wound+healing+ +an+overview

CME

Wound Healing: An OverviewGeorge Broughton II,

M.D., Ph.D., COL., M.C.,U.S.A.

Jeffrey E. Janis, M.D.Christopher E. Attinger,

M.D.

Dallas, Texas; and Washington, D.C.

Learning Objectives: After studying this article, the participant should be ableto: 1. Describe the actions of inflammatory mediators, growth factors, and nitricoxide involved in wound healing. 2. Describe the different cellular elements andtheir function in wound healing. 3. Discuss the three phases of wound healingand the relationships between mediators and cells for each. 4. Discuss thesimilarities and differences between keloids and hypertrophic scar and thetreatment options for each. 5. Discuss the systemic and external factors involvedin wound healing. 6. Discuss future wound-healing opportunities.Summary: Understanding wound healing today involves much more than sim-ply stating that there are three phases: inflammation, proliferation, and mat-uration. Wound healing is a complex series of reactions and interactions amongcells and “mediators.” Each year, new mediators are discovered and our un-derstanding of inflammatory mediators and cellular interactions grows. Thisarticle will attempt to provide a concise overview on wound healing and woundmanagement. (Plast. Reconstr. Surg. 117: 1e-S, 2006.)

Understanding wound healing today in-volves much more than simply statingthere are three phases: inflammation, pro-

liferation, and maturation. Wound healing is acomplex series of reactions and interactionsamong cells and “mediators.” Each year, newmediators are discovered and our understandingof inflammatory mediators and cellular interac-tions grows. Many intrinsic and extrinsic factorsaffect wound healing, and an enormous industryprovides the clinician with a huge and complexarmamentarium to battle wound-healing prob-lems. This article will provide the reader with awide overview of wound healing and wound-healing problems and solutions.

WOUND HEALINGWound healing has traditionally been divided

into three distinct phases: inflammation, prolifer-ation, and remodeling.1,2 A detailed review of thebasic science of wound healing can be found in

this Supplement. This discussion will serve as abroad overview of clinical wound healing. Table 1summarizes the inflammatory mediators by sourceand function.3,4

Hemostasis and Inflammation (fromImmediately upon Injury throughDays 4 to 6)

The inflammatory phase is characterized byhemostasis and inflammation. Collagen exposedduring wound formation activates the clotting cas-cade (both the intrinsic and extrinsic pathways),initiating the inflammatory phase. After injury oc-curs, the cell membranes release the potent vaso-constrictors thromboxane A2 and prostaglandin2-�. The clot that forms is made of collagen, plate-lets, thrombin, and fibronectin, and these factorsrelease cytokines and growth factors (Table 2) thatinitiate the inflammatory response.5 The fibrinclot serves as scaffolding for arriving cells, such asneutrophils, monocytes, fibroblasts, and endothe-lial cells.6 It also serves to concentrate the cyto-kines and growth factors.7

Chemotaxis and ActivationImmediately after the clot is formed, a cellular

distress signal is sent out and neutrophils are thefirst responders. As the inflammatory mediatorsaccumulate, and prostaglandins are elaborated,the nearby blood vessels vasodilate to allow for theincrease cellular traffic as neutrophils are drawninto the injured area by interleukin (IL)-1, tumornecrosis factor (TNF)-�, transforming growth fac-

From the Department of Plastic Surgery, Nancy L & PerryBass Advanced Wound Healing Laboratory, University ofTexas Southwestern Medical Center; and the GeorgetownLimb Center, Georgetown University Medical Center.Received for publication February 1, 2006; revised March18, 2006.The opinions or assertions contained herein are the privateviews of the author (G.B.) and are not to be construed asofficial or as reflecting the views of the Department of the Armyor the Department of Defense.Copyright ©2006 by the American Society of Plastic Surgeons

DOI: 10.1097/01.prs.0000222562.60260.f9

www.plasreconsurg.org 1e-S

tor (TGF)-�, platelet factor-4 (PF4), and bacterial“products.”8,9 Monocytes in the nearby tissue andin the blood will be attracted to the area andtransform into macrophages, usually around 48 to96 hours after injury. Activation of the inflamma-tory cells is critical, especially for the macrophage.An activated macrophage is important for thetransition into the proliferative phase. An acti-vated macrophage will mediate angiogenesis, fi-broplasia, and synthesize nitric oxide.10

Neutrophils will enter into the wound siteand begin clearing it of invading bacteria andcellular debris. The neutrophil releases causticproteolytic enzymes that will digest bacteria andnonviable tissue. The next cells present in thewound are the leukocytes and the macrophages(monocytes). The macrophage is essential forwound healing. Numerous enzymes and cyto-kines are secreted by the macrophage, includingcollagenases, which debride the wound; ILs andTNF, which stimulate fibroblasts (produce col-lagen) and promote angiogenesis; and TGF,which stimulates keratinocytes.

Proliferative Phase (Epithelization,Angiogenesis, and Provisional MatrixFormation; Day 4 through 14)

Epithelialization, angiogenesis, granulationtissue formation, and collagen deposition are theprincipal steps in this building portion of woundhealing. Epithelialization occurs early in woundrepair. If the basement membrane remains intact,the epithelial cells migrate upward in the normalpattern. The epithelial progenitor cells remainintact below the wound (in skin appendages), andthe normal layers of epidermis are restored in 2 to3 days. If the basement membrane has been de-stroyed, then epithelial cells located on the skinedge begin proliferating and sending out projec-tions to re-establish a protective barrier.4,11 Angio-genesis, stimulated by TNF-�, is marked by endo-thelial cell migration and capillary formation. Themigration of capillaries into the wound bed iscritical for proper wound healing. The granula-tion phase and tissue deposition require nutrientssupplied by the capillaries, and failure of this to

Table 1. Summary of Inflammatory Cytokines*

Cytokine Cell of Origin Function

EGF Platelets, macrophages Mitogenic for keratinocytes and fibroblasts,stimulates keratinocyte migration

FGF Macrophages, mast cells, T lymphocytes,endothelial cells

Chemotactic and mitogenic for fibroblasts andkeratinocytes, stimulates angiogenesis

IFNs (�, �, and �) Lymphocytes, fibroblasts Activate macrophages, inhibit fibroblastproliferation

ILs (1, 2, 6, and 8) Macrophages, mast cells, keratinocytes,lymphocytes

IL-1: induces fever and adrenocorticotrophichormone release; enhances TNF-� and IFN-�,activates granulocytes and endothelial cells; andstimulates hematopoiesis

IL-2: activates macrophages, T cells, natural killercells, and lymphokine-activated killer cells;stimulates differentiation of activated B cells;stimulates proliferation of activated B and Tcells; and induces fever

IL-6: induces fever and enhances release of acute-phase reactants by the liver

IL-8: enhances neutrophil adherence, chemotaxis,and granule release

KGF Fibroblasts Stimulates keratinocyte migration, differentiation,and proliferation

PDGF Platelets, macrophages, endothelial cells Cell chemotaxis, mitogenic for fibroblasts,stimulates angiogenesis, stimulates woundcontraction

TGF-� Macrophages, T lymphocytes, keratinocytes Mitogenic for keratinocytes and fibroblasts,stimulates keratinocyte migration

TGF-� Platelets, T lymphocytes, macrophages,endothelial cells, keratinocytes

Cell chemotaxis stimulates angiogenesis andfibroplasia

Thromboxane A2 Destroyed wound cells Potent vasoconstrictorTNF Macrophages, mast cells, T lymphocytes Activates macrophages, mitogenic for fibroblasts,

stimulates angiogenesisEGF, epidermal growth factor; FGF, fibroblast growth factor; IFN, interferon; IL, interleukin; KGF, keratinocyte growth factor; PDGF,platelet-derived growth factor; TGF, transforming growth factor; TNF, tumor necrosis factor.*From Henry, G., and Garner, W. Inflammatory mediators in wound healing. Surg. Clin. North Am. 83: 483, 2003; and Lawrence, W., andDiegelmann, R. Growth factors in wound healing. Clin. Dermatol. 12: 157, 1994.

Plastic and Reconstructive Surgery • June Supplement 2006

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occur results in a chronically unhealed wound.Epithelial cells located on the skin edge beginproliferating and sending out projections to re-establish a protective barrier against fluid lossesand further bacterial invasion. The stimulus forepithelial proliferation and chemotaxis is epider-mal growth factor (EGF) and TGF-� produced byactivated platelets and macrophages (fibroblastsdo not appear to synthesize TGF-�).4,11 Epitheliza-tion begins shortly after wounding and is first stim-ulated by inflammatory cytokines. IL-1 and TNF-�upregulate keratinocyte growth factor (KGF) geneexpression in fibroblasts. In turn, fibroblasts syn-thesize and secrete KGF-1, KGF-2, and IL-6, whichsimulate neighboring keratinocytes to migrate inthe wound area, proliferate, and differentiate inthe epidermis.12,13 It has been shown that, for hu-mans, KGF-2 is most important for directing thisprocess.14

The final part of the proliferative phase isgranulation tissue formation. Fibroblasts migrateinto the wound site from the surrounding tissue,become activated, and begin synthesizing collagenand proliferate. Platelet-derived growth factor(PDGF) and EGF are the main signals to fibro-blasts and are derived from platelets and macro-phages. PDGF expression by fibroblasts is ampli-fied by autocrine and paracrine signaling.Fibroblasts already located in the wound site(termed “wound fibroblasts”) will begin synthesiz-ing collagen and transform into myofibroblasts forwound contraction (induced by macrophage-se-creted TGF-�1); they have less proliferation com-pared with the fibroblasts coming in from thewound periphery.15–17 In response to PDGF, fibro-blasts begin synthesizing a provisional matrix com-posed of collagen type III, glycosaminoglycans,and fibronectin.18

Maturation and Remodeling (Day 8 throughYear 1)

Clinically, the maturation and remodelingphase is perhaps the most important. The mainfeature of this phase is the deposition of collagenin an organized and well-mannered network. Ifpatients have matrix deposition problems (fromdiet or disease), then the wound’s strength will begreatly compromised; if there is excessive collagensynthesis, then a hypertrophic scar or keloid canresult.

