect than bipolar or unipolar devices

(Carruthers et al. 2014). The depth of heatingdepends on the size and geometry of the treatmenttip (Bravo et al. 2013). Typically, the device heatsthe dermis from 65 �C to 75 �C, the temperature atwhich collagen denatures (Lolis and Goldberg2012).

Monopolar devices are most commonly usedfor tissue cutting (Lapidoth and Halachmi 2015)like the electrical bistoury; this is an electro-medical apparatus that uses the heat generatedby the passage of high-frequency current, of theorder of 1 MHz, between an active, punctiformelectrode and an electrode of greater surface areaplaced in close contact with the skin. Its functionis to perform tissue ablation (InternationalElectrotechnical Commissio).

Treatment effects with monopolar devicesdepend on the density of RF energy, which canbe controlled with RF power, and the size ofactive electrode (Lapidoth and Halachmi 2015):

• Tissue ablation: very high-density energy isrequired.

• Cutting instruments: a needle-type electrode isused to concentrated electrical current on avery small area.

• Coagulation hand pieces have a larger surfacearea than ablative devices.

• Subnecrotic heating is usually used for treat-ments related to collagen remodeling.

Monopolar RF can be used on all types of theskin because it is not reflected or absorbed byepidermal melanin or vasculature, as it passesthrough the skin, making it safer to use(Carruthers et al. 2014); also monopolar RF can

RF Monopolar RF Unipolar RF Bipolar

Skin

Electrode

Fig. 1 Types of radiofrequency: mechanism of action proposed

Non-ablative Radiofrequency for Cellulite (Gynoid Lipodystrophy) and Laxity 383

be used in different parts of the body such as thethighs, arms, neckline, neck, jowls, eyebrows,eyes, midfacial, cheeks, nasolabial folds, andmelolabial folds.

Some devices of monopolar radiofrequencyare available in the market, including ThermageThermaCool, Exilis, and Pellevé S5. Each of thembrings different advantage, as speed, vibration,cooling system, and progressive heating(Lapidoth and Halachmi 2015).

The most common adverse effects are burningsensation and heat in the area during the proce-dure. Edema and erythema usually disappearwithin hours after the procedure. Less frequentare burns, crust formation, erosion, depigmenta-tion, scar, and dysesthesia (Bravo et al. 2013;Lapidoth and Halachmi 2015).

Unipolar RadiofrequencyThe mechanism of action of unipolar RF differsfrom monopolar radiofrequency. In unipolar RF,no electric current is produced in the tissue (Bravoet al. 2013). Instead, a high-frequency electro-magnetic radiation is produced, resulting in afast alternating polarity of the electromagneticfield, inducing high rotating frequency in watermolecules (considered as chromophore). Suchsuperfast oscillations produce heat and later thatheat dissipates in the tissue. The electromagneticwave phase produced by this device is controlledin such a way that it allows for the penetration ofheat in the tissue to a depth of up to 20 mm. Theheat produced by the movement of water mole-cules allows the superficial temperature of the skinto stabilize in approximately 40� centigrade, whilethe highest temperatures of 50–75� centigrade areobtained in the reticular dermis (Bravo et al.2013).

Unipolar RF with high frequency is moreappropriate to define body contour, as it penetratesdeeper (20 mm) and reaches higher temperatures.Unipolar RF is considered more effective thanbipolar RF for the treatment of cellulite becauseof its penetration depth, as the penetration bipolarRF from 2 to 4 mm (Alexiades-Armenakas et al.2008). On the other hand, bipolar RF inducesdermal thickening, contributing to the skin irreg-ularity, a component of cellulite.

Bipolar RadiofrequencyBipolar RF consists of two active electrodesplaced within a short distance. In this type ofdevice, the current has a flow between electrodes,which means that the treatment is symmetric andis limited to the tissue between them. The pene-tration depth is low, approximately half the dis-tance between the two electrodes (Lapidoth andHalachmi 2015).

It can be used in all types of skin, as otherRF. The mechanism of action is similar to themonopolar RF. The heat promoted by RF inducesextracellular fiber contraction and then stimulatesnew collagen fiber production in the dermis,increasing dermis thickness, which contributes toavoid fat herniation into the dermis. Clinically it isobserved as a smoother skin.

The association of bipolar with unipolar is veryuseful to treat body contour, laxity, and celluliteby the fact that they can reach different depth. Anew technology in which the same device pro-motes RF energy able to reach different depths ofskin at same treatment session was developed,called HD 3D (Alma Lasers, Israel). This devicehas a special tip in which rollers promote a mas-sage with the rollers, improving local circulationand lymphatic drainage.

The most common adverse effects are hot sen-sation during the procedure, erythema, and lightedema, which last some minutes after the proce-dure. Burn and post-inflammatory hyper-pigmentation are rare and operator dependent.

TriPollar RFTriPollar RF produces homogeneous and deepvolumetric heating of tissue, thus combining theeffects of monopolar and bipolar RF modalities inone applicator. The RF current flows betweenthree poles (electrodes). This arrangement of elec-trodes causes each to act as a common pole, elim-inating the need for cooling of the electrodes andskin, optimizing safety and simultaneously heatssuperficial and deep skin layers at the same time.The densely focused current between three polesresults in a high-power density in the treatmentarea and therefore low-power consumption, pro-viding clinical effects with longer-term resultsover successive treatment sessions without

384 B.S.F. Bravo et al.

discomfort (Manuskiatti et al. 2009; McKnightet al. 2015). This novel technology has a specialelectrode configuration that produces high densityand focused RF energy of approximately 18 W/cm (Goldman et al. 2006) deep into all skin layers(Manuskiatti et al. 2009). The total maximumpower of the TriPollar RF powered system is30 W compared to 200–300 W in unipolar sys-tems. This relatively low-power consumptionenables the TriPollar configuration to achievesafe and effective results without any activecooling (Manuskiatti et al. 2009).

Studies demonstrate in ex vivo human skinstatistically significant increases in collagen syn-thesis in the superficial andmid-dermis, a lipolyticactivity, a draining activity, and a firming effect onthe skin (Boisnic 2008). The adverse effects likeerythematous papules, papular urticaria, primarydegree burns, blisters, and bruising could be pro-voked by an inadequate amount of glycerin oilused (Manuskiatti et al. 2009).

Combination of Radiofrequency with OtherTechnologiesSome devices, as VelaShape (Syneron MedicalLtd.), combine bipolar RF energy, vacuum, andinfrared light. The combination improves colla-gen contraction and neocollagenesis. The vacuumstimulates the lymphatic (Alexiades-Armenakaset al. 2008; Sadick and Magro 2007; Adattoet al. 2014). The effects seem to be long lasting,but new sessions of treatment are required forfurther improvement (Alster and Tanzi 2005).Temporary side effects include erythema, edema,and bruising. Blisters, peeling, infection, hypo-pigmentation, and hyperpigmentation can rarelyoccur (Sadick and Magro 2007).

The mechanical manipulation generated byvacuum and rollers in the special tip increaseslocal and lymphatic drainage(Adatto et al. 2014).

Cellulite and Radiofrequency: ClinicalStudies

Bravo et al. (2013) conducted a study in eightfemale patients, with II and III grade of cellulitein buttocks and legs. These patients were

submitted for four sessions of unipolar radio-frequency (Accent RF system – Alma Lasers)with 2 weeks interval. Patients were clinicallyevaluated through comparative before and afterpictures, as well as through laboratorial tests andultrasonography (US) images. Pictures and USimages were performed before starting the treat-ment and 30 days after the last session.Laboratorial tests to evaluate possible side effectswere done before and after the first and the lastsession of treatment. All of the eight patientsshowed clinical improvement, and US imagesshowed increasing in the thickness of the dermisin seven of the eight patients. No alteration in thelaboratorial exams was reported. Authors con-cluded that this type of unipolar RF was an effi-cient and safe method in the treatment of cellulite(Figs. 2 and 3). These authors also reported goodresults for photodamaged skin treatment, as dem-onstrated in Fig. 4 the improvement of the laxityin the neck.

Hexel et al. (2011) conducted a pilot study witha device combining bipolar RF technology, infra-red light, vacuum, and mechanical massage. Theyevaluated nine patients that had a bodymass index(BMI) of 18–25 kg/kg and at least 6� in the sever-ity scale of cellulite (CSS) (Hexsel et al. 2009).The scale used in this article was described byHexel and consists in five key clinical morpho-logic features of cellulite: (A) the number of evi-dent depressions; (B) depth of depressions;

Fig. 2 Before and after five sessions (RF –Accent –AlmaLasers). Improvement of the skin depressions in numberand depth on the buttocks

Non-ablative Radiofrequency for Cellulite (Gynoid Lipodystrophy) and Laxity 385

(C) morphological appearance of skin surfacealterations; (D) grade of laxity, flaccidity, or sag-ging skin; and (E) the classification scale origi-nally described by Nürnberger and Müller(Hexsel et al. 2009). Authors reported reductionon cellulite severity and on corporal circumfer-ence of the buttocks in all patients. Poor resultswere observed in the thighs with the same treat-ment (Hexsel et al. 2011).

Goldberg et al. (2008) evaluated the efficacy ofthe unipolar device (Accent RF system – AlmaLasers) in 30 patients with III/IV cellulite grade inthe upper part of the thigh. They were treated withsix sessions every 15 days and were evaluated

6 months after the treatment. Clinical circumfer-ence measurements, skin biopsy, MRI, and bloodlipid evaluation were performed. Twenty-sevenpatients showed clinical improvement. The reduc-tion on the circumference of the thighs was2.45 cm in average. Histological changes showeddermal fibrosis. No changes in the lipids bloodlevel were observed nor in the MRI of the treatedpatients.

Sadick and Magro (2007) conducted a study in20 patients aging from 28 to 59, phototypes I to VI,in which he used different intensities of bipolar RF,infrared light, and levels of vacuum. Sixteen of the20 patients remained in the study. Twelve sessionsof 30 min were performed twice a week, 3 days apart, for 6 weeks. The RF energy, the optic energy,and the levels of vacuum were adjusted frompatient to patient to ensure that the optimum param-eters of the treatment were reached. Clinical resultswere evaluated through photographies, circumfer-ence measurements of the leg, and dermatologicalexams by the researchers. A total of 65% of thepatients had a reduction in the circumference of theleg; 50% of the patients had an improvementgreater than 51%. In most patients, some degreeof improvement could be observed in the appear-ance of cellulite.

Adatto et al. (2014) conducted a study with35 healthy female patients with skin laxity andsubcutaneous fat deposits localized in the abdo-men, buttocks, or thighs, using a new high-powerradiofrequency technology combined with infraredlight and mechanical manipulation. Sixty percentof the patients showed improvement of 24.1%;27% of the patients showed improvement between25% and 49% and 5% showed improvementbetween 50% and 74%, while only 8% of thepatients did not show any improvement.

Take Home Messages

– Cellulite, also known as gynoid lipodystrophy,is a multifactor disorder of the dermis, epider-mis, and subcutaneous cellular tissue.

– Although cellulite is still considered as anunclear etiological condition, there are manyhypotheses trying to explain this disorder.

Fig. 3 Before and after five sessions (RF –Accent –AlmaLasers). Improvement of the irregular appearance of theskin surface on the buttocks

Fig. 4 Before and after five session (RF – Accent – AlmaLaser). Improvement of the skin laxity on the neck area

386 B.S.F. Bravo et al.

– In the last years, the idea of having an idealsculpting body changed the concept of cellulitefrom a cosmetic problem to a disease.

– Treatments can be invasive and noninvasive.Noninvasive treatments include topical treat-ments, controlled diets, cryolipolysis, focusedultrasound, endermology, laser, andnon-ablative radiofrequency.

– Radiofrequency (RF) or RF spectrum is thename given to one of the parts of the electro-magnetic spectrum, with frequencies from3 kHZ to 300 GHz.

– The energy generated by RF can spread intridimensional volumes of the tissue, to con-trolled depths.

– The depth of the RF depends onmultiple factorssuch as the tissue over which it is applied (der-mis, epidermis, subcutaneous tissue), the con-figuration of the electrodes if desired(monopolar, bipolar, tripolar), the programmingof the RF waves, and the applied temperature.

– RF does not have absorption or dispersion dueto epidermic melanin and therefore cannot beused in all types of skins and generate signifi-cant heat without a risk for the epidermis.

– Radiofrequency (RF) contracts collagen andstimulates neocollagenesis by thermal heat,promoting thickening of the dermis andavoiding fat herniation.

– RF can also promote improvement in localcirculation due to the vasodilatation and lym-phatic drainage. Clinically it improves the lax-ity and the irregularity of the skin surface.

– New RF devices have been developed associat-ing other technologies to reach different layersof the skin and to improve lymphatic drainage.

– Many studies report efficacy with RF for cel-lulite and body laxity with few sessions andminimal side effects.

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Bertin C, Zunino H, Pittet JC, et al. A double-blind evalu-ation of the activity of an anti-cellulite productcontaining retinol, caffeine, and ruscogenine by a com-bination of several non-invasive methods. J CosmetSci. 2001;52:199–210.

Boisnic S. Evaluation du dispositif de radiofréquence tri-polaire Regen™ en utilisant un modèle experimental depeau humaine. Nouv Dermatol. 2008;28:331–2.

Bravo BSF, Issa MCA, Muniz RLS, TorradoCM. Tratamento da lipodistrofia ginoide com radio-frequência unipolar: avaliação clínica, laboratorial eultrassonográfica. Surg Cosmet Dermatol. 2013;5(2):138144.

Brightman L, et al. Improvement in arm and post-partumabdominal and flank subcutaneous fat deposits and skinlaxity using a bipolar radiofrequency, infrared, vacuumand mechanical massage device. Lasers Surg Med.2009;41:791–8.

Carruthers J, Fabi S, Weiss R. Monopolar radiofrequencyfor skin tightening: our experience and a review of theliterature. Dermatol Surg. 2014;40 Suppl 12:S168–73.https://doi.org/10.1097/DSS.0000000000000232.

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De Peña J, Hernández-Pérez M. Lipodistrofia ginecoide(celulitis). Rev Cent Dermatol Pascua. 2005;3:132–5.

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Non-ablative Radiofrequencyfor Hyperhidrosis

Mark S. Nestor, Alexandria Bass, Raymond E. Kleinfelder,Jonathan Chan, and Michael H. Gold

AbstractHyperhidrosis is the most common sweatingdisorder and can cause significant interferenceon quality of life. Current treatment optionsinclude topical aluminum chloride, lasers, tapwater iontophoresis, oral glycopyrrolate, botu-linum A toxin, surgical excision of the skin andsweat gland layer, or sympathetic nerve blocks.In recent years, thermotherapy has emerged asan alternative treatment option. Radio-frequency thermotherapy (RFTT) utilizes elec-tromagnetic radiation to produce electriccurrent. When this current meets resistancewithin the tissue, it produces heat to denatureproteins and permanently destroy sweat

glands. Fractional radiofrequency differs frommonopolar, unipolar, and bipolar radio-frequency as it allows unaffected regions toserve as a reservoir of cells to acceleratehealing and maintain skin integrity. Whencompared to other types of radiofrequency,fractional delivery causes less patient discom-fort and less downtime. Studies have shown asignificant decrease in the amount of sweatingand improvement in quality of life. Radio-frequency is a promising alternative treatmentmethod to those with hyperhidrosis.

KeywordsHyperhidrosis •Thermotherapy •Radiofrequency

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390

Radiofrequency Thermotherapy . . . . . . . . . . . . . . . . . . 390

Types of Radiofrequency . . . . . . . . . . . . . . . . . . . . . . . . . . . 390Monopolar Radiofrequency . . . . . . . . . . . . . . . . . . . . . . . . . 390Unipolar Radiofrequency . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391Bipolar Radiofrequency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391Fractional Radiofrequency . . . . . . . . . . . . . . . . . . . . . . . . . . . 391

Clinical Trials Using Radiofrequencyfor Hyperhidrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393

Take Home Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394

Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394

M.S. Nestor (*)Center for Clinical and Cosmetic Research, Center forCosmetic Enhancement, Aventura, FL, USA

Department of Dermatology and Cutaneous Surgery,University of Miami, Miller School of Medicine, Miami,FL, USA

Department of Surgery, Division of Plastic Surgery,University of Miami, Miller School of Medicine, Miami,FL, USAe-mail: nestormd@admcorp.com

A. Bass • R.E. Kleinfelder • J. ChanCenter for Clinical and Cosmetic Research, Aventura, FL,USAe-mail: al.bass@admcorp.com; r.kleinfelder@admcorp.com; jo.chan@admcorp.com

M.H. GoldGold Skin Care Center, Nashville, TN, USAe-mail: drgold@goldskincare.com

# Springer International Publishing AG 2018M.C.A. Issa, B. Tamura (eds.), Lasers, Lights and Other Technologies, Clinical Approaches and Procedures inCosmetic Dermatology 3, https://doi.org/10.1007/978-3-319-16799-2_29

389

Introduction

Sweating is a mechanism that occurs in humans tomaintain homeostasis, prevent overheating, and isnecessary for survival. The process is activated bythe autonomic nervous system. Triggers includebut are not limited to heat, emotions, gustatorysensations, and axon reflexes. All of these triggersstimulate the eccrine glands to produce sweat(a 99–99.5% aqueous solution in healthy individ-uals). However, some individuals experience dis-turbances in the sweating process and they arecategorized into two groups: hypohidrosis/anhidrosis (diminished or absent sweat produc-tion) and hyperhidrosis (excessive sweat produc-tion). Hyperhidrosis is the more commoncomplaint and affects 0.5% of the United States’population to an extent that it interferes with theirquality of life and activities of daily living. It canoccur anywhere on the body but most commonlyaffects the axilla, face, palms, and soles. It affectsboth sexes equally, but women often seek treat-ment more frequently and especially for axillaryhyperhidrosis (Hurley 2003; Schick et al. 2016;Solish et al. 2007).

There are several current treatment optionsavailable to people who suffer from hyperhidro-sis. Conservative methods include application ofaluminum chloride, lasers, tap water iontophore-sis, systemic anticholinergic agents such as oralglycopyrrolate, and frequent botulinum A toxininjections. Many patients find these conservativetreatments unsatisfactory due to the need for con-tinuous maintenance. On the contrary, there aremore permanent and effective surgical optionsavailable. These include surgical excision of theskin and sweat gland layer or sympathetic nerveblocks, but many patients find these methods tooinvasive (Hurley 2003; Schick et al. 2016).

Radiofrequency Thermotherapy

Due to this gap in current treatment, thermotherapyhas emerged as an alternative treatment option overrecent years. Using lasers, microwaves, and nowradiofrequency waves, thermotherapy uses heat ata temperature greater than 56 �C to denature

proteins and permanently destroy sweat glands.Radiofrequency thermotherapy (RFTT) isperformed by using a device, either using elec-trodes or microneedles, to give off thermal energy.It does this by using electromagnetic radiation toproduce electric current in the frequency range of3 kHz–300 MHz. When this current meets resis-tance within the tissue, it produces heat (Lolis andGoldberg 2012). The advantage of using radio-frequency over lasers is that it is not affected bytissue diffraction or chromophore absorption. Theenergy can be delivered to the target tissue moreprecisely than previous methods without damagingthe epidermis like older ablative methods.Depending on the penetration depth used andtype of radiofrequency, this non-ablative techniquehas been approved for wrinkle reduction, skintightening, treating striae, and, when penetrateddeeper, for hyperhidrosis (Schick et al. 2016; Elsaie2009) (see chapter ▶ “Non-ablative Radio-frequency for Facial Rejuvenation,” this volume).

Types of Radiofrequency

Monopolar Radiofrequency

Radiofrequency was first developed in the 1920sto be used for electrocautery. It evolved and isused most extensively now in dermatology forskin rejuvenation. It was first approved by theFDA in 2002 for facial wrinkle reduction andwas known by the names Thermage® andThermaCool®. These devices use monopolarradiofrequency, meaning they use one electrodeto deliver current and another electrode to contactthe skin and act as a grounding pad. This deviceheats the dermis to 65–75 �C to cause partialdenaturing of collagen which enables retractionand thickening of the collagen. A cooling spray isused simultaneously to protect the epidermis andkeep it between 35 �C and 45 �C. Since its devel-opment, this device has now been used to treatrhytids, acne scars, and cellulite. The mainreported limitations to monopolar radiofrequencyare patient discomfort and results that are moremodest when compared to more invasive proce-dures (Lolis and Goldberg 2012; Elsaie 2009).

390 M.S. Nestor et al.

Unipolar Radiofrequency

Unipolar radiofrequency is another form of radio-frequency used in dermatology. In contrast tomonopolar radiofrequency, unipolar uses high-frequency electromagnetic radiation at 40 MHzto produce heat, rather than electric current. Thismethod allows deeper penetration of the skin todepths of 15–20 mm, which is helpful in treatingdisorders of the dermis such as cellulite (Lolis andGoldberg 2012).

Bipolar Radiofrequency

Bipolar radiofrequency is performed by using twoactive electrodes over the treatment area ratherthan only one electrode that is used in monopolar.The current flows between the electrodes to adepth that is half the distance between the elec-trodes. Compared to monopolar radiofrequency,bipolar cannot penetrate as deep but produces lesspain and more controlled energy. It is commonlyused with light-based systems, electro-opticalsynergy (ELOS), vacuum systems, or functionalaspiration controlled electrothermal stimulation(FACES), to help control the energy depththrough the skin. Bipolar devices are used totreat facial laxity, rhytids, pigmented and vascularlesions, acne and acne scarring, hair removal, andcellulite (Lolis and Goldberg 2012; Elsaie 2009).

Fractional Radiofrequency

Fractional radiofrequency is a newer approachthat delivers bipolar energy either via electrodes

or microneedles arranged in pairs. The micro-needle method allows for even more precise deliv-ery of energy to the targeted tissue by creatingzones of affected skin adjacent to non-affectedskin (Fig. 1; Weiner 2013). This energy, like theother techniques, results in thermal damage inorder to stimulate collagen remodeling but differsby allowing the unaffected regions to serve as areservoir of cells to accelerate healing and main-tain skin integrity. When compared to other typesof radiofrequency, fractional delivery causes lesspatient discomfort and less downtime. In addition,this delivery technique has been studied for itsusage in treating hyperhidrosis (Schick et al.2016; Lolis and Goldberg 2012).

Clinical Trials Using Radiofrequencyfor Hyperhidrosis

In 2012, Hong et al. (2012) found that usingmicrowaves to treat axillary hyperhidrosis couldprovide long lasting effects. Since then, studiesevaluating the efficacy of using radiofrequencywaves to treat primary axillary hyperhidrosis(PAH) have been conducted.

Kim et al. (2013) conducted one of the first pilotstudies in 2013 looking at fractional microneedleradiofrequency (FMR) for PAH. Twenty subjectswith severe hyperhidrosis were enrolled and treatedwith two sessions of FMR at 4-week intervals.Outcome assessments were performed usingstarch-iodine tests to outline the area of excessivesweating and quantify sweat reduction. Eight weeksafter the second treatment they found a significantdecrease in the amount of sweating and 70% ofsubjects said they experienced greater than a 50%

Fig. 1 Fractionalmicroneedleradiofrequencydemonstrating howmicroneedles cause smallprecise fractional dermalinjury at multiple levels(Weiner 2013)

Non-ablative Radiofrequency for Hyperhidrosis 391

improvement in sweating (Fig. 2). Histologic sam-ples retrieved before and after the treatment sessionsshowed that the glands being targeted were at adepth between 2 and 4 mm. In addition, after1 month, a decrease in the density and size of theapocrine and eccrine glands was observed (Fig. 3).The most common side effects were transient andconsisted of tingling, swelling, and erythema. Twosubjects experienced compensatory hyperhidrosis.

Abtahi-Naeini and Fatemi Naeini et al. alsopublished three articles pertaining to FMR forPAH. In their 2014 study (Naeini et al. 2014),they enrolled 25 subjects with PAH who failedprevious conservative therapy to undergo 3 ses-sions of FMR at 3-week intervals. Each subject

was their own control with one axilla treated withFMR and the other with a sham device. Threemonths after the last treatment, significantimprovement was observed in these patientswith 80% reporting more than 50% satisfactionat the end of the study. Histological samples alsoshowed a decrease in the number of sweat glandson the treated side. The most common side effectswere erythema and pinpoint bleeding. In their2015 publication (Abtahi-Naeini et al. 2015),they evaluated the quality of life in these 25 sub-jects and found that there was a statistically sig-nificant improvement between the before and afterintervention questionnaires. In their 2016 article(Abtahi-Naeini et al. 2016), they continued to

Fig. 2 Starch-iodine photographs before and after FMR treatment. Patient 1 (a–c) and patient 2 (d–f) at baseline (a, d),1 month after the first treatment (b, e), and 2 months after the second treatment (c, f) (Kim et al. 2013)

392 M.S. Nestor et al.

follow these subjects and 1 year later, they found10 patients who did not experience any relapse oftheir hyperhidrosis. However, they did find a sig-nificant correlation between hyperhidrosis relapseand change in body mass index.

Most recently in 2016, Schick et al. (2016)conducted a trial for axillary hyperhidrosis. Thisstudy enrolled 30 subjects with axillary hyperhidro-sis who had all previously attempted conservativetreatment. They were all treated three times withradiofrequency thermotherapy at 6 week intervals,using the microneedle approach. Each treatmentconsisted of two consecutive rounds with a penetra-tion depth of 3 mm. After 6 months, 27 subjects sawimprovement in their sweating with an average

reduction of 72% in their sweating. The averagequality of life score also improved significantly.Side effects reported, startingwith themost frequent,were erythema, exudation or scab, postanesthesiapain, petechial bleeding during the procedure,twitching of the arm during the procedure, andneedle-puncture sites visible after 6 months.

Conclusion

In conclusion, radiofrequency therapy, especiallyusing FMR, can offer an alternative treatmentmethod to those with PAH who have failed

Fig. 3 Biopsy specimens before and after FMR treatment.(a) Skin sample obtained immediately after FMR treat-ment. Coagulation changes of the glands and dermis dueto heat were observed at high magnification. (b) Skin

sample from baseline. (c) Skin sample showing a decreasein the number and size of both apocrine and eccrine glandsafter treatment (Kim et al. 2013)

Non-ablative Radiofrequency for Hyperhidrosis 393

previous therapy. Further studies will need to beperformed in order to see consistent resultsregarding radiofrequency device settings andtheir long-term effects.

Take Home Messages

1. Hyperhidrosis is the most common sweatingdisorder and can cause significant interferenceon quality of life.

2. Radiofrequency thermotherapy (RFTT) uti-lizes electromagnetic radiation to produce elec-tric current. When this current meets resistancewithin the tissue, it produces heat to denatureproteins and permanently destroy sweatglands.

3. Fractional radiofrequency is a newer approachthat differs by allowing untreated areas to serveas a reservoir of cells to accelerate healing andmaintain skin integrity.

4. When compared to other types of radio-frequency, fractional delivery causes lesspatient discomfort and less downtime. In addi-tion, this delivery technique has beenstudied for its use in treating hyperhidrosis.

5. Studies have shown a significant decrease inthe amount of sweating and improvement inquality of life.

6. Radiofrequency is a promising alternativetreatment method for those with hyperhidrosis.

Cross-References

▶Ablative Radiofrequency in CosmeticDermatology

▶Non-ablative Radiofrequency for Cellulite(Gynoid Lipodystrophy) and Laxity

References

Abtahi-Naeini B, Naeini F, Adibi N, Pourazizi M. Qualityof life in patients with primary axillary hyperhidrosisbefore and after treatment with fractionated micro-needle radiofrequency. J Res Med Sci. 2015;20(7):631–5.

Abtahi-Naeini B, Naeini F, Saffaei A, Behfar S,Pourazizi M, Mirmohammadkhani M, Bolandnazar N.Treatment of primary axillary hyperhidrosis by frac-tional microneedle radiofrequency: is it still effectiveafter long-term follow-up? Indian J Dermatol. 2016;61(2):234.

Elsaie ML. Cutaneous remodeling and photorejuvenationusing radiofrequency devices. Indian J Dermatol.2009;54(3):201–5.

Hong CH, Lupin M, Oʼshaughnessy KF. Clinical evalua-tion of a microwave device for treating axillary hyper-hidrosis. Dermatol Surg. 2012;38(5):728–35.

Hurley HJ. Diseases of the eccrine sweat glands: hyperhi-drosis. In: Dermatology, vol. 1. Spain: Mosby byElsevier Limited; 2003. p. 567–75.

Kim M, Shin JY, Lee J, Kim JY, Oh SH. Efficacy offractional microneedle radiofrequency device in thetreatment of primary axillary hyperhidrosis: a pilotstudy. Dermatology. 2013;227(3):243–9.

Lolis MS, Goldberg DJ. Radiofrequency in cosmetic der-matology: a review. Dermatol Surg. 2012;38(11):1765–76.

Naeini FF, Abtahi-Naeini B, Pourazizi M, NilforoushzadehMA, Mirmohammadkhani M. Fractionated micro-needle radiofrequency for treatment of primary axillaryhyperhidrosis: a sham control study. AustralasJ Dermatol. 2014;56(4):279–84.

Schick CH, Grallath T, Schick KS, HashmonaiM. Radiofrequency thermotherapy for treating axillaryhyperhidrosis. Dermatol Surg. 2016;42(5):624–30.

Solish N, Bertucci V, Dansereau A, Hong HC, Lynde C,Lupin M, Storwick G. A comprehensive approach tothe recognition, diagnosis, and severity-based treat-ment of focal hyperhidrosis: recommendations of theCanadian Hyperhidrosis Advisory Committee.Dermatol Surg. 2007;33(8):908–23.

Weiner S. FINALLY. . .A radiofrequency (RF) skin tight-ening device that makes sense. Infini by Lutronic.Includes an overview of the RF skin tightening indus-try. 2013. https://stevenfweinermd.wordpress.com/2013/09/22/dr-steve-weiner-finally-a-radiofrequency-rf-skin-tightening-device-that-makes-sense-infini-by-lutronic/. Retrieved 2 Feb 2017.

394 M.S. Nestor et al.

Ablative Radiofrequency in CosmeticDermatology

Tania Meneghel and Maria Letícia Cintra

AbstractIn recent years, radiofrequency technology isbeing used in several medical skin caredevices.

More precisely, the fractional micro-plasmaradiofrequency technology was launched in2007. It uses the radiofrequency electromag-netic radiation to get the plasma. The skininteraction with the plasma may cause heating,coagulation, vaporization, or ablation of theskin. This technology is non-chromophoredependent and can be used in high photo-types.

The fractional ablative lasers, mostly CO2

and erbium:YAG, are excellent for treatment ofunaesthetic skin defects. However, they are notused for all types of skin and the CO2 in par-ticular has a long downtime. The fractionalmicro-plasma radiofrequency is indicated foracne scars, chicken pox scars, atrophic scars,surgical scars, stretch marks (striae), fine linesand wrinkles, skin tightening, skin resurfacing,and skin rejuvenation (photo-aged skin). It is asafe, efficient treatment, with short downtime.

KeywordsMicro-plasma • Fractional • Radiofrequency •Skin resurfacing • Scars • Striae

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396

Basic Concepts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396

History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396

Fractional Micro-plasma Characteristics . . . . . . . . 396

Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397

Pretreatment Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398

Pre-procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399

Post-procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399

Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399

Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399

Application Mode for Distensible Acne Scars . . . . 399

Application Mode for Non-distensible AcneScar or for Chicken Pox Scars . . . . . . . . . . . . . . . . . 401

Application Mode for Stretch Marks . . . . . . . . . . . . . 401

Application Mode for Wrinkles and for FineLines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401

Side Effects and Management . . . . . . . . . . . . . . . . . . . . . 401

Take Home Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401T. Meneghel (*)Clínica Renaissance, Americana, SP, Brazile-mail: taniameneghel@uol.com.br

M.L. CintraPathology Department, Medical Sciences School,Unicamp, Campinas, SP, Brazile-mail: marialet@fcm.unicamp.br

# Springer International Publishing AG 2018M.C.A. Issa, B. Tamura (eds.), Lasers, Lights and Other Technologies, Clinical Approaches and Procedures inCosmetic Dermatology 3, https://doi.org/10.1007/978-3-319-16799-2_30

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Introduction

The ablative fractional technologies are widelyused in procedures to correct unaesthetic skindefects. Until recently CO2 was the main avail-able treatment option (Tanzi et al. 2008;Alexiades et al. 2008). However it iscontraindicated for high photo-types (V andVI) and it has a long downtime. The other alter-native ablative fractional technology waserbium:YAG. It has a shorter downtime; how-ever, its ablation is superficial, unable to stimu-late the collagen accordingly. Both CO2 anderbium:YAG have water as their targetchromophore.

Recently the population is worried with theirphysical appearance, perhaps because the worldis more competitive. People have many activi-ties and little time for themselves. Conse-quently, they are looking for efficient estheticsprocedures, with short downtime. This explainsthe increasing trend in application of the abla-tive fractional technology. The fractional micro-plasma radiofrequency is independent of targetchromophore (Kono et al. 2009). The erbiumablation is more superficial than CO2 or micro-plasma radiofrequency, but micro-plasma radio-frequency ablation is very similar to CO2, withshorter downtime (Gonzalez et al. 2008;Fitzpatrick et al. 2008).

Basic Concepts

Fractional Laser: The fractional laser emits lightenergy beams that turn into thermal energy andreaches the skin fractionally, causing micro-per-forations (MTZ microthermal zone). It providesminimal and controlled thermal damage, allowingthe adjacent undamaged tissue, not reached bylaser, to promote a rapid recovery of the treatedareas (Manstein et al. 2004).

Ablation Lasers: The ablation lasers promoteremoval of the complete epidermis and a portionof the dermis.

Plasma: Plasma occurs when the gas is partiallyionized and dissociated. It is usually obtained

through electrical discharges in gases. The interac-tion of the plasma with the skin may result from asimple heating to vaporization or ablation and coag-ulation of the tissue, depending on the amount ofenergy used and the time the plasma remains incontact with skin (Fitzpatrick et al. 2008).

Radiofrequency: It is a type of electromagneticenergy. The fractional micro-plasma uses this typeof energy to produce plasma.

History

In the beginning the use of plasma in skin caredevices was unpredictable (Alster and Konda2007). Because the technology was notfractionated, it was difficult to control the thermaland ablative damage. In August 2007, the fractionalmicro-plasma was developed, solving this issue.

Fractional Micro-plasmaCharacteristics

This technology is incorporated inside a specialunipolar radiofrequency handpiece. The electro-magnetic energy (unipolar radio frequency) pro-duces ionization of the air between the tip and theskin, to provoke micro-plasma electricalsparks. These sparks cause ablation and createmultiple controlled micro-perforations on theskin (microthermal zone) producing the thermaland ablation damage zone, surrounded by ahealthy skin (Halachmi et al. 2010). Thisdevice can be used in stationary mode (stationarytip) or in motion (roller tip) (Figs. 1 and 2).

Perforations have 100–150 μm depth and80–120 μm diameter (depending on the pulseduration and the power used) (Halachmi et al.2010; Xiu et al. 2013).

The parameters for the stationary mode areaverage power of 50 W, pulse duration from 0.1to 0.3 s, and stack from one to five times. The tipwith the smaller diameter and lower number ofpins (large grate) is used for more aggressiveeffect. The number of stacks depends on the

396 T. Meneghel and M.L. Cintra

desired level of penetration, i.e., the greater thenumber of stacked passes, the greater the penetra-tion. The lower tip with the same energy producesmost thermal damage (Halachmi et al. 2010).

The parameters for the rotative tip depend onthe skin photo-type:

(i) Photo-types I–III: average power from 45 to60 W, with pulse duration between 6 and 30 sand two to seven passes

(ii) Photo-types IV to V: average power from40 to 50 W, with pulse duration between6 and 30 s and two to seven passes

The number of passes depends on the desiredlevel of penetration, i.e., the greater the number,the greater the penetration.

The treatment technique both for the stationaryor the in motion application involves softly touch-ing the surface of the skin with the tip. The appli-cator should not be pressed on the skin, but onlytouch it to obtain the ablative damage linked withthe thermal damage. (If the tip is applied with toomuch pressure, the ablative damage is lost.) Whenthe applicator is correctly positioned, it is possibleto notice sparks on the skin, which produces theablation effect.

Indications

This technology is indicated for the treatment ofwrinkles (Halachmi et al. 2010), fine lines, atro-phic scars (Kono et al. 2009), distensible and non-

Fig. 2 Rotative tip (roller)

Fig. 1 Stationary tips’diameters

Ablative Radiofrequency in Cosmetic Dermatology 397

distensible acne scars (Gonzalez et al. 2008; Leeet al. 2008), chicken pox scars (Halachmi et al.2010), stretch marks, resurfacing, photo rejuvena-tion, skin tightening, and post-burn hyper-pigmentation (Wang et al. 2015).

Pretreatment Care

The pretreatment begins 1 month before, withsunscreen every day and glycolic acidand bleaching agents during the night to avoid

Fig. 3 Day-by-day ablative results

398 T. Meneghel and M.L. Cintra

post-hyperpigmentation. One day before, herpessimplex virus prophylaxis is introduced, withoral antiviral agents.

Pre-procedure

After the area to be treated is washed with waterand antiseptic soap, a topical anesthetic (lidocaine7% + tetracaine 7%) is applied for 1 h. The patientshould also take 1 tablet of Tylex® 7,5 mg.

Before starting the procedure, the topical anes-thetic is removed, and the region to be treated iswashed again with water and antiseptic soap.Then dehydrate the skin with alcohol or acetone.It is necessary to use mask and smoke evacuatorfor particles and virus during the procedure. Theuse of Zimmer helps the patient feel less pain.

Post-procedure

Immediately after the procedure, apply Vaseline andcover with plastic film. It provides a sense of com-fort and avoids the nerve endings to be exposed tothe environment. It is recommended that the patientdoes not wash the treated area for 24 h to preventburning. After 24 h, the patient can wash the areawith water and soap and apply moisturizer andsunscreen. The erythema usually lasts 24 h, withmild edema in areas where the procedure was moreaggressive. The patient may feel some burningwhen exposed to heat (e.g., hot bath).

Contraindications

The contraindications for the procedure arephoto-type VI, pacemaker, active bacterialand/or viral infection, impaired immune sys-tem (e.g., isotretinoin, cancer), unstable diabe-tes, pregnancy, metal implant under thetreatment area, ablative procedures in the past3 months, recent use of botulinum toxin orfillers, and collagen diseases (Halachmi et al.2010).

Results

The ablative result can be noticed after a week(Fig. 3). The effective collagen production beginsafter 1 month and continues for 3 months (Figs. 4and 5). Therefore, minimal interval between ses-sions is 45 days.

Application Mode for Distensible AcneScars

For the treatment of distensible acne scars, it isapplied five stacks on each scar, using themedium stationary tip, with pulse duration of0.2 s and power of 50 W, followed by sevenpasses on full face, using the rotative tip inseveral directions, with 50 W power and pulseduration of 30 s (Fig. 6).

Fig. 4 Fifteen days aftertreatment: thin band ofcollagen tissue separates theepidermis from the elastoticdermis (H&E, originalmagnification �100)

Ablative Radiofrequency in Cosmetic Dermatology 399

Fig. 6 Before (left) andafter (right) treatment ofdistensible acne scars

Fig. 5 Thirty days aftertreatment: high reticulardermis, formerly elastotic,was almost entirelyreplaced by dense collagentissue (H&E, originalmagnification �100)

Fig. 7 Before (up) andafter (down) treatment ofnon-distensible acne scars

400 T. Meneghel and M.L. Cintra

Application Mode for Non-distensibleAcne Scar or for Chicken Pox Scars

For the treatment of non-distensible acne scars, itis applied five stacks on each scar (specially theborders), using the medium stationary tip, withpulse duration of 0.2 s and power of 50 W,followed by seven passes on full face, using therotative tip in several directions, with 50W powerand pulse duration of 30 s (Fig. 7).

Application Mode for Stretch Marks

For the treatment of stretch marks, make severalpasses (five to ten) with the rotative tip, with 50Wof power and 30 s of pulse duration, in differentdirections, until bleeding points are observedthroughout the treatment area.

Application Mode for Wrinklesand for Fine Lines

For the treatment of wrinkles and fine lines, it isapplied three stacks on fine lines and five stackson wrinkles, using the medium stationary tip, withpulse duration of 0.2 s and power of 50 W,followed by seven passes on full face, using therotative tip in several directions, with 30 s pulseduration and 50 W power.

Side Effects and Management

The most important side effect is post-inflammatoryhyperpigmentation (Kono et al. 2009). In order toavoid it, always prepare patients 1 month before theprocedure (especially higher photo-types or patientsof mixed descent) with glycolic acid and bleachingagents. As soon as the complete reepithelialization isobtained, begin applying sunscreenUVA/UVB50+.Hyperpigmentation usually begins in the second orthird week after the procedure; thus, after 10 daysstart using topic corticosteroids in the morningunder sunscreen associated with bleaching agentsat night for a month. Additionally, the use of oralantioxidants is recommended (pycnogenol, resvera-trol, and Polypodium leucotomos).

Take Home Messages

• The fractional micro-plasma RF is a kind offractional laser.

• It is indicated for several aesthetic procedures,e.g., acne scars, striae, and skin rejuvenation.

• Results are similar to the ones obtained withfractional CO2 but with a smaller downtime.

References

Alexiades AM, Dover JS, Ardnt KA. The spectrum of laserskin resurfacing: non-ablative, fractional and ablativelaser resurfacing. J Am Acad Dermatol.2008;58:719–37.

Alster TS, Konda S. Plasma skin resurfacing for regenera-tion of neck, chest and hands: investigation of a noveldevice. Dermatol Surg. 2007;33:1315–21.

Fitzpatrick R, Bernstein E, Iyer S, Brown D, Andrews P,Penny K. A histopathologic evaluation of the plasmaskin regeneration system (PSR) versus a standard car-bon dioxide resurfacing laser in an animal model.Lasers Surg Med. 2008;40:93–9.

Gonzalez MJ, Sturgill WH, Ross V, UebelhoerNS. Treatment of acne scars using the plasma skinregeneration (PSR) system. Lasers Surg Med.2008;40:124–7.

Halachmi S, Orenstein A,Meneghel T, Lapidot M. A novelfractional micro-plasma radio frequency technology fortreatment of facial scars and rhytids: a pilot study. JCosmet Laser Ther. 2010;12:208–12.

Kono T, Groff WF, Sakurai H, Yamaki T, Soejima K,Nozaki M. Treatment of traumatic scars using plasmaskin regeration (PSR) system. Lasers Surg Med.2009;41:128–30.

Lee HS, Lee JH, AhnGY, Lee DH, Shin JW, KimDH, et al.Fractional photothermolysis for the treatment of acnescars: a report of 27 Korean patients. J DermatologTreat. 2008;19:45–9.

Manstein D, Herron GS, Sink RK, Tanner H, AndersonRR. Fractional photothermolysis: a new concept ofthermal injury. Lasers Surg Med. 2004;34:426–38.

Tanzi E, Wanitphakdeedecha R, Alster TS. Fraxel laser indi-cations and long-term follow-up. Aesthet SurgJ. 2008;28:675–8.

Wang LZ, Ding JP, Yang MY, Chen DW, ChenB. Treatment of facial post-burn hyperpigmentationusing micro-plasma radiofrequency technology. LasersMed Sci. 2015;30:241–5.

Xiu F, Li-hong L, Alexiades-Armenakas MR,Luebberding S, Cui-ping S, Yue H, et al. Histologicaland electron microscopic analysis of fractional micro-plasma radio-frequency technology effects. J DrugsDermatol. 2013;12:1210–4.

Ablative Radiofrequency in Cosmetic Dermatology 401

Part IV

Ultrasound and Cryolipolysis

Ultrasound for Lipolysis

Shirlei Schnaider Borelli, Maria Fernanda Longo Borsato, andBruna Backsmann Braga

AbstractBody sculpting refers to the use of either sur-gical or noninvasive techniques to modify theappearance of the body. Throughout the yearsnoninvasive procedures for body sculptinggained interest of patients because of thereduced risks and complications. Technologiesaiming aesthetic body sculpting includecryolipolysis, radiofrequency, light energy,low-intensity nonthermal focused ultrasound,or the combination of low-energy sources withmechanical manipulation. In this followingchapter, we are going to discuss a new nonin-vasive technology using high-intensityfocused ultrasound (HIFU) for ablation of theunwanted adipose tissue, evidencing its mech-anisms and possible results for body sculpting.

KeywordsBody sculpting • Adipose tissue • Ultrasound •High-intensity focused ultrasound • Noninva-sive techniques

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405

Basic Concepts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406

HIFU Device . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406

Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406

Indications and Contraindications . . . . . . . . . . . . . . . . 407

Efficacy and Fat Reduction . . . . . . . . . . . . . . . . . . . . . . . . 407

Side Effects and Their Managements . . . . . . . . . . . . . 407

Procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408

After Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408

Take Home Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408

Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409

Introduction

Body sculpting procedures are becoming increas-ingly popular in all over the world. Body sculptingrefers to the use of either surgical or noninvasivetechniques to modify the appearance of the body(Jewell et al. 2011a). Body sculpting is indicatedfor focal adiposity (abdomen, thighs, or hips);skin laxity (neck, arms); or both. Patients whohave both focal adiposity and skin laxity usuallyrequire combined treatment (Jewell et al. 2011a;Kennedy et al. 2015). For many years a widerange of invasive procedures including liposuction

S.S. Borelli (*) • M.F. Longo Borsato • B.B. BragaBrazilian Society of Dermatology, Private Office in SãoPaulo, São Paulo, Brazile-mail: clinica@dermat.com.br; shirleiborelli@hotmail.com; mfernandaborsato@hotmail.com; bruna.bbraga15@gmail.com

# Springer International Publishing AG 2018M.C.A. Issa, B. Tamura (eds.), Lasers, Lights and Other Technologies, Clinical Approaches and Procedures inCosmetic Dermatology 3, https://doi.org/10.1007/978-3-319-16799-2_31

405

were available for body sculpting (Jewell et al.2011a; Mordon and Plot 2009). Although liposuc-tion is extremely effective at removing largeamounts of excess fat, it is accompanied by sig-nificant risk of complications and severe adverseeffects. These may include postprocedural pain,infection, prolonged recovery, scarring, hema-toma, ecchymosis, or edema (Kennedy et al.2015; Mordon and Plot 2009).

Recently there is a tendency to achieve bodyfat reduction without substantial risks and finan-cial costs, without long recovery time and withless postprocedure complications. The number ofpatients seeking cosmetic minimally invasive pro-cedures had increased 110% from 2000 to 2010.Technologies aiming aesthetic body sculptinginclude cryolipolysis, radiofrequency, lightenergy, low-intensity no thermal focused ultra-sound, or the combination of low-energy sourceswith mechanical manipulation. A new noninva-sive technology using high-intensity focusedultrasound (HIFU) for ablation of unwanted adi-pose tissue has shown positive results (Jewellet al. 2011a, b).

Basic Concepts

Adipocytes, commonly known as fat cells, areconnective-tissue cells specialized to synthesizeand contain large globules of fat. Ultrasound canlyse adipocytes through mechanical and thermalmechanisms (Jewell et al. 2011a). Ultrasound isan oscillating pressure wave that propagates at thespeed of sound. Ultrasonic waves are character-ized by intensity, expressed in W/cm2, and fre-quency, expressed as kilohertz (kHz) ormegahertz (MHz). When ultrasonic waves pene-trate and travel through tissue, they lose energy asthey are reflected, scattered, or absorbed by thetissues. Sufficient quantities of absorbed energycreate molecular vibrations in body tissues, gen-erating heat (Haar and Coussios 2007).

There are two categories of ultrasound used forbody sculpting: a low-intensity/low-frequencynonthermal ultrasound and HIFU. The nonther-mal ultrasound disrupts adipose tissue through

mechanical stress generated from inertial cavita-tion. In general, cavitation is less predictable thanHIFU thermal effects (Jewell et al. 2011a).

HIFU Device

The ultrasonic energy used in HIFU device isgenerated by an internally focused transducer,which focuses the waves so that they converge ata specified depth and location. LipoSonix system(Medicis Technologies Corporation, Scottsdale,AZ, USA) uses this technology.

Mechanism of Action

Sound is a mechanical compression wave thattravels through a medium. They are not electro-magnetic waves like RF, Laser or IPL. High-intensity focused ultrasound (HIFU) is a noninva-sive technology which mechanisms involve ther-mal ablation of the adipose tissue. It has intensity1000 times greater than diagnostic ultrasound.HIFU crosses skin and superficial tissue withoutcausing injury. This energy quickly deposited in asmall area, creating heat. High intensities in theHIFU focal zone result in nonlinear effects in theultrasonic beam that multiply the heating rateseveralfold (Jewell et al. 2011a). By raising localtemperature above 56 �C at a focal point withinsubcutaneous tissue, HIFU results in a coagulativenecrosis and subsequently rapid cell death withinthe targeted area, but it doesn’t affect the tissue inthe ultrasound propagation path (Fatemi and Kane2010). Irreversible cell death of fat cells occursafter 1 s at temperature >56 �C.

For body sculpting, thermal HIFU focusesenergy adequate for ablation of targeted adi-pose tissue using ultrasonic waves at a fre-quency of 2 MHz and an intensity exceeding1000 W/cm2. At 2 MHz, a tightly focusedHIFU beam creates a lesion in adipose tissueabout 1 mm in diameter and 10 mm in length(Haar and Coussios 2007). This frequency hasbeen proven capable of disrupting adipocytesand contracting collagen fibers present in the

406 S.S. Borelli et al.

subcutaneous layer to tighten skin (Ferraroet al. 2008). Lesions do not affect the overly-ing dermis or underlying fascia. There are noinjuries to major vascular and nervous tissueoutside the targeted treatment areas (Gadsdenet al. 2010).

The disrupted adipocytes and the released tri-glyceride content are subsequently resorbedthrough a normal physiological pathway viainflammatory cells. The adipose tissue removaldoes not induce any clinical significant acute orchronic changes in lipid metabolism, free fattyacids, glucose metabolism, and liver function(Murray et al. 2005a).

Pathophysiological changes, induced by HIFU,occur from several hours until 8 weeks. Histolog-ical findings during the peri-acute (hours) and acute(7 days) phase revealed a well-demarcated zone ofadipocyte disruption with minimal inflammatoryresponse consisting predominantly of macro-phages. Scavenger macrophages with abundantfoamy cytoplasm are found within the treatmentzones at the fourth week. After 8 weeks, 75% ofresolution of the treated adipose tissue occurs withcollapse of the surrounding fibrovascular stroma(Murray et al. 2005b).

Indications and Contraindications

The indication of the treatment areas may varydepending on the locality:

In USA: Indicated for noninvasive circumferencereduction (i.e., abdomen and flanks)

In Europe: Indicated for trunk and lower extrem-ities, excluding inner leg (i.e., abdomen,flanks, thighs, buttocks)

In Canada: Indicated for abdomen, flanks, thighs,buttocks.

The procedure is indicated for patients withbody mass index lower than 30, an overall healthylife style, an average skin tightness, and lack ofskin folds in the treated area. There needs to be aminimal quantity (1.0 cm) of subcutaneous tissuebelow the focal area, which can be detected by an

impingement test. Impinge test must measure atleast 2.5 cm of fat to indicate the treatment.

Patients with body mass index higher than30, scars and/or wounds in the focal areas, severeskin flaccidity, or redundant folds in the skin areconsidered inappropriate candidates for theprocedure.

Contraindications include the presence of her-nia in the treated area, pregnancy or the suspicionof pregnancy. Additional contraindicationsinclude implants or foreign bodies of any kind inthe treatment area; the use of medicaments toprevent blood coagulation or platelets aggregation(low daily dose aspirin are allowed); the use ofsteroid or chronic immunosuppressive therapy;systemic or localized skin disease; past of lipo-suction, lipolysis injection, abdominoplasty; sur-geries, laser, RF, cryolipolysis within the last90 days.

Efficacy and Fat Reduction

In literature, studies about HIFU efficacy forabdomen area or waist treatment report circum-ferential reduction greater than 2 cm (Jewell et al.2011a, b). Three HIFU studies reported reductionsof 4.1–4.7 cm (Fatemi and Kane 2010; Fatemi2009; Teitelbaum et al. 2007) and four showedreductions of 2.1–2.5 cm (Shek et al. 2014; Solishet al. 2012; Hotta 2010; Gadsden et al. 2011). OneHIFU study showed a 1.6 cm reduction in thethighs (Teitelbaum et al. 2007). In our experience,it is possible to achieve reductions of approxi-mately 10% of the initial measurement of thearea treated after one single session.

Side Effects and Their Managements

Patients should be advised about all the stages ofHIFU treatment. Possible sensations during treatmentinclude discomfort, cold, heat, tingling, and stinging.HIFU studies reported procedural pain (90.2%), post-procedural pain (56.6%), ecchymosis (66.4%),edema (9–72%), dysesthesia (59%), and erythemaon treatment sites (45%) (Solish et al. 2012;

Ultrasound for Lipolysis 407

Hotta 2010). Most of these adverse eventsresolved spontaneously within 4 weeks, but theycan last 12 weeks. Hard lumps, prolonged tender-ness, discomfort, burning sensation, mild blisters,and purpura had also been reported (Fatemi 2009;Teitelbaum et al. 2007; Hotta 2010).

The pain is handled with oral analgesic, whichcan be offered just after the procedure andsustained until necessary.

Ecchymosis can last 2–3 weeks and it issolved by itself, but if patients ask for treatmentsome creams containing cumarin and heparin orvitamin K can be applied until completeresolution.

If nodules occur, therapeutic massages areindicated after 3 weeks.

Procedure

• Evaluate, measure, and photograph the patient.• Shave (if the area is very hairy) and clean the

treatment area.• Marking the circle of treatment(s) while the

patient is standing. Reassess the area of treat-ment, with patient in dorsal decubitus.

• Mark the treatment area with thenumbered grid.

• Remove excess paint.• Select the treatment model and fluency.• Align the treatment head on the treatment site

and activate the device.• Execute three or more shots at the same loca-

tion (site) until reaching the appropriate totalfluence 140–180 J/cm2.

• Clear the area after completion of all treatmentpoints.

After Treatment

The way to handle the expectations of the patientis very important. The patient should be advisedthat the reduction of the measure is gradual. Themaximum effect of treatment with HIFU will usu-ally be seen approximately 8–12 weeks after treat-ment (Figs. 1, 2, and 3).

Some studies have reported satisfaction ratesranging from 47.5% to 85% (Fatemi and Kane2010; Fatemi 2009; Hotta 2010). However, asother aesthetic procedures, up to 20% of patientsmay not have satisfactory results.

Measures and good photography are essentialfor patient satisfaction. Follow-up visits should bescheduled with the patient for measurements andphotos. The same person should perform thepatient’s measurements at each visit to decreasevariability.

Take Home Messages

• With the aim of reaching best results the appro-priate patient selection is essential.

• Adjusting realistic expectation is always a con-cern when approaching body-sculptingtechniques.

Fig. 1 Before and after 12 weeks (diagonal view)

408 S.S. Borelli et al.

• Results are usually seen between 8 and12 weeks after the treatment.

• Individual results may vary. It is possible toachieve reductions of approximately 10% ofthe initial measurement.

Cross-References

▶Cryolipolysis for Body Sculpting

References

Fatemi A. High-intensity focused ultrasound effectivelyreduces adipose tissue. Semin Cutan Med Surg.2009;28(4):257–62.

Fatemi A, Kane MA. High-intensity focused ultrasoundeffectively reduces waist circumference by ablatingadipose tissue from the abdomen and flanks: a retro-spective case series. Aesthet Plast Surg. 2010;34(5):577–82.

Ferraro GA, De Francesco F, Nicoletti G, Rossano F,D’Andrea F. Histologic effects of external ultrasound-assisted lipectomy on adipose tissue. Aesthet PlastSurg. 2008;32(1):111–5.

Gadsden E, Smoller B, Rock L, Aguilar MT, Jewell M,Glogau R. The clinical safety and histologic changesFig. 3 Before and after 8 weeks (lateral view)

Fig. 2 Before and after 12 weeks (lateral view)

Ultrasound for Lipolysis 409

associated with the use of a novel high-intensityfocused ultrasound device for noninvasive bodysculpting. J Am Acad Dermatol. 2010;62(3):AB142.

Gadsden E, Aguilar MT, Smoller BR, JewellML. Evaluation of a novel high-intensity focused ultra-sound device for ablating subcutaneous adipose tissuefor noninvasive body contouring: safety studies inhuman volunteers. Aesthet Surg J. 2011;31(4):401–10.

Haar GT, Coussios C. High intensity focused ultrasound:physical principles and devices. Int J Hyperth.2007;23(2):89–104.

Hotta TA. Nonsurgical body contouring with focused ultra-sound. Plast Surg Nurs. 2010;30(2):77–82. quiz 83–4.doi: 10.1097/PSN.0b013e3181dee9c9.

Jewell ML, Solish NJ, Desilets CS. Noninvasive bodysculpting technologies with an emphasis on high-intensity focused ultrasound. Aesthet Plast Surg.2011a;35(5):901–12.

Jewell ML, Baxter RA, Cox SE, Donofrio LM, Dover JS,Glogau RG, et al. Randomized sham-controlled trialto evaluate the safety and effectiveness of a high-intensity focused ultrasound device for noninvasivebody sculpting. Plast Reconstr Surg. 2011b;128(1):253–62.

Kennedy J, Verne S, Griffith R, Falto-Aizpurua L, NouriK. Non-invasive subcutaneous fat reduction: areview. J Eur Acad Dermatol Venereol. 2015;29(9):1679–88.

Mordon S, Plot E. Laser lipolysis versus traditional lipo-suction for fat removal. Expert Rev Med Devices.2009;6(6):677–88.

Murray EG, Rivas OEA, Stecco KA, Desilets CS, Kunz L.Evaluation of the acute and chronic systemic andmetabolic effects from the use of high intensity focusedultrasound for adipose tissue removal and non-invasivebody sculpting: P27. Plast Reconstr Surg.2005a;116(3):151–2.

Murray EG, Rivas OEA, Stecco KA, Desilets CS, KunzL. The use and mechanism of action of high intensityfocused ultrasound for adipose tissue removal andnon-invasive body sculpting: P80. Plast ReconstrSurg. 2005b;116(3):222–3.

Shek SY, Yeung CK, Chan JC, Chan HH. Efficacy of high-intensity focused ultrasonography for noninvasivebody sculpting in Chinese patients. Lasers Surg Med.2014;46(4):263–9.

Solish N, Lin X, Axford-Gatley RA, Strangman NM, KaneM. A randomized, single-blind, postmarketing study ofmultiple energy levels of high-intensity focused ultra-sound for noninvasive body sculpting. Dermatol Surg.2012;38(1):58–67.

Teitelbaum SA, Burns JL, Kubota J, Matsuda H, Otto MJ,Shirakabe Y, et al. Noninvasive body contouring byfocused ultrasound: safety and efficacy of the ContourI device in amulticenter, controlled, clinical study. PlastReconstr Surg. 2007;120(3):779–89.

410 S.S. Borelli et al.

Ultrasound for Tightening

Guilherme Bueno de Oliveira and Carlos Roberto Antonio

AbstractUltrasound is a well-known method used formedical imaging. However, microfocused ultra-sound differs for emitting a convergent beam ofenergy at a specific point. For this, the differenttypes of devices that use ultrasound energy areused for a small focal point, where high temper-atures are adequate to cause tissue coagulation.The technology exclusively depends on heat forits effects on the tissue. The objective is to raisethe local temperature to at least 65 �C, which is atemperature suitable for collagen contraction. Bydirecting the focused energy wave into deepareas, it causes thermal coagulation points spar-ing adjacent nontarget tissues. The resultobtained when treating this structure is of tissuecontraction with effective noninvasive lifting ofthe skin of the neck and face, in addition to theimprovement of fine lines and wrinkles. Thischapter is going to describe basic concepts ofthis new technology and explain the procedureand its indications.

KeywordsUltrasound • Tightening • Flaccid skin •SMAS • Collagen

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411

Patient Selection: Indicationsand Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . 412

Application Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413Pretreatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413Demarcation of the Area to Be Treated . . . . . . . . . . . . . 413Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 415Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 415

Side Effects and Their Managements . . . . . . . . . . . . . 415Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 415Transient Erythema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 417Less Common Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . 417

Take Home Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 417

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 418

Introduction

The Dermatology participates in the revolution ofdevelopment of noninvasive technologies for tissuecontraction and consequent lifting effect. Amongthe numerous devices and variety of energy tech-nologies that have been recently developed for thispurpose, microfocused ultrasound is also included.For this, according to Alam et al. (2010) the differ-ent types of devices that use ultrasound energy areused for a small focal point, where high tempera-tures are adequate to cause tissue coagulation.

G.B. de Oliveira (*)Faculdade de Medicina Estadual de São José do Rio Preto– FAMERP, São José do Rio Preto, SP, Brazile-mail: drguilhermebueno@hotmail.com

C.R. AntonioFaculdade de Medicina Estadual de São José do Rio Preto– FAMERP, São José do Rio Preto, SP, Brazil

Hospital de Base de São José do Rio Preto, São Paulo,Brazile-mail: carlos@ipele.com.br

# Springer International Publishing AG 2018M.C.A. Issa, B. Tamura (eds.), Lasers, Lights and Other Technologies, Clinical Approaches and Procedures inCosmetic Dermatology 3, https://doi.org/10.1007/978-3-319-16799-2_32

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Similar to the traditional ultrasound used for medi-cal imaging, the focused beam of energy can passinoffensively through the epidermis, allowing thefocal point to reach deeper tissues, such as the deepdermis, subcutaneous and superficial aponeuroticmuscular system (SMAS),where a temperaturereaches approximately 65 �C and causes proteindenaturation within milliseconds.

According to Kim et al. (2008), one distinctionmust be made between the two main types offocused ultrasound used in medicine. High-inten-sity focused ultrasound (HIFU) uses high-energywaves and is primarily used for deep tissue med-ical applications between 1.1 cm and 1.8 cm, suchas for ablating adipose tissue to the contour of thebody. In contrast, microfused ultrasound (MFU)uses much lower energy waves to treat the moresuperficial layers of the skin, between 1.5 mm and4.5 mm. Despite its lower energy, the MFU is ableto stimulate tissue heating above 60 �C, producingsmall coagulation points (less than 1 mm3) to adepth of up to 5 mm, reaching the deep dermis andSMAS, sparing the overlying epidermis.

According to Baumann and Zelickson (2016),the MFU only depends on heat to achieve itseffects on the tissue. The goal is to raise the localtemperature to at least 65 �C, which is the temper-ature at which collagen contraction begins. Bydirecting the focused energy wave into deepareas, the MFU causes thermal coagulation pointssparing adjacent nontarget tissues. In addition tolocal coagulation, the application of heat causesthe collagen fibers in the SMAS and subcutaneousfat layer to become denatured and contract. Thisoccurs by breaking intramolecular hydrogenbonds, determining the fold of the collagen chainsand consequent configuration more stable andwith thicker fiber. In addition, neo-collagen for-mation occurs within the areas of thermal tissuecoagulation and new forms of viscoelastic colla-gen are produced, resulting in tissue contraction offlaccid skin. The MFU aims to treat facial SMAS,a fan-shaped structure that covers the face andconnects the facial muscles with the dermis. Theresult obtained when treating this structure is oftissue contraction with a noninvasive lifting effectof all the skin of the neck and face, in addition tothe improvement of fine lines and wrinkles.

The treatment with MFU can be customized tomeet the unique physical characteristics of eachpatient, adjusting the energy and focal depth of theemitted ultrasound wave. These options differ intheir focus and wavelength, wherein the depth andamount of energy delivered during the treatmentmay be varied to achieve a desired effect withinthe target tissue layer. Currently available trans-ducers emit 10.0 MHz, 7.0 MHz, and 4.0 MHzfrequencies with focal depths of 1.5 mm, 3.0 mm,and 4.5 mm, respectively. Two 10 MHz/1.5 mmand 7.0 MHz/3.0 mm transducers are also avail-able to allow the release of energy into smalleranatomical regions that are harder to reach withlarger transducers. Together, these transducers canbe used in combination to achieve superficial der-mis (1.5 mm), deep dermis (3.0 mm), or subcuta-neous tissues and SMAS (4.5 mm).

According to Dayan et al. (2014), there arecommercially available MFU devices that arealso capable of generating high-resolution ultra-sound imaging, allowing the tissue plane to beviewed at a depth of 8 mm and making the usersee where the energy will be applied. Accordingto Hitchcock and Dobke (2014), each handpieceuses high-resolution ultrasound that is capable ofclearly generating the image of the target facialanatomy, including skin, subcutaneous fat,SMAS, facial muscles, and underlying bone.This ensures a treatment at the appropriate depthand allows avoiding inadvertent treatment of non-target tissue, such as bone and larger blood ves-sels. The image also allows the operator to becertain of the appropriate acoustic couplingbetween the transducer and the skin prior to apply-ing power from the MFU.

Patient Selection: Indicationsand Contraindications

According to Oni et al. (2014), there are relativelyfew absolute contraindications to the use of MFU.These include infections and open cutaneouslesions in the treatment area, severe acne or activecystic, presence of active metal implants such aspacemakers or defibrillators in the treatment area.Precautions include treatment directly on keloids,

412 G.B. de Oliveira and C.R. Antonio

permanent dermal fillers, and the presence of fac-tors that could alter or impair wound healing, suchas smoking.

Although not all people achieve a full aes-thetic benefit with the MFU, patient satisfactionwill be enhanced by appropriate patient selectionand realistic expectations. MFU is best suited forpatients with mild to moderate muscle and skinaccording to MacGregor and Tanzi (2013), flac-cidity. An ideal patient is younger with normalhealing, since the clinical response to treatmentwith MFU depends in part on the synthesis ofnew collagen and the so-called wound healing.Patients older or heavily damaged by light, sag-ging skin, marked looseness of the platysmalbands may require a higher energy density dur-ing a single treatment or more than one treatmentto achieve the maximum benefits of the technol-ogy. In this way, older patients with extensivephotodamage, severe skin sagging, and verymarked platysma bands are not good candidatesfor treatment with MFU, and surgical treatmentor other adjuvant technologies should berecommended.

Application Technique

Pretreatment

In the author’s practice, patients typically receivethe topical application of lidocaine 12% andingested paracetamol 500 mg + codeine 30 mg45 mins before the procedure, diazepam 5–10 mgis administered only if there is much anxiety.

Demarcation of the Area to Be Treated

The MFU devices have standardized protocol ofshots according to the type of transducer to beused and to the region. According to Brobst etal. (2012, 2014), these protocols have standarddemarcation and predeterrminated number ofshots in each region. It is important to respectthe demarcation to avoid side effects, as MFUshould not be applied in area where there aresuperficial nerves.

The demarcation recommended by the industryis followed by a marking ruler that accompanies theapparatus. This has the correct size because it is theappropriate space between the lines of applicationof the transducer. In this way, there is greater secu-rity for not overcoming shots of the MFU in theregion to be treated. According to Fabi (2015), themarking should be done with white pencil, and itmust obey the following steps: (1) draw a line onthe entire mandibular contour and mental region;(2) draw a line over the arc line of the zygomaticbone, bypassing the orbital region, until it reachesthe nasal region; (3) demarcate the regions of dan-ger for application of the MFU on the face – draw aline in the nasogenian sulcus, extending to the jawline. In the encounter of these lines, mark 2 cm forlateral and 1 cm for top to make a square of protec-tion of the branch of the marginal nerve of themandible. To mark the infraorbital nerve region asa danger area follow these steps: (4) on the upperthird of the face, draw a line between the lateralepicanto and the capillary implant line and, with thesize of a ruler above this line, draw a second line,thus creating an application space; draw a linebetween the eyebrow tail and the capillary implantline and, as long as an application ruler is on themedial side, draw a second line, thereby creating anapplication space in the frontal region. (5) In theregion of the neck palpate the eminence of thethyroid cartilage, mark 1 cm up and 1 cm on eachside of it and draw a safety area running down theentire region of the trachea, draw a second line overthe clavicular line. (6) After these defined lines, wemust make markings on the face and neck, all withthe size of onemarking ruler, vertically, totaling twoto three areas of application on the face by side andtwo to three areas of application in the neck per side,added of one central area. Each area has the totalnumber of shots defined by manufacturers andvaries according to the machine the user owns.

In the author’s practice, the marking isperformed after the identification of the saggingvectors. The flaccidity vectors of the face and neckobey a diagonal fall in the median direction. Thisangulation of the vector is determined by palpa-tion in clinical examination, since this saggingSMAS is variable among patients. The evaluationtechnique consists of clamping the fingers on a

Ultrasound for Tightening 413

part of the skin and its traction to a point wherethere is better lifting effect response. Thus, wedemarcate the necessary angulation to draw thelines of application of the MFU. We respect allthe safety lines, changing only the direction ofthe marking lines, following the order: (1) Drawa line on the entire mandibular contour and men-tal region; (2) Draw a line over the arc line of thezygomatic bone, bypassing the orbital region,until it reaches the nasal region; (3) Demarcatethe regions of danger for application of the MFUon the face – draw a line in the nasogeniansulcus, extending to the jaw line. In the encounterof these lines, mark 2 cm for lateral and 1 cm fortop to make a square of protection of the branchof the marginal nerve of the mandible. To markthe infraorbital nerve region as a danger areafollow these steps: (4) on the upper third of theface, draw a line between the lateral epicanto andthe capillary implant line and, with the size of aruler above this line, draw a second line, thuscreating an application space; draw a linebetween the eyebrow tail and the capillary

implant line and, as long as an application ruleris on the medial side, draw a second line, therebycreating an application space in the frontalregion. (5) In the region of the neck palpate theeminence of the thyroid cartilage, mark 1 cm upand 1 cm on each side of it and draw a safety arearunning down the entire region of the trachea,draw a second line over the clavicular line.(6) After these defined lines, we must makemarkings on the face and neck, all with the sizeof one marking ruler, diagonally opposite thesagging vectors identified by the techniquedescribed above, totaling three to five areas ofapplication on the face by side and four to sixapplication areas in the neck for side, added ofone central area. The total number of shots perarea is defined by immediate clinical response atthe time of the procedure. The total number ofshots in the area never exceeds the total releasedby the company, but the total per space of appli-cation is not equal between them. They dependon the immediate response of the patient’s skin.(Figs. 1 and 2).

Fig. 1 Diagonal marking, right side Fig. 2 Diagonal marking, left side

414 G.B. de Oliveira and C.R. Antonio

Application

The number of shots with each transducer hasbeen previously determined between minimumand maximum numbers of shots by the companyfor each region. Preference is given to the maxi-mum energy of the device, which is decreased ifthe patient’s pain sensitivity is low. It shouldalways be started with transducers that reach agreater depth and come superficial with the othertransducers.

In the author’s technique, the number of shotsis respected between the minimum and maximumpredetermined by the company. However, thefinal number is determined clinically by theimmediate treatment outcome.

Results

The effectiveness of MFU treatment is superiorwhen multiple transducers are used. The benefi-cial effects of double depth treatment are evalu-ated by the lifting effect of the middle third of theface, mandibular definition, and reduction of

sagging of the submental skin. The final resultoccurs at 90 days post treatment. New sessioncan only be held after this time period. Usuallythe maintenance is carried out between 10 and18 months.

See results with Ulthera® (Ultherapy®; UltheraInc.) in Figs. 3, 4, and 5 and with AccuTyte®

(Vydence®) in Fig. 6.

Side Effects and Their Managements

Pain

According to Pak et al. (2014), the most com-monly reported side effect associated with MFUis painful discomfort during the treatment session.In the literature, studies do not report significantpain. According to Kakar et al. (2014), sugges-tions for minimizing discomfort during treatmentinclude pretreatment with oral paracetamol, non-steroidal anti-inflammatory drug or narcotic anal-gesic, topical anesthetics with lidocaine whenusing the 1.5 mm transducer, and applying themost energy possible according to the tolerance.

Fig. 3 Improvement of the mandibular contour after treatment

Ultrasound for Tightening 415

Fig. 4 Improvement of the mandibular contour with facial tightening

Fig. 5 Improvement of the mandibular contour after treatment

416 G.B. de Oliveira and C.R. Antonio

In the author’s practice, patients typically receivethe topical application of lidocaine 12% andingested paracetamol 500 mg + codeine 30 mg45 mins before the procedure. Diazepam 5–10 mgis administered only in cases of great anxiety.