Net collagen synthesis will continue for at least4 to 5 weeks after wounding. The increased rate ofcollagen synthesis during wound healing is notonly from an increase in the number of fibroblastsbut also from a net increase in the collagen pro-duction per cell.19,20 The collagen that is initiallylaid down is thinner than collagen in uninjuredskin and is orientated parallel to the skin. Overtime, the initial collagen threads are reabsorbedand deposited thicker and organized along thestress lines. These changes are also accompaniedby a wound with an increased tensile strength,indicating a positive correlation between collagenfiber thickness/orientation and tensile strength.5The collagen found in granulation tissue is bio-chemically different from collagen from unin-jured skin. Granulation tissue collagen has agreater hydroxylation and glycosylation of lysineresidues, and this increase of glycosylation corre-lates with the thinner fiber size.21 The collagen inthe scar (even after a year of maturing) will neverbecome as organized the collagen found in unin-jured skin. Wound strength also never returns to100 percent. At 1 week, the wound has only 3percent of its final strength; at 3 weeks, 30 percent;and at 3 months (and beyond), approximately 80percent.22

Table 2. Mediators Found in a Blood Clot

Mediator Action

Fibrin, plasma fibronectin Coagulation, chemoattraction, adhesion, scaffolding for cellmigration

Factor XIII (fibrin-stabilizing factor) Induces chemoattraction and adhesionCirculatory growth factors Regulation of chemoattraction, mitogenesis, fibroplasiaComplement Antimicrobial activity, chemoattractionCytokines, growth factors Regulation of chemoattraction, mitogenesis, fibroplasiaFibronectin Early matrix, ligand for platelet aggregationPlatelet-activating factor Platelet aggregationThromboxane A2 (via platelet COX-1) Vasoconstriction, platelet aggregation, chemotaxisSerotonin Induces vascular permeability, chemoattractant for neutrophilsPlatelet factor IV Chemotactic for fibroblasts and monocytes, neutralizes activity of

heparin, inhibits collagenase

Volume 117, Number 7S • Wound Healing

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FACTORS IN WOUND HEALINGThe complexity of wound healing makes it

vulnerable to interruption at many levels. Factorsthat affect physiologic responses and cellular func-tion can potentially influence wound healing. Thissection will briefly highlight the effect several fac-tors have on wound healing.

Local FactorsSeveral local factors can greatly influence

wound healing. Ischemic tissues, wounds with for-eign bodies, infection, contamination, and so on,will all affect wound healing. The Venn diagram(Fig. 1) highlights these obstacles.

IschemiaHealing is an energy-dependent process and

requires an adequate supply of the energy cur-rency, adenosine triphosphate (ATP). The initialanaerobic conditions following injury stimulatecells to adopt anaerobic production of ATP viaglycolysis.23 The proliferative phase of healing ischaracterized by increased metabolism and pro-tein synthesis requiring much larger quantities ofATP via oxidative phosphorylation. This demandsa rich blood supply to provide glucose and oxygen.Hypoxia (or decreased glucose) has the potentialto slow or halt the healing process.24

The physiologic response of the vascular en-dothelium to localized hypoxia in the early phaseof wound healing is to precipitate vasodilation,stimulate fibrin deposition, and increase proin-flammatory activity, capillary leak, and neovascu-

larization. The endothelial cell response to sus-tained hypoxia is a TNF-� induction of apoptosis.Sustained hypoxia will result in endothelial cellapoptosis.25

Wound neutrophil activity has been demon-strated to be impaired at lower oxygen tensionsidentified in wounds. Low temperature, low pH,and elevated glucose concentrations also limit leu-kocyte function.26 Fibroblasts exposed to longerperiods of hypoxia may not participate in the for-mation of the extracellular matrix, thus delayinghealing.27

InfectionLocal wound infection and foreign bodies af-

fect healing by prolonging the inflammatoryphase. If the bacterial count in the wound exceeds105 organisms per gram of tissue, or if any beta-hemolytic Streptococcus is present, the wound willnot heal by any means, including flap closure, skingraft placement, or primary sutures.28 The bacte-ria prolong the inflammatory phase and interferewith epithelialization, contraction, and collagendeposition. The endotoxins themselves stimulatephagocytosis and the release of collagenase, whichcontributes to collagen degradation and destruc-tion of surrounding, previously normal tissue.Wound contamination in association with tissuehypoxia potentially suppresses macrophage-regu-lated fibroblast proliferation.29

Foreign BodiesForeign bodies (which also include nonviable

tissue) are a physical obstacle to wound healingand an asylum for bacteria. Foreign bodies pro-long the inflammatory phase. Wounds with for-eign bodies cannot contract, repopulate the areawith capillaries, or completely epithelize (depend-ing on the size and location of the foreign body).Wounds with necrotic tissue will not heal until allthe necrotic tissue is removed.30

Edema/Elevated Tissue PressureThe edema and locally raised pressures asso-

ciated with ischemic tissue injury can potentiallyfurther compromise perfusion. The inflammatoryresponse to wounding may be prolonged as a re-sult, thus delaying the healing process. This isdramatically demonstrated in the development ofcompartment syndrome in limb skeletal musclesfollowing ischemia and reperfusion.31 Mast cells inskeletal muscle have been demonstrated to pro-duce most of the nitric oxide associated with isch-emia-reperfusion injury.32 Mast cells are residentFig. 1. Local factors affecting wound healing.


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tissue inflammatory cells that, when stimulated,release numerous cytokines and histamines re-sponsible for an intense inflammatory reactionand edema.

Raised tissue pressure, either externally (pres-sure) or internally (compartment syndrome), in-duces increased capillary closure through its effecton critical closing pressures. Compromised cellu-lar function due to prolonged, severe hypoxia mayrapidly progress to cell death, with necrosis of skin,adipose tissue, and muscle, thus precipitating ul-ceration and further contributing locally to im-paired healing. In critical illness, additional riskfactors, including depletion of soft-tissue adiposeand protein components, tissue edema due to low-ered plasma oncotic pressures, leaky endothe-lium, and potentially compromised peripheralperfusion, may further compromise tissue perfu-sion by raising interstitial pressures.31

SYSTEMIC OBSTACLESA patient may already have characteristics that

predispose him or her to soft-tissue wound-healingdysfunction. This has been studied in surgical pat-ents in an attempt to predict wound complicationsin abdominal and breast reconstructive surgery.33–35

These characteristics include obesity, cardiovasculardisease affecting tissue perfusion, respiratory diseaseaffecting adequate blood oxygenation, metabolicdisease, endocrine disease, and renal and hepaticfailure. Diabetes mellitus affects soft-tissue healingvia metabolic, vascular, and neuropathic pathways,as typified in diabetic foot disease.36 Increasing ageis associated with delayed healing, but it is difficult toseparate the effects of age alone from those diseasescommonly associated with age.37 Supplementationusing topical estrogen has been demonstrated toimprove healing in elderly women.38

Malignancy and its treatments can have pro-found effects on the ability of a patient to mounta response to injury and infection. Poor nutrition,specific organ compromise, ectopic hormone pro-duction, and immune and hematological effects,together with aggressive therapies, including po-tent antimetabolic, cytotoxic, and steroidal agentsand radiation, are all associated with compro-mised immunity, increased susceptibility to sepsis,and failure of tissue repair.39–41

The stresses associated with critical illness mayfurther significantly affect healing. Critical illnessplaces higher demands on tissue oxygen supplybecause of the stresses of acute illness and therequirements of increased cellular activity associ-ated with wound healing.42

Diabetes MellitusIncreased serum glucose has a major effect on

wound healing. This is most likely a multifactorialprocess due to hyperglycemia-related deleteriouseffects on molecular and cellular physiology. Al-though traditional teaching is that the etiology ofdiabetic complications is microvascular occlusivedisease, recent research does not support this.43

Several defects that may influence the healing pro-cess are now known. Sorbitol, a toxic byproduct ofglucose metabolism, accumulates in tissues and isimplicated in many of the renal, ocular, and vas-cular complications associated with diabetes.44 In-creased dermal vascular permeability results inpericapillary albumin deposition, which impairsthe diffusion of oxygen and nutrients.43 Hypergly-cemia-associated nonenzymatic glycosylation in-hibits the function of structural and enzymaticproteins. In addition, glycosylated collagen is re-sistant to enzymatic degradation and less solublethan the normal protein product.44

Experimental studies of diabetic animal mod-els and wound healing show decreased granula-tion, decreased collagen in granulation tissue, anddefects in collagen maturation.45 Human studiesof healing in diabetic patients parallel these find-ings, showing slow wound maturation and de-creased numbers of dermal fibroblasts. Growthfactor abnormalities have also been shown in re-cent studies.