Transient Erythema

The second most commonly reported side effect isthe combination of transient erythema and edema(Fig. 7a–c). This is usually transient, giving inmost cases within 3 h after the session. It is dueto regional warming with stimulation of theinflammatory reaction and vasodilation. Patientsdo not usually complain it; however, cold com-presses can be made at most to speed up theimprovement of these symptoms.

Less Common Side Effects

Occasional side effects include postinflammatoryhyperpigmentation after 1 month of treatment, mus-cle weakness and transient local numbness, striated

linear skin excoriations, or papule formation. Thepapules appear to be due to nonideal technique andare more likely to be associated with the use of3 mm and 1.5 mm transducers.

The most serious effects reported in the litera-ture are facial paralysis. The reported cases had amodification of the facial anatomy by previoussurgical facelift or by application in areas knownto be not safe.

Take Home Messages

• Microfocused ultrasound (MFU) aims to treatfacial SMAS, a fan-like structure that covers theface and connects the facial muscles to thedermis.

• The MFU uses special acoustic transducersthat direct the energy of the ultrasound to asmall focal point, where the high temperaturesare able to cause tissue clotting.

• Treatment with MFU should be customized tomeet the unique physical characteristics ofeach patient, adjusting the energy and focal

Fig. 6 Frontal treatmentfor right eyebrow correction

Ultrasound for Tightening 417

depth of the emitted ultrasound wave. Theseoptions differ in their focus and wavelength, inthat the depth and amount of energy suppliedduring the treatment.

• MFU is best suited for patients with mild tomoderate muscle and skin flaccidity. Patientsatisfaction will be enhanced by appropriatepatient selection and realistic expectations.

• Older patients with extensive photodamage,severe sagging skin, and very marked platysma

bands are not good candidates for treatment withMFU, and surgical treatment or other adjuvanttechnologies should be recommended.

References

AlamM,White LE, Martin N, Witherspoon J, Yoo S, WestDP. Ultra-sound tightening of facial and neck skin: arater-blinded prospective cohort study. J Am AcadDermatol. 2010;62:262–9.

Fig. 7 (a) Immediate effect face, frontal view. (b) Immediate effect face, right view. (c) Immediate effect face, left view

418 G.B. de Oliveira and C.R. Antonio

Baumann L, Zelickson B. Evaluation of micro-focusedultrasound for lifting and tightening neck laxity. JDrugs Dermatol. 2016;15(5):607–14.

Brobst RW, Ferguson M, Perkins SW. Ulthera: initial andsix month results. Facial Plast Surg Clin NorthAm. 2012;20:163–76.

Brobst RW, Ferguson M, Perkins SW. Noninvasive treat-ment of the neck. Facial Plast Surg Clin NorthAm. 2014;22:191–202.

Dayan SH, Fabi SG, Goldman MP, Kilmer SL, GoldMH. Prospective, multi-center, pivotal trial evaluatingthe safety and effectiveness of micro-focused ultra-sound with visualization (MFU-V) for improvementin lines and wrinkles of the décolletage. Plast ReconstrSurg. 2014;134(4 suppl 1):123–4.

Fabi SG. Noninvasive skin tightening: focus on new ultra-sound techniques. Clin Cosmet Investig Dermatol.2015;8:47–52.

Hitchcock TM, DobkeMK. Review of the safety profile formicrofocused ultrasound with visualization. J CosmetDermatol. 2014;13(4):329–35.

Kakar R, Ibrahim O, Disphanurat W, et al. Pain in naïveand non- naïve subjects undergoing nonablative skintightening dermatologic procedures: a nested ran-domized control trial. Dermatol Surg. 2014;40(4):398–404.

Kim YS, Rhim H, Choi MJ, Lim HK, Choi D. High-intensity focused ultrasound therapy: an overview forradiologists. Korean J Radiol. 2008;9:291–302.

MacGregor JL, Tanzi EL. Microfocused ultrasound forskin tightening. Semin Cutan Med Surg.2013;32:18–25.

Oni G, Hoxworth R, Teotia S, Brown S, KenkelJM. Evaluation of a microfocused ultrasound systemfor improving skin laxity and tightening in the lowerface. Aesthet Surg J. 2014;34(7):1099–110.

Pak CS, Lee YK, Jeong JH, Kim JH, Seo JD, HeoCY. Safety and efficacy of ulthera in the rejuvenationof aging lower eyelids: a pivotal clinical trial. AestheticPlast Surg. 2014;38(5):861–8.

Ultrasound for Tightening 419

Cryolipolysis for Body Sculpting

Roberta Bibas, Alexandra Cariello Mesquita,Diego Cerqueira Alexandre, and Maria Claudia Almeida Issa

AbstractCryolipolysis is a nonsurgical technique forlocalized fat reduction and it is a promisingprocedure for nonsurgical fat reduction andbody contouring. It presents a compellingalternative to liposuction or any other invasivemethods. This procedure appears to be safe inthe short term, with limited adverse effects, andresults in significant fat reduction when usedfor localized adiposities.

KeywordsCryolipolysis • Nonsurgical fat reduction •Body contouring • Lipolysis • Liposuction

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421

Localized Fat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 422

Cryolipolysis’ Mechanism of Action . . . . . . . . . . . . . . 422

Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426

Procedure and Authors’ Experience . . . . . . . . . . . . . . 427

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427

Take Home Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 428

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 428

Introduction

Body contouring is the most common cosmeticsurgical procedure performed in the United States.Data from the American Society of Aesthetic Plas-tic Surgery indicate that breast augmentation is nolonger the most popular surgical procedure. Lipo-suction has replaced breast augmentation in 2013,with 363,912 procedures (Ingargiola et al. 2015).

Although liposuction constitutes an effectivetherapy for the removal of excess fat tissue, itremains an invasive procedure and carries theinherent risks associated with surgery. Nowadays,novel modalities have been described to addressbody contouring from a less-invasive perspective.These modalities selective destruct adipose cells,targeting the physical properties of them, whichdifferentiate from the overlying epidermis anddermis cells. Devices using high frequency ultra-sound, radiofrequency energy, and laser light havethe potential to improve efficiency, minimizeadverse consequences, and shorten postoperativerecovery time. Thermal destruction, cavitationaldestruction, or creation of a temporary adipocytecell membrane pore induce a reduction of the

R. Bibas (*) • A.C. MesquitaBrazilian Society of Dermatology, Rio de Janeiro, Brazile-mail: rb@robertabibas.com.br;alexandradermato@gmail.com

D.C. AlexandreFluminense Federal University, Niterói, RJ, Brazile-mail: diegocerqueira_dca@hotmail.com

M.C.A. IssaDepartment of Clinical Medicine – Dermatology,Fluminense Federal University, Niterói, RJ, Brazile-mail: dr.mariaissa@gmail.com;maria@mariaissa.com.br

# Springer International Publishing AG 2018M.C.A. Issa, B. Tamura (eds.), Lasers, Lights and Other Technologies, Clinical Approaches and Procedures inCosmetic Dermatology 3, https://doi.org/10.1007/978-3-319-16799-2_37

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number of adipocytes, which results in a measur-able reduction of fat (Ingargiola et al. 2015; Man-stein et al. 2008; Zelickson et al. 2009; Ferraroet al. 2012; Sasaki et al. 2014).

Cryolipolysis is the noninvasive, selectivedestruction of adipose tissue by controlledcooling. The methodology was based on theobservation that lipid-rich cells are more suscep-tible to cryoinjury than the surrounding water-richcounterparts, such as in the overlying dermis andepidermis. The device consists in a cup-shapedapplicator that draws a roll of skin and subcutane-ous adipose tissue between two cooling plates.The temperature of the tissue roll must decreaseto about 0 �C, which normally takes 1 hour. Crys-tallization of cytoplasmic adipocytes lipids initi-ates a cascade of events, characterized byadipocyte apoptosis, panniculitis, and eventualloss of adipocytes. Clinically, this is expressedby an effective decrease in fat layer thickness. In2008, the United States Food and Drug Adminis-tration (FDA) initially approved cryolipolysis forthe noninvasive reduction in focal adiposity of theflanks and later for the abdomen in 2011. Com-mon side effects of the treatment can occur, forexample, temporary erythema, edema, and mildpain. Occasionally, posttreatment pain may lastfor days after treatment (Jalian et al. 2014).

Localized Fat

Obesity is commonly defined as the high accu-mulation of body fat due to imbalancebetween received and burnt calories. Over thepast 20 years, obesity has been raised as ahighly common nutritional disorder and themain risk factor for chronic noninfectious dis-eases worldwide. The prevention and manage-ment of obesity are highly complicatedbecause there is no clear and easy solution.A large proportion of obese individuals needhelp with their weight management. To pre-vent and treat obesity, there are currently dif-ferent types of slimming and beauty systemsof noninvasive intervention such as radio-frequency, cryolipolysis, and surgical inter-ventions such as liposuction, and laser

lipolysis. (chapter ▶ “Ultrasound for Lipoly-sis,” this volume). There are also preventivemethods such as change of lifestyle and diet.The effectiveness, safety, and cost-effectiveness of noninvasive and invasiveinterventions to treat obesity are still unclear.

Recently, novel technologies involving nonin-vasive, energy-based techniques have been devel-oped, signaling a potential paradigm shift in fatreduction and body contouring practices. Themajor goal of these modern therapies includesreduction of tissue mass, with a possible endpoint of noninvasive body contouring (Mansteinet al. 2008; Ferraro et al. 2012).

Cryolipolysis’ Mechanism of Action

In 1970, Epstein and Oren conceived the termpopsicle panniculitis after describing the presenceof an erythematous indurated nodule followed byshort-term fat necrosis in the cheek of an infantwho had been sucking a popsicle. Although cold-induced panniculitis was first described in infants,it has also been observed in adult patients. Theseobservations led to the concept that lipid-rich cellsare more susceptible to cold injury than the sur-rounding water-rich cells (Ingargiola et al. 2015;Manstein et al. 2008; Beacham et al. 1980;Epstein and Oren 1970).

In 2007,Manstein introduced a new noninvasivemethod, termed cryolipolysis, for fat reduction withfreezing technique. This technique is performed byusing an applicator on the targeted area, set at aspecific cooling temperature, for a preset period oftime. This targets adipocytes while sparing the skin,nerves, vessels, and muscles (Manstein et al. 2008).

Cryolipolysis damages exclusively fat cellsthrough a programmed cooling of the skin. Thetreatment received FDA approval for fat reductionof theflanks in 2010, of the abdomen in 2012, and ofthe thighs in 2014. Studies have also demonstratedsafety and effectiveness for treatment of undesirablefat in the back, arms, and chest (Zelickson et al.2009; Stevens et al. 2013; Munavalli 2013).

This technique is based on the concept that fatcells are more sensitive to low temperatures thanthe surrounding tissue. Cold exposure can induce

422 R. Bibas et al.

selective damage to the subcutaneous tissue viainduction of panniculitis, resulting in reduction ofthe superficial fat layer. This damage triggers thedeath of adipocytes, which are subsequentlyengulfed and digested by macrophages. Adipo-cytes undergo apoptosis and necrosis followingexposure to cold temperatures (Manstein et al.2008; Zelickson et al. 2009; Ferraro et al. 2012;Beacham et al. 1980; Nelson et al. 2009; Boey andWasilenchuk 2014).

Initial adipocyte damage is noted histologicallyat day 2 and increases throughout the next month.By 14–30 days of treatment, macrophages andother phagocytes surround, envelope, and digestthe lipid cells as part of the body’s natural responseto injury. Four weeks after the treatment, theinflammation lessens and the adipocyte volumeare decreased. Two to 3 months after the proce-dure, the interlobular septa are distinctly thickenedand the inflammatory process further decreases.By this time, the fat volume in the treated area isapparently reduced and the septa represents themajority of tissue volume (Nelson et al. 2009).

Although its mechanism is not completelyunderstood, it is believed that the vacuum suctionwith regulated heat extraction cuts off the bloodflow and induces lipid crystallization of the targetedcells. In addition, this cold ischemic injury mightpromote cellular damage in adipose tissue via cel-lular edema, reduced Na-K-ATPase activity,reduced adenosine triphosphate, elevated lacticacid levels, and mitochondrial free radical release.Another mechanism described proposes that theinitial lipid crystallization and cold ischemic injuryis further compounded by ischemia reperfusioninjury, causing generation of reactive oxygen spe-cies, elevation of cytosolic calcium levels, and acti-vation of apoptotic pathways. Finally, lipidcrystallization and cold ischemic injury of thetargeted fat cells induce apoptosis of them and apronounced inflammatory response, resulting intheir eventual removal from the treatment sitewithin the following weeks (Ingargiola et al. 2015;Manstein et al. 2008; Zelickson et al. 2009; Sasakiet al. 2014; Pinto et al. 2012; Pinto et al. 2013).

Histological studies show that macrophagesare mostly responsible for clearing the damagedcells and debris. Cryolipolysis may raise blood

lipid and liver enzymes levels due to the removalof adipocytes internally, which might bring addi-tional risk to the patient, particularly for cardio-vascular parameters. However, multiple studieshave demonstrated that cholesterol, triglycerides,low-density lipoprotein, high-density lipoprotein,aspartate/alanine transaminase, total bilirubin,albumin, and glucose blood levels remainedunaltered during and after this procedure.(Ingargiola et al. 2015; Ferraro et al. 2012;Riopelle and Kovach 2009; Coleman et al. 2009;Klein et al. 2009)

As cryolipolysis is a relatively recent technology,some points still need to be considered and investi-gated, including what type of patient would benefitmost from this procedure. Studies suggested that theresults were most visible in patients with discretelocalized adipose tissue and cellulite (Ingargiolaet al. 2015; Ferraro et al. 2012).

Common treatment areas include abdomen,brassiere rolls, lumbar rolls, hip rolls/flanks,inner thighs, medial knee, peritrochanteric areas,arms, and ankle. Follow-up length generallyranges from 2 to 6 months. One study presentedtwo patients at 2 and 5 years after treatment,emphasizing the persistent reduction of fattissue at these time points, when comparingpretreatment and posttreatment photographs(Bernstein 2013) (Figs. 1, 2, 3, 4, 5).

Although a fat reduction in every area examinedwas observed, it is still unknownwhich areas are themost susceptible to cryolipolysis. Various factorsmay contribute to the fat reduction observed afterthis procedure, for instance the vascularity, localcytoarchitecture, and metabolic activity of the spe-cific fat depots (Ingargiola et al. 2015).

A subsequent treatment leads to further fatreduction; nevertheless, the extent of improve-ment was not as expressive as the first session.However, one study demonstrated that a secondtreatment enhanced fat layer reduction in theabdomen area, but not the love handles. Thediminished effect of the second session might beexplained by the fat exposed to the second heatextraction that is closer to the muscle layer. Thevascular supply to the muscle layer may contrib-ute to the inefficiency of heat extraction, notreaching the preset optimal temperature of 4 �C.

Cryolipolysis for Body Sculpting 423

Fig. 1 Before and2 months after one sessionon the dorsal region

Fig. 2 Before and twomonths after one session forlocalized fat on theabdomen. (a)frontal view,(b) posterior view

424 R. Bibas et al.

Fig. 3 Before and2 months after one sessionson the flanks (a) anteriorview, (b) left lateral view

Fig. 4 Before and2 months after one sessionon the abdomen

Cryolipolysis for Body Sculpting 425

Another hypothesis is that adipocytes that sur-vived the first treatment have a higher toleranceto cold (Ingargiola et al. 2015; Munavalli 2013;Boey and Wasilenchuk 2014; Pinto et al. 2012).

Besides subsequent treatment, posttreatmentmassage was also evaluated to explain why thistechnique enhances the efficacy of a singlecryolipolysis treatment. One hypothesis for thepotentially improved efficacy with posttreatmentmanual massage is an additional mechanism ofdamage to the targeted adipose tissue immediatelyafter cooling, perhaps from tissue-reperfusioninjury. Histological analysis revealed no evidenceof necrosis or fibrosis resulting from the massage,thus showing that posttreatment manual massageis a safe and effective method to further reduce thefat layer after cryolipolysis, with excellent out-comes (Ingargiola et al. 2015; Sasaki et al. 2014;Boey and Wasilenchuk 2014).

Adverse Effects

One of the main advantages of cryolipolysis is thelow profile of adverse effects, especially whencompared with more invasive procedures. Onlymild, short-term side effects, such as erythema,bruising, changes in sensation, hypersensitivityand hyposensitivity, and pain, were reported inthe literature. These effects can be mostlyexplained by the strength of the vacuum and the

temperature at which the tissue is kept forextended durations and poses no threat to thepatients (Ingargiola et al. 2015; Ferraro et al.2012; Avram and Harry 2009).

Patients usually observe a red color in thetreated site, which disappear in a few hours. Insome cases, bruises may appear, which could lastfor a week. A feeling of dumbness may occur insome of the treated areas. The decreased nervesensation takes 1–6 weeks (mean 3.6 weeks), butit completely disappears after 2 months. This caseof reduced sensation is self-limited and it does notneed any intervention. No persistent ulcerations,scarring, paresthesias, hematomas, blistering,bleeding, hyperpigmentation or hypo-pigmentation, or infections have been described.Swelling and bruising of the area were shown to aslightly lesser extent than erythema, but arebelieved to be because of the same processes.These complications also subsided shortly after(Ferraro et al. 2012; Nelson et al. 2009).

In one study, pain during the procedure wasgenerally nonexistent to tolerable 96% of the time.Some studies showed no long-term changes tonerve fibers through nerve biopsy taken after nor-mally at 3 months of treatment, concluding thattemperature and duration of cryolipolysis have nopermanent effect on peripheral nervous tissue.Rare side effects that have been described includevasovagal reaction and paradoxical adiposehyperplasia. Jalian et al. estimated an incidence

Fig. 5 Before and2 months after one sessionon the abdomen

426 R. Bibas et al.

of 0.0051 percent, or approximately one in20,000, for paradoxical adipose hyperplasia(Ingargiola et al. 2015; Jalian et al. 2014).

Histologic outcomes were evaluated in a hand-ful of studies. No evidence of fibrosis was noted.Most studies demonstrate an inflammatoryresponse at different stages after cryolipolysis,with inflammatory cell infiltrates peaking at30 days (Coleman et al. 2009).

Contraindications to cryolipolysis includecold-induced conditions, such as cryoglobu-linemia, cold urticaria, and paroxysmal coldhemoglobinuria. Cryolipolysis should not beperformed in treatment areas with severe varicoseveins, dermatitis, or other cutaneous lesions(Ingargiola et al. 2015; Avram and Harry 2009).

Procedure and Authors’ Experience

In our experience, the cryolipolysis treatmentdoes not require a preparation or restriction pre-procedure. The patient should not be fasting andthere is no need to discontinue medications ofregular use. We advise the patient to bring a bikinior trunks to use during the cryolipolysis session.

Firstly, we perform a corporal evaluation of thearea to be treated, which includes photographicdocumentation, measure of the treated area, andfat percentage obtained with an adipometer.

The consent term, given to all patients, clarifiesthe mechanism of action, expected outcome, con-traindications, and adverse effects.

In agreement with the treatment, we mark thearea to be treated, in the proper positions for betteresthetic results (e.g., diamond technique in theabdomen).

When patient’s position is suitable for the cou-pling and comfortable to remain during the treat-ment time, we apply the protective blanket withgel, specific to the device and then, we couple thetip to begin the suction.

During the first 10 minutes, there is a painfuldiscomfort, which ceases due to the analgesiaobtained by freezing the area. The process offreezing a tip takes about 1 hour, varying withtip type and/or manufacturer.

After finishing the treatment cycle, decouplethe tip and notice the formation of a frozen “mass”with the shape of the tip (Fig. 6). The skin of thetreated area should be red, slightly swollen, butintact. Erosions, blisters, or other injuries are notexpected after the procedure. We should then startthe manual massage with gentle movementsaiming to warm the treated area.

Regarding the adverse effects, we commonlyobserve transitory pain, erythema, and edema.Ecchymosis and nodules can occur. In our expe-rience, the greatest discomfort is during the treat-ment of the abdomen. The pain is handled withoral gabapentin, which can be offered just after theprocedure and sustained for 2 weeks if necessary.The edema should not be drained. Ecchymosiscan last 2–3 weeks and it is solved by itself, butif patients ask for treatment some creamscontaining cumarin and heparin or vitamin K canbe applied until complete resolution.

There is no restriction of physical activity in theposttreatment. Also, we do not usually indicate mas-sages as part of the treatment program. The patient isevaluated in 2months and if necessary,we repeat thetreatment aiming at greater loss of local fat.

Conclusion

Cryolipolysis is becoming one of the most popu-lar alternatives to liposuction for local reductionof adipose tissue. Due to its ease of use and limited

Fig. 6 Frozen “mass” with the shape of the tip withErythema and edema immediately after cryolipolysis onthe abdomen

Cryolipolysis for Body Sculpting 427

adverse effects, this procedure is becoming theleading technology of noninvasive techniques aswell. As cryolipolysis is a considerably novelprocedure, treatment protocols still have to beameliorated to maximize results.

Compared with traditional cosmetic surgicalprocedures side effects, cryolipolysis possesses aminor threat to patients, with a very low incidenceof complications. Some studies have comparedcaliper, ultrasound, three-dimensional imaging,and manual tape measurements withcryolipolysis. Although no single study has com-pared all of these modalities, the available datasuggest that these techniques have a good corre-lation with each other.

Cryolipolysis was first described in 2007, andalthough its popularity has increased dramatically,the available literature remains limited. Tremen-dous variability exists in study design, machineryused, and outcome measures. Due to this lack ofuniformity, comparing size effect becomes chal-lenging, and the value of a meta-analysis of theavailable data is limited.

Take Home Messages

Body contouring remains among the most com-mon cosmetic surgical procedure performed inthe United States.

Cryolipolysis is a promising nonsurgical tech-nique for localized fat reduction and bodycontouring.

Cryolipolysis is becoming one of the most popu-lar alternatives to liposuction for spot reductionof adipose tissue.

Cryolipolysis consists of selected damaging of fatcells induced by a programmed cooling of theskin.

Rare side effects that have been described.

References

Avram MM, Harry RS. Cryolipolysis for subcutaneous fatlayer reduction. Lasers Surg Med. 2009;41(10):703–8.

Beacham BE, Cooper PH, Buchanan CS,Weary PE. Equestrian cold panniculitis in women.Arch Dermatol. 1980;116(9):1025–7.

Bernstein EF. Longitudinal evaluation of cryoli-polysis efficacy: two case studies. J Cosmet Dermatol.2013;12(2):149–52.

Boey GE, Wasilenchuk JL. Enhanced clinical outcomewith manual massage following cryolipolysis treat-ment: a 4-month study of safety and efficacy. LasersSurg Med. 2014;46(1):20–6.

Coleman SR, Sachdeva K, Egbert BM, Preciado J,Allison J. Clinical efficacy of noninvasive cryolipolysisand its effects on peripheral nerves. Aesthet Plast Surg.2009;33(4):482–8.

Epstein Jr EH, Oren ME. Popsicle panniculitis. N Engl JMed. 1970;282(17):966–7.

Ferraro GA, De Francesco F, Cataldo C, Rossano F,Nicoletti G, D’Andrea F. Synergistic effects ofcryolipolysis and shock waves for noninvasive bodycontouring. Aesthet Plast Surg. 2012;36(3):666–79.

Ingargiola MJ, Motakef S, Chung MT, Vasconez HC,Sasaki GH. Cryolipolysis for fat reduction and bodycontouring: safety and efficacy of current treatmentparadigms. Plast Reconstr Surg. 2015;135(6):1581–90.

Jalian HR, Avram MM, Garibyan L, Mihm MC,Anderson RR. Paradoxical adipose hyperplasia aftercryolipolysis. JAMA Dermatol. 2014;150(3):317–9.

Klein KB, Zelickson B, Riopelle JG, Okamoto E,Bachelor EP, Harry RS, Preciado JA. Non-invasivecryolipolysis for subcutaneous fat reduction does notaffect serum lipid levels or liver function tests. LasersSurg Med. 2009;41(10):785–90.

Manstein D, Laubach H, Watanabe K, Farinelli W,Zurakowski D, Anderson RR. Selective cryolysis: anovel method of non-invasive fat removal. LasersSurg Med. 2008;40(9):595–604.

Munavalli G. Cryolipolysis for the treatment of male pseudo-gynecomastia. Lasers Surg Med. 2013; 45(S25):16.

Nelson AA, Wasserman D, Avram MM. Cryolipolysis forreduction of excess adipose tissue. Semin Cutan MedSurg. 2009;28(4):244–9.

Pinto HR, Garcia-Cruz E, Melamed GE. A study to eval-uate the action of lipocryolysis. Cryo Letters.2012;33(3):177–81.

Pinto H, Arredondo E, Ricart-Jane D. Evaluation ofadipocytic changes after a simil-lipocryolysis stimulus.Cryo Letters. 2013;34(1):100–5.

Riopelle JT, Kovach B. Lipid and liver function effects ofthe cryolipolysis procedure in a study of male lovehandle reduction. Lasers Surg Med. 2009;41(S21):82.

Sasaki GH, Abelev N, Tevez-Ortiz A. Noninvasive selec-tive cryolipolysis and reperfusion recovery for local-ized natural fat reduction and contouring. AesthetSurg J. 2014;34(3):420–31.

Stevens WG, Pietrzak LK, Spring MA. Broad overview ofa clinical and commercial experience withcoolsculpting. Aesthet Surg J. 2013;33(6):835–46.

Zelickson B, Egbert BM, Preciado J, Allison J, Springer K,Rhoades RW, et al. Cryolipolysis for noninvasive fatcell destruction: initial results from a pig model.Dermatol Surg. 2009;35(10):1462–70.

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Ultrasound-Assisted Drug Deliveryin Fractional Cutaneous Applications

Joseph Lepselter, Alex Britva, Ziv Karni, andMaria Claudia Almeida Issa

AbstractCutaneous biodistribution and bioavailabilityof most topically applied drugs are quite low.For a topical agent to be active, it must firsttraverse the rate-limiting barrier of the stratumcorneum. Many medications are too large(size >500 Da in molecular weight) to pene-trate this barrier which require either an inject-able or systemic delivery. Fractional ablativeskin therapy became a common modality inprocedural dermatology with the ability to cre-ate ablative microscopic channels of varyingdepths in the stratum corneum and other epi-dermal layers in a predictable manner, thuscreating new opportunities in drug delivery.Pairing fractional ablation skin perforationwith physical-assisted modality for theenhancement of drug delivery would seemattractive option for various skin indications.That said, the extent of collateral damage cre-ated by the ablative fractional technology onthe microchannels and the unavoidable exu-dates created by the natural wound healing

process would prove problematic for passivedrug delivery. Recently, a novel ultrasound-assisted drug delivery device (IMPACT™)was introduced and clinically used in pairingwith fractional ablation technology for pushingand enhancing the delivery of substancesimmediately after the skin perforation for thepurpose of increasing biodistribution and bio-availability through the microchannels forvariety of cutaneous indications such as scars,striae distensae, actinic keratosis, or dysplasticskin lesions in photodynamic therapy. Thisultrasound-assisted drug delivery deviceshould be used by a qualified practitioner thatmust possess an understanding in cutaneousanatomy in relation to the local target (indica-tion), appropriate training, and comfort leveland familiarity with the properties and appro-priate selection of the topical agent.

KeywordsTransepidermal drug delivery • Transdermaldrug delivery •Transcutaneous administration •Transdermal administration • Laser •Ultrasound

J. Lepselter (*) • A. Britva • Z. KarniLaser and Ultrasound Laboratory, Alma Lasers Ltd.,Caesarea, Israele-mail: yossil@almalasers.co.il; alexb@almalasers.co.il;zivk@almalasers.co.il

M.C.A. IssaDepartment of Clinical Medicine – Dermatology,Fluminense Federal University, Niterói, RJ, Brazile-mail: dr.mariaissa@gmail.com; maria@mariaissa.com.br

# Springer International Publishing AG 2018M.C.A. Issa, B. Tamura (eds.), Lasers, Lights and Other Technologies, Clinical Approaches and Procedures inCosmetic Dermatology 3, https://doi.org/10.1007/978-3-319-16799-2_33

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ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430

Ultrasound-Skin Interaction in CutaneousApplication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431

Laser-Assisted Skin Permeation inTransepidermal Drug Delivery . . . . . . . . . . . . . . . . 432

Ultrasound-Assisted Drug Delivery inFractional Cutaneous Applications . . . . . . . . . . . 434

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 441

Take Home Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 441

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 442

Introduction

The skin is one of the most readily accessibleorgans of the human body, covering a surfacearea of approximately 2 m2 and receiving aboutone third of the body’s blood circulation Theskin is a complex system consisting of the epi-dermis, the dermis, and skin appendages, suchas hairs, interwoven within the two layers. Theoutermost layer of the skin, the epidermis, isavascular, receiving nutrients from the underly-ing dermal capillaries by diffusion through abasement membrane. The outermost layer ofthe epidermis is called the stratum corneum,the protective covering that serves as a barrierto prevent desiccation of the underlying tissuesand to exclude the entry of noxious substancesfrom the environment, including agents appliedto the skin. This layer consists of corneocytesembedded in lipid regions (Michael et al. 2002).

Transdermal (or transcutaneous) drug deliveryoffers advantages over traditional drug deliverymethods, such as injections and oral delivery. Inparticular, transdermal drug delivery avoids gastro-intestinal drug metabolism, reduces side effects, andcan provide sustained release of therapeutic com-pounds. The term “transdermal” is used genericallybecause, in reality, transport of compounds by pas-sive diffusion occurs only across the epidermiswhere absorption into the blood via capillariesoccurs (Elias and Menon 1991).

However, the diffusion rate of topically appliedcompounds will vary because of both internal(physiological) and external (environmental)

factors. The diffusion rate is also dependentupon physical and chemical properties of the com-pounds being delivered. The patient’s skin needsto be carefully evaluated to minimize the natural,internal barriers to transdermal drug delivery (e.g.,dry skin, thick skin, dehydration, poor circulation,poor metabolism) and to maximize the naturalenhancers (e.g., ensuring the patient is wellhydrated and selecting an area of skin that isthin, warm, moist, and well perfused). The stra-tum corneum is considered to be the rate-limitingbarrier for transdermal delivery, and so diffusionis often enhanced. Various methods include pre-heating the skin to increase kinetic energy anddilate hair follicles and covering the area with anocclusive dressing after the drug application tomaintain moisture and activate the reservoircapacity of the skin (Scheuplein and Blank1971; Prausnitz et al. 2012; Kurihara-Bergstromand Good 1987).

Enhancers of transcutaneous drugs are usuallyused to alter the nature of the stratum corneum toease diffusion. This alteration may result fromdenaturing the structural keratin proteins in thestratum corneum, stripping or delaminating thecornified layers of the stratum corneum, changingcell permeability, or altering the lipid-enrichedintercellular structure between corneocytes.Enhancers are incorporated into transdermal-controlled drug delivery systems, or they areused prior to, during, or after the topical applica-tion of a drug. Preferred enhancers allow drugs todiffuse actively and quickly, but do not inactivatethe drug molecules, damage healthy epidermis,cause pain, or have toxicological side effects(Haftek et al. 1998; Menon and Elias 1997;Akomeah 2010).

Even though ultrasound has been used exten-sively for medical diagnostics and physical ther-apy, it has only recently become popular as anenhancer of drug delivery. Numerous studieshave demonstrated that ultrasound is generallysafe, with no negative long-term or short-termside effects, but the mechanisms by which ultra-sound works for the purpose of transepidermaldrug delivery as an enhancer are less clearlyunderstood (Nino et al. 2010; Prausnitz andLanger 2008; Smith 2007).

430 J. Lepselter et al.

Ultrasound-Skin Interactionin Cutaneous Application

Ultrasound is defined as an acoustic wave at fre-quency of between 20 kHz and 10 MHz. Theproperties defining the ultrasound are the ampli-tude and the frequency of the acoustic waves.Similar to audible sound, ultrasound wavesundergo reflection and refraction, when theyencounter another medium with dissimilar prop-erties. If the properties of the encountered mediumare different from those of the transmittingmedium, the acoustic energy of the transmittedultrasound beam is attenuated by being reflectedfrom this medium. Attenuation of ultrasound byits absorption and scattering in tissue also limitsits depth of penetration (Anselmo and Mitragotri2014; Byl 1995; Mitragotri 2004a).

Ultrasound may bring various reactions whenpropagated in biological tissue. The resultingeffects include thermal, mechanical, chemical,and optical reactions. Mechanical effects, morespecifically, may consist of acoustic cavitation,radiation force, shear stress, and acoustic stream-ing/microstreaming (David and Gary 2010).

The use of ultrasound to enhance the transportof a substance through a liquid medium is referredto as sonophoresis or phonophoresis. It may beused alone or in combination with otherenhancers, such as chemical enhancers, iontopho-resis, electroporation, magnetic force fields, elec-tromagnetic forces, mechanical pressure fields orelectrical fields (Mitragotri 2004b).

Both the thermal and non-thermal character-istics of high-frequency sound waves canenhance the diffusion of topically applieddrugs. Heating from ultrasound increases thekinetic energy of the molecules (mobility) inthe drug and in the cell membrane, dilates pointsof entry such as the hair follicles and the sweatglands, and increases the circulation to thetreated area. These physiological changesenhance the opportunity for drug molecules todiffuse through the stratum corneum and becollected by the capillary network in the dermis.Both the thermal and non-thermal effects ofultrasound increase cell permeability. Themechanical characteristics of the sound wave

also enhance drug diffusion by oscillating thecells at high speed, changing the resting poten-tial of the cell membrane and potentiallydisrupting the cell membrane of some of thecells in the area (David and Gary 2010;Mitragotri 2004b). One of the theories of ultra-sound phoresis postulates that the main factor isincreasing the permeability of a skin by creatinglipid bridges between keratin layers in stratumcorneum (Mason 2011; Guy 2010; Pitt et al.2004).

Another important factor that may affect drugdiffusion is related to the shear forces (or shockwaves) that occur when adjacent portions of thesame membranous structures vibrate with differ-ent displacement amplitudes. The acoustic wavescause streaming and/or cavitation in the drugmedium and the skin layers, which helps thedrug molecules to diffuse into and through theskin. “Streaming” is essentially oscillation in aliquid that forces the liquid away from the sourceof the energy, while “cavitation” is the formationof bubbles in a liquid that is subjected to intensevibration. Cavitation is the result of rarefactionareas during propagation of longitudinal acousticwaves in the liquid when the waves have anamplitude above a certain threshold (Mitragotri2005; Pua and Pei 2009).

When these bubbles occur in specific cells ofthe skin, fatigue or rupture of the cells can occur asthe bubbles reach an unstable size. Destruction ofcells in the transmission path of the ultrasoundmay facilitate intercellular diffusion of drug mol-ecules. Cavitation may also destruct the organiza-tion of lipids in the stratum corneum, resulting inan increase in the distance between the lipidlayers. As a result, the amount of water phase inthe stratum corneum increases thereby enhancingthe diffusion of water-soluble componentsthrough the intercellular space (Sivakumari et al.2005). As the permeation pathway for topicallyapplied products is mainly along the tortuousintercellular route, the lipids in the stratumcorneum play a crucial role in proper skin barrierfunction.

Ultrasound (sonophoresis, phonophoresis, andultraphonophoresis) is a technique for increasingthe skin permeation of drugs using ultrasound

Ultrasound-Assisted Drug Delivery in Fractional Cutaneous Applications 431

(20–16 MHZ) as a physical force. It is a combi-nation of ultrasound therapy with topical drugtherapy to achieve therapeutic drug concentra-tions at selected sites in the skin. In this technique,the drug is mixed with a coupling agent usually agel, but sometimes a cream or ointment is usedwhich transfers ultrasonic energy from the deviceto the skin through this coupling agent (Lee andZhou 2015). Application of low-frequency ultra-sound (20–100 KHZ) enhances skin permeabilitymore effectively than high-frequency ultrasound(1–16 MHZ). The mechanism of transdermal skinpermeation involves disruption of the stratumcorneum lipids, thus allowing the drug to passthrough the skin. A corresponding reduction inskin resistance was observed due to cavitation,microstreaming, and heat generation (Park et al.2014; Mormito et al. 2005; Mitragotri and Kost2001).

With this in mind, burning and abrasion of theepidermis are a serious consideration when usingultrasound. Ultrasound should act as a mechanicalacoustic pressure agent without destructing theepidermis of the skin. However, cavitation in theliquid coupling the sonotrode to the skin mayproduce cavitation erosion of the epidermis andthe dermis. While this cavitation assists withactive penetration of the substance being deliv-ered, such cavitation may also destruct the epider-mis. A further challenge when using ultrasound is

that it is low in efficiency due to cavitation in thebuffer suspension and the low acoustic pressureand ultrasonic energy that is required to preventburning and other injury (Tang et al. 2002;Terahara et al. 2002; Mitragotri and Kost 2000;Mitragotri et al. 1995).

There is an ongoing need for improved devicesand methods to enhance transdermal medical andcosmetic compound delivery. In particular, thereis an ongoing need for ultrasound-based devicesand techniques for transdermal drug or cosmeticdelivery. A low-frequency (kHz) ultrasound-assisted drug delivery technology was developedfor the purpose of transepidermal delivery of top-ical ingredients, i.e., drugs or cosmeceuticals,used in pairing with fractional laser orradiofrequency-assisted technology (Fig. 1a, b).

Laser-Assisted Skin Permeationin Transepidermal Drug Delivery

Fractional ablation of the skin is a special laser-skin interaction event of photo-thermolysis firstdescribed in 2004. Fractional ablative lasers(erbium:YAG and CO2) or other fractional abla-tive modalities such as radiofrequency ablate theskin in fractions, splitting the laser beam intomicrobeams. These microbeams create micro-scopic vertical channels of ablation in the skin.

Fig. 1 A low-frequency (kHz) ultrasound-assisted drug delivery technology (IMPACT™). The ultrasound applicator (a)handpiece and its sonotrode (b)

432 J. Lepselter et al.

The creation of these channels may provide accesspathways for topically applied drug moleculesthat would otherwise be too large to traverse theepidermal layer. The location, diameter, depth,and other characteristics of these channels can becontrolled or manipulated by the settings of thelaser or radiofrequency technology (Mansteinet al. 2004; Alexiades-Armenakas et al. 2008;Haak et al. 2011; Lin et al. 2014; Carniol et al.2015; Forster et al. 2010).

Investigation into the in vitro/in vivo effective-ness of fractional laser devices for facilitatingdrug permeation in animals is abundant. How-ever, few studies have examined clinical studiesof the laser-assisted drug delivery in humans.

Oni et al. (2012) demonstrated in vivo lido-caine absorption by the fractional Er:YAG laserusing pig as the animal model. The drug level inthe serum was detected after topical application of4% lidocaine. The serum concentration wasundetectable in the nontreated group. The serumlevel was detectable following laser treatment.Peak levels of lidocaine were significantly greaterat 250-μm pore depth (0.62 mg/l), compared to500 μm (0.45 mg/l), 50 μm (0.48 mg/l), and 25 μm(0.3 mg/l). The greater depth of the microchannelsdid not guarantee greater enhancement.

Haersdal et al. (2010) evaluated skin deliveryassisted by the fractional CO2 laser by usingmethyl aminolevulinic (MAL) as the modelpermeant. MAL is an ester prodrug ofaminolevulinic acid (ALA). Yorkshire swinewere treated with the fractional CO2 laser andwere subsequently applied with MAL. Fluores-cence derived from protoporphyrin IX (PpIX)was measured by fluorescence microscopy at askin depth of 1800 μm. The fractional laser cre-ated cone-shaped channels of 300 μm in diameterand 1850 μm in depth. This ablation enhanceddrug delivery with higher fluorescence in thehair follicles and dermis as compared to intactskin. The fractional laser irradiation facilitatestopical delivery of porphyrin precursor deep intothe skin. Haedersdal et al. (2011) also investigatedthe MLA permeation enhanced by fractional CO2

laser quantifying PpIX skin distribution and pho-todynamic therapy (PDT)-induced photo-bleaching from the skin surface to the depth of

1800 μm in Yorkshire swine. The red light forcreating photobleaching was light-emitting diodearrays delivered at fluencies of 37 and 200 J/cm2.The fraction of porphyrin fluorescence lost byphotobleaching was less after 37 J/cm2 than after200 J/cm2. The fractional laser greatly facilitatedthe skin PpIX, and the fraction of photobleachedporphyrins was similar for the superficial anddeep skin layers. Distribution of PpIX into laser-treated skin may depend on the microchanneldepth and the drug incubation period. Haak et al.(2012a) further evaluated whether the depth of thefractional laser and the incubation time affectmethyl ALA permeation. Yorkshire swine weretreated with the fractional CO2 laser at 37, 190 and380 mJ to create microchannel depths of300 (superficial), 1400 (mid) and 2100 μm (deepdermis/subcutaneous), respectively. The incuba-tion times for methyl ALA cream were 30, 60,120, and 180 min. Similar fluorescence of PpIXwas induced throughout the skin layers indepen-dent of the laser channel depth by a 180-minincubation. Laser irradiation and the followingmethyl ALA incubation for 60 min increasedfluorescence in the skin surface compared to intactskin. Laser exposure and the subsequent methylALA incubation for 120 min increased fluores-cence in the follicles and the dermis compared tointact skin.

Treatment of scars, including hypertrophicscars and keloids, intrinsically poses a deliverychallenge given their variable and fibrotic nature,especially when considering penetration into themid-to-deep dermis. Corticosteroids, 5- fluoroura-cil (5-FU), imiquimod, methotrexate, and otherimmunomodulators have been used as adjuvantscar therapies for years. However, when usedtopically, these agents demonstrate only mild effi-cacy and may carry risks such as corticosteroid-related epidermal atrophy. Intralesional use mayprove more efficacious but may also be associatedwith significant pain, atrophy, pigmentarychanges, and a high recurrence rate (Haak et al.2012a; Brauer et al. 2014). Furthermore, theextent of collateral damage created by fractionalablative lasers or non-laser fractional technologyand the post-trauma exudate (interstitial fluid orfibrin) within the microchannels would prove

Ultrasound-Assisted Drug Delivery in Fractional Cutaneous Applications 433

problematic for drug delivery. This is because, thehydrostatic forces pushing the exudative fluid outof the tissue into the channels would directlycompete with the diffusion of the substanceapplied topically. This, therefore, reduces anypotential for passive transdermal diffusion andemphasizes the need for pressure-assisted tech-nology that will immediately push the substanceinto the viable microchannels space (Haedersdalet al. 2011; Haak et al. 2012a, b; Erlendsson et al.2014a).

Ultrasound-Assisted Drug Deliveryin Fractional Cutaneous Applications

In the past two decades, numerous studies havedescribed the usefulness of that low-frequencyultrasound to improve skin permeability. Onlyrecently, application of fractional ablative methodsusing lasers and radiofrequency has been describedfor potential therapeutic purposes in investiga-tional and procedural dermatology, aiming at cre-ating microchannels in the epidermis to increasepermeability of tropically applied drugs in indica-tions such as hypertrophic and atrophic scars andother skin imperfections (Bloom et al. 2013; Sklaret al. 2014; Gauglitz 2013; Arno et al. 2014;Waibel and Rudnick 2015; Rkein et al. 2014;Waibel et al. 2013; Togsverd-Bo et al. 2012,2015; Taudorf et al. 2014; Erlendsson et al.2014b). Table 1 depicts assisted-drug deliverycompounds currently tested and used with frac-tional ablative applications.

A novel ultrasound-assisted drug deliverydevice (IMPACT™) is displayed in Fig. 1. Theultrasound applicator is an acoustic wave propri-etary technology (Britva et al.) that operates at lowfrequency (kHz). The ultrasound applicator has asonotrode that emits acoustic waves and createsmechanical air pressure which helps to advancetopical cosmetic products/substances into the toplayers of the skin, creating cycles of negative/positive pressure – “push and pull” effect(Fig. 2a, b) – within the preliminary organizedchannels to release the buildup of intracellularfluid and help the cosmetic product more rapidlyadvance into the skin to the targeted tissue depth.

The sonotrode serves various functions such asconversion of the acoustic waves, by increasingthe amplitude of the oscillations, modifying thedistribution, and matching acoustic impedance tothat of the substrate. Resonance of the sonotrode,which increases the amplitude of the acousticwave, occurs at a frequency determined by thecharacteristics of modulus elasticity and densityof the material from which the sonotrode is made,the speed of sound through the material, and theultrasonic frequency. The size and shape (round,square, profiled) of a sonotrode will depend on thequantity of vibratory energy and a physicalrequirements for each specific application.Sonotrodes connected to ultrasound transducers,especially those employed for transdermal deliv-ery of drugs, typically have a length L, expressedby the equation L = n(λ/2), where λ is the wave-length of the ultrasound in the sonotrode and n is apositive integer. In this case, the maximum ampli-tudes of the acoustic wave are found at the prox-imal end of the sonotrode and at the λ/2 lengthbeyond the foot of the sonotrode. The vibratingcolumn of air within the bore in the distal end ofthe sonotrode, together with the vibration of theannular end surface of the foot portion, has theeffect of cyclically reducing and increasing the

Table 1 Assisted drug delivery of compounds in frac-tional ablative applications

ALA and MAL (PDT)

Topical anesthetics

NSAIDS

Opioids

Chemotherapeutic drugs

Corticosteroids

Vaccinations

Topical ascorbic acid (vitamin C)

Imiquimod

Allogenic mesenchymal stem cells

Botulinum toxin

Antioxidants

Beta-blockers

Antifungals

Bone marrow transplantation

5-Fluorouracil (5-FU)

Interferons

Filler agents

Sklar et al. (2014) and Brauer et al. (2014)

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pressure at the skin interface, and this sucking andblowing action facilitates the transport of the com-pound to be delivered through the microchannelperforations created by ablative fractional laser orradiofrequency across the stratum corneum(Britva et al.).

The mode of operation is based on mechanical(acoustic) pressure and torques by propagation ofUS wave via the sonotrode to the distal horn andthe creation hammering-like effect (“push andpull”) in the thin layer between the cosmetic prod-ucts and the distal surface of sonotrode. Thesonotrode is applied normally to the surface ofthe skin contacting continuously with the skinsurface. The vibrational cycles (push-pull)enhance its delivery via the skin microchannels.Thus, this ultrasound-assisted technology emitsacoustic waves producing ultrasonic pressureand creating a “push and pull” effect within thechannels to release the buildup of intracellularfluid and enhances the cosmetic ingredients orthe drugs to the tissue depth.

Ultrasound is applied via a sonotrode, alsotermed an acoustic horn. The sonotrode servesvarious functions such as conversion of the acous-tic waves, by increasing the amplitude of theoscillations, modifying the distribution, andmatching acoustic impedance to that of the

substrate. Resonance of the sonotrode, whichincreases the amplitude of the acoustic wave,occurs at a frequency determined by the charac-teristics of modulus elasticity and density of thematerial from which the sonotrode is made, thespeed of sound through the material, and the ultra-sonic frequency. The size and shape (round,square, profiled) of a sonotrode will depend onthe quantity of vibratory energy and a physicalrequirements for each specific application. Theultrasonic acoustic waves emitted by the flaredfoot (Figs. 1 and 2) of the sonotrode are believedto assist in spreading through the dermis the com-pound that has been transported through the per-forated stratum corneum, and the flaring of thefoot serves to spread the ultrasonic waves over agreater area to assist in diffusion of the compound.

The shape of the sonotrode is believed toachieve two effects. First, the hollow neck createsa vibrating air column that blows and sucks alter-nately, serving to transfer the medicament throughthe stratum corneum. Second, the setting of thelength of the sonotrode to λ/6 allows the acousticenergy to be focused to a point that is betweenapproximately 0.3 and 2 mm beneath the surfaceof the skin. This positioning of the maximumacoustic wave amplitude at a point deeper in thetissue magnifies the sonophoresis effect of

Fig. 2 The sonotrode thatemits acoustic waves andcreates mechanicalupstream/positive (a) anddownstream/negative (b)cyclic-vibrational airpressure

Ultrasound-Assisted Drug Delivery in Fractional Cutaneous Applications 435

cavitation, lipid destruction, etc. and increasesabsorption of the drug or cosmetic.

The pairing of fractional ablative technologyand ultrasound-assisted technology in proceduraldermatology has gained attention for the purposeof skin permeation to facilitate transepidermaldrug delivery. In the past 5 years, clinical efficacyand safety of the IMPACT technology has beentested and validated in various preclinical andclinical ex vivo and in vivo models.

Lepselter et al. (2013) analyze transepidermalenhancement following fractional ablative skinpermeation in a rat model. Rats (Sprague Dawley,either sex) were anesthetized with a mixture ofketamine (60 mg/kg) and xylazine (10 mg/kg)injected ip or im. Rats were shaved and preppedon their dorsal and lateral sides. Skin perforation(SP) followed by low-frequency ultrasound-assisted device (IMPACT) was studied in fivedifferent conditions: normal skin (control), topicalEvans blue (EB), topical EB + US, topical SP +EB, and topical SP + EB + US. Frozen sectionsfrom skin biopsies were taken at 0 and 15 minincubation time for histological examinationusing a high-resolution digital microscope. Pene-tration area (penetration depth + width) and col-oration between distances of penetration wereanalyzed by advanced imaging software. Reflec-tance intensity by spectroscopy was measuredunder two wavelength conditions: 665 nm(EB sensitive) and 772 nm (EB insensitive). The665/772-nm ratio was used as a penetration indi-cator – low ratio denoted to higher EB penetrationand high ratio to low EB penetration. Biopsieswere taken and frozen for histological examina-tion, using digital microscope (Olympus, Japan)and data analysis using image processing ImageJsoftware (Burger and Burg, Hagenberg, Austria).Penetration area was defined as the colored areadivided by the crater area and expressed in %.Penetration width was defined as width line dividedby crater width, expressed in %. Penetration depthwas defined as depth line divided by crater depth,expressed in %. To visualize and analyze theultrasound-assisted device effect, a polarizationimaging system was used. A CCD camera (Olym-pus, Japan) was located above the prepared skin

sample slide for image acquisition. EB color inten-sity versus distance (depth and width) was signifi-cantly higher for the SP + EB + US (99.66 �23.67 pixels) versus SP + EB (52.33 � 25.34pixels) and SP + EB + US (80.83� 15.41 pixels)versus SP + EB (66.83 � 28.56 pixels), respec-tively (p < 0.05–0.01). Similarly, topical EB(2.1 � 0.4) and topical EB + US (1.8 � 0.3)spectrometry reflectance intensity ratios werehigh, indicating low EB penetration. In contrast,SP + EB + US (0.4 � 0.02) versus SP + EB(1.4 � 0.08) ratios were low, indicating signifi-cant higher EB penetration for the former( p < 0.01). Histology frozen sections of high-resolution digital photographs were in agreementwith the objective measurements. At 0-min incu-bation time, EB penetration was significantlyhigher at 70 versus 40 W ( p < 0.01). At 15 min,EB penetration was significantly higher whencompared to 0 min for 70 versus 40 W, respec-tively. EB color intensity versus distance (depthand width) was significantly higher for the RF +EB + US (99.66 � 23.67 pixels) versus RF +EB (52.33 � 25.34 pixels) and RF + EB + US(80.83 � 15.41 pixels) versus RF + EB (66.83� 28.56 pixels), respectively ( p < 0.05–0.01).Similarly, topical EB (2.1 � 0.4) and topicalEB + US (1.8 � 0.3) spectrometry reflectanceintensity ratios were high, indicating low EB pen-etration. In contrast, RF + EB + US (0.4 � 0.02)versus RF + EB (1.4 � 0.08) ratios were low,indicating significant higher EB penetration forthe former ( p < 0.01). Histology frozen sectionsof high-resolution digital photographs were inagreement with the objective measurements. Itwas concluded that the ultrasound-assisted devicefollowing ablative RF permeation significantlyenhances the amount of EB penetration asevidenced by depth, width, and color intensity(Fig. 3a–d).

The assisted-ultrasound drug delivery devicefirst clinical experience was reported in 2011 byKassuga and colleagues (2011). This case studydescribed two female patients with multipleactinic keratosis (AK). The study evaluated theeffectiveness of the transepidermal (TED) appli-cation of methyl aminolevulinate (MAL)

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prodrugs in PDT combined with the ultrasound-assisted drug delivery device. Clinical efficacyevaluation was based on reducing the AK numberand improving skin texture and color. The twopatients were simultaneously treated with thestandard MAL-PDT (left forearm) and modifiedprotocols – fractional radiofrequency (RF) com-bined with MAL and the ultrasound device in theopposite forearm (MAL-GT). Improvements inthe texture and pigmentation of the skin wereobserved after a single treatment on both sidesand were more evident on the side previouslytreated in the MAL-GT modality (in 6-month fol-low-up visit). Patient 1 had 34 lesions on rightforearm (MAL-GT protocol) and 54 lesions on thecontralateral forearm (standard MAL-PDT proto-col). After 6 months of protocol implementation,there were 8 AK injuries on the MAL-GT condi-tion treated side and 34 on the MAL-PDT condi-tion treated side. These results demonstrated a76.4% and a 37% decrease in right and left treatedforearms respectively. Patient 2, initially with24 and 21 lesions on the right and left forearms,respectively, had presented after PDT, two and sixlesions, respectively, which represents a 91.6%and a 71.4% decrease, respectively. Overall, itwas concluded that for these cases, the PDT

associated with TED of the MAL with an incuba-tion time of 1 h not only is effective in the AKtreatment but also shows better results than thestandard protocol.

Issa et al. (2013a) evaluated efficacy, safety,and patient’s satisfaction in using ablative frac-tional RF technology (Pixel RF) associated withretinoic acid 0.05% cream and an acoustic pres-sure wave ultrasound (US) in patients with alba-type striae distensae (SD) on the breast. Eightpatients were treated with a three-step procedure(Michael et al. 2002): fractional ablative RF forskin perforation (Elias and Menon 1991), topicalapplication of retinoic acid 0.05% on the perfo-rated skin, and (Scheuplein and Blank 1971) USapplied to enhance penetration. Additional eightpatients with abdominal alba-type SD were sub-mitted to RF treatment isolated without retinoicacid or US. Three patients with SD on the breastarea improved from “severe” to “moderate,” twopatients from “severe” to “mild,” two patientsfrom “moderate” to “mild,” and one patient from“marked” to “mild.” Clinical assessment demon-strated significant improvement in appearance ofSD in all patients within this (P = 0.008), withlow incidence of side effects and high level ofpatient’s satisfaction. Among the patients treated

Fig. 3 Histology frozen sections of high-resolution digitalphotographs without Evans blue (EB) (a) and with EBultrasound-assisted device (b) following ablative RF per-meation significantly enhance the amount ofEB. Fluorescent microscopy of high-resolution digital

photos without aminolevulinic acid (ALA) (c) and withALA ultrasound-assisted device (d) following ablativefractional CO2 laser permeation significantly enhancesthe amount of ALA

Ultrasound-Assisted Drug Delivery in Fractional Cutaneous Applications 437

only with RF, two patients improved from“severe” to “marked,” one patient from “marked”to “moderate,” and one patient from “marked” to“mild.” Four patients did not show any sort ofimprovement.

Clinical assessment demonstrated no signifi-cant improvement in the appearance of SD treatedwith RF isolated with low incidence of sideeffects, but low level of patient’s satisfaction. Itwas concluded that ablative fractional RF andacoustic pressure US associated with retinoicacid 0.05% cream is safe and effective for alba-type SD treatment.

The aim of the study conducted by Issa et al.(2013b) was to evaluate clinical response and sideeffects of transepidermal drug delivery (TED)technology in hypertrophic scars in body andface using ablative fractional radiofrequency(RF) associated with low-frequency acoustic pres-sure ultrasound (US). Four patients with hypertro-phic scars were treated with triamcinolone usingfractional ablative RF and US. The treatment pro-cedure comprised three steps: (i) ablative frac-tional RF for skin perforation, (ii) topicalapplication of triamcinolone acetonide 20 mg/mlon the perforated skin, and (iii) acoustic pressurewave US applied to enhance penetration. Studyresulted in complete resolution after one sessionin patients with scars on the nose and mandibulararea. The scar on the neck (tracheostomy) showedcomplete resolution after four sessions (Fig.4a, b).The scar on the knee showed a marked

improvement after four sessions. Mild and homo-geneous atrophy was observed in hypertrophicscars on the neck.

The method used in this study was shown toimprove efficacy of steroids in hypertrophic scartreatment, minimizing risks of localized atrophyand irregular appearance of the treated lesion. Thesame method, with the three-step procedure(Fig. 5), can be used to improve the quality ofnon-hypertrophic scar in which retinoic acid andvitamin C, instead of triamcinolone, are betterindicated (Fig. 6a, b).

In a recent study, Trelles et al. (Trelles andMartínez-Carpio 2014) aimed to evaluate efficacyand safety of transepidermal delivery (TED)method for treating acne scarring. A total of19 patients with moderate to severe scarringwere treated using unipolar fractional ablativeRF technology (Pixel RF) to create dermal micro-channels followed by acoustic pressure ultra-sound. All patients underwent four treatmentsessions at 3-week intervals. The study illustratedsignificant improvement in scarring on the face,back, and shoulders (P < 0.0001). In a 2-monthfollow-up, fading on total scarring was 57% onthe face and 49% on the back and shoulders. After6 months, percentage increased to 62% and 58%on the face and on the back/shoulders, respec-tively. Patients reported to be somewhat satisfied(16%), satisfied (53%), and very satisfied (31%).No unexpected side effects to the ablation and nohypersensitive were observed. It was concluded

Fig. 4 Tracheostomy scar (a) on the neck showed com-plete resolution after four sessions (b) with ablative frac-tional RF for skin perforation, topical application of

triamcinolone on the perforated skin, and acoustic pressurewave US applied to enhance penetration

438 J. Lepselter et al.

that the bimodal procedure is safe and effective inreducing acne scarring.

Earlier, Trelles et al. (2013) aimed to determineefficacy and safety of facial rejuvenation usingfractional carbon dioxide (CO2) laser (iPixelCO2), an ultrasound emitter (IMPACT), and acosmeceutical preparation to be applied

intraoperatively. Fourteen patients were enrolledto this split-face, double-blind randomized pro-spective study; for each patient, one half of theface was treated with a fractional CO2 laser alonewhile the other half receiving the same laserfollowed by acoustic pressure ultrasound ofcosmeceuticals. Both treatments achieved

Fig. 5 The treatment procedure comprised three steps: (i) ablative fractional RF for skin perforation, (ii) topicalapplication of drug on the perforated skin, and (iii) acoustic pressure wave US applied to enhance penetration

Fig. 6 Before (a) and after treatment (b) with ablative fractional RF + retinoic acid and vitamin C + acoustic pressurewave US; improvement of the traumatic non-hypertrophic scar on the face (temporal area)

Ultrasound-Assisted Drug Delivery in Fractional Cutaneous Applications 439

significant improvements in all parameters evalu-ated, yet combined US and cosmeceutical treat-ment had better scores for reduced fine lines andwrinkles as well as 80% overall improvement offacial aging in 6-month follow-up. Treatment waswell tolerated and no adverse effects wereobserved. Eighty-six percent of patients statedthat they were satisfied or very satisfied withtheir results. The conclusion was that one sessionof fractional ablative CO2 laser and acoustic pres-sure ultrasound technology for TED ofcosmeceuticals is an effective method for facialrejuvenation.

Recently, Issa and her colleagues (2015) stud-ied the clinical efficacy and side effects of TED inareata alopecia (AA) using ablative fractionalmethods and acoustic pressure ultrasound(US) to deliver triamcinolone solution into theskin. Treatment comprised three steps, ablativefractioned RF or CO2 laser followed by topicalapplication of triamcinolone and inserting it using

acoustic pressure wave US. Number of sessionsvaried according to clinical response (range 1–6).Treatment resulted in complete recovery of thearea treated in all patients; four of them had evenpresented results in a 12-month follow-up. Two ofthe patients were treated with ablative fractionalRF + triamcinolone + US and had completeresponse after three and six sessions. The othertwo treated with ablative fractional CO2 + triam-cinolone + US had a complete response after onesession (Fig. 7). Researchers concluded thatfractioned ablative resurfacing associated withacoustic pressure wave US is a new option toAA treatment with good clinical result and lowincidence of side effects.

In a recent study Waibel et al. (2015) evaluatedin vivo if there is increased efficacy of fractionalablative laser with immediate transdermal acousticwaves (IMPACT) to enhance drug delivery via his-tologic immunofluorescent evaluation.Aminolevulinic acid (ALA) has been chosen toevaluate if the combination of fractional ablativelaser with immediate transdermal ultrasound willenhance drug delivery. Six patients were treatedwith four treatment sites – one area treated withtopically applied ALA, one area with fractionalablative laser (iPixel CO2) and ALA topicallyapplied, one area with fractional ablative laser andtransdermal delivery system, and a final area ofALA topically applied with transdermal deliverysystem. Comparison of the difference of magnitudeof diffusion both lateral spread of ALA and depthdiffusion of ALA was measured by fluorescencemicroscopy. With laser + ALA + acoustic device,the protoporphyrin IX lateral fluorescence was0.024 mm on average versus fractional laser, andALAwas only 0.0084. The diffusionwith the acous-tic air device was an order of magnitude greater. Theauthors concluded that the combined approach offractional CO2 laser and the IMPACT device dem-onstrated the best results of the increased depth ofpenetration of the ALA (Fig. 3).

Suh et al. (2012) had conducted a study toevaluate effectiveness and safety of enhancedpenetration of platelet-rich plasma (PRP) withultrasound after plasma fractional radiofrequencyfor the treatment of striae distensae. Participants

Fig. 7 Complete response of the alopecia areata patchafter one session treatment with ablative fractional CO2 +triamcinolone + acoustic pressure US (before, after1 month, and after 3 months; from top to bottom)

440 J. Lepselter et al.

were treated with the ultrasound-assisted drugdelivery device in pairing with fractional radio-frequency technology (Pixel RF) for three ses-sions in 3 weeks interval. In order to enhanceplatelet-rich plasma penetration, ultrasound isapplied. Two months after last treatment, averagewidth of the widest striae had decreased from 0.75to 0.27 mm; from a total of 18 participants,13 were evaluated by two blinded reviewers as“excellent” or “very good” overall improvement.72.2% of the participants reported “very satisfied”or “extremely satisfied” with overall improve-ment. Only side effect reported was post-inflammatory hyperpigmentation (11.1%). Theresearchers concluded that fractional radio-frequency and transepidermal delivery of PRPusing ultrasound are effective and safe in thetreatment of striae distensae.

In a recent prospective, controlled study,Trelles et al. (2015) used florescent technique(fluorescein) to qualitatively and quantitativelydetermine the transepidermal penetration of acosmeceutical after permeabilizing the skinusing the ultrasound-assisted drug deliverydevice and fractional ablative radiofrequencytechnology (Pixel RF) techniques. The treat-ments were performed in the retroauriculararea in 16 patients, and biopsies were taken at10 min and at 15 h after the procedure. Theintensity of dermal fluorescence in the treatedsamples was compared to that of auto-fluorescence controls (AC) and technical con-trols (TC). The results have demonstrated thatthe samples treated with the Pixel RF+ USdisplayed a greater intensity of fluorescencethan the AC and TC, both at 10 min and 15 hafter the treatment. The increases in fluores-cence were graded as moderate or intense, butin no case as nil or slight. The results at 10 minwere Pixel RF + US (55.4 � 10.1), AC(8.6 � 2.8), and TC (8.2 � 3.6). At 15 h, theresults were Pixel RF + US (54.2 � 7.2), AC(8.9 � 1.7), and TC (8.3 � 2.4). The differ-ences between the samples and the controlswere significant, both at 10 min and at 15 h( p < 0.0008). The authors concluded thatthe transepidermal delivery procedure carried

out facilitated a prolonged and effectivedermal penetration of the topically appliedproducts.

Summary

This reviewed novel ultrasound-assisted drugdelivery device creates mechanical air pressure,which helps to advance topical cosmetic products/substances into the top layers of the skin and,more importantly, to create cycles of negative/positive pressure (“push and pull”) effect withinthe perforated microchannels that may release thebuildup of intracellular fluid and help the cosmeticproduct, thus enhancing the substance into theskin to the targeted tissue depth.

The idea of ablative fractionation treatment priorto application of topical agents in an attempt toenhance drug delivery is one that continues to garnerincreasing attention and interest in procedural der-matology (Brauer et al. 2014; Loesch et al. 2014).

In view to mitigating the drawbacks and limi-tations of topically applied compounds, this novelultrasound-assisted drug delivery device providesnew possibilities for assisted-drug delivery. Theuse of this ultrasound-assisted drug deliverydevice in pairing with fractional energy deliverytechnology has been tested and validated clini-cally in the past 5 years and is a promising methodthat can pave future opportunities in trans-epidermal delivery in challenging cutaneous indi-cations such as photodynamic therapy or skincancer or aesthetic indications such as scars,acne, or alopecia in procedural dermatology.

Take Home Messages

Many medications are too large (size >500 Da inmolecular weight) to penetrate the barrier ofthe stratum corneum, which require either aninjectable or systemic delivery.

Fractional ablative skin therapy became a commonmodality in procedural dermatology with theability to create ablative microscopic channelsof varying depths in the stratum corneum and

Ultrasound-Assisted Drug Delivery in Fractional Cutaneous Applications 441

other epidermal layers in a predictable manner,thus creating new opportunities in drug delivery.

The novel ultrasound-assisted drug deliverydevice creates mechanical air pressure, creat-ing cycles of negative/positive pressure effectwithin the perforated microchannels, pre-formed by ablative methods.

This push and pull effect may release the buildupof intracellular fluid inside the microchannels,increasing the cosmetic/drug penetration intothe skin.

The use of this ultrasound-assisted drug deliverydevice in pairing with fractional energy deliv-ery technology has been reported as an effec-tive method to improve drug permeation intothe skin in many different dermatoses (Bloomet al. 2013).

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Part V

Transepidermal Drug Delivery

Transepidermal Drug Delivery:Overview, Concept, and Applications

Andrés Már Erlendsson, Emily Wenande, andMerete Haedersdal

AbstractLaser-assisted drug delivery (LADD) is cur-rently being implemented in the dermatologi-cal clinic as a new method to enhance skinuptake of topical therapeutics. Compared toconventional topical use, clinical evidenceshows benefit for neoplastic lesions, photo-damaged skin, scars, onychomycosis, and top-ical anesthetic procedures. Particularlycompelling evidence is available for photody-namic therapy (PDT), where improved andlonger-lasting remission using laser-assistedmethyl aminolevulinate (MAL) treatment foractinic keratosis is established compared toconventional PDT. Still, safety concernsrelated to increased risks of local and systemicside effects remain, especially whenperforming LADD over large skin areas. Pro-vided responsible development, however,LADD holds promise as a new delivery modal-ity with the potential to improve treatment ofnumerous dermatological conditions.

KeywordsAblative fractional laser • Non-ablative frac-tional laser • Cutaneous • Drug delivery •Laser • Laser-assisted drug delivery • Topicaladministration • Transepidermal • Trans-epidermal drug delivery

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 448The Skin Barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 448Overcoming the Skin Barrier . . . . . . . . . . . . . . . . . . . . . . . . 448Physical Enhancement Techniques . . . . . . . . . . . . . . . . . . 448

Fractional Laser-Assisted Drug Delivery . . . . . . . . . 448History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 448Fractional Laser Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450AFXL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450AFXL: Theoretical Concepts . . . . . . . . . . . . . . . . . . . . . . . . 451AFXL: Drug Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 452Clinical Applications of AFXL Drug Delivery . . . . . 452NAFXL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454NAFL Drug Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 456

Safety Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 456

Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 456

Take Home Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 457

Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 457

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 457

A.M. Erlendsson • E. Wenande •M. Haedersdal (*)Department of Dermatology, Bispebjerg Hospital,University of Copenhagen, Copenhagen, Denmarke-mail: andres.erlendsson@gmail.com; emily.cathrine.wenande@regionh.dk; mhaedersdal@dadlnet.dk

# Springer International Publishing AG 2018M.C.A. Issa, B. Tamura (eds.), Lasers, Lights and Other Technologies, Clinical Approaches and Procedures inCosmetic Dermatology 3, https://doi.org/10.1007/978-3-319-16799-2_34

447

Introduction

The Skin Barrier

Topical drug therapy is a basic principle in der-matology. The therapeutic efficacy of topicaldrugs relates to both their inherent potency andability to penetrate different skin layers. Themajor rate-limiting step of drug permeation ispassage through stratum corneum (SC). Com-posed of densely packed corneocytes embeddedin a hydrophobic nonpolar extracellular lipidmatrix organized in a “brick and mortar” architec-ture, this outermost epidermal skin layer is anefficient barrier to cutaneous drug delivery (Eliasand Menon 1991). Transport across the SC isprimarily by passive diffusion in accordancewith Fick’s law. Thus, topically applied drugspass along concentration gradients and penetrateinto skin via intercellular and follicular diffusionpathways before reaching target cells in specificskin compartments. In general, topical therapeu-tics demonstrate poor total absorption and cutane-ous bioavailability, with only 1–5% beingabsorbed into the skin (Surber and Davis 2002).

Overcoming the Skin Barrier

Intact SC is permeable for small, lipophilic,uncharged molecules up to approximately 500 Dal-tons (Da). In contrast, hydrophilic, charged, andlipophilic compounds with molecular weightsover 500Da do not readily penetrate the skin barrier(Morrow et al. 2007; Govil 1988). Accordingly,many topical drugs are limited in their ability toreach target cells at deeper skin layers. There hastherefore been considerable interest in developingnovel drug delivery methods.

Currently available drug delivery strategiesinclude chemical biomodulation as well as physicalenergy-based techniques to disrupt the skin barrier(Benson 2005). Chemical biomodulation of topicalmedications increases skin permeability and drugdiffusion due to optimized drug-vehicle composi-tion, achieved through penetration enhancers,supersaturated systems, prodrugs, liposomes, nano-particles, and other carrier systems (Benson 2005;

Pathan and Setty 2009; Brown et al. 2006). How-ever, limitations to overall drug delivery persist, asthe cutaneous barrier is not fundamentally changed.Chemical biomodulation has therefore traditionallybeen used to deliver small compounds and com-pared to physical enhancement techniques showsonly limited success in enhancing cutaneous pene-tration of macromolecules (Paudel et al. 2010).

Physical Enhancement Techniques

Physical enhancement techniques involve the useof external energy to disrupt the skin barrier, aidinguptake of topically applied drugs. Several conceptshave been developed, involving the use of electro-poration, iontophoresis, lasers, microdermabrasion,microneedles, pressure, radiofrequency, andsonophoresis (Table 1). This armamentarium oftechniques has demonstrated improved cutaneousand transcutaneous delivery of various therapeutics,ranging from small topical and systemic drugs (e.g.,aminolevulinic acid (ALA) (Fang et al. 2004;Mikolajewska et al. 2010; Krishnan et al. 2013)and methotrexate (MTX) (Lee et al. 2008;Alvarez-Figueroa and Blanco-Méndez 2001)) tolarger macromolecules exceeding 20,000 Da [e.g.,human growth hormone (Fukushima et al. 2011;Ameri et al. 2014) and erythropoietin (Mitragotriet al. 1995)]. The literature however largely relieson in vitro experiments, and the majority of tech-niques have yet to gain substantial clinical impactdue to various practical impediments. Still, manystrategies including microneedling, radio fre-quency, and fractional lasers show promise andare increasingly gaining precedence in the derma-tological clinic. In the following chapter, we focuson fractional laser-assisted drug delivery.