HypothyroidismExperimental data and anecdotal series show

that hypothyroidism causes delayed woundhealing.46,47 Rats pharmacologically rendered hy-pothyroid have decreased collagen production, asmeasured by extractable soluble hydroxyprolinelevels.48 Hypothyroidism also significantly de-creases wound tensile strength in rats.49 Irradia-tion of hypothyroid pigs resulted in poorhealing.50 These studies indicate the deleteriouseffect of inadequate thyroid hormone levels onfibroblast function and subsequent woundstrength. Compounding these local effects are thesystemic complications (i.e., higher risk of heartfailure, risk of intraoperative hypotension, neuro-psychiatric disturbances, and lack of postoperativefever) for which the postoperative hypothyroidpatient is at risk.51

AgeIt is well accepted that aging patients have

higher rates of complications and mortality thando younger persons undergoing major surgery.52


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It also is widely accepted that elderly patients healsmore slowly than younger patients.53,54 This infor-mation should be balanced with the fact that olderpatients generally have more comorbidities thanyounger patients. Coronary artery disease, periph-eral vascular disease, diabetes, and pulmonarycompromise are more common with advancedage and may affect the healing process indepen-dent of age. Experimental studies show that theinflammatory and proliferative phases are less ef-ficient in older animals, particularly comparedwith very young subjects.54 A longitudinal study ofhamster fibroblast cultures over the span of theanimal’s life showed progressively decreasing pro-liferative capacity over time.55 Studies of healthyhuman volunteers do not completely supportthese findings. Skin graft donor sites have slowerreepithelialization rates in older persons, al-though the deposition of dermal collagen is equiv-alent between young and older, healthy volun-teers. The fact that proteins other than collagenare less abundant in older subjects’ wounds mayindicate age-related differences in the productionof the extracellular matrix.56 Studies suggest thatthe defect in age-related wound healing is relatedto abnormal initiation of healing as a result ofinsufficient presence of growth factors.57

Fetal Wound HealingTissue repair in the mammalian fetus is fun-

damentally different from normal postnatal heal-ing. “In adult humans, injured tissue is repaired bycollagen deposition, collagen remodeling, andeventual scar formation. [In contrast], fetalwound healing seems to be more of a regenerativeprocess with minimal or no scar formation.”58

Siebert et al.59 examined healing fetal woundshistologically and biochemically and found thatthey contained a small amount of collagen iden-tical to that found in the exudate from wounds inadults (i.e., type III collagen but no type I). Thefetal wound matrix was also rich in hyaluronicacid, which has been associated experimentallywith decreased scarring postnatally. The authorsproposed a mechanism of a hyaluronic acid/col-lagen/protein complex acting in fetal woundhealing to check scar formation, and concludedthat healing in fetuses involved a much more ef-ficient process of matrix reorganization than thatwhich takes place after birth. True regenerationapparently does not play a role in fetal healing,based on the few appendage elements seen.

Rowsell60 suggests that the collagen present infetal wounds is “structural” rather than “scar tis-

sue” collagen. Not only are the amounts of colla-gen deposited in fetal and in adult wounds mark-edly different but the deposited collagen is alsohandled differently. The fetal pattern of woundhealing “is characterized, at least in the early fetus,by the deposition of glycosaminoglycans at thewound site into which rapidly proliferating mes-enchymal cells of all types migrate, differentiate,and mature.”61 The transition from fetal to adultpatterns of wound healing for different tissuesprobably occurs at different times during gesta-tion.

In their review of scarless wound healing in themammalian fetus, Mast and coworkers58 state that“a striking difference between postnatal and fetalrepair is the absence of acute inflammation in fetalwounds,” and offer several hypotheses to explainthis phenomenon. Epithelialization occurs at amuch faster rate in fetal wounds, but adult-likeangiogenesis is absent. More importantly, the fetalwound matrix is markedly different from theadult’s in that it lacks collagen and instead con-tains predominantly hyaluronic acid.25,62 The fetalwound contains a persistent abundance of hyal-uronic acid, while collagen deposition is rapid,nonexcessive, and highly organized,63 so that thenormal dermal structure is restored and scarringdoes not occur. The authors speculate about theapplications of scarless fetal healing, namely, forintrauterine repair and in the treatment of patho-logic, postnatal processes.

Whitby and Ferguson61 conclude that it may bepossible to manipulate the adult wound to pro-duce more fetal-like, scarless wound healing bytherapeutically altering the levels of growth sub-stances and their inhibitors. This hope is shared byother groups,64–69 though it has not yet emergedin the clinical setting. Bone morphogeneticprotein-2,70 hypoxia-inducible factor 1�,71 decorin(a TGF-� modulator),72 �- and �-fibroblast growthfactor,73,74 IL-6,74 and IL-869 are also under study.

Tenascin (cytotactin) is a large, extracellularmatrix glycoprotein synthesized by fibroblasts thatis present during embryogenesis but only sparselydistributed in the connective tissue papillae ofadults. Tenascin is present earlier in fetal wounds,compared with adult wounds, and may be respon-sible for initiating cell migration and the rapidepithelialization of fetal wounds.75 Someinvestigators75,76 believe that tenascin could be amodulator of cell growth and movement and thatit may influence the deposition and organizationof other extracellular matrix glycoproteins duringtissue repair.


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Tissue PerfusionDisruption of tissue perfusion can be catego-

rized as local (from small vessel occlusion-embolior external compression) or general (from de-creases in circulatory volumes, cardiac insuffi-ciency, inotropic infusions, or large vessel disrup-tion). Inadequate tissue perfusion (the definitionof shock) results in tissue hypoxia.

Hypothermia and PainHypothermia also has a profound effect on

cutaneous perfusion by inducing peripheral vaso-constriction; therefore, the thermal insulation ofwounds is important. Painful stimuli cause a dif-fuse adrenergic discharge, leading to cutaneousvasoconstriction; thus, adequate pain control canimprove cutaneous perfusion and potentially im-prove healing.42

Major Trauma and BurnsSevere trauma and tissue loss can result in

hypovolemic shock as a consequence of circula-tory volume loss or compromised cardiac func-tion. The systemic inflammatory response syn-drome that occurs in major trauma states ischaracterized by elevation of circulating cytokinesand inflammatory mediators, including TNF-�, re-sulting in activation and consumption of clottingfactors and platelets potentially leading to clottinganomalies, disseminated intravascular coagula-tion, and subsequent delays in wound healing.77

The infusion of large volumes of packed red bloodcells also will affect coagulation, largely by dilu-tional effects, as will cold intravenous fluidreplacement.78 The development of a posttrau-matic immunoparalysis has implications in devel-oping sepsis and subsequent delays in wound heal-ing. Maintenance of a normovolemic state andbody temperature together with good analgesiawill facilitate adequate peripheral perfusion tosoft-tissue injuries. Deep soft-tissue burns, in par-ticular, elicit a major and often prolonged localinflammatory response associated with local tissueischemia, thrombosis, and an intense vasoconstric-tion resistant to the effects of nitric oxide.79 Thereis evidence that peripheral vasoconstriction per-sists for up to 60 hours after hypovolemia, despiteadequate resuscitation and a normal mean arterialpressure. Mild or moderate anemia does not ap-pear to deleteriously affect healing in a well-per-fused wound, with collagen deposition being pro-portional to wound tissue oxygenation andperfusion.80 The reperfusion of injured tissue it-self can be deleterious to wound healing, with the

release of anaerobic metabolites and reactive ox-ygen species creating additional oxidative stresses.Fat emboli and disseminated intravascular coag-ulation following severe trauma can cause respi-ratory complications and occlusion of both largerand smaller cutaneous vessels, as well as generaland focal tissue hypoxia and multiple-organ dys-function syndrome.81,82

SepsisThe sepsis-associated mortality rate in an in-

tensive care setting remains high. The endotoxin-related excessive secretion of proinflammatorymediators is believed to be important in the de-velopment of whole-body inflammation and septicshock. Systemic inflammation in sepsis appears tohave a biphasic pattern, which includes a hypoin-flammatory state associated with immunodefi-ciency characterized by monocyte deactivationand immunoparalysis.83 A compromised leuko-cytic activity and deranged inflammatory responsewill have inhibitory effects on wound healing.84

Septicemia can have profound effects on coagu-lation. Activation of the clotting cascade, via plas-ma- and endothelial-related inflammatorychanges, can lead to disseminated intravascularcoagulation with a profound decrease in plateletsand loss of a functional, organized clotting system.Disseminated intravascular coagulation in sepsis,as in major trauma, is associated with microcircu-latory thrombosis, with potentially widespread ef-fects on tissue perfusion in the soft tissues andmajor organs leading to multiple-organ failure.85

These factors will compromise hemostasis and,therefore, healing. The systemic inflammatory re-sponses in sepsis affect plasma viscosity and eryth-rocyte rheologic characteristics.86 This may haveimportant implications in tissue perfusion, partic-ularly in situations where the capillary blood ve-locities are reduced. Hypothermia, potentiallymade worse by the infusion of cold intravenousfluid and fresh-frozen plasma (or an equivalent),will compromise clotting and healing.

Specific Organ Failure

Gut FailureA critically ill patient may have impaired gut

absorption, either directly as a result of abdominalcatastrophe or gastrointestinal surgery or indi-rectly as a result of dysfunctional bowel secondaryto severe metabolic anomaly, trauma, or denerva-tion causing a paralytic ileus. Bacterial transloca-tion of gut bacteria and toxins to the portal cir-


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culation can occur, causing sepsis and increasedoxidative stress.

Hepatic FailureDecreased clotting factors, low plasma pro-

teins, decreased bactericidal activity, and failure ofglucose regulation can all contribute to soft-tissuewound failure.

Renal FailureAcute or chronic renal impairment may re-

quire dialysis treatment. Raised levels of uremictoxins and metabolic acidosis will affect woundhealing by influencing both the innate and adap-tive immune systems. Hemodialysis and peritonealdialysis are associated with increased susceptibilityto infections. Downregulation of circulating neu-trophils due to their repeated activation triggeringby dialysis membranes has been demonstrated.Circulating reactive oxygen species are also in-creased as a result of dialysis membrane activation.Deficient responses of both B and T lymphocytesalso are associated with renal dialysis.87

Respiratory FailureAdequate gaseous exchange is essential for all

biological systems, including wound healing. Tis-sue hypoxia secondary to hypoxemia will have pro-found effects on healing at all levels.