Fractional Laser-Assisted DrugDelivery

History

Laser-assisted drug delivery (LADD) was firstdescribed in 1988, initially practiced with fullyablative lasers that removed the stratum corneum

448 A.M. Erlendsson et al.

Table 1 Different types of physical enhancement techniques to enhance skin permeability, their proposed mechanism ofaction (MoA), and examples of delivered compounds

TypeTechniqueExternal driving energy force Proposed MoA

Examples ofdelivered compound

Electroporation High-voltage (�100 V) electricpulses

Formation of transienttransmembrane pores anddisruption of cell membranes

ALA (177 Da)(Fang et al. 2004)Methotrexate(455 Da) (Lee et al.2008)Bleomycin(1500 Da) (Gothelfet al. 2003)Vaccines (Sardesaiand Weiner 2011)

Iontophoresis Low-level electric current (max0.5 mA cm2)

Active ion flow driven by anapplied electric field

ALA (177 Da)(Fang et al. 2004)Lidocaine (234 Da)(Marro et al. 2001)Methotrexate(455 Da) (Alvarez-Figueroa andBlanco-Méndez2001)Botulinum toxin(150 kDa) (Paciniet al. 2007)

Laser techniques (1) Tissue ablation(2) Photomechanical waves(3) Fractional tissue ablation

(1) Thermal removal of stratumcorneum and cutis(2) Light energy converted tomechanical energy(3) Fractional ablative andnon-ablative resurfacing

5-Fluorouracil(130 Da) (Lee et al.2002;Wenande et al.2016)ALA/MAL(177–182 Da) (Fanget al. 2004; Doukasand Kollias 2004)Lidocaine (234 Da)(Baron et al. 2014)Methotrexate (455Da) (Lee et al. 2008)

Microdermabrasion Mechanical abrasion Exfoliative crystals orsandpaper, mechanicallyremoving stratum corneum

5-Fluorouracil(130 Da) (Lee et al.2006)Ascorbic acid(176 Da) (Lee et al.2003)ALA (177 Da)(Fang et al. 2004)Insulin (5.8 kDa)(Andrews et al.2011)

Microneedles Mechanical introduction of anarray of needles

Physical disruption of skinbarrier with verticalmicrochannels through the skin

Ascorbic acid(176 Da) (You et al.2010)ALA/MAL(177–182 Da)(Mikolajewska et al.2010)Tretinoin (300 Da)(Kim et al. 2013)

(continued)

Transepidermal Drug Delivery: Overview, Concept, and Applications 449

in its entirety (Jacques et al. 1987). The concept offractional photothermolysis was developed in2004, using focused laser beams to create arraysof microscopic injuries in the skin while leavingintermediate skin intact (Manstein et al. 2004).The first devices operated at non-ablative wave-lengths, generating localized tissue coagulationwhile preserving the SC layer (Laubach et al.2006). In 2007, ablative fractional lasers (AFXL)were introduced. By generating small ablationchannels in the skin, AFXL provided a seeminglystraightforward and useful means of drug deliveryto, and through, the skin (Hantash et al. 2007a;Haedersdal et al. 2010).

Fractional Laser Systems

Fractional laser systems comprise bothnon-ablative (NAFL) and ablative devices. Thesystems in most widespread use include erbium-doped yttrium aluminum garnet (Er:YAG: AFXL;λ = 2940 nm), carbon dioxide (CO2; AFXL;λ = 10,600 nm), and erbium-doped glass

(NAFL; λ = 1530–1560 nm) lasers, all operatingin the absorption spectra of water (>1000 nm).Wavelength-dependent variations in waterabsorption result in vastly different tissueresponses between devices. By operating in thenear-infrared spectra where water absorption isfair, NAFLs result in localized tissue denaturationwith heat deposition. Emitting in the mid-infraredspectra where water absorption is enhanced, AFXLson the other hand generate greater energy deposi-tions and localized tissue evaporation. The histo-logical response to NAFL and AFXL treatmentsare depicted in Fig. 1.

AFXL

AFXL is an advantageous drug delivery techniqueas it provides predictable, controlled tissueresponses and enables fast, sterile, and concurrenttreatment of large skin areas (Hantash et al.2007b; Taudorf et al. 2014). In AFXL-assisteddrug delivery, there are two main parameters thatcan be adjusted for a given laser: laser channel

Table 1 (continued)

TypeTechniqueExternal driving energy force Proposed MoA

Examples ofdelivered compound

hGH (22.1 kDa)(Fukushima et al.2011)

Pressure Mechanical pressure force External pressure Caffeine (194 Da)(Treffel et al. 1993)Polyethylene glycol(400 Da)

Radiofrequency High-frequency alternating current(~100 kHz)

Ionic vibrations within cells,causing localized heating andablation

ALA (177 Da) (Parket al. 2016b)hGH (22.1 kDa)(Levin et al. 2005)

Sonophoresis Ultrasound. Most oftenlow-frequency waves are used inthe range of 20–100 kHz. High-frequency sonophoresis may alsobe used (> 3 MHz)

Primary mechanism isconsidered transient cavitationin intercellular lipids. Alsothermal effects, induction ofconvective transport, andmechanical effects due topressure variation

ALA (177 Da)(Krishnan et al.2013)Diclofenac (296 Da)(Rosim et al. 2005)Hydrocortisone(363 Da) (Griffinet al. 1967)EPO (48.0 kDa)(Mitragotri et al.1995)

ALA aminolevulinic acid, EPO erythropoietin, hGH human growth hormone, MAL methyl aminolevulinate

450 A.M. Erlendsson et al.

density and depth. Density represents the ablatedskin surface area, which is regulated by spot sizeand number of applied channels per unit skin area.Channel depth represents how deep laser channelsextend into the skin and is mainly controlled bypulse energy. By calibrating laser density anddepth, it is possible to (1) increase the accumu-lated drug amount in the skin to improve clinicalefficacy and (2) adjust drug delivery rate, whichcan be used to reduce incubation time. Dependingon the applied pulse energy and wavelength,residual thermal damage may vary; CO2 lasersinduce greater coagulation zones than Er:YAGlasers, due to lower water absorbance at10,600 nm (800 cm�1) (Marini and Krunic2015) compared to 2940 nm (12,800 cm�1)(Walsh & Deutsch 1989). Although the impor-tance of the residual thermal damage is currentlyunknown, bleeding is less common after treatmentwith CO2 lasers, a factor that may prove advanta-geous for AFXL-assisted drug delivery.

AFXL: Theoretical Concepts

The basic concept of AFXL-assisted cutaneousdrug delivery can be illustrated by Fick’s law of

diffusion, which describes passive diffusionthrough a medium (flux) as J ¼ �D� K δc

δl . Thesimplest way to describe how AFXL impacts drugdelivery is to assume steady-state conditions witha constant drug concentration in the vehicle and anegligible drug concentration at the bottom of thedermal layer. Flux is then constant and can bedescribed as J ¼ D� K ΔC

L . Under these assump-tions, delivery of a particular drug depends onfour conditions: (1) concentration gradient (ΔC),(2) partition coefficient between vehicle and skin(K), (3) diffusivity in skin (D), and (4) diffusiondistance (L) (Franz 1983). By removing fractionsof the SC, drug diffusion is facilitated by creatingdirect access to cellular epidermis and dermis.Over the laser channels, partition (K) thus occursbetween vehicle and aqueous viable skin,enabling improved delivery of hydrophilic com-pounds. Upon leaving the vehicle, the drug entersdirectly into cellular skin where diffusivity (D) ishigher than in SC, which results in a wide andrapid distribution of both small and large mole-cules around the channel. For therapeutic targetslocated in deeper dermis, the depth of the laserchannels can be increased to minimize diffusiondistance (L), in theory aiding delivery to deeperskin layers.

Fig. 1 Histological tissue responses in skin followingAFXL and NAFL exposure. A Hematoxylin and eosin(H&E)-stained skin section illustrating a microscopic abla-tion zone (MAZ) following fractional ablative exposureusing a 10,600 nm CO2 laser (GME DotScan 10,600) at30 mJ/microbeam, 1 millisecond pulse duration.

BHematoxylin and eosin (H&E)-stained skin section illus-trating a microthermal zone (MTZ) following fractionalnon-ablative exposure using a 1540 nm erbium/glasslaser (StarLux-500TM superficial Extra-Fast handpiece)at 26 mJ/microbeam, 15 millisecond pulse duration

Transepidermal Drug Delivery: Overview, Concept, and Applications 451

AFXL: Drug Delivery

AFXL has successfully enhanced delivery of thevast majority of drugs investigated thus far,including both lipophilic and hydrophilic mole-cules with molecular weights ranging from 177 to13,300 Da. In preclinical trials, examined com-pounds include ALA, MAL (Haedersdal et al.2010, 2011, 2014; Haak et al. 2012a, 2016; For-ster et al. 2010; Huth et al. 2016), imiquimod (Leeet al. 2011a), ingenol mebutate (Erlendsson et al.2015), diclofenac (Bachhav et al. 2011), metho-trexate (Taudorf et al. 2015, 2016), 5-fluorouracil(Wenande et al. 2016), prednisolone (Yu et al.2010), tranexamic acid (Hsiao et al. 2015), tretin-oin (Chen et al. 2013), tetracycline (Chen et al.2013), ascorbic acid (Hsiao et al. 2012), lidocaine(Bachhav et al. 2010a; Oni and Brown 2012),minoxidil (Lee et al. 2014a), diphencyprone(Lee et al. 2014a), small interfering RNA(siRNA) (Lee et al. 2014b), and polymeric micro-particles containing triamcinolone acetonide(Singhal et al. 2016).

Drug delivery can be adjusted with laser den-sity, and cutaneous drug accumulation increaseswith density to a point of saturation after whichenhancement ceases. The specific relationshipbetween laser density and skin deposition is bestestablished for MAL, where laser density up to5% coverage results in increased uptake, while nofurther enhancement is obtained from use ofhigher laser densities (Haak et al. 2016). MALdistributes horizontally up to 1.5 mm away fromsingle laser holes, providing the rationale for whylow laser densities may suffice (Haedersdal et al.2010). Analogous results have been confirmed forother small-size drugs such as ingenol mebutate(431 Da) (Erlendsson et al. 2015), diclofenac(296 Da) (Bachhav et al. 2011), and tretinoin(300 Da) (Chen et al. 2012). At present, densitiesbeyond 5% seem unwarranted for use inAFXL-assisted drug delivery, although moreinformation concerning the parameter’s effect oncutaneous diffusion pattern and biodistribution iscurrently needed (Haak et al. 2012b; Bachhavet al. 2010b).

Laser channel depth could in theory be regu-lated to target delivery to a specific, predetermined

skin layer. However, studies have failed to agree onthe relation between channel depth and drug depo-sition. While depth-dependent uptake has beendescribed for hydrophilic compounds, e.g., metho-trexate, (logP �1.85), and slightly lipophilic com-pounds, e.g., prednisone (logP 1.46) and diclofenac(logP 1.90), more hydrophobic drugs, such as lido-caine (logP 2.44), ingenol mebutate (logP 2.51),and imiquimod (logP 2.7), demonstrate no suchrelationship. Interstitial fluid and fibrin plugs havebeen reported to occupy the channels shortly afterlaser treatment, possibly inhibiting drugs and vehi-cles from filling deeper channel portions. Takingadvantage of channel depth may thus depend onthe individual drug’s ability to partition and diffusein the medium filling channels, and variousmethods to actively fill the channels are currentlyunder investigation (Erlendsson et al. 2016;Waibelet al. 2016; Alexiades 2015). At present, however,the specific relationship between laser channeldepth and drug accumulation remains to be clari-fied for individual drugs.

Clinical Applications of AFXL DrugDelivery

AFXL-assisted delivery has been shown toenhance topical treatment efficacy for different der-matological conditions, including actinic keratoses(AKs), non-melanoma skin cancer (NMSC),actinic cheilitis, topical anesthetic treatment,rythids, scars, wound healing, hemangiomas, viti-ligo, and cutaneous infections such asonychomycosis, warts, and leishmaniasis(Vachiramon et al. 2016; Haedersdal et al. 2016;Park et al. 2016a; Gupta and Studholme 2016;Basnett et al. 2015; Ma et al. n.d.; Waibel et al.2015). Principal findings for the most common ofthese indications are summarized below.

Neoplastic Lesions The bulk of evidence ondysplastic lesions centers on PDT with methylaminolevulinate (MAL) for AKs, demonstratingsuperior efficacy with AFXL compared to PDTalone. Thus, randomized controlled clinical trialsreport AK clearance rates of 87–92% forAFXL-assisted PDT versus 61–67% PDT alone

452 A.M. Erlendsson et al.

3 months posttreatment (Choi et al. 2015a; Koet al. 2014a; Togsverd-Bo et al. 2012). The long-term benefit of AFXL-assisted PDT versus con-ventional PDT is similarly supported for actiniccheilitis (85% vs. 29%) (Choi et al. 2015b) andBowen’s disease (79% vs. 45%) (Ko et al. 2014b).Prolonged remission after AFXL-assisted PDThas also been described with recurrence rates of8–10% at 12 months follow-up compared to22–27% with conventional PDT (Haedersdalet al. 2016). In addition to improved efficacy,AFXL may reduce PDT incubation time, andAK clearance rates after AFXL-assisted PDTwith 2- (77%) (Choi et al. 2015a) and 1.5 h(71.4%) (Song et al. 2015) incubation are similarto conventional 3-h PDT (64.7–66%). Althoughside effects occur more frequently followingAFXL-assisted versus PDT alone, treatmentsappear safe and side effects tolerable (Choi et al.2015a, b; Ko et al. 2014a, b; Togsverd-Bo et al.2012, 2015; Haak et al. 2015). For individualstaking immunosuppressants or with fields ofsevere actinic damage, AFXL-assisted PDT mayfurther provide a more potent therapy requiringfewer treatment courses than conventional PDT(Togsverd-Bo et al. 2015; Helsing et al. 2013).

In contrast to AK treatment, there is not suffi-cient evidence supporting a beneficial effect ofAFXL-assisted PDT for nodular basal cell carci-noma (BCC), although AFXL-assisted topical 5%5-fluorouracil (5-FU) for Bowens disease andsuperficial BCC has shown initial promise (Hsuet al. 2016). Still, both AFXL-assisted 5-FU andPDT require further improvement to warrant rec-ommendation for NMSC (Haak et al. 2015;Lippert et al. 2013). Figures 2 and 3 offer a prac-tical, stepwise illustration of AFXL-assisted PDTusing MAL (Fig. 2) and 5-FU (Fig. 3) for thetreatment of multiple AKs.

Anesthetics AFXL prior to application of topicalanesthetics has been shown to offer significant,subject-reported pain reduction compared tosham laser pretreatment in few clinical trials(Meesters et al. 2016; Tian et al. 2016). As anindication of the importance of vehicle formula-tion, greater benefit of AFXL has also been notedusing articaine hydrochloride + epinephrine liquid

solution (AHES) compared to topical lido-caine + prilocaine in cream (Meesters et al. 2016).

Aesthetics In addition to providing a new admin-istration strategy, fractional laser-assisted deliveryoffers the potential for improved treatment out-comes with aesthetic and antiaging agents(Alexiades 2015; Mahmoud et al. 2015;Shin et al. 2012a). Of note, AFXL-assisted topicalbotulinum toxin A delivery has offered superiorclinical efficacy for rhytides compared toAFXL-delivery of normal saline (Mahmoudet al. 2015). Superior outcomes followingAFXL-delivery of cosmeceuticals are furtherreported for treatment of photoaging, dyschromia,and acne scarring (Alexiades 2015).AFXL-delivery of aesthetic agents remains new,however, and future studies are needed to revealboth its full potential and safety for this indication.

Scars Initial evidence on topical AFXL-assisteddrug delivery in the treatment of scars appearspromising (Ali and Al-Niaimi 2016).AFXL-assisted betamethasone is reported to offera 50% clinical improvement average for treatment-resistant keloids (Cavalié et al. 2015), andenhanced appearance consisting of improved scartexture, reduced hypertrophy, and dyschromia arenoted for hypertrophic scars followingAFXL-delivery of triamcinolone acetonide (aver-age improvement 2.73 on a 0–3 scale) (Waibelet al. 2013). For atrophic scars, combinedAFXL + poly-L-lactic acid (PLLA) treatment hasoffered a reported average clinical enhancement of2.18 (scale 0–3) (Rkein et al. 2014), and improve-ment following AFXL + autologous platelet-richplasma is shown to be comparable to intradermalinjection (Gawdat et al. 2014). Though a multitudeof scar types may benefit form AFXL-assistedtreatments, randomized controlled clinical trialsare in the future nonetheless needed before recom-mendations can be made.

Onychomycosis Indicating increased efficacywith LADD, AFXL-assisted topical amorolfinetreatment for Trichophyton (T) rubrum-,T. mentagrophytes-, and Epidermophytonfloccosum-infected nail plates has demonstrated

Transepidermal Drug Delivery: Overview, Concept, and Applications 453

a 50% clinical andmycological cure rate 12 weeksafter three treatment sessions (Lim et al. 2014a).More recently, fractional CO2 laser-assisted deliv-ery of terbinafine resulted in a 92% negative cul-ture rate at 3 months and 80% rate 6 months afterthree treatment sessions (Bhatta et al. 2016). Aswith scar treatment, future randomized controlledtrials are needed to substantiate the benefits ofAFXL-delivery of antimycotic drugs.

NAFXL

Due to the weaker absorption by water, NAFLs donot establish direct access by microporation, butrather induce cylindrical zones of thermal damage,also known as microthermal zones (MTZs; Fig. 1).MTZs extend into underlying epidermis and dermis,leaving the SC with its low water content relativelyintact (Laubach et al. 2006; Alexiades-Armenakas

Fig. 2 A course of fractional CO2 laser-assistedMAL-PDT for actinic keratosis (AK) (Note: Figs. 2 and 3illustrate two treatments performed concurrently on sepa-rate legs in a single patient). A 72-year-old woman withmultiple actinic keratoses (AKs) on her thigh receivestargeted AFXL-assisted photodynamic therapy (PDT)using topical methyl aminolevulinate (MAL) cream. (a)Prior to PDT treatment. (b) During fractional CO2 laserexposure of AKs at 20–40 mJ/microbeam depending on

degree of hyperkeratosis. Close-up illustration of laser gridat 5% density (Deep FX, Lumenis

®

UltraPulse). (c) Topicalapplication of MAL cream on AK lesions, left underocclusion for 3 h. (d) Illumination of treatment area usinga red light source (630 nm, 37 J/cm (Surber and Davis2002), 8 min, Aktilite

®

). (e) Local skin reactions demon-strated 14 days posttreatment. (f) Treatment effect demon-strated 10 weeks posttreatment

454 A.M. Erlendsson et al.

et al. 2008; Ganti and Banga 2016). Similar toAFXL, depth and density ofMTZs represent adjust-able parameters during NAFL treatment (Kim et al.2016) and may be proven valuable to regulateLADD. However, investigation of the relationbetween laser settings and drug uptake remains inits initial phase for NAFL.

Increased TEWL values after NAFL give indi-cation of temporary disruption of the skin’s barrierfunction (Ganti and Banga 2016; Lim et al. 2014b;

Kim et al. 2016). However, the mechanisms bywhich NAFLs increase topical drug deliveryremain unclear. Beyond generation of MTZs viaNAFL’s direct photothermal effect, possible theo-ries include temporary expansion of cutaneousintercellular spaces by photomechanical wave(PW) with formation of epidermal vacuoles anddermal-epidermal junction disruption (Laubachet al. 2006; Ganti and Banga 2016; Lim et al.2014b; Lee et al. 2002; Ruiz-Rodriguez et al.

Fig. 3 A course of AFXL-assisted 5% 5-FU treatment foractinic keratosis (AK) (Note: Figs. 2 and 3 illustrate twotreatments performed concurrently on separate legs in asingle patient). A 72-year-old woman with multiple actinickeratoses (AKs) on her thigh receives targetedAFXL-assisted treatment with 5% 5-fluorouracil (5-FU)cream. (a) Prior to treatment. (b) After fractional CO2

laser exposure of AKs at 5% density (Deep FX,Lumenis

®

UltraPulse). (c and d) Topical application of5-FU cream on AK lesions, left under occlusion for5 days. (e) Local skin reactions demonstrated 14 daysposttreatment. (f) Treatment effect demonstrated10 weeks posttreatment

Transepidermal Drug Delivery: Overview, Concept, and Applications 455

2007). At this time, however, additional studiesare needed before a mechanism of action forNAFL-assisted drug delivery can be definitivelyestablished.

NAFL Drug Delivery

Compared to AFXL, fewer studies to date exam-ine the applicability of NAFL as a drug deliverystrategy. In preclinical settings, NAFLs have beenshown to enhance topical drug uptake ofdiclofenac, sumatriptan succinate, ALA,imiquimod, tretinoin, and peptides (Ganti andBanga 2016; Lee et al. 2016). In addition, clinicaltrials have indicated benefit of NAFL in combina-tion with the following drugs: topical tretinoin(Prens et al. 2013), bimatoprost (Massaki et al.2012), MAL (Ruiz-Rodriguez et al. 2007), ALA(Lim et al. 2014b), platelet-rich plasma (Shin et al.2012b), tacrolimus (Chitvanich et al. 2016;Wolfshohl et al. 2016), and botulinum toxin A(Fan et al. 2016). Going forward, it is conceivablethat NAFL’s combined drug delivery capabilitiesand favorable safety profile will provide new ave-nues for fractional LADD. However, whetherNAFL is as effective as AFXL in enhancing cuta-neous topical drug penetration has yet to be seen.

Safety Aspects

AFXL-assisted delivery breaks the natural skinbarrier and provides access to the viable skin andpapillary plexus (Oni and Brown 2012). Localskin responses are often aggravated by the com-bined effects of laser and topical drugs, and prox-imate access to the vascular system may result insystemic toxicity and introduction of virulentpathogens from the cutaneous flora or from non-sterile formulations (Oni and Brown 2012;Togsverd-Bo et al. 2012). Topical preparationsdesigned for intact skin often include ingredientsnot intended for intradermal or systemic entry.Though these risks are reported to be significantlylower compared to fully ablative procedures (Oniet al. 2013a; Zaleski-Larsen and Fabi 2016), intro-duction of such agents may cause unwanted

toxicity and potential immunological sensitiza-tion, resulting in hypersensitivity or anaphylaxis.

The reduced impact on the SC by NAFL signif-icantly decreases the severity and duration oftreatment-related side effects (Hantash andMahmood 2007).WhileNAFL- andAFXL-assisteddrug delivery safety profiles have yet to be ade-quately examined in direct comparison, potentialadvantages of NAFL include lower downtime andreduced post-inflammatory hyperpigmentation, ery-thema, crusting, and pain (Fan et al. 2016; Yang andLee 2011). NAFL further carries a lower risk ofinfection, and in contrast to AFXL, skin permeationof bacteria following NAFL is reported comparableto that of intact skin (Lim et al. 2014b). Whendetermining which laser technique to apply duringLADD, the improved safety profile of NAFL shouldhowever be balanced against the prospect of reducedefficacy as compared toAFXL (Laubach et al. 2006;Prens et al. 2013).

In sum, LADD should be exercised with caution,and it seems appropriate to consider the techniqueonly in well-controlled settings, using formulationsand doses suitable for local injection. Whenperforming fractional LADD, providers must beobservant of known, laser-related side effects,signs of infection, hypersensitivity reactions, therisk of systemic uptake and potential for adverseevents not previously described. Growth factorsand platelet-rich plasma are increasingly applied toreduce downtime after AFXL treatments, andwhether they promote proliferation of aberrantcells has yet to be investigated; the long-term con-sequences of AFXL-assisted delivery are thus cur-rently unknown, and clinical studies are needed tofully evaluate the safety profile of combination withindividual topical drugs (Lee et al. 2011b; Ai et al.2013).

Perspectives

The full potential of fractional LADD has yet to berealized. To date, a number of emerging studiesdemonstrate that AFXL not only enhances cuta-neous and transdermal delivery of topical drugsbut also therapeutic antibodies, macromolecules,nucleic acids, allergens, scaffold materials, cells,

456 A.M. Erlendsson et al.

as well as assist in delivery of light (Lee et al.2013, 2014b; Yu et al. 2011; Oni et al. 2013b;Bachhav et al. 2013; Bach et al. 2012). Successfulimmunization with AFXL-assisted delivery ofovalbumin vaccines has been conducted, and thecombination of AFXL with other drug deliverytechniques such as iontophoresis, electroporation,and acoustic pressure wave is forthcoming. Topi-cal application of systemic drugs not previouslydelivered through the skin is further made possi-ble by AFXL and NAFL, providing new pharma-ceutical treatment options and administrationroutes in the management of a multitude of dis-eases. Though still in its infant phase, fractionalLADD thus holds promise as a useful, minimallyinvasive drug delivery system – both in dermatol-ogy and beyond.

Take Home Messages

1. Fractional ablative and non-ablative laser-assisted drug delivery (LADD) is increasinglyused to enhance cutaneous uptake and inten-sify clinical efficacy of topical drugs.

2. In particular, current preclinical and clinicalevidence substantiates the use of ablative frac-tional laser (AFXL) in photodynamic therapyfor actinic keratosis.

3. Fractional LADD potentially offers increasedpotency of currently approved, topical treat-ment regimes.

4. When performing fractional LADD, providersmust be observant of enhanced local skin reac-tions, potential for systemic uptake, signs ofinfection, hypersensitivity to drug formulationingredients, as well as new adverse events notpreviously described.

Cross-References

▶Biophotonics▶Laser Safety▶Transepidermal Drug Delivery with AblativeMethods (Lasers and Radiofrequency)

▶Transepidermal Drug Delivery and Photody-namic Therapy

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Transepidermal Drug Delivery: Overview, Concept, and Applications 461

Transepidermal Drug Deliverywith Ablative Methods (Lasersand Radiofrequency)

Maria Claudia Almeida Issa and Paulo Santos Torreão

AbstractThe skin is almost impermeable for mosthydrophilic and charged molecules. A molec-ular weight (MW) of 500 Da is generallyaccepted as the upper limit for passive diffu-sion of lipophilic molecules. Several strategieshave been used to improve many drugpenetrations into the skin: microneedle, ultra-sound, and more recently transepidermaldrug delivery (TED). TED is a techniquebased on applying a medication following anablative method (CO2 laser, erbium lasers,ablative radiofrequency). So far, there havebeen many reports about ablative fractionallasers, which create vertical channels to assistthe delivery of topically applied drugs into theskin. In this chapter, ablative methods such asradiofrequency, lasers, and microneedlingare going to be discussed. See also chapters▶ “Transepidermal Drug Delivery: Overview,Concept, and Applications,”▶ “TransepidermalDrug Delivery and Photodynamic Therapy,”

and ▶ “Microneedling for TransepidermalDrug Delivery on Stretch Marks,” this volume.

KeywordsAblation • Transepidermal drug delivery •Transdermal drug delivery laser • Radio-frequency, resurfacing, and ablative methods

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 464

Histopathological Studies . . . . . . . . . . . . . . . . . . . . . . . . . . 464

Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 466TED for Photodynamic Therapy . . . . . . . . . . . . . . . . . . . . 466Scars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 466TED for Photoaging and Melasma . . . . . . . . . . . . . . . . . . 469TED for Other Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . 470

Protocol of Application and Directions . . . . . . . . . . . 470

Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 470

Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 470

Take Home Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 470

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 471

M.C.A. Issa (*)Department of Clinical Medicine – Dermatology,Fluminense Federal University, Niterói, RJ, Brazile-mail: dr.mariaissa@gmail.com;maria@mariaissa.com.br

P.S. TorreãoHospital dos Servidores do Estado do Rio de Janeiro,RJ, Brazile-mail: pstorreao@gmail.com

# Springer International Publishing AG 2018M.C.A. Issa, B. Tamura (eds.), Lasers, Lights and Other Technologies, Clinical Approaches and Procedures inCosmetic Dermatology 3, https://doi.org/10.1007/978-3-319-16799-2_35

463

Introduction

Fractional ablation of the skin is a special laser-skin interaction of photo-thermolysis firstdescribed in 2004. Fractional ablative lasers(erbium:YAG and CO2) or other fractional abla-tive modalities such as radiofrequency ablate theskin in fractions. Microscopic vertical channelsare created providing access pathways for largedrug molecules topically applied that would nototherwise traverse the epidermal layer. The pene-tration of small molecules is also enhanced. Thelocation, diameter, depth, and other characteristicsof these channels can be controlled or manipu-lated by the settings and type of the laser orradiofrequency technology (Mitragotri et al.1995;Manstein et al. 2004; Alexiades-Armenakaset al. 2008; Haak et al. 2011; Lin et al. 2014;Carniol et al. 2015; Forster et al. 2010).

The use of fractional ablative lasers for TEDpurpose, such as erbium:YAG and CO2 lasers, hasbeen reported inmany different studies (Haerdersdalet al. 2010; Gómez et al. 2008; Stumpp et al. 2005;Wang et al. 2004; Lee et al. 2003; Baron et al. 2003).To form the micro-channels in epidermis, lasersproduce vaporization, coagulation, other thermaleffects in different proportions depending on thewavelength, and laser settings (Haerdersdal et al.2010). Apart from lasers, RF device does not uselight but another source of electromagnetic energywhich is then transformed into thermal energy. Tocause ablation with RF, it is necessary to ionize theoxygen, producing microplasma (sparks) on theskin surface. It is possible when there is thin layer(space) between the RF handpiece and the skin;therefore, micro-sparks are formed on the surface,producing micro-channels in the epidermis.

Different drugs can be used for TED andshould be chosen accordingly to the disease tobe treated, as will be described.

In 2010 a low-frequency and high-pressureUS, called impact US, was created in order toenhance the penetration of substances with TEDtechnique. These US waves act by propellingmolecules through preformed channels. Itdepends on the previous use of an ablativemethod to perform its function, frequentlynamed as ITED (impact US + TED) (Fig. 1a–c)

(see chapter ▶ “Microneedling forTransepidermal Drug Delivery on StretchMarks”).

Histopathological Studies

In laser-treated tissues, through hematoxylin andeosin (H&E) staining, it is possible to observevertical channels created by columns of vaporiza-tion. This is true for ablative fractional lasers thatcreate a grid of microscopic treatment zones(MTZ) (Skovbølling Haak et al. 2011). EachMTZ is composed of the ablated channels, themicroscopic ablation zones (MAZ), and a borderof carbonization surrounded by coagulated tissue,the microscopic thermal zone (Sklar et al. 2014),that result from thermal damage by the lightsource (Taudorf et al. 2014).

The ideal parameters needed to create the skinchannels absolutely vary on the laser type, devicemodel, and settings. Also, the available data involv-ing the best energies and channel depth for skin drugdelivery is a bit contradictory. Nevertheless, there issome evidence showing that for hydrophilic andslightly lipophilic molecules, the drug uptake waschannel depth-dependent, while lipophilic drugshave shown a channel depth independent uptake(Haedersdal et al. 2016; Wenande et al. 2017).

Haak et al. described the impact of laser treat-ment density (% of skin occupied by channels)and molecular weight (MW) for fractional CO2

laser-assisted drug delivery. Ablative fractionaltreatment substantially increased intra- and trans-cutaneous delivery of polyethylene glycols(PEGs) in a MW that ranged from 240 to4,300 Da. Increasing laser density from 1% to20% resulted in augmented intra- and transdermaldelivery, but densities higher than 1% resulted inreduced delivery per channel. Mass spectrometryindicated that larger molecules have greater intra-cutaneous retention than transcutaneous penetra-tion (Haak et al. 2012; Haedersdal et al. 2014).

Skovbølling et al. conduced a histopathologi-cal study on an ex vivo animal skin model with afractioned CO2 laser (Medart, Hvidovre, Den-mark), with the aim to establish a standardmodel to document the histological tissue damage

464 M.C.A. Issa and P.S. Torreão

profiles after ablative fractional laser treatment. Itwas shown that the studied laser produced acone-shaped lesion with the base being the circu-lar epidermal surface lesion and the apex pointingtoward the dermis, and a proposed mathematicalformula was able to predict cone volume. It wasalso demonstrated that ablation depth increased ina linear relation with increased laser energies,dermal ablation width increased slightly withincreasing energies, and thickness of coagulationzone reached a plateau at a certain energy level(Skovbølling Haak et al. 2011).

Taudorf et al. conducted an animal ex vivostudy with a 2,940 nm laser with the aim ofestablishing the impact of laser parameters, stakedpulses and the tissue effects. It was shown that lowpulse energy and high repetition rate requiredmany stacked pulses at the same spot to induceablation, whereas high pulse energy delivered bydecreased pulse repetition rate and fewer stackedpulses led to ablation by less applied total energy.Ablation depth was likewise affected not only by

total energy delivered by pulse stacking but alsoby variations in pulse energy, pulse repetition rate,and pulse duration. Low pulse repetition rate(Hz) and reduced number of stacked pulses areimportant to avoid progressive accumulation ofresidual heat by allowing the exposed tissue tocool and ablation plume to be evacuated betweenpulses, otherwise leading to shallow-wide cratersinstead of increasing ablation depth. It was alsodiscussed that the advantage of using Er:YAG(2,940) laser instead of CO2 laser is the possibilityof creating purely ablated tissue with virtual nocoagulation zone. Although the importance of thecoagulation zone is not completely established, athick coagulation zone may pose a significantinduced barrier for molecules delivery (Taudorfet al. 2014). Brauer et al. demonstrated that frac-tional treatment results in untreated areas betweenthe MTZs allowing a more rapid healing response(Brauer et al. 2014).

Banzhaf et al. have published that 100% of thechannels created by a fractional ablative CO2

Fig. 1 (a–c) TED procedure in three steps: ablative RF, topical drug application, and impact US

Transepidermal Drug Delivery with Ablative Methods (Lasers and Radiofrequency) 465

laser were kept opened for the first 30 minutesafter the intervention. From this point on, therewas a gradual decrease in the percentage of chan-nels opened, with substantial decreased from 6hours on (Banzhaf et al. 2017). Olesen et al.have shown that liquid based vehicles were betterfor transepidermal drug delivery purposes thancream or gel (Olesen et al. 2017).

It not possible to establish the parametersneeded to perform the ideal drug delivery. Never-theless when doing this treatment, it is importantto take in account the laser type, the device model,the laser settings, and the desired effect. CO2

lasers may create thicker coagulation zones,when compared to Er:YAG lasers. Treatmentwith high energy, very short pulse width, andlow density may facilitate the penetration ofdrugs, specially for hydrophilic and slightly lipo-philic molecules.

Indications

TED for Photodynamic Therapy

It has already been reported the use of ablative lasers(erbium:YAG or CO2 lasers) prior to the applicationof methyl aminolevulinate (MAL) for PDT treat-ment (Haerdersdal et al. 2010; Shen et al. 2006).Some studies also describe the use of microneedlingtechnique applied before the application of the pho-tosensitizer (Donelly et al. 2008; Mikolajewskaet al. 2010). See chapter ▶ “Transepidermal DrugDelivery and Photodynamic Therapy”.

A recent study was conducted to evaluate andcompare clinical effects induced by PDT(MAL-PDT with red light) alone versus PDT(MAL-PDT with red light) associated with TEDusing fractional ablative RF. The results showedthat even reducing the incubation time of thephotosensitizing agent (MAL) from 3 to 1 h,improvement of actinic keratosis and skin texturecould be observed. TED + PDTwas more effectivein reducing the number of actinic keratosis lesionsin the forearms compared to PDTalone. Moreover,an improvement in the texture and pigmentationwas better observed on the side treated with theTED + PDT side (Kassuga et al. 2012).

Scars

Hypertrophic scars and keloids are disorders ofthe healing process in predisposed individuals inresponse to different types of injuries to the der-mis, such as trauma, inflammation, surgery, burns,and even insect bites (Wolfram et al. 2009).Despite the increasing knowledge in the field ofwound repair and collagen metabolism, its treat-ment remains a challenge for dermatologists andplastic surgeons. Clinically, hypertrophic scars arelimited to the original site of injury, while thekeloid exceeds this threshold and reaches the adja-cent skin. Hypertrophic scars appear after 4 weeksof the triggering event, grow intensely for a fewmonths, and then regress. In keloids, collagenproduction is 20 times greater than the normalhealing (Wolfram et al. 2009) and rarely disap-pears spontaneously. It can be difficult to distin-guish them in the initial growth phase.

Intralesional steroids are the first-line therapy(Al-Attar et al. 2006). The most widely used ste-roid is triamcinolone acetonide, a synthetic corti-costeroid derived from hydrocortisone withpotent anti-inflammatory action (Chrousos andMargioris 2003), whose mechanism of action isthe inhibition of fibroblast proliferation and colla-gen synthesis, increase in collagenase production,and reduction of collagenase inhibitors (Al-Attaret al. 2006). It should be applied every 2–6 weeksuntil clinical improvement of the lesion or theappearance of local side effects that prohibitstheir use. The use of intralesional corticosteroidis painful and its distribution is not homogeneous.

Garg et al. (2011) demonstrated that the use ofCO2 ablative laser alone was not sufficient topermanently treat keloids, requiring intralesionalapplication of triamcinolone every 3–4 weeks fora period of 6 months after ablation.

The use of steroid injections in keloid treat-ment is the most popular therapy modality forsuch problem because it is technically easy andless costly for the patient, not to mention the mostsatisfactory result compared with other proposedmethods. On the other hand, injections are painfuland sometimes intolerable, and it is also difficultto apply it evenly causing localized areas of atro-phic lesion.

466 M.C.A. Issa and P.S. Torreão

Issa et al. (2012) conducted a study abouttransepidermal application of triamcinoloneassisted by fractional RF associated with theimpact US in the treatment of hypertrophicscars. The results showed improvement or com-plete resolution of the hypertrophic scars with anexcellent aesthetic result. This technique wasalso considered less painful than regular injec-tions (Fig. 2a, b). It is noteworthy that in anotherstudy, not published, using the same techniquefor the treatment of keloids, the same effective-ness was not observed.

Atrophic StriaeStriae are a common and easily recognizedamendment, which rarely cause significant medi-cal problems, but often are a source of stress fortheir carriers. The origin of striae is not wellknown. There are a number of therapeutic modal-ities, but none of them is considered effective, andno single therapy is considered essential to thisproblem. With high incidence and poor treatmentresults, there is a tendency in targeting theresearch for consensus and optimal treatment.Therapeutic strategies are numerous, and no sin-gle therapy has been more consistent than theothers. The treatment of the striae remains a prob-lem to dermatologists. Recent striae may betreated with topical medication, such as tretinoin,and show better results after various surgical pro-cedures such as subcisions. Striae withlongstanding course do not show the same result.The future of treatment strategies is encouraging,

with advances in laser therapy. Many sourcesreported the use of lasers to diminish the appear-ance of striae (Elsaie et al. 2009; Bak et al. 2009).

A recent study about TED using 0.05% tretin-oin cream after fractional ablative method(RF) (Issa 2013) has shown the efficacy in thetreatment of atrophic white striae. When compar-ing the treatment of stretch marks located in theabdomen with ablative fractional RF alone orTED (RF + 0.05% tretinoin cream + US impact),the latter was more effective. Authors concludedthat TED using ablative RF to permeate the tre-tinoin cream + impact US to increase this perme-ation is a new interesting method for white oldstriae, mainly on the breast (Fig. 3a, b).

Alopecia AreataAlopecia areata (AA) is the most common cause ofnon-scarring alopecia. It is suspected to be an auto-immune disease with a genetic predisposition. Envi-ronmental and ethnic factors seem to be involved. Itpresents commonly as oval or circular plates ofnon-scarring hair loss. Steroids are widely used totreat AA, and intralesional triamcinolone is a veryeffective and painful method. Issa et al. (2012)reported five cases of AA treated with TED usingablative fractional resurfacing (CO2 laser or RF) +triamcinolone + acoustic pressure wave US. Triam-cinolone solution was dropped above the ablatedarea, and the impact US was applied just after themedication to push the drug into the skin. In allcases, patients exhibited an excellent improvement,and only one patient did not sustain the result after

Fig. 2 (a, b) Hypertrophic scar on the nose: before and after one session (RF 45 W + triamcinolone 20 mg/ml + impactUS, 50HZ, 80%)

Transepidermal Drug Delivery with Ablative Methods (Lasers and Radiofrequency) 467

12 months of follow-up. In the cases of alopeciaareata treated with CO2 laser + triamcinolone + US,excellent results were reached with only one session(Fig. 4a–c). When using ablative RF +

triamcinolone + US for AA treatment, good resultswere also reached, but more than one session wasnecessary. Authors observed a minimal clinicalimprovement in the patch treated with fractional

Fig. 4 (a–c) Areata alopecia: before, after one session, and after three sessions (RF 45W+ triamcinolone 20 mg/ml + US60 HZ, 80%)

Fig. 3 (a, b) Atrophic white striae: before and after treatment (three sessions) with RF 45 W + topical tretinoin 0,05%cream + impact US, 50HZ, 80%

468 M.C.A. Issa and P.S. Torreão

ablation CO2 laser + triamcinolone without US, butany clinical improvement was observed on the patchtreated with fractional ablation CO2 laser isolatedwithout applying triamcinolone or US.

TED for Photoaging and Melasma

The drugs used for photoaging and melasmatreatment include tretinoin 0.05% cream, vita-min C (Farris 2005; Hsiao et al. 2012) 5–10%cream or serum alone or combined with othercomponents such as ferulic acid (Waibel andWulkan 2013), hyaluronic acid 5% for rejuve-nation (Fig. 5a, b), and hydroquinone 4% asso-ciated or not with glycolic acid 10% cream formelasma.

In the case of melasma, CO2 laser should beused at very low energy, only with the aim toproduce micro-channels on the skin surface;good results with hydroquinone 4% cream wereobtained without post-inflammatory hyperpig-mentation (Fig. 6a, b) (study conducted by theauthor, not published yet).

In a split-face comparison study forphotodamaged skin, CE ferulic acid formula(L’oreal-SkinCeuticals) was evaluated after frac-tional laser ablation showing decrease in postop-erative recovery time and increase inneocollagenesis in the treated side (Waibel andWulkan 2013). Topical vitamin C after laser frac-tional ablation was also assessed for this purpose,but further investigation is needed (Hsiao et al.2012).

Fig. 5 (a, b) Photodamaged skin: before and after four sessions (RF 45 W + tretinoin 0,0 5% + vitamin C + US 50 Hz,80%)

Fig. 6 (a, b) Melasma:before and after threesessions with CO2 laser(10 mJ/pixel rollerhandpiece) + hydroquinone5% cream + US 50 Hz, 80%

Transepidermal Drug Delivery with Ablative Methods (Lasers and Radiofrequency) 469

TED for Other Indications

There are some investigations about the use ofgrowth factors for wound healing and the use ofantifungal agents and antimicrobials to targetinfections (Brauer et al. 2014).

Axillary and palmar-plantar hyperhidrosis isanother possible indication. It has been evaluatedin some patients in a clinical trial in which botuli-num toxin was applied through TED one side andthrough the standard injectable application on theother for comparison. In the first cases, reduction ofsweating was observed in the iodine-starch testwith both techniques (study about to be published).

Protocol of Application and Directions

The first step is to clean the skin using a cleanserwithout soap and chlorhexedine solution. Thefractional ablative method is applied imediatlybefore the topcial medication, which is chosenaccording to the disease to be treaed. These canhave its vehicle as cream, solution, or serum, withthe same concentrations as the products used top-ically at home, with no need for high concentra-tions as in the case of solutions for peelings. Ifpossible the impact US can be used. This is the laststep with the aim to push the drug into the dermisthrough the channels preformed by the ablativemethods, as a “hammering effect.”

Post-procedure directions include properhygiene with antiseptic soap, which starts after8 h of the intervention. Avoid friction in the treatedarea, not wearing tight clothes. The use of healingmoisturizer is advised, three to five times a day,avoiding crust formation. Patients are advised notto remove crusts, these should flake off spontane-ously, and to avoid sun exposure throughout thehealing time (7–14 days depending on the area).Topical photoprotection should be started at thethird day. Oral photoprotection can also be indi-cated, and it is very important in cases of melasma.

Antiviral prophylaxis is advised with the usualtreatment dose, starting 3 days before the proce-dure when treating the facial region, no matter theherpes simplex history.

Residual hyperpigmentation prevention can bedone with the use of despigmentant substances for3 weeks before the first session and restarting imme-diately after the skin recovery in each session,maintaining throughout the treatment period.

Side Effects

For all indications, side effects are usually lessintense than those after fractioned ablative lasersisolated, as less density are used for TED. On theother hand, side effects can be related to the lasersand to the drugs applied. Moreover systemic sideeffect is a possibility. Adverse effects include red-ness, swelling, pain, crusting, and transient residualhyperpigmentation. Usually the topically appliedmedications, even retinoic acid, do not change theintensity of discomfort caused by the laser or RFpreviously used. Infections can also occur.

Conclusions

When using fractioned ablative methods for TED,it is possible to achieve a more homogeneous andconvenient application of intralesional drugs, aswell as more effective treatment comparing to theuse of topical drugs or laser isolated.

According to the literature, TED with both RFand lasers (CO2 and erbium) can promote goodresults in many different treatments. It seems thateach method has its advantages and disadvan-tages. RF can be used in all phototypes as it doesnot cause dyschromia; on the other hand, CO2

laser can bring better results with fewer sessions.TED can be considered effective for many

diseases and also for cosmetic indications.

Take Home Messages

1. TED through ablation methods producesmicro-perforations in the epidermis, allowingthe permeation of drugs topically applied intothe skin through these micro-channels.

470 M.C.A. Issa and P.S. Torreão

2. The ideal parameters needed to create the skinchannels will absolutely vary on the laser typeand device model. It has been shown, although,that the best results in drug permeation consistof an ablation of low density,

3. Many substances, cosmeceuticals or medica-ments, can be used for TED purpose and arechosen according to the disease to be treated.

4. TED with ablative methods can be indicatedfor PDT, scars, striae distensae, areata alopecia,melasma, and photorejuvenation treatment,among others.

5. Better clinical results can be reached with TEDcomparing to laser isolated

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472 M.C.A. Issa and P.S. Torreão

Transepidermal Drug Deliveryand Photodynamic Therapy

Marianna Tavares Fernandes Pires, Livia Roale Nogueira, andMaria Claudia Almeida Issa

AbstractTransepidermal drug delivery (TED) has beenused with the aim to increase drug penetrationinto the skin, and its association with photody-namic therapy (PDT) is described for non-melanoma skin cancer, porokeratosis, andphotorejuvenation treatment. TED with PDThas been reported with fractional ablativemethods (ablative laser and ablative radio-frequency), as well as with non-ablative lasersand with microneedles. TED with PDT is con-sidered an effective method for actinic kerato-sis (field of cancerization) and forphotorejuvenation.

KeywordsPhotodynamic therapy • Photoaging • Rejuve-nation • Skin drug administration • Drug deliv-ery • Transepidermal drug delivery • Actinickeratosis • Field of cancerization

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 473

Photodynamic Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . 474History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 474Concept . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 474Photosensitizers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 474Source of Light . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475Procedure and Follow-up in Conventional PDT

(MAL-LED) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 478

Transepidermal Drug Delivery . . . . . . . . . . . . . . . . . . . . 478

Transepidermal Drug Delivery and PhotodynamicTherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479

Procedure in TED Associated with TopicalConventional PDT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479

Literature Review and Author’s Experience . . . . . . . . 479

Take Home Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 482

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483

Introduction

Topical photodynamic therapy (PDT) is approvedfor nonmelanoma skin cancer, actinic keratosis(AK), basal cell carcinoma (BCC), and Bowen’sdisease (BD). However, conventional PDT canfail to treat thick lesions of NMSC, due to thelimited penetration of the photosensitizer, whichcauses limited local bioavailability.

The stratum corneum is a significant barrier topercutaneous drug and particle absorption.The association of several modalities, such as abla-tive methods (fractional ablative lasers and

M.T.F. Pires (*) • L.R. NogueiraUniversidade Federal Fluminense, Niterói, RJ, Brazile-mail: marianna.pires@gmail.com; liviaroale@gmail.com

M.C.A. IssaDepartment of Clinical Medicine – Dermatology,Fluminense Federal University, Niterói, RJ, Brazile-mail: dr.mariaissa@gmail.com; maria@mariaissa.com.br

# Springer International Publishing AG 2018M.C.A. Issa, B. Tamura (eds.), Lasers, Lights and Other Technologies, Clinical Approaches and Procedures inCosmetic Dermatology 3, https://doi.org/10.1007/978-3-319-16799-2_36

473

fractional ablative radiofrequency), non-ablativelasers, and microneedling with PDT, has been stud-ied, in the last years, with the aim to enhance pho-tosensitizer penetration into the skin. This newconcept of treatment is called transepidermal drugdelivery (TED). TED and methyl aminolevulinate(MAL)-PDT has been studied, showing efficacy inAK and field cancerization treatment in immuno-competent and immunosuppressed patients.

It is also reported that there are benefits of skinrejuvenation during the field of cancerizationtreatment, such as improving skin texture, pig-mentation, wrinkles, and laxity, after TED andconventional PDT, even when photosensitizer’sincubation time is reduced. Some new protocolsusing TED and daylight PDT has been evaluatedwith good results.

Photodynamic Therapy

History

Oscar Raab, a German medical student, describedthe first photodynamic reaction in 1900. Hereported that neither acridine orange, a dye, norlight alone was toxic to paramecia; however,when both were combined, they could inducecell death in less than 2 h. He realized this whileusing acridine orange in paramecia during a coin-cidental thunderstorm (Raab 1900). Later, vonTappeiner and Jesionek used eosin and lighttogether to treat skin cancer, lupus vulgaris, andcondyloma lata. At this time, they speculated thateosin, like acridine, after being incorporated intothe cell, would produce a cytotoxic reaction whenexposed to an adequate light source in the pres-ence of oxygen (von Tappeiner and Jesionek1903). In 1990s, Kennedy et al. described theuse of aminolevulinic acid (ALA), a protoporphy-rin IX (PpIX) precursor, to be topically appliedavoiding systemic photosensitivity (Kennedyet al. 1990).

Since 1999, the US Food and Drug Adminis-tration (FDA) have approved photodynamic ther-apy (PDT) with topical ALA in dermatology for

the treatment of actinic keratosis (AK). In Europe,methyl aminolevulinate (MAL), an esterifiedform of ALAwith lipophilic properties, has beenapproved for the treatment of AK and basal cellcarcinoma (BCC) since 2001 (Sandberg et al.2008a). In 2004, MAL was approved for the treat-ment of AK in the United States. In 2006, MALwas approved in Brazil for AK and for superficialand nodular BCC. MAL is currently approved inmany countries of Europe, Asia, and the Americasfor the treatment of AK, BCC, and Bowen’s dis-ease. In 2009, MAL was also approved in Brazilfor Bowen’s disease.

Concept

PDT is defined as a photochemical reaction used toselectively destroy target tissue. Photodynamicaction requires three components: light, oxygen,and a photosensitizer agent. When these compo-nents are combined, they become toxic to the targetcell. It is a two-stage therapeutic technique thatemploys light activation of localized photosensitizedtissue in an oxygen-dependent process, which initi-ates oxidative stress, inflammation, and cell death.

Photosensitizers

There are two main prodrugs used for topicalPDT: ALA and MAL. Both are precursors of anendogenous photosensitizer, PpIX (Kalka et al.2000). After topical application, photosensitizersare mainly absorbed into abnormal cells andconverted, via the heme cycle, to PpIX. Abnormaltumor cells have low ferrochelatase activity andlower ferric ion concentrations, limiting the laststep in the heme cycle, promoting the accumula-tion of PpIX (Ericson et al. 2008).

Porphyrin-based photosensitizer agents areselectively concentrated in human cancerous tissueand are activated by light in the presence of oxygento initiate cytotoxic chemical reactions. Based on thecomparison of fluorescence intensities on a sameindividual from normal and tumor tissues of the

474 M.T.F. Pires et al.

same pigmentation, ratios of up to 15:1 for PpIXfluorescence between nonmelanoma skin cancerand normal skin have been reported with ALAsensitizer (Svanberg et al. 1994).

Source of Light

Light must be absorbed by PpIX, which has apeak of excitation in the blue-violet light part ofthe spectrum (Soret band) with maximum at410 nm. This part of the spectrum has very poortissue penetration (1 mm). For this reason, redlight (630–635 nm), which is also absorbed byPpIX and has deeper penetration (up to 6 mm), isusually used.

PDT is based on the chemical reaction in whichPpIX is photoactivated by different sources oflight, including incoherent, continuous-wave redor blue light, intense pulsed light (IPL), as well aspulsed dye laser (PDL) (Friedmann et al. 2014).The light-emitting diode (LED) is the main sourceof light for topical PDT treatment (Moseley et al.2006) with easier maintenance and lower costswhen compared with lasers (Brancaleon andMoseley 2012).

Recent studies have shown that natural daylightcan be successfully used for topical PDT. DaylightPDT (DLPDT) is a new modality for actinic kera-toses (AKs) and field of cancerization treatment.DLPDT is considered as effective as conventionalPDT with the advantage of being almost painless(Rubel et al. 2014) (see chapter▶ “Daylight Photo-dynamic Therapy and Its Relation to PhotodamagedSkin” – author Beni Grinblat).

Indications

Topical PDT is approved for nonmelanoma skincancer, actinic keratosis (AK), basal cell carci-noma (BCC), and Bowen’s disease (BD). Regard-ing squamous cell carcinoma, althoughoccasionally resulting in initial encouragingresults, it is associated with unacceptable recur-rence rates, and PDTwould not be recommended(Ericson et al. 2008).

There are many randomized, controlled, andopen studies in which the role of topical PDT inAK, BD, and BCC has been examined, and bothBritish and European guidelines for the use ofPDT are available (Morton et al. 2013a, b). PDTis a very important and effective treatment forfield of cancerization, and many authors reportednot only cure of AKs but also skin rejuvenationwith texture, wrinkle, and pigmentation improve-ment on the area treated. For this reason, PDT hasbeen also studied and indicated for skin rejuvena-tion (see chapter ▶ “Photodynamic Therapy forPhotodamaged Skin” – Issa e Ferola).

1. Actinic keratosis

AKs are common epidermal lesions associatedwith chronic exposure to ultraviolet(UV) radiation, which have the potential of pro-gressing to squamous cell carcinoma (SCC), withthe highest incidence in the aged and fair-skinnedpopulation (Traianou et al. 2012). AK is the sec-ond most common diagnosis by dermatologists inthe United States, with direct cost of therapy esti-mated at more than US$ 1 billion per year andindirect cost nearing US$ 300 million (Neideckeret al. 2009).

The early identification and treatment of AKsare necessary because it is very difficult or evenimpossible to predict which lesions may becomeinvasive and develop into metastatic SCC. Thefact that 65–97% of squamous cell carcinomasdevelop from AKs or areas of field cancerizationhighlights the need for effective treatment of theselesions (Rosen and Lebwohl 2013).

The aim of photodynamic therapy is not onlyto treat clinical or visible AKs but also to treatsubclinical lesions. PDT may also have thepotential to decrease expression of earlymarkers of cutaneous neoplasia Ki-67 and p53,as demonstrated in multiple studies followingmethyl aminolevulinate-PDT (MAL-PDT)using incoherent red light (Bagazgoitia et al.2011). In comparative studies between PDTand cryotherapy for AK treatment, clinicalresults were equal or even better, with superior

Transepidermal Drug Delivery and Photodynamic Therapy 475

cosmetic outcome, in the cases reported in PDTgroups (Tarstedt et al. 2005). Some authorsreported better results and cosmetic outcomewith MAL-PDT compared with trichloroaceticacid (TCA 50%) for AK treatment (Di Nuzzoet al. 2015).

2. Bowen’s disease

Bowen’s disease (BD) is an in situ carcinoma,clinically presented as an erythematous-squamousplaque with sharply demarcated, irregular borders.Sometimes, it can be a verrucous, hypo- or hyper-pigmented, and, eventually, exulcerated lesion. Itsevolution is slow and progressive, generallyasymptomatic. However, local pain, irritation, pru-ritus, and bleeding can occur (Moraes 2002).

Treatments include surgery, radiotherapy,5-FU, curettage, cryotherapy, and PDT. To choosethe best option, dermatologists should take intoaccount the patient’s age and frailty,comorbidities, and lesion’s body site. PDT iswell recommended to treat lesions located inareas that are difficult to heal, such as lowerlimbs (Cox et al. 2007).

In comparative studies, ALA-PDT has beenshown to be more effective and cause less adverseeffects than cryotherapy or 5-FU for the treatmentof BD (Morton et al. 1996). A large randomizedcontrolled trial comparing topical MAL-PDTwitheither cryotherapy or 5-FU reported that asustained response after 12 months followingtreatment was 80% for PDT, 67% for cryotherapy,and 69% for 5-FU with a superior cosmetic out-come in the PDT group (Morton et al. 2006).

3. Organ transplant recipients

The relative risk of SCC is estimated to be 65- to250-fold in organ transplant recipients (OTRs)compared with the rest of the population, increasingwith time after transplantation and depending on thetype of organ transplant (Hartevelt et al. 1990).

Topical PDT may potentially be used in thetreatment of organ transplant recipients who areat markedly increased risk of developing dysplas-tic skin changes and nonmelanoma skin cancers.Initial cure rates of topical PDT for AK and BD in

immunosuppressed patients were equivalent tothose in immunocompetent subjects, but withlonger-term follow-up, higher relapse rates werereported (Dragieva et al. 2004). The PDT protocolfor immunosuppressed patients are the same usedfor immunocompetent patients, but the number ofsessions in one treatment and the interval betweentreatments may vary for better results..

4. Basal cell carcinoma

Basal cell carcinoma (BCC) is the most com-mon skin cancer. It is derived from non-keratinizing cells that originate in the basal layerof the epidermis. There are more skin cancers inthe population of the United States than there areall other cancers combined, and it is estimated thatone in five Americans will develop skin cancerduring their lifetime (over 95% will be non-melanoma skin cancers) (Rigel et al. 1996).

BCC should not be considered the first treat-ment option in some conditions, due to the highrisk for complications (Morton et al. 1998;Kaviani et al. 2005; Lien and Sondak 2011).These conditions include patient’s age (24 yearsold or younger), immunocompromised patient,genetically predisposed patients (e.g., Gorlin’ssyndrome), recurrent or incompletely treatedBCC, lesions on nose and lips (includingnasofacial sulci and nasolabial folds) or aroundthe eyes (periorbital) or ears, flat lesion, hardthickened skin (appearance of morphoeic BCC),poorly defined margins, some histological sub-types (morphoeic, micronodular, infiltrative, andbasosquamous), and lesions greater than 2 cm indiameter below the clavicle or greater than 1 cmabove the clavicle (Table 1). Furthermore, veryheavily pigmented BCCs are not recommendedfor PDT because pigment might cause difficultlight absorption into tumoral cells. Likewise,morphoeic, infiltrative BCCs are aggressivetumors and do not selectively accumulate PpIXfollowing ALA or MAL application. They do notrespond well to topical PDT and should beavoided (Lien and Sondak 2011).

PDT is a minimally invasive procedure, whichachieves acceptable short-term cure rates forBCC. Topical MAL-PDT is considered effective

476 M.T.F. Pires et al.

to treat superficial BCC and thin nodular BCC dueto its deeper tissue penetration, comparing toALA. However, nodular BCC greater than 2 mmin histological thickness are unlikely to respondwell to topical PDT (Morton et al. 1998).

A randomized multicenter open non-inferioritystudy compared MAL-PDT with standard exci-sion surgery for superficial BCC (8–20 mm diam-eter). Similar high efficacy rates were seen at12 months for the two treatment arms with 9.3%recurrence for PDT and no recurrences in thesurgery group. However, superior cosmetic out-come was reported with PDT (Szeimies et al.2008). PDT has equivalent efficacy and superiorcosmetic outcome when compared with cryother-apy for both superficial and thin nodular BCC(Wang et al. 2001).

5. Photodamaged skin

Aging is a complex and multifactorial processthat occurs in all individuals, influenced by envi-ronmental, hormonal, and genetic factors. Thephotoaging, or extrinsic aging, is due to exposureto many different environmental factors, mainlythe ultraviolet (UV) light. The clinical signs asso-ciated with photoaging include laxity, wrinkles,dyspigmentation, a yellow hue, a leathery appear-ance, telangiectasia, and cutaneous malignanciesin the sun-exposed area such as the face, neck, anddorsum of hands (Chung et al. 2003).

The main constituent of dermal extracellularmatrix (ECM) is collagen, particularly collagentypes I and III, which provides skin’s strength andresilience. However, in photoaged skin, the produc-tion of procollagen, the precursor of collagen, is

reduced. Transforming growth factor-b (TGF-b) isthe major regulator of ECM synthesis in humanskin. It stimulates fibroblast proliferation in the der-mis to enhance collagen synthesis. An impairedTGF-b/Smad pathway, caused by UV irradiation,might play a role in the pathology. UV radiation isalso responsible to induce the expression of matrixmetalloproteinases (MMPs), mainly MMP-1, pro-moting collagen degradation (Chung et al. 2003).

Many significant histological changes inphotodamaged skin are reported after PDT treat-ment, photodynamic rejuvenation. Epidermismodifications include reduction of the epidermisthickness (stratum corneum) and atypicalkeratinocytes. The expression of p53, an earlymarker of epidermal carcinogenesis, notexpressed in normal skin, is also reduced afterPDT. Dermis modifications include reduction inelastotic material, increase of procollagen andcollagen types I and III, and decrease of collagenand elastin degrading metalloproteinases(MMP-1, MMP-3, and MMP-12) expression. Allthese histological changes in epidermis and der-mis can explain the clinical effects observed afterPDT treatment (Sjerobabski Masnec and Situm2014; Hai-yan Zhang et al. 2014; Orringer et al.2008; Park et al. 2009).

Disadvantages of topical PDT are largelyrelated to minor and expected adverse events fol-lowing the procedure. Pain and erythema occurduring and after procedure. Mild crusting andedema also occur in variable degree. High ALAconcentration and photosensitizer’s long incuba-tion time often results in an increased severity ofside effects, such as severe pain, erythema, andedema (Hai-yan Zhang et al. 2014).

Table 1 Risk factors for basal cell carcinoma

Clinical risk factor Low risk High risk

Location and size Low-risk area < 20 mma

Middle-risk area < 10 mmb

High-risk area < 6 mmc

Low-risk area > = 20 mma

Middle-risk area > = 10 mmb

High-risk area > = 6 mmc

Primary and recurrent Primary lesion Recurrent lesion

Tumor subtype Nodular, superficial Aggressive growth pattern

Legend: aLow-risk area: Trunk and extremities, excluding pretibial surface, hands, feet, nail, and anklesbMiddle-risk area: Cheeks, forehead, neck, jawline, scalp, and pretibial surfacecHigh-risk area: Central face, eyelids, eyebrows, periorbital, nose, lips, chin, mandible preauricular and postauricularskin, temple, ear, genitalia, feet, nail unit, ankles, nipples, and areola

Transepidermal Drug Delivery and Photodynamic Therapy 477

Procedure and Follow-upin Conventional PDT (MAL-LED)

The area to be treated is prepared with a superfi-cial curettage. Topical anesthesia with lidocaine,prilocaine, or tetracaine has been found to provideinsufficient pain relief and may also interfere withPDTefficacy because of pH changes (Borelli et al.2007). MAL should be applied on the skin on thearea to be treated, with 1 mm thick layer on topand 5 mm around AK, BCC, or Bowen’s disease.The area should be occluded with plastic film andlaminated paper for 3 h before illumination withred light with a dose of 37 J/cm2. One session isrecommended for AK and two sessions 1 weekapart for BCC and Bowen’s disease. Assessmentis recommended at 3 months, and re-treatment iscarried out with a second treatment cycle if indi-cated based on clinic and histological grounds.Patients treated for Bowen or BCC are followedup up to 5 years.

Transepidermal Drug Delivery

The skin is the largest organ of the human bodyoccupying an area of 2 m2 and 15% of an adultbody mass, receiving approximately 1/3 of theblood circulating through the body. The stratumcorneum is a significant barrier to percutaneousdrug and particles absorption. Several modalities,such as ablative methods (fractional ablativelasers and fractional ablative radiofrequency),non-ablative lasers, and microneedling, havebeen studied to reduce this barrier to enhancedrug penetration through the skin (Zhang et al.2015; Sklar et al. 2014).

1. Ablative and non-ablative methods

Fractional ablative laser produces micro-channels in epidermis, increasing topical drugpermeation into skin (Sklar et al. 2014). Thereare two main types of ablative fractioned lasersthat are used to assist drug delivery: erbium/yttrium-aluminum-garnet (Er:YAG) laser and the

carbon dioxide (CO2) laser. These fractionedlasers create microscopic vertical channels ofablation surrounded by coagulated tissue. A nor-mal healthy tissue is preserved between channels(Sklar et al. 2014; Manstein et al. 2004). Thesechannels are preformed in the skin immediatelybefore applying the medication chosen for thetreatment. The depth and diameter of these chan-nels vary according to the type of laser and to thelaser’s parameters, which are directly related tolaser-tissue interaction.

Many different substances have been used forTED in the last years. Topical anesthesia (lido-caine) had been reported after Er:YAG laser treat-ment with the aim to decrease needle prick pain(Baron et al. 2003). This method has been used foractinic keratosis treatment using 5-FU (Lee et al.2002), imiquimod (Lee et al. 2011), and PDT(Kassuga et al. 2011). Lee et al. (2011) reportedincreased transdermal delivery of 5-FU followingpretreatment with Er:YAG and CO2 laser foractinic keratosis (AK). Kassuga and Issa (Kassugaet al. 2011) described better results associatingMAL with ablative RF for AK treatment.

The use of triamcinolone solution topicallyapplied just after fractional ablative methods hasdemonstrated very good results for hypertrophicscars and areata alopecia (Issa et al. 2013a, 2015).Issa et al. (2013b) reported that topical delivery ofretinoic acid 0.05% cream after fractional ablativeRF was effective and safe for stretch marks treat-ment. Other substances such as vitamin C anddiclofenac have also been evaluated (Hsiao et al.2012; Bachhav et al. 2011). Issa et al. are investi-gating the use of botulinum toxin for palmarhyperhidrosis after CO2 laser (not published yet).

Non-ablative fractional lasers promote a con-trolled dermal heating without significant struc-tural damage of the epidermis. They have beendescribed as an option for TED with a differentmechanism of action. It involves lost of cohesionbetween cells in the epidermis, facilitating drugpenetration (Lim et al. 2014a). Some authorsdescribed the pretreatment with a 1550 nm frac-tional erbium glass laser for AK treatment andconcluded that incubation time could bereduced due to the greater ALA uptake (Limet al. 2014b).

478 M.T.F. Pires et al.

2. Microneedling

Microneedling is a recent therapy in dermatol-ogy. They are micrometer-scale needles, whichcause a minimal skin trauma, promoting the releaseof growth factors and stimulating the formation ofnew collagen and elastin in the papillary dermis(Aust et al. 2008). They disrupt the skin barrier inaminimally invasive and painlesswaywithminimalor no bleeding and therefore can be considered anew technique for TED (Gill and Prausnitz 2007;Wermeling et al. 2008; Mikolajewska et al. 2010).During TED treatment, the needles perforate thestratum corneum and create microconduits (holes).It has been shown that rolling with a dermaroller(192 needles, 200 μm length, and 70 μm diameter)over an area, for 15 times, will result in approxi-mately 250 holes/cm2. Themicroneedles are usuallydesigned in arrays in order to improve the surfacecontact with the skin. Due to microscopic projec-tions on microneedle arrays, compounds can bedelivered either precisely into or just beyond theepidermis. Delivery using microneedles is almostpain-free in comparison with hypodermic needles.

For PDT treatment, microneedles create micro-perforations in the stratum corneum, modifyingthe intercellular lipids, increasing the photosensi-tizer diffusion, and therefore increasing PpIX pro-duction. It is reported that microneedle associatedwith PDT improves skin quality, promoting skinrejuvenation (Torezan et al. 2013; Clementoniet al. 2010). Torezan et al. used 1.5-mm longmicroneedles to create virtual holes and facilitateMAL penetration. The MAL cream was appliedbefore microneedling to mechanically promote itspenetration. It was demonstrated thatmicroneedles-assisted PDT resulted in greaterimprovement of the photoaging. The procedurewas a safe and effective method and had a bettercosmetic result comparing to conventionalMAL-PDT. They reported better improvement inthe quality of the skin (pigmentation and finelines), but the reduction in the number was similarto the isolated PDT (Torezan et al. 2013).Clementoni et al. (2010) reported theassociation of microneedling with PDT (redlight) and intense pulsed light for photodynamicrejuvenation.

Transepidermal Drug Deliveryand Photodynamic Therapy

Conventional PDTcan fail to treat thick lesions ofNMSC. It occurs due to the limited penetration ofthe photosensitizer, which causes limited localbioavailability, resulting in insufficient PDTresponse in deep tissue layers. For this reason,some new studies evaluated the effectiveness ofassociating TED and PDTwith the aim to improvephotosensitizer’s penetration into the skin (Haaket al. 2012; Sandberg et al. 2008b).

Procedure in TED Associatedwith Topical Conventional PDT

When associating ablative methods and PDT, theprotocol is the following: The lesion is preparedwith a superficial curettage, and the ablative laseror ablative RF is applied on the area to be treated,with low density. MAL is applied immediatelyafter laser or RF, and it occluded with plasticfilm and laminated paper. The incubation timecan be reduced for 1–2 h (Issa et al. 2013a).Illumination with red light, dose of 37 J/cm2, isperformed, as in the standard conventional PDTprotocol (Fig. 1).

Literature Review and Author’sExperience

Some studies have been published about PDTassociated with an ablative method for non-melanoma skin cancer, extramammary Paget’sdisease, and porokeratosis treatment with goodresults (Haak et al. 2012; Fukui et al. 2009).AFXL-assisted MAL-PDT has been studied inclinical practice, showing benefit to immunocom-petent patients and immunosuppressed patientswith AK and field cancerization (Paasch andHaedersdal 2011; Haedersdal et al. 2011;Togsverd-Bo et al. 2012).

Kassuga and Issa et al. (Kassuga et al. 2011)reported that the incubation time could be reducedfor 1 h when associating ablative RF before topi-cal PDT for AK treatment, maintaining the AK

Transepidermal Drug Delivery and Photodynamic Therapy 479

cure rate and with better skin rejuvenation(Fig. 2.) The authors also have good experiencewith CO2 laser before PDT for AK field ofcancerization treatment (Figs. 3 and 4).

Three groups of AFXLs was described forTED x PDT: CO2-laser (10,600 nm), Er:YAG(erbium/yttrium-aluminum-garnet, 2,940 nm)laser and Er:YSSG (yttrium-scandium-gallium-garnet, 2,790 nm) laser. These lasers create verti-cal channels that facilitate the penetration of top-ically applied MAL into superficial and deep skinlayers and promote an intensified PDT response(Haak et al. 2012; Paasch and Haedersdal 2011;Haedersdal et al. 2011).

It is reported that once the stratum corneum isdisrupted by ablative fractional laser treatment,there will be no further benefit from drillingdeeper laser channels for the delivery of topicalphotosensitizer. For this reason, some authors

reported good results with erbium laser, which isnot able to promote deep channels as CO2 laserdoes (Haak et al. 2012). The benefit of deeperchannels produced by CO2 laser comparing witherbium lasers is still questioned.

Pretreatment with fractional laser resurfacingmay be a new alternative technique to improve theefficacy of PDT for actinic cheilitis by increasingthe bioavailability of MAL within the skin andenhancing the PDT response (Choi et al. 2015).

Very recently, daylight photodynamic therapy(DLPDT) was approved for AK treatment andfield of cancerization with similar efficacy andless side effects, with few or no pain, comparingto conventional PDT (Morton et al. 2015). Clini-cal improvement in texture and pigmentation canalso be observed after DLPDT treatment and forthis reason can be indicated for skin rejuvenation.DLPDT is contraindicated for skin tumors.

Fig. 1 Step 1: Lesion is prepared with a superficial curettage; Step 2: Fractional ablation; Step 3: MAL is applied in theregion to be treated; Step 4: Occlusion with plastic film and laminated paper; Step 5: Red light illumination

480 M.T.F. Pires et al.

The protocol for DLPDT isolated is alreadyestablished, and a superficial curettage is donesimilar to the conventional PDT. However, achemical sunscreen should be applied on theskin 15 min before applying MAL (not covered).Patient should be indoor for maximum 30 minbefore daylight exposure for 2 h. DLPDTwith TED is a very new modality of treatment,and very few data are reported. DLPDTassociated

with TED seems to have better results forphotorejuvenation, comparing with DLPDTisolated.

According to authors, experience to bothmicroneedling and laser is safe to be used associ-ated with DLPDT, but it seems that CO2 laserbefore DLPDT has better results comparing tomicroneedling associated with DLPDT for fieldof cancerization treatment (Fig. 5).

Fig. 3 Before and after 3 months: comparison of the standard PDT (3 h) on right arm to the CO2 laser + PDT withreduced incubation time (1 h) on left arm

Fig. 2 Before and after6 months: TED + PDTusing ablative RF + PDTfor AK (field ofcancerization) on forearms

Transepidermal Drug Delivery and Photodynamic Therapy 481

Take Home Messages

1. PDT allows simple and effective treatment ofmultiple lesions simultaneously, avoidingnumerous surgeries and unaesthetic scars.

2. When treating NMSC with conventional PDT,it is supposed that inferior treatment outcomescan occur in thick lesions due to the limitedpenetration of the photosensitizer.

3. Many studies evaluated the effectiveness ofassociating TED with PDT with the aim toimprove photosensitizers delivery throughthe skin.