NutritionSeptic, surgical, and trauma patients in hyper-

metabolic states associated with the release of en-dogenous cytokines from activated leukocytes ex-perience excessive protein loss in an effort tomaintain normoglycemia; these patients requireadditional caloric input to counter a negative ni-trogen balance. Such patients consume bodystores of fat and protein, particularly skeletal mus-cle, more rapidly than patients with normal me-tabolism. This, together with depletion of micro-nutrients and immunonutrients, has implicationsin immune system function and healing.88 Ele-vated steroid levels because of stress are intimatelyinvolved in muscle catabolism. Insulin adminis-tration may help modulate muscle protein lossesin patients with severe burns.89 Growth hormonestimulates wound healing, but its effects in criticalillness need further study.90

Glucose is the main fuel for wound repair.Protein malnutrition and particularly deficienciesin the amino acids arginine and methionine areassociated with compromised wound healing be-cause of prolonged inflammation and disruptionof matrix deposition, cellular proliferation, andangiogenesis.91,92 Malnutrition is associated withdecreased deposition of collagen in skin wounds.93

Glutamine has been reported to enhance the ac-tions of lymphocytes, macrophages, and, in par-ticular, neutrophils, and may be of particular ben-efit in severe infection and trauma.90 Glycine hasinhibitory effects on leukocytes and may have animportant role in reducing inflammation-relatedtissue injury.9 Micronutrients such as vitamins andminerals are critically important in immune func-tion and wound healing. Many trace metals, in-cluding manganese, magnesium, copper, calcium,and iron, are cofactors in collagen production,and deficiencies influence collagen synthesis.91

Zinc influences reepithelialization and collagendeposition.94 Zinc has also been demonstrated togreatly influence B and T lymphocyte activity, butmany other nutrients, including copper, sele-nium, several other metals, and several vitamins,including A, B, C, and E, have been implicated inimmune dysfunction.95 Vitamin C is the main vi-tamin associated with poor healing, because of itsinfluence on collagen modification.91 L-Arginineis required in a variety of metabolic functions,wound healing, and endothelial function. It is im-portant in the synthesis of nitric oxide, and defi-ciency is linked to immune dysfunction and failureof wound repair. Maintenance of plasma oncoticpressure is dependent on adequate production ofplasma proteins and is important in maintainingbody water distribution and preventing soft-tissueedema. Vitamins and minerals, particularly ascor-bic acid, zinc, and selenium, are essential forwound repair. Copper recently has been linked tothe production of vascular endothelial growthfactor.12

SmokingClinicians have long suspected that smoking

has a poisonous effect on healing wounds, espe-cially postsurgical flaps and grafts. In 1977, Moselyand Finseth96 demonstrated the detrimental effectof smoking on healing hand wounds. Many studieshave since confirmed that smoking is harmful toa healing wound. Goldminz and Bennett97 re-viewed 916 flaps and full-thickness grafts andfound that 1-pack-per-day smokers had threetimes the frequency of necrosis as nonsmokersand that 2-pack-per-day smokers had necrosis sixtimes more frequently than nonsmokers did.97

The mechanism of these harmful effects is likelymultifactorial. Nicotine is an addictive and vaso-constrictive substance that decreases proliferationof erythrocytes, macrophages, and fibroblasts. Hy-drogen cyanide is inhibitory to oxidative metab-olism enzymes. Carbon monoxide decreases the


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oxygen-carrying capacity of hemoglobin by com-petitively inhibiting oxygen binding.98 In onestudy using human volunteers, subcutaneous par-tial pressure of oxygen decreased significantly af-ter 10 minutes of cigarette smoking. The effectlasted for almost 1 hour.99 Taken together, thistriad has obvious implications for reduction of thecellular response and efficiency of the healingprocess.

Smoking also increases platelet aggregationand blood viscosity and decreases collagen depo-sition and prostacyclin formation, all of which neg-atively affect wound healing.100 Vasoconstrictionassociated with smoking is not a transient phe-nomenon. Smoking a single cigarette may causecutaneous vasoconstriction for up to 90 minutes;hence, a pack-a-day smoker sustains tissue hypoxiafor most of each day.

Smoking also affects the cosmetic appearanceof wounds,101 which has serious ramifications forthe smoker who desires facial cosmetic surgery.

CorticosteroidsAnti-inflammatory steroid medications glo-

bally inhibit cell growth and production.102 Theyare also well known to have widespread negativeeffects on the wound-healing process. This is seenclinically and experimentally. A decreased inflam-matory infiltrate is the most obvious effect ofsteroids.103 The macrophage response to chemo-tactic factors is inhibited. Effective phagocytosis bypolymorphonuclear neutrophils and macro-phages also is decreased as a result of the stabi-lizing effect of steroids on lysosomes.104 Because ofthe lack of an appropriate initial inflammatoryresponse, these cells do not produce the typicalgrowth factor profile.105 This has been shown ex-perimentally. Glucocorticoids also inhibit epithe-lial regeneration. The application of hydrocorti-sone to epidermal cultures decreases cellproliferation.

Steroids have a direct inhibitory effect on thefibroblast genome, which has been shown in cellculture.105,102 Corticosteroid-treated rat fibroblastshave minimal endoplasmic reticulum, indicating alow-secretory state.106 Without the appropriatedeposition and maturation of collagen, there isless wound strength and wound dehiscence islikely. Vitamin A restores the inflammatory re-sponse and promotes epithelialization and thesynthesis of collagen and ground substances. Vi-tamin A does not reverse the detrimental effects ofglucocorticoids on wound contraction andinfection.107 The recommended dose of vitamin A

is 25,000 IU by mouth daily preoperatively108 andfor 3 days postoperatively. Vitamin A supplemen-tation should not be given to pregnant women.

Ionizing Radiation and ChemotherapyIonizing radiation either directly damages the

genome or injures the DNA through the productionof free radicals.104 This effect has short- and long-term consequences for radiated tissue. In patientswith acute radiation injury, the skin becomes ery-thematous and edematous. Histologically, dilationof fine blood vessels, endothelial edema, and lym-phatic obliteration are seen. As the acute responseabates, thrombosis and fibrinoid necrosis of capil-laries occur.109 In this setting, although perfusion ofradiation-damaged skin is seen with fluoresceininjection,107 effective tissue oxygenation is inade-quate. Blood vessel appearance is varied, eitherthick-walled, telangiectatic, or thrombosed. Thedeposition of dense, hyalinized collagen character-izes radiated dermis. The endpoint of chronic radi-ation damage is the nonhealing ulcer. Obvious ne-crotic tissue is seen, and there is loss of epithelialcoverage.110 Electron microscopy of human radia-tion ulcers reveals varying degrees of vascular injuryand few myofibroblasts.110

The mechanisms of radiation damage and in-hibited wound healing are currently being stud-ied. Experimentally, healing immediately after ir-radiation is hampered by slowed fibroblastproliferation, migration, and contraction.111,112

Impairment of the acute inflammatory responseand granulation formation also occurs.109,111 Theproduction of mRNA coding for collagen is de-layed up to 2 weeks.109 Clinically, few surgical pro-cedures are performed on patients with acutelyradiated tissues. The greater concern lies with thepatient who has chronic radiation damage.

Fibroblast cultures from radiation ulcers pro-liferate at a slower rate compared with cultures ofcells from nearby unirradiated tissue.110,113 Effectsvary between patients. Each person has a differingsensitivity to radiation injury. Human fibroblastscultured from patients with severe radiation reac-tions have poor survival rates relative to those frompatients who have a less severe injury.100 Thus,fibroblast defects have emerged as a central prob-lem in the inhibited healing of chronic radiationinjury.

Cellular mechanisms of phagocytosis and bac-teriocidal metabolic functions in polymorphonu-clear neutrophils harvested from tissue withchronic radiation damage also are impaired. Theeffect increases as time passes after therapy, which


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cannot be a result of a direct effect of radiation onthe neutrophils because their life span is too short.The local wound environment is the spotlight ofthe problem. Irradiated tissue may not “prime” theneutrophils with the appropriate cytokines andgrowth factors needed for activation,114 which hasa major effect on the incidence of postoperativeinfection in previously irradiated patients.

The association between radiation damageand postoperative complications has been de-bated. In retrospective studies, patients undergo-ing surgery after failing primary radiotherapy forearly-stage tumors do not show an increase in se-verity of complications or length of hospitalstay.115,116 One prospective trial comparing antibi-otic regimens did not show any increase in woundinfection rate in radiated patients,117 althoughother investigators have shown increased rates ofpostoperative infections118 and major woundcomplications.119 With the advent of more aggres-sive radiation regimens, concern regarding in-creased operative complications has surfaced.Twice-a-day hyperfractionation protocols versusonce-a-day radiation do not seem to increase thesurgical morbidity.120

Chemotherapy now is included in many “or-gan preservation” protocols, in an attempt to curepatients with cancer without disfiguring or func-tionally devastating surgery. If chemotherapy isgiven perioperatively, the resultant bone marrowsuppression inhibits the formation of an adequateinflammatory response needed for the initiationof the healing process. Experimental studies showthe inhibition of fibroblast collagen production121

and a decreased ability to fight off woundinfection118 with the application of antineoplasticagents. These effects appear to be transient, asopposed to the progressive nature of radiationdamage. The combination of radiation and che-motherapy increases the risk of serious postoper-ative complications.122 This risk appears to de-crease if surgery is delayed for more than 1 year.123

Surgery for patients with previous radiotherapyshould be approached cautiously.

SYNDROMES ASSOCIATED WITHABNORMAL WOUND HEALING

There are several genetic syndromes that canadversely affect wound healing. The more com-mon of the rare syndromes are discussed below(Table 3).

Cutis LaxaThere are two broad classifications of cutis

laxa: congenital and acquired (Table 4). The con-genital form can be autosomal dominant, reces-sive, or X-linked recessive. Acquired cutis laxa canresult from drug ingestions, some solid and he-matogenous neoplasms, and inflammatory skinconditions.124

Ehlers-Danlos SyndromeThere are 10 identifiable phenotypes/clinical

subtypes of Ehlers-Danlos syndrome. The differ-ent types have autosomal dominant and recessiveinheritance. Individuals with the syndrome dem-onstrate connective tissue abnormalities as a resultof defects in the inherent strength, elasticity, in-tegrity, and healing properties of the tissues. All ofthe subtypes share varying degrees of the fourmajor clinical features: skin hyperextensibility,joint hypermobility, tissue fragility, and poorwound healing. As many as 50 percent of patientswith the syndrome do not have a type or form thatcan be classified easily on the clinical basis alone,which complicates the diagnostic process for theclinician because specific molecular diagnosis orconfirmation (if available) may not be possibleuntil a clinical subtype has been defined. Beightonet al.125 revised the nosology to “facilitate an ac-curate diagnosis of the Ehlers-Danlos syndromeand allow a clearer distinction of disorders that

Table 3. Syndromes Associated with Abnormal Wound Healing

Syndrome Brief Description Wound Result

Cutis laxa Defective elastin fibers; canbe acquired or congenital

Thick, stretchy skin; easy bruising; hernias arecommon

Ehlers-Danlos Deficit in collagen metabolism; has autosomaldominance and recessive inheritance

Total failure of the mechanicalproperties of the skin; poor wound healing,leading to wide, thin scars (classically describedas “cigarette paper scars”); skin tears easily

Homocystinuria Cystathionine synthetase deficiency Advanced arteriosclerosis; associated arterial andvenous thrombosis; platelet malfunction

Osteogenesis imperfecta Defective gene for type I collagen Wide scars


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overlap” with the syndrome. The new classificationscheme includes the following:

• Classic type (formerly types I and II)• Hypermobility type (formerly type III)• Vascular type (formerly type IV)• Kyphoscoliosis type (formerly type VI)• Arthrochalasia type (formerly type VIIB)• Dermatosparaxis type (formerly type VIIC)

This new classification scheme does not in-clude types V, VIII, IX, and X, all of which haveonly been described in one family. Most currentliterature still refers to Ehlers-Danlos syndromepatients as types I, II, or III (the most common).Elective surgery is considered contraindicated inpatients with Ehlers-Danlos syndrome,126 althoughsome would disagree.127

HomocystinuriaPatients with homocystinuria have wound-

healing problems because of poor wound perfu-sion secondary to thrombosis. These patients havedefects in methylation and/or transsulfuration en-zymes that cause the accumulation of homocys-teine. Homocysteine is formed from ingested me-thionine. Homocysteine has cytotoxic effects onvascular endothelium and causes intimal thicken-

ing, lipid-laden macrophages, and smooth cellproliferation. Homocysteine initiates the coagu-lation pathway by enhancing factor V activity, in-creasing factor Xa-catalyzed prothrombin activa-tion, suppressing protein C activation, andinducing endothelial cell tissue activity. Reducedantithrombin III activity has been seen in somepatients, but this association has not beenestablished.128–130 Patients with homocystinuriaare also at very high risk for coronary vasculardisease.131

Osteogenesis ImperfectaOsteogenesis imperfecta is a heritable disor-

der of connective tissue affecting bone and softtissues. The general clinical features of this disor-der include bone fragility, neonatal dwarfism, de-formities of the long bones, scoliosis, ligamentouslaxity, blue sclerae, defective dentinogenesis, anddeafness. There are four major forms, but all havemutations in the genes that encode type Icollagen.132

ADJUNCTS TO WOUND HEALINGFailures of wounds to heal are generally the

result of wound hypoxia, infection, edema, andmetabolic abnormalities. Wounds require a min-

Table 4. Cutis Laxa*

Classification of Cutis Laxa Clinical Features

CongenitalAutosomal dominant Hyperextensible skin, hernias, benign courseAutosomal recessive Multisystem involvement

Type I Emphysema, cardiovascular abnormalities, diverticula,hernias

Type II (congenital cutis laxa with ligamentouslaxity and delayed development)

Retarded growth, skeletal dysplasia, facialdysmorphism

Type III (de Barsy syndrome) Mental retardation, corneal clouding, jointhypermobility, growth retardation, facialdysmorphism, skeletal dysplasia

X-linked recessive (defect in lysyl oxidase activity) Hyperextensible skinAcquired

Drug ingestion Generalized skin involvement associated withingestion of penicillamine, penicillin, isoniazid,melphalan, and phenacetin

Paraneoplastic Skin manifestation of paraneoplastic syndromesassociated with solid or hematogenous neoplasias(chronic neutrophilic leukemia, chronicmyelogenous leukemia)

Postinflammatory (Sweet syndrome, bowel bypasssyndrome, postinflammatory elastolysis andcutis laxa, Marshall syndrome)

Hyperextensible skin lesions with inflammatoryinfiltrates; Sweet syndrome is a hypersensitivityreaction to bacterial antigens that leads to alocalized increase in granulocytes. Neutrophilsrelease elastase and destroys elastic fibers and mayeventually lead to hypoelastosis of skin. If cutis laxadevelops as a consequence of Sweet syndrome, thecondition is called Marshall Syndrome

*Banks, N. D., Redett, R. J., Mofid, M., et al. Cutis laxa: Clinical experience and outcomes. Plast. Reconstr. Surg. 111: 2434, 2003.


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imum oxygen tension of 30 mmHg for normal celldivision. Oxygen also increases fibroblast migra-tion and replication, normal collagen production,and leukocyte killing.133 Infection keeps thewound in the inflammatory phase.28 Woundedema acts as a barrier to oxygen and nutrients byincreasing the distance that they must diffuseacross.133 Metabolic derangements affect woundhealing in a variety of ways, depending on theabnormality. “Time heals all wounds” is a well-known proverb; Bennet and Schultz134 introducedthe acronym TIME to highlight the four key clin-ical scenarios the clinician should check throughwhen a patient’s wound healing stalls: tissue non-viable or deficient, infection or inflammation,moisture imbalance, and edge of wound nonad-vancing or nonmigrating.135 Adjuncts to woundhealing attempt to address and correct these ob-stacles to wound healing. They include bioengi-neered skin, electrostimulation, growth factors,hydrotherapy, hyperbaric oxygen, lasers, light-emitting diodes, negative pressure therapy, andultrasound.

Bioengineered SkinLiving bioengineered skin equivalents are

“food on the hoof” for the wound, providing aliving supply of growth factors and cytokines anda collagen matrix to build upon. A summary of thebioengineered skin replacements and the pro-healing factors found in living products are shownTables 5 and 6.136,137

The mechanism of action is not fully understoodon how these skin equivalents initiates wound heal-ing, but it has been studied extensively with the Apli-graf product. The cells contained in the Apligrafgrow and proliferate, producing growth factors, col-lagens, and extracellular matrix proteins, whichstimulate reepithelialization, formation of granula-tion tissue, angiogenesis, and neutrophil and mono-cyte chemotaxis. Extensive clinical experience sug-gests that Apligraf acts as a potent cellular remedythat can provide a different and adaptable responsein acute and chronic wounds.137 After Apligraf is

placed in chronic wounds, outgrowth of previouslydormant keratinocytes at the wound edge is ob-served, suggesting that Apligraf releases factors thatactivate keratinocytes and stimulate migration andreepithelialization.138–140

It is believed that Apligraf stimulates woundhealing in two phases.137 During the initial phase,the release of growth factors from Apligraf cellsresults in healing from the skin edge. Apligrafcovers the wound, provides a barrier, and interactswith the wound bed to stimulate wound healing.141

In the second phase, there is cellular communi-cation between the tissue-engineered product andthe cells in the wound and other cells attracted tothe wound site through the release of wound-heal-ing–related growth factors and cytokines.

ElectrostimulationElectrical current in skin was first described as

far back as 1860 by DuBois-Reymond. In 1945, itwas observed that wounds had a positive potentialcompared with the surrounding skin. In 1982,Barker described the “skin battery.” He found thatthe skin surface was always negatively charged(compared with the deeper skin layers), and hemeasured transcutaneous voltages up to 40mV.142,143

Table 5. Bioengineered Skin Replacements*

Composition Structure Living Trade Name

Cultured keratinocytes autografts Epidermal Yes EpicelTreated cadaver skin allograft Dermal No AlloDermBovine collagen/glycosaminoglycan/Silastic Dermal No IntegraNeonatal fibroblasts/polyglactin mesh allograft Dermal Yes DermagraftNeonatal fibroblasts/keratinocytes collagen allografts Composite Yes Apligraf, OrCel†*From Limova, M. New therapeutic options for chronic wounds. Dermatol. Clin. 20: 357, 2002.†OrCel is a product made by Ortec International that is very similar to Apligraf. It was formerly known as Composite Cultured Skin.

Table 6. Pro-Wound Healing Factors Found in LivingBioengineered Skin Equivalents*

Cytokines andGrowth Factors

ExtracellularMatrix Molecules

TGF-� Collagen, types IV and VIIAmphiregulin LamininIL-1, IL-3, IL-6, IL-8 KalininTNF-� FibronectinGranulocyte-macrophage CSF ThrombospondinPDGF GlycosaminoglycansBasic FGF Plasminogen activatorTGF-�Nerve growth factorCSF, colony-stimulating factor; FGF, fibroblast growth factor.*From Limova, M. New therapeutic options for chronic wounds.Dermatol. Clin. 20: 357, 2002; and Jimenez, P. A., and Jimenez, S. E.Tissue and cellular approaches to wound repair. Am. J. Surg. 187: 56S,2004.