4. AFXL-assisted MAL-PDT has been studied inclinical practice, showing benefit to immuno-competent patients and immunosuppressedorgan transplant recipients with AK and fieldcancerization.

5. TED is also new option to enhance the deliveryof ALA or MAL through the skin when usingPDT for skin rejuvenation. For this purpose,TED and PDT have been described using micro-needling technique and fractional ablative laser.

6. Authors have good experience with ablativeRF and CO2 laser before conventional PDTusing MAL and red light.

Fig. 5 Before and 30 days after CO2 laser associated with daylight PDT (MAL-DLPDT) for field of cancerizationtreatment in an immunocompetent patient

Fig. 4 CO2 laser associated with red light PDT (1 h incubation time) for field of cancerization treatment in animmunosuppressed patient

482 M.T.F. Pires et al.

7. The association of DLPDT with laser andmicroneedling is a promising new modalityfor skin rejuvenation.

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Transepidermal Drug Delivery and Photodynamic Therapy 485

Microneedling for TransepidermalDrug Delivery on Stretch Marks

Gabriela Casabona and Paula Barreto Marchese

AbstractStretch marks (SMs) are a well-recognized,common skin condition that rarely cause anysignificant medical problems but are often asignificant source of distress to those affected.The origins of SM are poorly understood, and anumber of treatment modalities (Elsaie et al.2009) are available for their treatment, yetnone of them is consistently effective, and nosingle therapy is considered to be consensusfor this problem. Multiple sittings of treatmentssuch as chemical peelings, micro-dermabrasion, nonablative and ablative lasertechniques, and light and radiofrequencydevices are performed to improve the SMappearance. Microneedling and transepidermaldrug delivery together are a new modality oftreatment for SM. It is based on stimulation ofcollagen production and enhancement of thepenetration of certain active substances acrossthe skin with which it is possible to achievesatisfactory results.

KeywordsMicroneedling • Transdermal drug delivery •Transepidermal drug delivery • Stretch marks •Collagen

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 488

Stretch Marks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 488

Microneedling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 490History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 490The Devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 490Mechanisms of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 491Microneedling and SM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 492

Microneedling and Transepidermal DrugDelivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 492

Vitamin A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 493Ascorbic Acid (Vitamin C) . . . . . . . . . . . . . . . . . . . . . . . . . . 493Platelet-Rich Plasma (PRP) . . . . . . . . . . . . . . . . . . . . . . . . . . 494Uses and Doses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 494Procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 494Other Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 496Advantages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 496Disadvantages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 496

Side Effects and Their Management . . . . . . . . . . . . . . 496Microneedling and Vitamin C Drug Delivery

Plus Calcium Hydroxylapatite Fillers: A Pilotretrospective Study for Stretch Marks . . . . . . . . . . . 496

Authors’ Experience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497

Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 498

Take Home Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 499

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500

G. Casabona (*) • P.B. MarcheseClinica Vida – Cosmetic, Laser and Mohs Surgery Center,São Paulo, Brazile-mail: grcasabona@uol.com.br;paulabarreto_@hotmail.com

# Springer International Publishing AG 2018M.C.A. Issa, B. Tamura (eds.), Lasers, Lights and Other Technologies, Clinical Approaches and Procedures inCosmetic Dermatology 3, https://doi.org/10.1007/978-3-319-16799-2_38

487

Introduction

Stretch marks (SMs) are an undesirable cutaneousdisorder, which causes significant cosmetic prob-lems with an evident psychological impact. Thereis loss of the normal random collagen distribution tothe level of the mid-dermis or deeper (Singh andKumar 2005). A single treatment modality that isconsistently effective with minimal adverse effectsdoes not exist to date. There are several modalitiesof treatment such as topical tretinoin 0.1% cream,topical 20% glycolic acid, microdermabrasion,lasers, and light and radiofrequency devices. Micro-needling therapy is a new addition to the treatmenttechniques for SM. It is a simple, inexpensive officeprocedure, with small downtime that allows colla-gen stimulation and transepidermal drug delivery(TDD). Percutaneous collagen induction goal is tostimulate collagen production by using the chemicalcascade that happens after any trauma. Approxi-mately 5 days after the skin injury, a fibronectinmatrix forms with an alignment of the fibroblaststhat determines the deposition of collagen(Widgeron 2012). Treatment with skin needlingshould be able to promote the removal of old dam-aged collagen and induce more collagen growthbeneath the epidermis. The microneedling deviceshave micron-sized needles that can perforate theskin in a minimally invasive and low pain levelmanner (Kaushik et al. 2001), thereby creating aque-ous transport pathways within the skin referred to asmicrochannels. Many active substances can bedelivered into the skin by microneedling. In thischapter, we will focus on the delivery of three com-ponents, which are effective on treating stretchmarks. They are vitamin A, vitamin C, andplatelet-rich plasma (PRP). The development ofmicroneedling associated with drug delivery seemsto be a good option in SM treatment. Combined,they are able to effectively change the collagenorganization, transforming the SM skin into amore healthy skin.

Stretch Marks

Stretch marks (SMs) are an undesirable cutaneousdisorder, which causes significant cosmetic prob-lems with an evident psychological impact. It

occurs mainly in adolescence, pregnancy, andobesity (Satish 2009).

Causes of SM are not clear, and a number oftheories were proposed. Infection leading to therelease of striatoxin that damages the tissues in amicrobial toxic way, mechanical effect ofstretching, which is proposed to lead to ruptureof the connective tissue framework (e.g., preg-nancy, obesity, weight lifting), normal growth asseen in adolescence and the pubertal spurt thatleads to increase in sizes of particular bodyregions, increase in the levels of adrenocorticotro-pic hormone and cortisol which are thought topromote fibroblast activity leading to increasedprotein catabolism and thus alterations to collagenand elastin fibers (Cushing’s syndrome, local orsystemic steroid therapy), genetic factors (absenceof striae in pregnancy in people with Ehlers-Danlos syndrome and their presence as one ofthe minor diagnostic criteria for Marfan syndromesuggest an important genetic element).

SM can be divided into striae rubrae (Fig. 1a)and striae albae (Fig. 1b). They are distinct, evo-lutionary linked forms of SM and their distinctionhas therapeutic implications. The color of the SMis related to the stage of evolution and to melano-cyte mechanobiological influences.

Striae rubra is an erythematous striae; as itmatures, it becomes white and more atrophic inthe end; it is an atrophic dermal scar with overly-ing epidermal atrophy. Initially, striae appear asflattened areas of thinned skin with a pink-red huethat may be pruritic. They usually increase inlength and width and acquire a darker reddish-purple appearance over time. The typical white,depressed appearance of older striae developswith time along the long axis aligned parallelwith the normal lines of skin tension.

Histologically, striae display an atrophic, thinnedepidermis with a flattening of the rete pegs. There isloss of the normal random collagen distribution tothe level of the mid-dermis or deeper. Elastin stainsreveal scarce or absent elastin fibers and reducedfibrillin in the papillary and reticular dermis withinaffected areas; the elastin fibers present appear tan-gled and frayed. The pathogenesis and those pre-disposed to developing SMmay have an underlyingdeficiency of fibrillin 54. This histologic appearance

488 G. Casabona and P.B. Marchese

probably likely results from mast cell degranulationand macrophage activation (McDaniel 2002) withresultant destruction of both collagen and elastinfibers (Budamakuntla 2013).

A universal approach to evaluating the severityof SM and a treatment modality that is consis-tently effective with minimal adverse effects donot exist to date.

There are several modalities of treatment:

(a) Topical treatments– Tretinoin 0.1% cream is thought to work

through its affinity for fibroblasts andinduction of collagen synthesis (Bernard2002). It has maximal efficacy in striaerubrae and poor, unpredictable responsesin striae albae. It seems to decrease in meanlength and width of the SM after months ofdaily use. Studies have demonstrated thatimprovement in the clinical appearance ofstriae after treatment with retinoic acid cor-relates with new fibrillin production(Fisher 1995).

– Creams and lotions that contain actives suchas Centella asiatica extract, vitamin E,vitamin A, collagen-elastin hydrolysates,panthenol, and menthol are widely used,mainly by women during pregnancy. Scien-tific data available are not sufficient to con-clude that such creams are effective, andlarger studies are needed to determine theefficacy and safety of such products. Thereis no statistically significant evidence tosupport their use in the prevention of SM.

– Topical 20% glycolic acid (GA) pure ormixed with other substances such as0.05% tretinoin or 10% L-ascorbic acid

improves the appearance of striae alba,but the precise mechanism of action ofGA is still unknown. It is reported thatGA stimulates collagen production byfibroblasts and increase their proliferation,but further investigations and studies arerequired to prove such theory.

(b) Lasers and light devices: intense pulsed light(515–1.200 nm), 585 nm flashlamp-pumpedpulsed dye laser (PDL), 308 nmxenon chloride(excimer laser), 577 nm copper bromide laser,1.450 nm diode laser, 1.064 nmNd:YAG laser,carbon dioxide (CO2) laser, fractionated 1550nm erbium-doped fiber laser and fractionalphotothermolysis are some examples of tech-nologies that can be used in SM treatment(Alster and Handrick 2000, 2005). Prior toselecting one device, one must perform thecorrect analysis of the SM and of the patients’Fitzpatrick skin type to diminish the risk ofinjuries and pigmentary alterations.

(c) Radiofrequency (RF) devices: the effects ofdermal heating are well recognized andinclude immediate effects on collagen struc-ture with stimulation of dermal fibroblastsinducing a synthesis of new collagen fibers(neocollagenesis) and elastic fibers (neo-elastogenesis) (Al-Himdani et al. 2014; Gold2015), improving the appearance and histo-logical findings in SM (Suh et al. 2007).

(d) Microdermabrasion is a skin resurfacing tech-nique using aluminum oxide. It has beenreported to increase type I collagen and has agreater effect on stretch marks. This techniquecan be used in combination with intradermalplatelet-rich plasma (PRP); in a study, patientswere treated with a combination of intradermal

Fig. 1 (a) Striae rubrae,(b) striae albae

Microneedling for Transepidermal Drug Delivery on Stretch Marks 489

PRP and microdermabrasion in the same ses-sion. There was significant clinical improve-ment of SM in patients treated with acombination of PRP and microdermabrasionwhen compared with patients treated with justmicrodermabrasion.AcombinationofPRPandmicrodermabrasion in the same session showedbetter results in short duration (Ibrahim et al.2015).

(e) Microneedling therapy is a new addition to thetreatment techniques for SM. It is a simple,inexpensive office procedure, with small down-time that allows collagen stimulation and trans-epidermal drug delivery (TDD). Substancessuch as vitamin A (retinyl palmitate and retinylacetate), vitamin C, and platelet-rich plasma(PRP) can be used for TDD. In this chapter, weare going to describe the use of the microneed-ling technique as a way of stimulating collagenand facilitating the delivery of active ingredientsto the skin affected by stretch marks.

Microneedling

History

In 1995 Orentreich described collagen percutaneousstimulation with dermal needling for scars. Then, in1997, Camirand and Doucet described needle

dermabrasion using a “tattoo pistol” to treat scars.And only in 2006 a doctor from South Africa, DrDesmond Fernandes, developed percutaneous col-lagen induction therapy with the dermaroller(Dermaroller®) (Henry et al. 1998) (Fig. 2). In2010 a new electronic pen-shaped device(Dermapen

®

) (Fig. 3) was developed in Australiafor a more cost-effective procedure. Using the penyou can choose different needle lengths and speedvibration providing not only microneedling but alsoa certain level of dermabrasion depending in theused technique.

Since then, the use of the microneedlingdevices is growing along with the number ofindications. The addition of transepidermal drugdelivery to the microneedling technique made iteven more interesting to treat certain conditions,such as stretch marks and melasma.

The Devices

Since 2006, when the first dermaroller was usedby Dr Fernandes, the device suffered numerouschanges to get more ergonomic and resistant.The standard dermaroller used for acne scars isa drum-shaped roller studded with 192 finemicroneedles in 8 rows, 0.5–1.5 mm in lengthand 0.1 mm in diameter. The microneedles aresynthesized by reactive ion etching techniqueson silicon or medical-grade stainless steel. The

Fig. 2 Dermaroller®

device

Fig. 3 Dermapen®

device

490 G. Casabona and P.B. Marchese

instrument is sterilized by gamma irradiation.Now you can find thinner versions and largerversions, and the length of the needles can comeup to 2.5 mm.

As it is supposed to be disposable, if you havemore than one needle length indication, the doc-tor would have to use more than one roller, whichis not cost-effective to the patient. For example,if you want to treat the patient under the eyesand for a scar in the malar area, we wouldhave to use both 1.0 mm- and 1.5–2.0 mm-longneedles.

Other electronic pen-shaped microneedledevices were developed with disposable needles.The length and the speed vibration of the exposedneedle, in and out, can be controlled. In the end,with these devices, we can not only create micro-tunnels but also achieve a certain level of derm-abrasion of the epidermis, if that is the goal.

Mechanisms of Action

The microneedle devices create microtunnels thatvary from 0.5 to 2.5 mm in depth (Cho 2010).Percutaneous collagen induction goal is to stimu-late collagen production by using the chemicalcascade that happens after any trauma. There arethree phases in the body’s wound healing process(Tejero-Trujeque 2001), which follow each otherin a predictable fashion. This has been well

described in The Biology of the Skin by Falabellaand Falanga (Falabella et al. 2000). Platelets andeventually neutrophils release growth factors suchas the connective tissue growth factor, TGF-B1,TGF-B3, platelet-derived growth factor, connec-tive tissue activating protein III, and others thatwork together to increase the production ofintercellular matrix (Lynch 1989; Tran 2004;Faler 2006) (Fig. 4). Only then, monocytes alsoproduce growth factors to increase the productionof collagen III, elastin, glycosaminoglycans, andso on (Johnstone 2005).

Approximately 5 days after the skin injury, afibronectin matrix forms with an alignment of thefibroblasts that determines the deposition of col-lagen. Eventually, collagen III is converted intocollagen I, which remains for 5–7 years. Due tothis conversion, the collagen tightens naturallyover a few months (Martin 2005).

Normally, during the usual conditions ofwound healing, scar tissue is formed with minimalregeneration of normal tissue (Fenske 1986). Per-cutaneous collagen induction causes even furthertightening of lax skin and smoothening of scarsand wrinkles several weeks or even months afterthe injury (Fernandes 2002). In addition, percuta-neous collagen induction has proven to be veryeffective in minimizing acne and burn scars, bypromoting the replacement of scar collagen withnormal collagen and the reduction of depressedand contracted scars (Ruszczak 2003).

Phase IInflammatory

Phase IIProliferation

Phase IIIRemodeling

Growth FactorsTGF-b1/3

PDGFExtracellular matrix

proteins

Proliferation:Monocytes/ Fibroblats/

KeratinocytesFibronectin matrix

COLLAGEN DEPOSITION( type III)

Conversioncollagen III-!

Tissue remodelingVascular

maturation

Fig. 4 Cascade of healing after trauma injury and collagen deposition

Microneedling for Transepidermal Drug Delivery on Stretch Marks 491

Treatment with skin needling should be able topromote the removal of old damaged collagen andinduce more collagen growth beneath the epider-mis. Puncturing the skin multiple times in acnescars increases the amount of collagen and elastindeposition. Thus, it was hypothesized that skinneedling would also be useful in SM becausethese seem to be dermal scars with epidermalatrophy (Majid 2009).

Microneedling and SM

A study made in South Korea in 2012 enrolled16 volunteers with SM, who received three treat-ments with a microneedling device at 4-weekintervals. Clinical response to treatment wasassessed by comparing pre- and posttreatmentclinical photographs, skin biopsies, and patientsatisfaction scores. The general histopathologicfeatures of the lesional specimens collected beforetreatment showed epidermal thinning with finedermal collagen bundles arranged in straightlines. After treatment, the epidermis was thick-ened, and the amounts of dermal collagen andelastic fibers were increased (McCrudden et al.2015). This study proved that microneedling canbe effectively and safely used for SM treatment.

In addition to this technique, the trans-epidermal drug delivery can be associated inorder to increase the collagen production.

Microneedling and TransepidermalDrug Delivery

The dispersion and effectiveness of active ingre-dients into the skin, without prior perforation, areseverely limited by the inability of the largemajority of drugs to cross the skin at therapeuticrates due to the great barrier imposed by the skin’souter stratum corneum layer (Menon et al. 2012).

In 2004, Prausnitz (Prausnitz 2004), describedthe use of microneedles for transdermal drugdelivery. The outstanding motivation for micro-needles is that they can provide a minimally inva-sive means to transport molecules into the skin(Oh et al. 2015).

As with lasers, the microneedling techniquestarted being used as a way to trespass the stratumcorneum to deliver active ingredients to the skin ina more efficient way (Brauer et al. 2014).

The stratum corneum (SC), the skin’s outer-most layer, is a barrier that prevents moleculartransport across the skin. Therapeutic agents,such as peptides, proteins, and oligonucleotides,are difficult to reach deeper layers of the skin byconventional methods or topical delivery(Petchsangsai et al. 2014).

The microneedling technique (MT), as shown,uses micron-sized needles that can perforate theskin in a minimally invasive and low pain levelmanner, thereby creating aqueous transport path-ways within the skin referred to as microchannels(Park et al. 2012).

Moreover, these microchannels present no lim-itation regarding the size of molecules that canpass through their tunnels (Kumar and Banga2012). While, in terms of size, the microchannelsare in the range of microns, the macromoleculesdelivered are typically nanometers in size.

The only question that remains is if, after themicroneedling, blood and fibrin will invade themicrochannels creating a new barrier for this pen-etration (Milewski et al. 2010). Consequently, werecommend, as the biopsies presented in Fig. 5, toproceed in an inverse technique, where the drug isapplied prior to the microneedling technique andprior to each step to guarantee more efficientdelivery of the active ingredient.

In the past, local microinjections, the so-calledmesotherapy, were introduced in France by Pistor(Pistor 1979). Mesotherapy is a widely used tech-nique in medicine. This technique consists ofintradermal or subcutaneous microinjections of0.05–0.1 mL of highly diluted drug mixtures ora single drug, on body parts affected with medicalor aesthetic problems. Nevertheless, recent stud-ies show that the drug delivery with micro-needling is more effective than mesotherapybecause it not only allows the penetration of activeingredients into the skin but also induces thechemical cascade that takes place after a traumawhich will stimulate collagen production.

Many active substances can be delivered intothe skin by microneedling. Depending on the

492 G. Casabona and P.B. Marchese

disease you wish to treat, there are a number ofsubstances that can be chosen, for example, ste-roids (triamcinolone acetonide) for hypertrophicscars and areata alopecia, tranexamic acid formelasma, minoxidil for androgenetic alopecia,and aminolevulinic acid for actinic keratosis.

In this chapter, we will focus on the delivery ofthree components, which are effective on treatingstretch marks. They are vitamin A, vitamin C, andplatelet-rich plasma (PRP).

Vitamin A

The possibility of using vitamins A and C forpercutaneous collagen induction has beendescribed by Aust in (2008). Vitamin A, a retinoicacid, is an essential vitamin also considered ahormone for the skin. It expresses its influenceon many genes that control proliferation and dif-ferentiation of all the major cells in the epidermisand dermis (Rosdahl 1997). Percutaneous colla-gen induction and vitamin A switch on the fibro-blasts to produce collagen and therefore increasethe need for vitamin C. Vitamin Amay control therelease of TGF-B3 in preference to TGF-B1 andTGF-B2 because, in general, retinoic acid seemsto favor the development of a regenerative lattice-patterned collagen network rather than the paralleldeposition of scar collagen found with cicatriza-tion (Oliveira Marcela et al. 2016).

Retinyl palmitate (RP) is an ester of retinol andis the major form of vitamin A found in the epi-dermis. It has a high molecular weight and a stableformulation. To be active, RP has to be enzymat-ically converted in the skin to retinol by cleavageof the ester linkage and then be converted totretinoin via oxidative processes. It has beenestablished that the topical administration of RPfor 14 days in rats resulted in increased proteinand collagen and an epidermal thickening (Ro etal. 2015).

Ascorbic Acid (Vitamin C)

Ascorbic acid (AA) or vitamin C is also essentialfor the production of normal collagen. Percutane-ous collagen induction and vitamin A stimulatethe fibroblasts to produce collagen and thereforeincrease the need for vitamin C. Topical vitaminsA and C both maximize initial release of growthfactors and stimulate collagen production (Palma2006).

Apart from its role as a potent antioxidant, it hasalso been demonstrated that AA functions as anessential cofactor for the enzymes lysyl hydroxy-lase and prolyl hydroxylase, both of which arerequired for the posttranslational processing oftypes I and III collagen (Nusgens 2001).

AA stimulates collagen production in the der-mis and can cause a dramatic increase in fibroblast

Fig. 5 Histopathology of the skin after methylene blue inkdiluted in the same vitamin C vehicle used to do the drugdelivery. Applied prior every dermroller pass, 20 passes

(a) After 0,5 dermaroller, (b) after 1 mm dermaroller. Bothshowed penetration of the ink in different levels accordingto the needle length

Microneedling for Transepidermal Drug Delivery on Stretch Marks 493

proliferation potentially resulting in greater colla-gen production; it might be presumed that AAalso possesses the potential to increase collagenproduction for SM appearance reduction. AAeven plays a role in collagen synthesis at thelevel of gene expression. It has been shown toupregulate collagen synthesis and increase thesynthesis of the inhibitor of metalloproteinase-1which decreases UV-induced collagendegradation.

Platelet-Rich Plasma (PRP)

PRP is a source of numerous growth factors whichfacilitate repair and healing. It is a potential reser-voir of essential growth factors, includingplatelet-derived growth factor, vascular endothe-lial growth factor, transforming growth factor-beta 1, and insulin-like growth factor which playan important role on the recovery of the skin(Sonker et al. 2015).

It has been found to accelerate endothelial,epithelial, and epidermal regeneration, stimulateangiogenesis, enhance collagen synthesis, pro-mote soft tissue healing, decrease dermal scarring,enhance the hemostatic response to injury, andreverse the inhibition of wound healing causedby glucocorticoids.

There are different preparation protocols toobtain PRP, and physicians should select properPRP preparations after considering their biomo-lecular characteristics and patient indications.

A split-face comparative study published in2014 of microneedling with PRP versus micro-needling with vitamin C in treating atrophic post-acne scars revealed better results with micro-needling and PRP. Thirty patients with post-acneatrophic facial scars were offered four sittings ofmicroneedling with PRP on one side and micro-needling with vitamin C on the other side of theface at an interval of 1 month. Overall results werebetter with microneedling and PRP (Chawla2014).

PRP along with microneedling would intensifythe natural wound healing cascade because of thehigh concentration of patients own growth factors.It acts synergistically with growth factors induced

by skin needling in order to enhance the woundhealing response. As stretch marks are atrophicscars, we can hypothesize that microneedling andPRP would have good results for them.

Uses and Doses

It is very important to assure that the substancesthat are going to be applied on the skin surfaceprior microneedling are substances that could beused intradermally or intravenously.

For stretch marks’ treatment, we indicate theuse of:

– Fifteen to 20% vitamin C (L-ascorbic acid0,15 g/ml or L-ascorbic acid 0,2 g/ml) ampoules.

– Retinyl palmitate (an ester of retinol) ampoulesfor endovenous administration can be safelyapplied topically.

– MTS® ampoules: a combination of palmitoyltripeptide-28 3% and growth factors 10%.

– PRP preparations (follow proper protocols).

Procedure

During treatment, the needles pierce the stratumcorneum and create microconduits (holes) withoutdamaging the epidermis. It has been shown thatrolling with a dermaroller (192 needles, 200 mmlength and 70 mm diameter) over an area for15 times will result in approximately 250 holes/cm2.

Microneedling is a mild pain drug delivery.Because the skin’s stratum corneum barrier hasno nerves, skin anatomy provides the opportunityto pierce needles across the stratum corneum with-out stimulating nerves. Although, the microneedlesare inserted only deep enough to reach the superfi-cial dermis, which is not much painful, probablybecause their small size reduces the odds ofencountering a nerve or of stimulating it to producea strong painful sensation (Figs. 6a, b and 7a, b).

1. Take photographs of the area you are going totreat using a consistent background, position,and lighting, and they will be compared withthe posttreatment images.

494 G. Casabona and P.B. Marchese

2. Anesthetize using a thick application of topicalanesthetic cream for about 60 min. Remove itcompletely before starting the procedure toprevent topical anesthetic intoxication.

3. Clean the area with alcoholic chlorhexidine.4. Choose a device: roller or pen.5. Choose depth of the needle and speed of the

pen (quicker vibrations lead to less abrasion).6. Choose the active ingredient to use (the use of

sterile and injectable products is important toavoid the risk of infection and also diminishthe risk of contact dermatitis).

7. Apply a thin layer of the liquid with a dispos-able brush.

8. Pass the device and repeat the process over andover. Roll at least 20 passes in the same area indifferent ways, and pen pass at least ten times ineach area making circular movements.

9. Clean just the excess of liquid and blood (leavea thin layer of blood for at least 4 h to functionas a natural PRP dress that helps to heal).

10. Cover the skin with a sterile active ingredientin an oleous vehicle such as glycosaminogly-cans (Antiage Flash

®

Mesoestetic) to preventwater loss through the skin.

11. Cover with a thin plastic drape.12. Instruct the patient to follow strict photo-

protective measures. Schedule sittings are atintervals of 4 weeks.

Other Indications

• Androgenetic alopecia, areata alopecia, acnescars, hypertrophic scars, melasma, skin regen-eration, and preparation of skin prior to fatgraft

Fig. 7 Before (a) and after 30 days (b): one session Dermapen®

TDD with sterile vitamin C + AH non-cross-linked

Fig. 6 (a) 1 day before treatment; (b) 30 days after one session of microneedling with TDD of vitamin C and non-cross-linked hyaluronic acid

Microneedling for Transepidermal Drug Delivery on Stretch Marks 495

Contraindications

• History of contact dermatitis especially tometal and to the active ingredients that aregoing to be used

• Chronic Urticaria• Immunosuppression• Diabetes• Pustular or nodular rosacea or acne• Anticoagulant medications• Pregnancy• Moles (always verify moles prior to treat the

area and try to avoid using microneedling ontop of them)

• Keloids• Skin infection• Psoriasis (Koebner phenomenon)

Advantages

– Nonablative.– Healing process is fast (1–5 days depending on

needle length and number of passes) and hasless chance for complications if compared toablative techniques.

– The immediate effects are a thicker and moreresistant skin.

– Can be used in every skin type even off face.– Low cost if compared to lasers.

Disadvantages

– Training required.– If a very high density or coverage is used, then

the healing time and erythema can last longer.– Does not promote immediate tightening of the

collagen fibers.– Requires more than one session to achieve

good results.

Side Effects and Their Management

The microneedling treatment is well tolerated.Minor side effects reported are mild pain at thetreating area, erythema, spotty bleeding, and

pruritus for 2 or 3 days after the procedure,which are solved without any specific treatment.Moisturizing creams can be applied to keep thearea hydrated, which diminishes the discomfort.

Infection at the treating area is very unlikely tohappen. As the microholes close almost immedi-ately, postoperative infections are rare. If theyoccur, oral or topic antibiotics can be used fortreatment.

Irritant or allergic contact dermatitis can occurdepending on the characteristics of the substanceapplied on the skin surface and the immunologicalcharacteristics of the patient. Oral antihistaminesand topical steroids can be used if necessary(Soltani-Arabshahi et al. 2014).

Hyperpigmentation is uncommon, but if it hap-pens, topical Kligman formula can be applied. Forlong-lasting erythema, micropulsed YAG laser,pulsed dye laser (PDL), and intense pulsed light(IPL) devices can be used. The emergence ofpapules and pustules on the treating area must betreated with topical or oral antibiotics used in acneand rosacea treatment.

A case report study published in 2014 reportsthree patients who developed facial allergic gran-ulomatous reaction and systemic hypersensitivityafter microneedling drug delivery therapy. Micro-needles are powerful means of transdermal deliv-ery of drugs. Thus, only chemicals approved forintradermal injection are safe to be used in con-junction with microneedling. Application of vari-ous nonapproved topical products before amicroneedling procedure can introduce immuno-genic particles into the dermis and potentiate localor systemic hypersensitivity reactions (Lima et al.2013). For facial allergic granulomatous reactionand systemic hypersensitivity, oral steroids andminocycline can be used, but the treatment is notalways effective.

Microneedling and Vitamin C DrugDelivery Plus Calcium HydroxylapatiteFillers: A Pilot retrospective Studyfor Stretch Marks

Calcium hydroxyapatite (CH) is a white substancemade of microspheres (45 mm) of CH in a

496 G. Casabona and P.B. Marchese

carboxymethyl cellulose gel and is a filler andbiostimulator because it is supposed to induceneocollagenesis during the first 6 months afterinjection. CH can be used either in the subcutane-ous layers to volumize a region or in the dermis tocorrect dermal atrophy. It is made to be applied inmore deep planes such as subcutaneously, andwhen it is injected more superficially, it can givea yellowish look. The CH injection into SM in alldepths intends to improve atrophy (Casabonae Michalany 2014) through the stimulation ofthe production of endogenous collagen and alsoto promote a yellowish look to the striae promot-ing a more natural appearance matching the colorof the normal skin (Berlin et al. 2008; Parvicic2015).

Authors’ Experience

A Retrospective study conducted at privateoffice in São Paulo, Brazil (publishing process),during a 3-year period (January 2012 to July2015), enrolled 35 patients with stretch marksin different regions of the body (gluteus, thighs,knees, abdomen, and breasts) and evaluated theefficacy of a new combined treatment for SM;the dermal injection of calcium hydroxyapatiteand microneedling with vitamin C drug deliverywere put together to enhance the appearanceof SM.

Among 35 patients, there was one male(2.85%) and 34 females (97.14%). Twenty five(71.42%) had red SM and ten (28.57%) hadwhite SM. Ages ranged between 21 and34 years, and they were submitted to the sametreatment for SM (Table 1).

Patients had their SM evaluated by a physicianobserver and scores were assigned in accordanceto a visual analogue scale, the Manchester ScarScale (Table 2). This evaluation was performed atthe beginning and after the end of treatment ses-sions. Both scores were compared in order toidentify if there was an improvement in theappearance of stretch marks.

Patients were submitted to four treatment ses-sions with a 4-week interval between them. The

first session included the dermal injection of cal-cium hydroxyapatite (Radiesse®) followed bymicroneedling (Dermapen®) and topical applica-tion of 20% vitamin C onto the affected areas. Thethree remaining sessions included microneedlingwith vitamin C drug delivery, with no dermalinjections.

All the 35 patients had better scores accordingto the Manchester Scar Scale evaluation at the endof the study. Thirty patients were asked about theirlevel of satisfaction with the treatment: 8 patients(27%) were very satisfied, 15 patients (50%) weresatisfied, 5 patients (7%) were neither satisfied nordissatisfied, 2 patients (6%) were unsatisfied, andnone answered very unsatisfied.

Table 1 Drugs and vitamins with scientific evidence to beused prior to microneedling and its effects

Substance Effect

Vitamin A Growth factor release, regulatesdifferentiation and proliferation of theepidermis and dermis, skinregeneration, increased protein andcollagen, epidermal thickening

Vitamin C Stimulates collagen production in thedermis, increases fibroblastproliferation resulting in greatercollagen production

Platelet-richplasma

Enhances collagen synthesis

Table 2 Side effects: how to manage

Side effect Management

Infection Oral or topicalantibiotica

Contact dermatitis Oral antihistamine andtopical can be steroids

Hyperpigmentation Topical Kligmanformula

Long-lasting erythema Micropulsed YAG laser,pdl or ipl

Acne and rosacea Oral antibiotica andtopical acne treatment

Facial allergicgranulomatous reaction andsystemic hypersensitivity

Oral steroids,minocycline

aLymecycline, minocycline, tetracycline)

Microneedling for Transepidermal Drug Delivery on Stretch Marks 497

Results are encouraging. With the injectioncalcium hydroxyapatite and microneedling withvitamin C topical application, it is possible tostimulate collagen production in three differentpathways at the same time. This combined tech-nique may have better results than those obtainedwhen each technique is performed alone (Figs. 8a,b, 9a, b, 10a–f, and 11a–d).

Conclusions

The improvement in the appearance of SM, ratherthan its complete removal, is a more realisticclinical goal. Complete disappearance of SM

may be occasionally observed; nevertheless, thisoccurrence is uncommon and should not be pre-sented to patients as a realistic goal.

Using combination of treatments over a pro-longed period of time can improve the appearanceof striae. Unless a revolutionary monotherapybecomes available that dramatically improvesstriae treatment results, the use of multimodaltreatments tends to increase (Goldberg et al.2005) consistently.

The development of microneedling associ-ated with drug delivery seems to be a goodoption in SM treatment. Combined, they areable to effectively change the collagen organi-zation, transforming the SM skin into a morehealthy skin.

Fig. 8 Before (a) and after (b) two sessions of Dermapen®

TDD with sterile vitamin C. In this case one session of CaHainjection was also done before TDD

Fig. 9 Before (a) and after (b) two sessions of Dermapen®

TDD with sterile vitamin C. In this case one session of CaHainjection was also done before TDD

498 G. Casabona and P.B. Marchese

Take Home Messages

• Stretch marks are often a significant source ofdistress to those affected, and no single therapyis considered to be a consensus for this problem.

• Microneedling and transepidermal drug deliverytogether are an option of treatment, with which itis possible to achieve satisfactory results.

• Skin needling promotes the removal of olddamaged collagen, induces more collagen

Fig. 10 Before and after two sessions of Dermapen®

RTDD with sterile vitamin C. In this case two sessions ofCaHa injection were also done before TDD. Inner thigh

before (a) and after (b). Gluteus left side before (c) andafter (d); gluteus right side before (e) and after (f)

Microneedling for Transepidermal Drug Delivery on Stretch Marks 499

growth beneath the epidermis, and createsaqueous transport pathways within the skinfor drug delivery.

• Vitamin A, vitamin C, and platelet-rich plasmaare substances that can be used for drug delivery.

• Microneedling with drug delivery is a cost-effective office procedure, well tolerated, andwith few minor side effects and short down-time that can be safely used for SM treatment.

• The injection of calcium hydroxyapatite intoSM prior the microneedling with vitamin Ctopical application is an innovative combinedtechnique that may have even better results.

• The improvement in the appearance of SM,rather than its complete removal, is a morerealistic goal.