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Electrostimulation is believed to restart or ac-celerate the wound-healing process by imitatingthe natural electrical current that occurs in skinwhen it is injured.142–145 This current of injury wasfound to vary in specific ways during the regen-eration process, with current ceasing to flow ashealing is completed or arrested.146 Electrical cur-rent applied to wounded tissue increases the mi-gration of cells vital to the wound-healing process(i.e., neutrophils, macrophages,147–149 andfibroblasts).146,150,151 Investigators have found thatelectrostimulation resulted in a 109 percent in-crease in collagen,150 a 40 percent increase in ten-sile strength,152 and a 36 percent increase in tensilestrength.153 Electrostimulation may also play a rolein wound healing through improved bloodflow.154,155

These findings have sparked investigators touse electrostimulation to promote wound heal-ing in chronic wounds. There are four primarytypes of stimulation use: direct current, low-fre-quency pulsed current, high-voltage pulsedcurrent, and pulsed electromagnetic fields (Ta-ble 7).70,126,133,156 –171

Current polarity has been found to have someunique actions on wound healing. These effectsare summarized in Table 8.133

Growth FactorsCurrently there are four commercially pre-

pared growth factor products available (Table9).136,172–178

HydrotherapyWhirlpool treatments are one of the oldest

adjunctive therapies still in use. Whirlpool therapysupports wound healing by debriding the wound,warming the injured extremity, and providingbuoyancy and gentle limb resistance for physicaltherapy.133 Whirlpool treatments have fallen indisfavor because of nosocomial contaminationand transmission of virulent infections.179–182

Whirlpool treatments for open wounds requirestrict adherence to guidelines to minimize thisrisk.180 New forms of hydrotherapy that are replac-ing the whirlpool are pulsed lavage and the Ver-saJet (Smith & Nephew, Inc., Largo, Fla.). Pulsedlavage delivers an irrigating solution under pres-sure (4 to 15 psi). Haynes et al.183 demonstratedthat the rate of granulation tissue formation wasgreater in patients receiving pulse lavage com-pared with those receiving whirlpool therapy. TheVersaJet Hydrosurgery System is a water jet–pow-ered surgical tool designed to efficiently debridea wound by removing damaged disuse and con-

Table 7. Electrostimulation Modalities in Clinical Practice

Description Clinical Trials

Direct currentA negative or positive electrode is placed in the wound with

the other one distant to the wound. A current of 0.03 to1 mA is passed across the wound for 1 to 3 hours, untilthe wound is healed. As healing plateaus, the polarity isreversed. This mode is rarely used today, because thereare more efficient forms of electrostimulation.

Ischemic ulcers,133 venous ulcers,156 nonunion bonehealing157,158

Low-frequency pulsed current (tetanizing current)Physical therapists have been using this modality for more

than 25 years to treat muscular pain as transcutaneouselectrical nerve stimulation. A current of 50 mA, with afrequency of 2 to 100 Hz, is delivered in pulses of 45 to500 �sec and causes contraction of surrounding muscle,resulting in increased blood flow.133

Pressure ulcers159–161 (especially in spinal cord injurypatients)

High-voltage pulsed currentThe negative electrode is placed in the wound and the

positive electrode is placed on the wound edge. Acurrent of 100 to 150 V (usually �200 V), with shortpulse duration and a low current (15–40 mA), is applied.Once the healing rate plateaus, the polarity is reversed.133

Pressure ulcers,162–165 mixed-chronic ulcers159, 166

Pulsed electromagnetic fieldA pulsed electromagnetic field delivers 27.12 MHz of

energy at a pulse rate of 80 to 600 pulses per second anda per-pulse power range of 293 to 975 peak Watts. Thetherapy is given twice a day for 30 minutes per sessionuntil the wound is healed.133

Nonunion bone healing,70,126,167,168 pressure ulcers,169

venous ulcers170,171


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taminants precisely, without the collateral traumaassociated with traditional surgical modalities(heat and aggressive sharp debridement).184

Hyperbaric OxygenOxygen therapy has its roots dating back to

1662, with the construction of a pressurized room,or “domicillium,” by an English physician namedHenshaw. The room was pressurized by bellowsthat raised the air pressure a few pounds persquare inch above ambient pressure. This,claimed Henshaw, was good for most afflictions ofthe lungs and bowels. Junod treated pulmonarydiseases in 1834 by placing patients in a chamberwith 2 to 4 atmospheres of pressure. Dr. OrvalCunningham constructed the largest hyperbaricchamber in 1928; it was five stories high, 64 feet indiameter, and had multiple floors, each holding12 beds. Cunningham never recorded his thera-pies, and the American Medical Association con-demned his treatments in 1942 for a lack of sci-entific proof.185

Atmospheric pressure at sea level is 1 ATA. At1 ATA, the oxygen dissolved in blood is 1.5 ml/dl;at 3 ATA, dissolved oxygen in blood is 6 ml/dl.Normal subcutaneous tissue oxygen tension is 30to 50 mmHg. Dividing cells in a wound require anoxygen tension of at least 30 mmHg. Tissues inwounds that are not healing have partial pressureof oxygen values of 5 to 20 mmHg. A “dive” of 2.4ATA will result in a wound partial pressure ofoxygen of 800 to 1100 mmHg.133

Many reports in the literature have demon-strated benefit from hyperbaric oxygen treatmentfor a variety of conditions, including amputations,186

osteoradionecrosis,187,188 surgical flaps, and skingrafts.185,189,190 The success of hyperbaric oxygentreatment for necrotizing soft-tissue infections hasbeen controversial. Studies have failed to show sta-tistically significant outcome differences with respectto mortality rates and length of hospitalization. Twostudies found that the mean number of debride-

ments was higher in patients treated with hyperbaricoxygen.191,192 There is, however, a bias for treatedpatients to be younger and have positive clostridialwound cultures and more severe infection.193 In ad-dition to simply providing more oxygen to thewound site, hyperbaric oxygen therapy also increasesexpression of nitric oxide, which is crucial for woundhealing.194 In an ischemic rabbit ear model, hyper-baric oxygen therapy in combination with PDGF orTGF-�1 had a synergistic effect that totally reversedthe healing deficits caused by ischemia.13

LasersLight amplification by stimulated emission of

radiation (or laser) management of open woundshas been used for more than 35 years in Europe andRussia. Only in the past 10 years has laser therapy forwounds been used in the United States. Lasers forwound management are low-energy lasers capable ofraising tissue temperature 0.1°C to 0.5°C.195 Low-energy laser treatment is called biostimulation.196

Low-energy lasers appear to function according tothe Arndt-Schulz law, which states that “less is more.”In other words, weak biostimulation excites physio-logical activity, moderate favors physiologic effect,strong impedes physiological processes, and verystrong stimuli arrests physiological stimulation and isdestructive. Low-energy stimulation of tissue resultsin increased cellular activity in wounded skin.197,198

The mechanism for enhanced physiologic activity isnot fully understood. It is believed to be caused bythe stimulation of ascorbic acid uptake by cells, stim-ulation of photoreceptors in the mitochondria re-spiratory chain, changes in cellular ATP or cyclicAMP levels, and cell membrane stabilization.199–201

The common types of low-energy lasers areshown in Table 10. The two most common lasersused clinically are the helium-neon laser and thegallium-arsenide (or infrared) lasers.

Lasers have been shown to increase the healing(especially when combined with hyperbaric oxygentreatments) of ischemic, hypoxic, and infected

Table 8. Effect of Polarity on Wound Healing

Positive Current Negative Current Both

Promotes epithelial growth Decreases edema around the electrode Stimulates neovasculatureand organization Lyses or liquefies necrotic tissue Has a bacteriostatic effect

Acts as a vasoconstrictor and induces clumping Stimulates growth of granulation tissue Stimulates receptor sites forDenatures protein Increases blood flow certain growth factorsAids in preventing postischemic Causes fibroblasts to proliferate

lipid peroxidation and make collagenDecreases mast cells in Induces epidermal cell migrationAttracts macrophages Attracts neutrophils

Stimulates neurite growth directionally


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wounds.202 Lasers affect wound healing at many dif-ferent levels. The helium-neon laser light at 633 nmwas optimal for wound healing195 using 1 mW ex-posures and greater to provide 4 J/cm2 energy den-sity. Later studies of in vitro skin fibroblast stimula-tion demonstrated that consecutive exposures to 660nm and 780 nm of laser light at 24-hour intervalsincreased collagen production fourfold comparedwith untreated cultures.203–205 Beauvoit et al.197,198

demonstrated that mitochondria provide 50 percentof the tissue absorption coefficient and 100 percentof the light scattering at 780 nm because of cyto-chrome aa3, cytochrome oxidase, and other mito-chondrial chromophores. Fibroblasts irradiated at660 nm with 2.16 J/cm2 increased fibroblast growthfactor synthesis and fibroblast proliferation.205 Con-current DNA synthesis measurements confirmedthis.206,207 Karu208 demonstrated increased DNA syn-thesis by irradiation at 680 nm, increased proteinsynthesis at 750 nm, and increased cell proliferation

at 890 nm, which was 10 times more effective thanother near-infrared wavelengths, requiring only 1J/cm2. Laser stimulation of collagen synthesis, mea-sured by incorporation of radioactive amino acids,was demonstrated at 693 nm, with similar results.Growth factor production and collagen synthesis maybe improved at wavelengths of 660 to 680 nm, andstimulation of new small blood vessel growth was pro-duced at a wavelength of 880 nm.209 Studies in humanwounds have shown that low-energy lasers promotegreater amounts of epithelialization for woundclosure210 and better tissue healing.206–208,211–214

Laser biostimulation has a variety of effects atdifferent wavelengths, and it would appear thatoptimal treatment of a wound would require sev-eral applications at different wavelengths.