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502 G. Casabona and P.B. Marchese

Index

AAbdomen, 248, 377Ablation, 154, 166, 432

fractional, 464lasers, 396MAZ, 464

Ablative fractional laser (AFXL), 108, 182, 183, 187,450–454

Ablative fractional photothermolysis (AFP), 155Ablative fractional technologies, 396Ablative laser, 31, 34, 116, 182, 191

and ablative radiofrequency, 479CO2 (see Carbon dioxide (CO2) laser)Erbium (see Erbium ablative laser)resurfacing, 142, 175

Ablative method, TED, see Transepidermal drugdelivery (TED)

Ablative radiofrequency, cosmetic dermatology, 466ablation lasers, 396contra-indications, 399distensible acne scars, 399fractional micro-plasma characteristics, 396–397history, 396indications, 397–398non-distensible acne scars, 401plasma, 396post-procedure, 399pre-procedure, 399pre-treatment care, 398–399results, 399side effects and management, 401stretch marks, treatment of, 401wrinkles and fine lines, treatment of, 401

Ablative technologies, 214, 215Absorption, 436

coefficient, 27of light, 28peaks, 254by water, 30

Acne, 78–80definition, 343mechanism of action, 344–345scars, 74, 156–158, 167, 311–312sebocytes apoptosis, 344

Acne vulgaris, 77Acoustic wave, 434Acremonium, 269, 270Acrochordon, 196Actinic cheilitis (AC), 206–207, 321, 326

photodynamic therapy (see Photodynamic therapy)risk factors, 322treatment, 323

Actinic keratosis (AK), 167, 315, 330, 436, 475–476Acute burning pain, 57Adipocytes, 246, 406Adipose tissue, 406, 412Adiposis edematosa, 376Adiposity, 246Adrenocorticotrophic hormone (ACTH), 173Adverse effects, 470Aging skin

early signs of, 93intrinsic ageing, 90non-ablative lasers (see Non-ablative lasers)prophylaxis of, 101

Aging, 329, 330Alexandrite laser, 224, 225, 227, 229, 254, 257Allergies, 58Alopecia, 235

androgenetic, 237areata, 240–241, 467–469CIA, 236totalis, 240universalis, 240

Alphastria, 174Aluminum chloride, 390Aminolevulinic acid (ALA), 205, 324, 332, 350–354,

474, 477Aminolevulinic acid-photodynamic (ALA-PDT), 259Androgenetic alopecia (AGA), 236, 237, 239, 241Angiofibromas, 167Anti-aging prevention, 83Anticholinergic agents, 390Antifungal drugs, 268, 273, 279Antiherpetic therapy, 167Anti-inflammatory properties, 84Antiviral prophylaxis, 470Areata alopecia (AA), 440

# Springer International Publishing AG 2018M.C.A. Issa, B. Tamura (eds.), Lasers, Lights and Other Technologies, Clinical Approaches and Procedures inCosmetic Dermatology 3, https://doi.org/10.1007/978-3-319-16799-2

503

Argon laser, 198Arm, 247Articulated arm, 14Aspergillus, 269, 271Atrophic acne scars, 362, 367Atrophic scars, 57, 115, 120, 155, 158, 183, 187, 397Atrophic striae, 467Atrophy, 56, 57, 433Axillary hyperhidrosis, 248

BBack, 248Bacterial infections, 57Bacterial resistance, 343, 347Band pass filters, 22Basal cell carcinoma (BCC), 330, 333, 349, 351, 355,

476–477Basic principles, 183–184Beam delivery system, 14Benign lesion, 90, 196, 201Benign pigmentary, 62Beta blockers, 378Biofilm, 270–272

Candida spp, 273extracellular matrix role, 272–273Fusarium spp, 273

Biologic effects, 145Biology of photo aging

extrinsic factors, 50intrinsic factors, 50permanent DNA damage, 50photo damaged skin, 50

Biophysics, IPL, 50–52Biopsy, 356, 436Biostimulation, 277Biotype, 378Bipolar radiofrequency, 364, 365, 367, 384Blood flow, 116, 124, 256Blue and red light combination LED phototherapy, 81Blue light phototherapy, 77, 318, 344, 475Body cellulite, 367Body contour, 247, 249, 421, 422Body fat reduction, 406Body mass index, 407Body sculpting, 405Botulinum A toxin injections, 390Botulinum toxin, 56Bowen’s disease (BD), 330, 333, 476Brazil, 350–351, 353, 356Burn scars, 121, 159, 188–190Buttocks, 377, 385, 386

CCandida, 168, 269–270, 279

biofilms, 273Cannula, 249

Cantharidin, 199Carbohydrates, 378Carbon dioxide (CO2) laser, 214, 215, 270, 280–281,

287, 289, 291, 293, 433, 439, 464,466, 469

actinic cheilitis, 206–207atrophic scars, 187basic principles, 183burn scars, 188DPN, 196–197exogenous ochronosis, 207–210Fordyce spots, 204–205genital warts, 200–201hypertrophic scars, 185mechanism of action, 184melanocytic nevus, 201–202photorejuvenation, 166

history, 166–167indications and contra-indications, 167post-laser, 167pre-laser, 167side effects and management, 167–169

plantar warts, 200post procedure, 191post-surgical/post-traumatic scars, 187–188pre-procedure, 190procedure, 190rhinophyma, 205–206sebaceous hyperplasia, 198seborrheic keratoses, 205side effects, 191syringoma, 203–204verrucous epidermal nevus, 202–203viral wart, 198–200xanthelasmas, 197–198

Cauterization/electrocoagulation, 198Cavitation, 431Cell death, 406Cellular photoactivation, 75Cellulite, 248

clinical description, 379clinical evaluation, 378–379clinical manifestations, 377clinical stages, 379history, 376hormonal variations, 378inflammatory alterations, 378non-ablative

radiofrequency (see Radiofrequency (RF))papillae adiposae, 377predisposed factors, 378treatments, 380vascular changes and edema, 377

Cheilitis actinic, 326Chemical peel, 201Chemical peelings, 56, 174Chemical topical treatment, 198Chemotherapy induced alopecia (CIA), 236

504 Index

Cherry angiomas, 90Chicken pox scars, 398Chromophore, 28, 51, 62, 128, 154, 225, 228

selective heating, 28Chronic rosacea, 205Chronic tanned skin, 50CIA, see Chemotherapy induced alopecia (CIA)Civatte poikilodermas, 62Classification, 297–298Clinical aspects of IPL, see Intense pulsed light (IPL)CO2 laser, see Carbon dioxide (CO2) laserCoagulation, 464Coagulative effect, 144Coherence, 7Collagen, 246, 412, 488, 493

collagen I, 366collagen III, 366contraction, 362dermal heating, 362–363fibers, 330fibers denaturation, 366injection, 173, 174production, 399remodeling, 52reorganization, 116, 124synthesis, 75trabeculae, 378

Collimated, 7, 9Color-blind, 41Combustible material, 303Complications, 160–162, 167Connective-tissue cells, 406Contact cooling, 255Continuous mode, 11Contracts collagen, 381Conventional PDT, 478Cooling systems, 50Corticosteroids, 433Cortisol, 173Cosmetic dermatology

acne scars, 311–312melasma, 310–311photorejuvenation, 309–310stretch marks, 312

Cosmetic outcomes, 324, 326Cryogen spray, 255Cryolipolysis, 380, 422, 428

adverse effects, 426–427mechanism of action, 422–426treatment, 427

Cryosurgery, 203Cryotherapy, 196, 198, 200Curettage, 196, 199, 205Cushing syndrome, 172Cutaneous drug delivery, 448Cutaneous retraction, 246, 248, 250Cut-off filters, 51, 52Cytochrome c oxidase, 76

DDamaged tissue, 182Dark circles eyes, 136

QS Nd:YAG laser, 136QSRL, 136

Dark spots, 56Darker skin, 213, 216Daylight PDT (DL-PDT), 475Daylight photodynamic therapy, 315Deep dermis, 41, 412Delta-amino levulinic acid, 344

photosensitizers, 346–347Dendrites, 130Deoxyhemoglobin, 254Depressions, 379, 385Dermabrasion, 130, 201, 203, 209Dermal collagen, 108Dermal heating, 363, 366Dermal lesions, 132Dermal melasma, 30Dermaroller, 490, 494Dermatological laser, 11, 13, 16, 39Dermatology, 74Dermatophyte fungi, 269Dermatophytoma, 272, 274, 279Dermatoscopy, 274, 276Dermatosis papulosa nigra (DPN), 196–197Dermis, 128, 433Dermis repair, 335Dermis thickness, 381, 384Dermopaniculosis deformans, 376Dichloroacetic acid, 205Diets, 378, 380Diffusion, 431Dimpled appearance, 377Diode laser, 117, 224, 225, 227, 254, 257Distensible acne scars, 398, 399Double-blind randomized prospective study, 439Drug delivery, 182, 280

AFL, 450, 451, 452laser-assisted, 448, 450transepidermal (see Transepidermal drug

delivery (TED))ultrasound (see Ultrasound)

Drugs penetration, 466Dyschromias, 58, 93, 101

EECM, see Extracellular matrix (ECM)Ectropion, 169Edema, 83

and venous returning, 377Edematose cellulite, 379Edematous fibrosclerotic panniculopathy, 376Elastic fibers, 330, 331Elbows, 248Electrical hazard, 303–305

Index 505

Electrical risk, 303Electrocautery, 197Electrocoagulation, 205Electrodes, 36Electrodessication, 196, 199Electromagnetic energy, 362Electromagnetic spectrum, 4, 5, 35Electro-Optical Synergy (ELŌS), 37, 43, 45Electroporation, 431Emerging economy countries, see BrazilEndogenous photosensitizer, 474Energy, 28, 128, 226Energy diffusion, 35Epidermal cooling systems, 255

continuous/independent, 29dynamic, 29static, 29

Epidermal necrosis, 255Epidermis, 128Epidermophyton, 269Epilation, 225, 226, 228Epithelialization, 114Eponychium, 268, 281Erbium ablative laser, 214, 291, 464

acne scars, 156burn scars, 159complications and side effects, 160hypertrophic scars and keloids, 158photothermal ablation, 154–155post trauma scars, 156post-procedure care, 160resurfacing, 156strech marks, 159

Erbium:Ytrium-Aluminum-Garnet (Er:YAG) lasers, 142,202, 287, 289, 291, 295, 346

complications, 149, 150indications, 147operator modes, 145post treatment, 149pre treatment, 147techniques, 148

Eruptive hidradenoma, 203Erythema, 83, 93, 97, 101, 130, 167, 259Estrogen activity, 378Estrogen treatments, 378Ethnic skin, 213, 217–220

fractional ablative lasers, 214–215fractional non ablative lasers, 215–216indications for lasers treatment, 216–217

Evans blue (EB), 436Excessive sweat production, 390Excitation source, 13Exclusion criteria for treatment, 53Exogenous ochronosis, 207–210Exposure time, 11, 28Extracellular matrix (ECM), 272–273Extrinsic factors, 50Eye protection, 228, 301Eye risk, 300–302

FFacial telangiectasia, 257Facial

rejuvenation, 366, 367, 370rhytides, 367, 371

Fat, 246accumulation, 378herniation, 377, 384light absorption, 247reduction, 246

Female pattern loss, 238, 241Ferrochelatase, 344Fibrillin-1, 173Fibrillin-2, 173Fibulin-5, 173Fibroblast, 76Fibroblast growth factor, 82Fibrosis, 182Field of cancerization, 317, 475, 480, 481Filiform warts, 199Filters, 62Fine lines, 397, 401Fingernails, 268–270Fire hazard, 303Fire risk, see Fire hazardFitzpatrick skin, 129Fitzpatrick’s Classification for Skin Types, 52Flaccid skin, 412Flaccidity, 246, 247, 249, 250Flanks, 248Flash-lamp, 22, 62Flashlamp-pumped pulsed dye laser, 116–117Flat collagen fibers, 331Fluence, 128, 129, 131, 133, 138, 226, 255

end point, 256Fluid, 369Fluorescence guided treatment, 351Fluorescence microscopy, 4335-Fluorouracil/intralesional bleomycin, 199Focused handpiece, 8Focused ultrasound, 380Follicular openings, 377Fordyce spots, 204–205Fractional ablative and non ablative lasers,

ethnic skin, see Ethnic skinFractional ablative methods, 432, 478Fractional ablative modalities, 464Fractional bipolar RF, 39Fractional CO2 laser, 183–190Fractional laser, 33–34, 95, 107, 396

resurfacing, 175technology, 142

Fractional micro-plasma, 396–397radio frequency, 396

Fractional photothermolysis (FP), 33, 95, 175,214, 215

Fractional radio frequency, 39–43, 365–366, 391Fractionation, 166Fraxel, 34Frequency, 132, 431

506 Index

Fungi, 274dermatophytes, 269nondermatophyte, 269–270, 274

Fusariosis, 270, 273Fusarium, 269, 272, 273, 279

biofilms, 273

GGas, 200Gas lasers, 15–16Genitourinary syndrome of menopause (GSM), 286

prevalence, 286symptoms, 286

Good results, ALA-PDT for acne, 345Googles, 302Gorlin’s syndrome, 476Granulation tissue, 114Grayish-brown pigmentation, 207Grey skin and blisters, 57Grid of microneedles, 39Gynecomastia, 246, 248Gynoid lipodystrophy, 371

HHair follicle, 224–226, 430Hair loss, 234, 235, 237, 238, 240, 241Hair removal, laser

complications, 229energy, 226fluence, 226hair follicle, 224–226history, 224home devices, 229IPL characteristics, 226–227patient selection and preparation, 227–228power, 226pulse duration, 226spot size, 226treatment, 228

Hamartoma, 202Handpiece, 14

collimated, 9focused, 8

Hazards area, 300–306Healing moisturizer, 470Heat, 128, 390, 406Hemangiomas, 62Hemoglobin (HgB), 62, 254Herpes simplex virus, 57Herpes virus, 227High-frequency electric current, 34High-intensity focused ultrasound (HIFU), 406, 412Hirsutism, 227Histopathological study, 464–466Histopathology findings, 52Home devices, 229Homeostasis, 390Home-use devices, 306–307

Homogentisic acid, 208Human cancerous tissue, 474Hyaluronic acid fillers, 56Hydroquinone, 130, 167Hyperhidrosis, 268, 390

bipolar radiofrequency, 391clinical trials, 391fractional radiofrequency, 391monopolar radiofrequency, 390radiofrequency thermotherapy, 390unipolar radiofrequency, 391

Hyperinsulinemia, 378Hyperpigmentation, 129, 130, 135, 137, 167Hypertrophic scars, 57, 74, 79, 81, 115, 120, 182, 183,

185–187, 227Hypertrophic scars and keloids, 68–69, 158–159Hyponychium, 269Hypopigmentation, 169Hypothyroidism, 269Hypoxia, 377

IIdeal pulse duration, 28Ideal wavelength, 28Immediate complications, 57Immediate end-point, 53Immunocompromised individuals, 268, 273Immunosuppressed individuals, 268Induction of collagen and cicatrization, 210Infantile hemangiomas, 260Infections, 57–58, 168Inflammatory alterations, 378Infrared low-level light therapies, 81Injury, 128Inner surface of thighs, 248Intense pulse light (IPL), 50, 62, 107, 174–175, 209, 225,

226–227, 229, 310, 345, 475botulinum toxin, 56chemical peelings, 56chromophores, 51collagen remodeling, 52complications after treatment, 69cooling systems, 50devices, 254exclusion criteria for treatment, 53histopathology findings, 52hyaluronic acid fillers, 56immediate complications, 57immediate end-point, 53incoherent, 23lasers, 56, 257late complications, 57–58mechanism of action, 64pigmentary lesions, 52polychromatic, 22–23principle, 62schematics of, 25selective photothermolysis, 51side-effects, 56

Index 507

Intense pulse light (IPL) (cont.)skin laxity and wrinkles, 52therapy, 65vascular lesions, 52wavelengths, 63

International recommendations, 297International standards, 297Intimate laser, 288, 289Intrapalpebral protector, 368, 369Intravascular thrombosis, 255Intrinsic ageing, 90Intrinsic factors, 50Invasive methods, 380In-vitro/in-vivo effectiveness, 433Ionic current, 37Iontophoresis, 390, 431IPL, see Intense pulsed light (IPL)Isotretinoin, 228

KKeloids, 57, 79, 81, 115, 121, 183, 227, 433Keratin, 269Keratinocytes, 129Keratinophilics, 269Keratolytic therapy, 269Knees, 248Koebner phenomenon, 228KTP laser, see Potassium Titanyl Phosphate Laser

(KTP) laser

LLactic acid, 199Lag telangiectasia, 67Lanugo, 225Laser, 56, 382, 390, 432–434, 440, 464, 466, 469

ablation, CO2 (see Carbon dioxide (CO2) laser)articulated arm, 14beam delivery system, 14CO2, 280–281 (see also Carbon dioxide (CO2)

laser)cutting, 203dermatology, 234, 312devices, 214, 215energy, power and fluency, 8–11erbium ablative (see Erbium ablative laser)ethnic skin (see Ethnic skin)excitation source, 13fractional laser systems, 33–34gas, 15–16hair removal, 56 (see also Hair removal, laser)in hair regrowth process, 234handpiece, 14hybrid systems, 43–44intense pulsed light, 22–23interaction with skin, 278–279laser light, characteristics of, 7–8

LEDs, 21–22light penetration depth, 29–33light-tissue interaction, 25–28liquid, 16melanin, 28–29Nd:YAG, 279–280operating modes of, 11–13optical fiber, 14physics (see Light amplification by stimulated

emission of radiation (LASER))pulse duration, 28QS (see Q-switched (QS) lasers)radiation, 278radio frequency, 34–43resonator/oscillator, 13resurfacing, 154, 155solid-state, 16–21sources, 234therapy, 174, 200, 206toning, 131treatment, 23, 277–278 (see also Erbium

ablative laser)variables, 301

Laser-assisted drug delivery (LADD),fractional, 448–450

Laser lipolysis, 174, 246clinical results, 250complications, 250indications and contraindications, 247–248local anesthesia, 249post-operative care, 250pre-operative considerations, 248–249

Laser safetyclassification, 297hazards area, 300home-use intense pulsed light and laser

devices safety, 306–307preventive measures, 298

Late complications, 57–58Laxity, 50, 52, 362, 377LED light sources, 345LED-based light sources, 354Lifting effect, 411Light amplification, 7Light amplification by stimulated emission of radiation

(LASER), 4–7Light emitting diode (LED), 21–22, 73, 310, 311, 433, 475

acne, 79indications, 79photobiomodulation (see Photobiomodulation)photodamaged skin, 82photomodulation, 74phototherapy, 81scars, 81

Light therapy, 73, 174Light-tissue interaction

absorption coefficient, 27absorption of light, 28

508 Index

chromophores, 28energy, 28exposure time, 28ideal pulse duration, 28ideal wavelength, 28laser pulse duration, 28photobiomodulation, 25photochemical, 25photomechanical, 25photothermal, 25selective photothermolysis, 25target tissue, 28

LIL, see Low intensity laser (LIL)Limited/hard cellulite, 379Lip cancer, 322Lipogenesis, 378Lipolysis, 422

laser (see Laser lipolysis)Lipoma, 248Liposclerosis, 376Liposuction, 247, 248, 250, 421, 422, 427Liquid laser, 16Local circulation, 384Localized fat, 247, 248Long-pulse 1064 Nd:YAG, 175Low intensity laser (LIL), 57Low level light therapy, 73, 75, 234, 240Low-dose QS, 128Lower energy waves, 412Lower limbs, 377Low-level laser therapy (LLLT), 234

alopecia areata, 240androgenetic alopecia, 237clinical benefits, 235in CIA, 236on hair growth, 235–236

Lumps, 377Lunula, 269Lymphatic drainage, 380, 384, 385

MMacules, 129Male pattern loss, 238, 239, 241MAL, see Methyl aminolevulinate (MAL)MAL-PDT protocol, 345, 351, 356Marfan syndrome, 172Marking grid, 369MASI, see Melasma Area Severity Index (MASI)Matrix metalloproteinase (MMP), 90Matrix of bipolar microelectrodes, 39Mechanical and thermal mechanisms, 406Mechanism of action, 184–185Melanin, 62, 128

production, 214Melanocytes, 129Melanocytic lesions, 50, 51, 202Melanocytic nevus (MN)

chemical peels, 201dermabrasion, 201laser ablation, 201non ablative methods, 202Q-switched ruby, Nd:YAG and

Alexandrite, 202surgical excision, 201

Melanophages, 129Melanosome, 128Melasma, 129, 310–311, 469

clinical feature, 130macules and patches, 129QS Nd:YAG laser, 131–134QSRL, 134–135

Melasma Area Severity Index (MASI), 132Menopause, 228, 286, 288, 293, 295Mesenchyme tissue, 376Methemoglobin, 254Methyl aminolevulinate (MAL), 324, 326, 332–333,

350–354, 433, 436, 474, 476, 478Methyl aminolevulinate-photodynamic Therapy

(MAL-PDT), 259Methyl ester of ALA (MAL), 344Micro perforations, 396Micro thermal zone (MTZ), 33, 396Micro-channels in epidermis, 464Microdermabrasion, 174

and laser, 196Microfocused ultrasound (MFU), 411

application technique, 413–415indications and contraindications, 412side effects and managements, 415–417

Microneedling, stretch marks, 479, 490, 492devices, 490history, 490mechanisms of action, 491transepidermal drug delivery (see Transepidermal

drug delivery (TDD))Micro-plasma, 396–397Micro-plasma electrical sparks, 396Microscopic ablation zones (MAZ), 464Microscopic epidermal necrotic debris

(MENDs), 96Microscopic treatment zones (MTZs), 96, 142, 175Microsporum, 269Micro-thermal zones (MTZ), 182, 184, 185Microvessels, 255Microwaves, 390Minimally invasive procedure, 247Mixed infections, 277, 278Molecular weight (MW), 464Monochrome, 7Monopolar radiofrequency (MRF), 362–364, 366,

368–370, 382–384Multi-Application Platform, 23Multicenter clinical trial, 351, 355Multipolar radiofrequency, 364–366, 368–370Mycotoxicosis, 270

Index 509

NNail matrix, 268Nasal skin and nodular deformation, 205Nasal telangiectasia, 67Nd:YAG laser, see Neodymium yttrium-aluminum-

garnet (Nd:YAG) laserNear infrared light (IR), 30, 77Near infrared radiation (NIR) laser, 254Neck, 247Neocollagenesis, 95, 155, 156, 159, 166, 182,

185, 187, 246, 248, 250, 363, 366, 370,381, 385

Neodymium yttrium-aluminum-garnet(Nd:YAG) laser, 224, 225, 227, 246,255, 257, 279–280

Nerve blockade, 167Nevi, 167Nitric acid, 199Nodular, 376Nodules, 377, 379Non melanoma skin cancer (NMSC), 330, 332, 333Non-ablative

devices, 366methods, 202technique, 368

Non-ablative laser, 31, 45, 116–118, 175, 182, 187, 478fractional lasers, 95, 108, 450, 454–456history of, 91mechanism of action, 92nonfractional lasers (see Nonfractional lasers)patient selection, 100treatment considerations, 100

Non-ablative radiofrequency, see Radiofrequency (RF)Non-ablative skin, 131Nonbeam hazards, 303–306Noncoherent, 62Noncoherent filtered flashlamp, 174Noncollimated, 62Nondermatophyte fungi, 269–270Non-distensible acne scars, 398, 401Nonfractional lasers, 93

mid infrared lasers, 95near infrared lasers, 94visible light lasers, 93

Non-invasive technologies, 406, 411Non-invasive treatments, 380Non-melanoma skin cancer, 350, 473, 475, 479Nonsurgical fat reduction,

cryolipolysis, see CryolipolysisNon-thermal light therapies, 7410.600nm, 166308-nm xenon-chloride excimer laser (XeCl), 175532-nm KTP, 94585/595-nm pulsed dye, 94585-nm flashlamp, 174755-nm Q-switched nanosecond and picosecond

Alexandrite, 94924 nm, 247975 nm, 247

1064-nm factional QS Nd:YAG laser, 991064-nm long pulsed, QS Nd:YAG lasers, 941320-nm Nd: YAG, 951440-nm diode, 991440-nm Nd:YAG laser, 98–991450-nm diode, 1981450-nm diode laser, 951540-nm erbium glass laser, 95, 971550-nm erbium glass laser, 971565-nm erbium-doped laser, 991720-nm diodes, 1981940-nm laser, 992940-nm laser, 142

OObesity, 422Ochronotic pigment, 208Onychomycosis, 268

biofilms, 270–273clinical evaluation, 274–276diagnosis, 274etiology and epidemiology, 269–270treatment, 276–281

Optical fiber, 14, 249Optical fiber laser, 20–21Optical scanners, 33Oral glycopyrrolate, 390Oral isotretinoin, 198, 205Orange skin appearance, 377Organ transplant recipients (OTRs), 476Oscillator, 7Overreaction, 182Oxyhemoglobin, 254

PPain, 83Paniculosis and cellulite hypodermosis, 376Paradoxical hypertrichosis, 229Parameters, 226, 228Patches, 129PDT, see Photodynamic therapy (PDT)Peau d’orange, 205Penetration depth, 29–33Percutaneous collagen induction, 174, 491, 493Periungual warts, 199Permanent DNA damage, 50Permeability, 431Permeation, 433Persistent PIHE, 58Persistent PIHO, 58Photoacoustic disruption, 94Photoaging, 330, 469, 477, 479

chronological and, 90features of, 90non-ablative lasers (see Non-ablative lasers)pathogenesis, 330–331treatment, 331

510 Index

Photobiomodulation, 73, 75, 82, 237, 278, 279, 281Photobiostimulation, 74Photobleaching, 355Photochemical effects, 278Photochemical reactions, 334Photodamage, 317Photodamaged skin, 50, 51, 53, 78, 82–84, 93, 96, 165,

330, 331, 335, 336Photodynamic therapy (PDT), 57, 76, 198, 203, 205,

254, 317, 326, 330, 331, 344, 433, 466adverse effects of, 346AKs, 475–476ALA and MAL production, 351–354BCC, 476–477BD, 476Brazil, 349, 350, 356concept and mechanism of action, 331conventional PDT, 478definition, 474device development, 354–355history, 474indications and contraindications, 324light sources, 332, 345management, 325–326mechanism of action, 323multicenter study results, 355–356non-oncologial protocols, 356OTRs, 476photodamaged skin, 477photosensitizers, 332–333, 474–475program and strategies, 351side effects, 325–326, 331source of light, 475uses and doses, 324

Photoexcitation, 79Photogenesis, 130Photoinhibition, 278Photoionization effects, 278Photomechanical effects, 278Photomedicine cream, 353Photorejuvenation, 136–138, 309–310, 318, 332,

334–337, 398, 481CO2 laser (see Carbon dioxide (CO2) laser,

photorejuvenation)IPL (see Intense pulsed light (IPL))non-ablative lasers (see Non-ablative lasers)

Photos, 53Photosensitizer, 315, 330–333, 474–475Phototherapy, 74Photothermal destruction, 129Photothermal effects, 278Photothermolysis, 110, 128, 224, 226, 432Phototype, 224, 226, 227Picosecond Nd: YAG lasers, 95Pigment, 128Pigmentary changes, 255Pigmentary lesions, 52Pigmentation, 214, 216Pigmented lesions, 90, 93, 95

PIHO, see Post-inflammatory hypochromia (PIHO)Planktonic cells, 270, 272Plasma, 366, 396Platelet rich plasma (PRP), 441Plume hazard, 305Plume risk, see Plume hazardPodophyllin, 199Poikiloderma of Civatte, 90, 259Polka dot effect, 258Polychromatic infrared light, 62Polychromatic light energy, 62Polycystic ovary syndrome, 228Porokeratosis treatment, 479Porphyrin-based photosensitizer agents, 474Port-wine stains (PWS), 62, 68, 260

postoperative complications, 261pulse duration, 256

Post procedure, 191Post trauma scars, 156Post-burn hyperpigmentation, 398Post-inflammatory hypercromia (PIHE), 58Post-inflammatory hyperpigmentation, 110, 214Post-inflammatory hypochromia (PIHO), 58Post-inflammatory hypopigmentation, 214Post-procedure care, 159–160Post-procedure directions, 470Post-pubertal women, 376Potassium Titanyl Phosphate Laser (KTP)

laser, 254, 256Power, 226Pregnancy, 378Premalignant lesion, 206Pre-procedure, 190Preventive measures, 298–299Procedure, 190Prodrugs, 474Propionibacterium acnes, 78, 344Protoporphyrin IX (PpIX), 351, 354–355, 433, 474, 476Puberty, 378Pulse, 128, 129, 131, 132, 136Pulse duration, 224, 226Pulse dye laser, 108Pulse technology, 142Pulsed dye laser (PDL), 174, 254, 256, 475Pulsed light, 22–23, 33Pulsed mode, 11Purpura, 57, 255

QQ switched Ruby laser (QSRL), 129

dark cicle eyes, 136melasma, 134–135

QS Nd:YAG laser, 128–129dark cicle eyes, 136melasma, 131–134

Q-Switch (QS)active, 12passive, 12

Index 511

Q-switched Alexandrite laser (QSAL), 129Q-switched mechanism, 225Q-switched (QS) lasers, 128, 209

and complications, 138and dark circles eyes, 136and melasma, 129–135and photorejuvenation, 136–138pre treatment procedure, 129QS Nd:YAG laser, 128–129QSAL, 129QSRL, 129

Q-switched Ruby laser 694-nm, 94

RRadiofrequency (RF), 16, 175, 227, 287, 310, 311,

432, 464, 466ablative devices, 367 (see also Ablative

radiofrequency, cosmeticdermatology)

application techniques, 369–370benefits, 368bipolar, 35–37, 384, 391clinical studies, 385–386clinical trials, 391–393combined treatments, 371contradictions, 368dermal heating, 362–363electrical current, frequency of, 381expected results, 370fractional, 39–43, 391high-frequency electric current, 34histopathological changes, 366immediate effects, 370–371indications, 367mechanism, 362monopolar, 35, 363–364, 382–384, 390multipolar, 37, 364–366non-ablative devices, 366patient selection, 367power, 382pre-procedure care, 368RF current, 35sublative RF, 41techniques, 174technologies, 385therapeutic arsenal for rejuvenation, 371–372tissue effects, 380–381tissue heating, 35treatment, 367TriPollar, 384–385unipolar, 37–39, 384, 391volumetric heat, 35waves, 381

Red light, 74, 318, 344, 475Reduced optical fluency, 44Reepithelialization, 114Refrigerated air cooling, 256

Rejuvenation, 167, 371–372, 474,475, 479

Relaxation time, 28Remodel collagen, 62Remodeling, 182, 185, 187Residual hyperpigmentation prevention, 470Resonator, 7Resonator/oscillator, 13Resurfacing, 31, 154–156, 467

with ablative lasers, 142non-ablative lasers

general clinical and treatmentconsiderations, 100

mechanism of action, 92Rhinophyma, 167, 205–206Rhytides, 362Risk, 58

electrical, 303eye, 300fire, 303–304plume, 305skin, 302teeth, 302

Rosacea, 62, 64, 65, 258Rough and sagging skin, 50Ruby laser, 224, 225

SSafety, laser, see Laser safetySagging, 50, 362, 367, 371Salicylic acid, 199Salt, 378Scarring, 257

erbium ablative laser (see Erbiumablative laser)

Scars, 57, 78, 81–82, 115–116, 397, 399,433, 466–467

atrophic, 183CO2 laser for (see Carbon dioxide (CO2) laser)erbium ablative laser (see Erbium

ablative laser)hypertrophic, 182, 183treatment, 120–122

Scattering of light, 29Scopulariopsis, 270Scytalidium, 270Sebaceous glands, 204, 345Sebaceous hyperplasia, 167, 196, 198Seborrheic keratoses, 90, 167, 205Selective photothermolysis, 25, 33, 44, 51, 62,

202, 224, 226, 253Selective thermal damage, 62Semiconductor laser, 19–20Shaving, 196, 199Shock waves, 431Side effects, 167–169, 191Singlet oxygen, 355

512 Index

Skin, 430aging, 330 (see also sagging)atrophy, 91color type, 52, 54, 56contraction, 246drug administration, TED (see Transepidermal

drug delivery (TED))epidermis, 430flaccidity, 407laxity, 370laxity, 52melanin, 28needling, 488, 492, 494regeneration, 33rejuvenation, 62, 74, 142, 330, 335remodeling, 115, 331resurfacing, 398risk, 302–303surface, 379, 382texture, 182tightening, 398ultrasound-skin interaction (see Ultrasound)vaporization, 154

Smoking, 378Soft/diffuse cellulite, 379Solar cheilosis, 322Solar elastosis, 90, 95, 99Solar lentigenes, 90, 92, 93Sonophoresis, 431Source of light, 475Spectral ranges, vascular laser technologies, 254Spectroscopy, 436Spider telangiectasia, 257Spot size, 62, 129, 226, 255, 256Squamous cell carcinoma (SCC), 206, 322,

323, 326, 475Staking, 369Stimulate the collagen, 396Stimulated emission, 4–6Stimulates neocollagenesis, 381Stimulation of angiogenesis, 75Stratum corneum, 430Stretch marks (SM), 107, 159, 167, 171,

312, 398, 401definition, 488microneedling (see Microneedling,

stretch marks)striae albae, 488, 489striae rubrae, 488treatment, 489

Striae, 171Striae alba, 106, 171Striae atrophicans, 171Striae distensae (SD), 67, 105, 171,

173, 437Striae gravidarum (SG), 105, 171Striae rubra, 106, 171Subcision, 380

Subcutaneous aponeurotic muscular system(SMAS), 412

Subcutaneous tissue, 406Sublative RF, 41Submental, 248, 249Sunlight, 345Superficial aponeurotic muscular system

(SMAS), 412Superficial layers, of skin, 412Superficial vessels, 256Surface lesion, 465Surgeries, 378Surgical excision

malignant transformation, 201primary suture, 203

Sweat glands, 431Sweating, 390Synechiae, 169Syringoma, 196, 203–204Systemic antibiotic, 343

TTarget chromophore, 254Target molecule, 62Target specific chromophores, 62Target structure, 62Target tissue, 28TCA, see Trichloroacetic acid (TCA)Technological development, 351Teeth risk, 300–302Telangiectasia, 50, 51, 53, 54, 56, 62, 90, 93,

99, 255Temperature, 412Term of Consentient, 53Terminal hair, 225Tetracycline, 209Texture, 62Thermage, 363–364Thermal and ablative damage, 396Thermal damage, 154, 396Thermal effect, 36, 155Thermal energy, 396Thermal heat, 381Thermal relaxation, 255Thermal relaxation time (TRT), 28, 128, 225, 226Thermotherapy, 390, 393Thickening of the fibrous septa, 377Thickness of the subcutaneous cellular tissue, 377Tightening, MFU for, see Microfused

ultrasound (MFU)Tissue coagulation, 142Tissue heating, 35, 412Tissue repair, 114Tissue vaporization, 144Tonofibrils, 269Topical administration, 448, 452Topical agents, 203

Index 513

Topical anesthesia, 167Topical PDT, 475, 477Topical treatments, 380Transcutaneous administration, see Transdermal drug

deliveryTransdermal administration, see Transdermal drug

deliveryTransdermal drug delivery (TDD), 430, 464, 492Transepidermal drug delivery (TED), 438, 440,

447–457, 474ablative and non ablative methods, 478advantages, 496contraindications, 496disadvantages, 496DLPDT, 481histopathological studies, 464–466indications, 466–470, 495management, 496microneedling, 479platelet-rich plasma, 494post-procedure directions, 470procedure, 494side effects, 470topical conventional PDT, 479uses and doses, 494vitamin A, 493vitamin C, 493

Treatment platforms, 23Tretinoin, 167, 174Trichloroacetic acid (TCA), 198, 199, 203, 210Trichophyton, 269, 274Trofolastin, 174Tropoelastin, 173Tumor response, 356Types of lasers, see Light amplification by

stimulated emission of radiation (LASER)

UUltrasonic waves, 406Ultrasound (US), 406, 430, 436, 440

acoustic wave, 434areata alopecia, 440cavitation, 431, 432cell permeability, 431definition, 431electroporation, 431energy, 411high pressure, 464IMPACT™ 434intercellular diffusion, 431iontophoresis, 431low frequency, 432, 464platelet rich plasma, 440shock waves, 431sonophoresis, 431sonotrode, 434, 435 (see also Microfused

ultrasound (MFU))

Unipolar radiofrequency, 384, 396Urinary incontinence, 286, 289, 291, 295Urticaria, 229Urticas, 57UV radiation, 334UVB radiation, 330

VVaginal laxity, 289, 291Vaginal rejuvenation

contra-indications, 289–290definition, 286indications, 289

Vaporization, 396, 464Vascular alterations, 377Vascular lesions, 52, 62, 94, 101, 254, 255

civatte poikiloderma, 66–67facial telangiectasia, 257hemangioma, 65–66hypertrophic scars and keloids, 68–69infantile hemangiomas, 260leg telangiectasia, 67nasal telangiectasia, 67Poikiloderma of Civatte, 259port-wine stains(PWS), 68, 260post-treatment, 264pre-treatment, 261Rosacea, 258spider telangiectasia, 257striae distensae(SD), 67telangiectasias, 255treatment, 64, 65venous lakes, 260

Vascular malformations, 62Vascular target, 255Vasodilatation, 380Vectors application, 369Vellus, 225Venous lakes, 260Verrucous epidermal nevus, 196, 202–203Vertical channels, 464Vessel clearance, 258Viral wart, 196, 198–200Visible light, 345Visible wavelengths, 30Volumetric heat, 35Vulvovaginal atrophy, 286

WWarts, 167Water metabolism disorder, 376Wavelength, 4, 62, 128, 129, 131, 136, 224, 227,

229, 253, 255Whitening, 132Widefield fluorescence visor, 354, 355Wood’s light, 130

514 Index

Wound healing, 74, 90, 93, 154, 155, 162Wrinkles, 50, 52, 56, 74, 90, 92, 95, 100,

397, 401

XXanthelasma

chemical cauterization, trichloroacetic acid andcryosurgery, 197

diode, 197electrosurgery, 197Erb:YAG, 197

KTP laser, 197periorbital region, 197pulsed dye laser, 197Q-switched Nd:YAG, 197surgical removal, 197, 198ultrapulsed CO2, 197xanthoma, 197

Xerosis, 90

YYAG family, 17–18

Index 515