Light-Emitting DiodesThe National Aeronautics and Space Admin-

istration has developed a light-emitting diode that

Table 9. Commercially Available Growth Factor Products

NameGrowth Factor

Type Indication Comments

Procuren(Curative HealthServices)

PDGF Diabetic footulcers

The first product to be commercially available.Patient’s blood is used to collect platelets. Because

blood is used, other growth factors may be partof the preparation.

Regranex(Ortho-McNeilPharmaceutical)

PDGF-BBfraction

Diabetic footulcers

The first recombinant human growth factor to beused in clinical practice

Shown to substantially increase wound healing indiabetic foot ulcers when compared withstandard care alone. However, the treatmentneeds to be carried out with aggressive standardwound care, including debridement of necroticor hyperkeratotic tissue and off-loading of thearea of the ulceration.172

It appears that Regranex can be useful in a varietyof other types of wounds, such as pressureulcers, and currently trials for venousinsufficiency ulcers are underway.173

There have also been select instances of casereports utilizing Regranex in other chronic andacute wounds, such as pyodermagangrenosum,174 ulcers of vasculitis, and acutesurgical defects.136

Leukine(Immunex Corp.)

GM-CSF Treatment forpatients withAML and bonemarrow rescue

Macrophages and inflammation play an importantrole in the first phase of wound healing; thismaterial has been tried in some chronic woundsas an injectable material around the area of theulcers and topically as an aqueous solution.175,176

Results have been promising, but it is notcurrently approved for use in chronic wounds.

Repifermin(Human GenomeSciences)

KGF-2 Treatment forcancertherapy-inducedmucositis,venous ulcers,skin grafts

Shown to significantly increase healing andepithelialization over the wound bed177

The initial trial in venous ulcers178 has shown verypromising results, and it is currently in phase 2clinical development.


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can be made to produce multiple wavelengths andbe arranged in large, flat arrays to treat largewounds. The treatment area for a laser is limited–-large areas must be treated in a grid-like pattern.The agency developed the light-emitting diode inresponse to their research on wound healing in aweightless environment. Studies on cells exposedto microgravity and hypergravity indicate that hu-man cells need gravity to stimulate growth. As thegravitational force increases or decreases, the cellfunction responds in a linear fashion. This posessignificant health risks for astronauts in long-termspace flight.201,209 Work done on shuttle missionsand on the space station has shown significantimprovements of wound healing using light-emit-ting diodes alone or in combination with hyper-baric oxygen treatment. Light-emitting diodetherapy is done at wavelengths of 680, 730, and 880nm simultaneously.209 The array was tested by theU.S. Special Operations Command on submari-ners. Reports indicated a 50 percent faster healingof lacerations in crew members treated with alight-emitting diode array with three wavelengthscombined in a single unit (670, 720, and 880 nm)compared those who underwent untreated con-trol healing (7 days compared with approximately14 days). This is significant because wound healingis slow aboard submarines due to the higher car-bon dioxide and lower oxygen levels.201 Light-emitting diode therapy is also being investigated astherapy for neural cancers,215,216 leukemia, lym-phomas, and Barrett’s esophagus.201

Negative Pressure TherapyNegative pressure therapy (or vacuum-assisted

closure), developed at the Bowman Gray School ofMedicine, uses a subatmospheric pressure dress-ing to convert an open wound into a controlledclosed wound.52,217,218 The negative pressure exertsmany effects on both gross and microscopic levels.The negative pressure removes interstitial fluidand edema to improve tissue oxygenation. It alsoremoves inflammatory mediators that suppressthe normal progression of wound healing.43,218

Granulation tissue forms more rapidly (103.4 �35.5 percent) than in controls, and 5 days of ther-apy decreases the wound bacterial count to lessthan 105 organisms per gram of tissue.52 The neg-ative pressure dressing is convenient to use; it re-quires changing every 48 to 72 hours and has fewcomplications. The dressing is used in a variety ofwound types, involving soft-tissue loss, exposedbone and hardware, and weeping wounds, and asa skin graft bolster. Negative pressure therapy is

contraindicated when (1) wounds contain ne-crotic tissue, (2) osteomyelitis is untreated, (3)body cavity or organ fistulas are present, (4) ma-lignancy is present in the wound, or (5) treatmentwould place the foam dressing directly over ex-posed arteries and veins. Negative pressure ther-apy should be used cautiously when there is activebleeding in the wound, when hemostasis is diffi-cult after debridement, and when anticoagulanttherapy is used.162 The vacuum dressing is a greattemporizer and gives the patient and surgeon timeto transform a hostile wound into a manageableone.

UltrasoundThe therapeutic effects of ultrasound therapy

are from its thermal and nonthermal properties.Ultrasound results when electrical energy is con-verted to sound waves at frequencies greater than20,000 Hz. Sound waves are transmitted to thetissue through a hydrated medium sandwichedbetween the tissue and the transducer. The depthof penetration depends on the frequency; thelower the frequency, the deeper the penetration.Ultrasound therapy has traditionally been used torelieve muscular spasm for musculoskeletal pain,but the thermal component (a setting of 1 to 1.5W/cm2) of ultrasound has also been used to im-prove scar outcome. The nonthermal componentof ultrasound (at a setting of 0.3 to 1 W/cm2)produces two effects: cavitation and streaming.133

Cavitation is defined as the formation of gas bub-bles, and streaming is a unidirectional, steady me-chanical force. These effects cause changes in thecell membrane permeability and enhance diffu-sion of cellular metabolites.37

Ultrasound’s effect on wound healing in the lab-oratory include cellular recruitment, collagen syn-thesis, increased collagen tensile strength, angiogen-esis, wound contraction, fibroblast and macrophagestimulation, fibrinolysis, reduction of the inflamma-tory healing phase, and promotion of the prolifer-

Table 10. Common Low-Energy Lasers

Laser System Wavelength (nm)

Argon (Ar) 488–514Carbon dioxide (CO2) 10,600Dye VariableGallium-arsenide (GaAs)

or infrared (IR) 904Gallium-aluminum-arsenide (GaAlAs) 830Helium-neon (HeNe) 632.8Neodymium:yttrium-aluminium-garnet

(Nd:YAG) 1064Ruby 694


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ative healing phase.133,219,220 Clinically, the results arenot as comparable. Ultrasound is used most often totreat venous stasis ulcers and pressure sores.Some217,221 have shown a demonstrable reduction inwound size compared with placebo. Mirastschijski etal.222 were unable to show any improvement inwound healing with ultrasound versus placebo. Ul-trasound treatment of pressure ulcers showed a sim-ilar division; some showed improvement223 andothers224,225 did not.

KELOIDS AND HYPERTROPHIC SCARSHypertrophic scars are raised scars that re-

main confined to the limits of the incision (Fig. 2).Keloids are scars that have overgrown their bound-aries (Fig. 3).

Differences between Keloids and HypertrophicScars

Histologic DifferencesLight microscopy reveals large collagen bun-

dles in keloidal scars but not in hypertrophicscars.226,227 Keloidal scars may have few macro-phages, but they have abundant eosinophils, mastcells, plasma cells, and lymphocytes226 and are as-sociated with a mucopolysaccharide ground sub-stance; hypertrophic scars have only scantamounts.226 No morphologic differences in keloi-dal and hypertrophic scar fibroblasts have beenfound, but their biological behavior is different.Hypertrophic scars have nodules containing cellsand collagen within the middle to deep part of thescar.228 Within these nodules are �-smooth muscleactin–staining myofibroblasts, which are absentfrom normal dermis, normal scars, and 88 percentof keloidal scars.

Differences Observed with ElectronMicroscopy

Ehrlich et al.228 found an amorphous sub-stance around keloidal fibroblasts that separatedthem from the collagen bundles. This substancewas not seen in hypertrophic scars. Kischer and

Hendrix229 found that collagen bundles were“crisp” in hypertrophic scars and more “glazed” inkeloidal scars. In addition, differences were foundin the degree of microvascular injury seen in thekeloidal scars.

Differences in Metabolic ActivityUeda et al.230 found that keloidal scars had

higher levels of adenosine triphosphate and fibro-blasts up to 10 years after formation, comparedwith hypertrophic scars. Nakaoka et al.231 found ahigher density of fibroblasts in both keloidal scarsand hypertrophic scars, but keloidal scars had ahigher expression of proliferating cell nuclear an-tigen, which the authors believed may help ex-plain the tendency of keloidal scars to grow be-yond the boundary of the original wound.

Other DifferencesAntinuclear antibodies against fibroblasts and

epithelial and endothelial cells have been foundin patients with keloidal scars but not in those withhypertrophic scars.232

EpidemiologyKeloids tend to occur during periods of phys-

ical growth and most often form between the agesof 10 and 30 years.233 A keloid rarely forms in anFig. 2. Hypertrophic scar.

Fig. 3. Ear keloid.


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elderly person. Keloids occur in persons of allraces; darkly pigmented skin is affected 15 timesmore often than is lighter skin.216,234 No reportsexist of the occurrence of a keloid in an albinoperson. In a rural African population, the inci-dence was noted to be approximately equal inmales and females (5.4 and 6.2 percent,respectively).235 The teenage population has ahigher incidence, with keloids occurring in 12.2percent of boys and 14.4 percent of girls.235 Al-though the three most common causes in Olu-wasanmi’s field survey235 were unspecified trauma,vaccinations, and tattoos, the most common pre-disposing factor in a hospital review was earlobepiercing. In a predominantly black and Hispanicpopulation, Cosman and Wolff236 noted the inci-dence of keloid formation to be between 4.5 and16 percent in a review of three large series. Dataregarding the incidence of recurrence based onethnicity or degree of skin pigmentation arenonexistent.237

PathogenesisThe etiology of keloid formation is not entirely

clear. Porter et al.237 compiled a list of possiblecauses derived from numerous treatment strate-gies that appear to have some benefit in the treat-ment and management of keloids.

TraumaTrauma seems to be the most common ante-

cedent factor to developing a keloid.216 Random(e.g., laceration, burn, vaccination, bug bite) andplanned (e.g., surgery, tattoos, ear piercing) trau-matic events were reported to cause the formation ofa keloid. Keloids may develop within 1 year of thetraumatic event, but occasionally they can formmany years later. After a traumatic injury, a keloidforms because fibroblasts haphazardly lay down col-lagen. Keloids can be seen on all parts of the body,but the sternum and supradeltoid regions are themost often affected. Keloids of the ears, penis, fe-male genitalia, corneum, intraoral region, and plan-tar region have also been reported.238

Abnormal Fibroblast ActivityFibroblasts from hypertrophic scars and keloi-

dal scars have different properties. Hypertrophicscar fibroblasts have a moderate increase in theirbasal level of collagen production, but they stillrespond normally to growth factors.239 In contrast,fibroblasts from keloidal scars produce high levelsof collagen,240 elastin,241 fibronectin,229,242 andproteoglycan243 and show abnormal responses tostimulation.244 Collagen type I is predominantlyproduced by keloidal fibroblasts.245 These fibro-

blasts have been show to have a greater capacity toproliferate.246

Increased Levels of Growth Factor andOther Cytokines

TGF-� has three subtypes: 1, 2, and 3.247 Levelsof types 1 and 2, which stimulate fibroblasts, areincreased in keloidal scars, whereas levels of type3 TGF-� are not increased. TGF-� type 1 has beenassociated with increased collagen239,248 and fi-bronectin synthesis242 by fibroblasts. IFN-� andIFN-� have been shown to reduce both collagensynthesis from fibroblasts and fibroblast prolifer-ation.

Decreased ApoptosisProgrammed cell death, or apoptosis, is be-

lieved to play a role in wound healing and possiblykeloidal scar formation.249 Lower rates of apopto-sis have been observed in keloidal fibroblasts.250 Ithas been suggested that keloidal fibroblasts resistphysiological cell death, continuing to proliferateand produce collagen.251

Increased Levels of Plasminogen ActivatorInhibitor-1

Fibrin plays an important part in wound heal-ing, leading to migration of inflammatory cells,formation of granulation tissue, and collagen syn-thesis. Regulation of fibrin is important in woundhealing; it is degraded by plasmin, which in turnis regulated by a number of activators (urokinaseand plasminogen activator) and inhibitors (tissueplasminogen activator inhibitor 1). Keloidal fibro-blasts have increased levels of plasminogen acti-vator inhibitor-1 and low levels of urokinase.252

This may lead to reduced collagen removal andcontribute to scar formation.252

Abnormal Immune ReactionsTheories that keloidal scars are generated by

specific immune reactions led researchers to ex-amine the levels of immunoglobulins within ke-loidal scars. The overall results are conflicting. Ithas been suggested that antigenic substances maybe present in keloidal scars.

Hypoxia as an Etiologic FactorTissue hypoxia has been implicated in keloidal

scar formation. Histologic examination shows oc-cluded microvessels with plump endothelial cellslining the vessel wall.253 The mechanism by whichhypoxia may lead to keloidal scar formation isunclear. Vascular endothelial growth factor(VEGF) has been shown to be released from fi-broblasts in response to hypoxia. Gira et al.254

found that VEGF production was abundant in ke-loids and that the source of the VEGF was theoverlying epidermis. Steinbrech et al.,255 however,


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found no difference in VEGF levels between ke-loidal fibroblasts and normal dermal fibroblasts.

Other Theories Regarding EtiologyThere is a theory that keloidal scars are caused

by an immune reaction to sebum.256 This theory issupported by the following observations: keloidalscars are more common in adolescence; theyrarely occur on the palms and soles; spontaneouskeloidal scars occur in skin areas with sebaceousactivity; and one scar may be keloidal, whereas anadjacent scar may be normal. Researchers positingthis theory suggest that the development of keloi-dal scars is dependent on random damage to pi-losebaceous structures.257

Keloids can be considered a mesenchymalneoplasm. Keloid fibroblasts have been shown tocontain the oncogene gli-1 and express the pro-tein Gli-1.258 Immunohistochemistry staining forgli-1 showed a strong presence in the cytoplasm,similar to basal cell carcinoma, which also ex-presses the gli-1 oncogene. This oncogene is notexpressed in fibroblasts from normal tissue andnonhypertrophic scars. Rapamycin (sirolimus)and tacrolimus (FK506) have been shown to bebeneficial for keloid regression, and both drugsbind the cellular receptor (FKBP12), which is acis-trans- prolyl isomerase–-the same target of theGli-1 protein. Table 11 summarizes the biochem-ical alterations seen in keloids and hypertrophicscars.

Clinical PresentationHypertrophic scars may regress with time and

occur earlier after injury (usually within 4 weeks).Most keloids form within 1 year of wounding, butsome may begin to grow years after the initial injury.

Surgical incision, trauma, burns, inflammation, in-fection, and puncture wounds are the most commoninciting events.216 Symptoms associated with keloidformation include pain, pruritus, hyperpigmenta-tion, disfigurement, and decreased self-esteem(which appears most commonly in the teenage pop-ulation). Pruritus is experienced transiently in nor-mal healing wounds, but persistent pruritus is asso-ciated with keloid formation.259 Lesions can belocated in various places but predominate on thehead, neck, and earlobe in those patients whopresent for treatment.235 Areas of the head and neckthat are spared include the eyelids and the mucousmembranes.259

Treatment OptionsThe availability of so many treatment options

speaks to the fact that none of them has proved tobe completely effective. The primary problem withtreatment of keloidal scars is the high rate of re-currence. Keloid recurrence rates range from 0 to100 percent. The literature is replete with retro-spective, uncontrolled studies with small samplesizes. The few randomized prospective studies thatdo exist also have small sample sizes, so statisticalsignificance may be lacking. Beyond the basicproblems of study design, these studies are notuniform with regard to outcome measures andduration of follow-up. To add further confusion,there is little standardization of analysis that takesinto account previous treatments that subjectshave had before the current study’s new and im-proved keloid treatment strategy. Finally, manystudies include both hypertrophic scars and ke-loids in the subject population. A summary of themost common treatment strategies is provided be-low.

Table 11. Biochemical Alternations Seen in Excessive Scar Formation*

Biochemical Alternation Observation

Prolyl hydroxylase Activity: keloid � hypertrophic scar � normalTotal collagen Synthesis: keloid � hypertrophic scar � normal

Cross-linking: normal � keloidCollagen type I Content: keloid � normalPlasminogen activator inhibitor-1 Levels: keloid � normalChondroitin-4-sulfate Content: keloid � hypertrophic scar � normalGlycosaminoglycans Content: hypertrophic scar � normalFibronectin Synthesis: keloid � normal

Receptor expression: keloid � normalElastin Synthesis: keloid � normalHyaluronic acid Degradation: normal � hypertrophic scarApoptosis Normal � keloidTGF-� Types 1 and 2: keloid � normal

Type 3: keloid � normalVEGF Content: keloid (keratinocytes) � normalgli-1 oncogene Present in keloid, absent in normal*Adapted in part from Aston, S. J., Beasley, R. W., and Thorne, C. H. M. (Eds.), Grabb and Smith’s Plastic Surgery, 5th Ed. Philadelphia:Lippincott-Raven, 1997. Chap. 1.


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Excision AloneExcision alone has not been successful in elim-

inating keloids. Recurrence rates range from 45 to93 percent.234,260 Excision is the most obvious treat-ment, but it has met with little success when it isperformed alone. Apfelberg et al.261 proposed us-ing the keloid epidermis as an autograft for woundclosure after keloid excision. Using the keloidalskin avoids donor-site morbidity, decreases theamount of tension on the closure, and lessens thecosmetic deformity. Only five patients were re-ported in his series, which had a 40 percent re-currence rate. Weimar and Ceilley262 incorporatedthe autograft technique for use with adjunctivemeasures, pressure therapy, and steroid injec-tions, but results were not provided. Adams126 de-scribed a suprakeloid flap with postoperative ra-diation therapy for the successful treatment of anearlobe keloid.

Core excision of a dumbbell keloid located onthe earlobe with anterior and posterior compo-nents has excellent cure rates when it is used alongwith steroids. Core excision results in a full-thick-ness defect; the anterior wound is closed primarilyand the posterior wound is allowed to granulateclose. Six patients were treated successfully in thismanner without recurrence at more than 1 year.263

Excision alone is not recommended as defin-itive therapy. Adjuvant therapy has become thestandard of care to improve outcomes.

Laser ExcisionDifferent forms of laser therapy for keloids

have been evaluated over the years. Lasers, whichcause a range of nonspecific to specific thermaltissue reactions, are believed to wound in such away so as to minimize scar contraction comparedwith scalpel wounds. Both carbon dioxide andargon lasers showed early promise in excision,creating a dry and bloodless surgical environmentwith limited damage in surrounding tissue. Theselasers are not frequently used at present, however,because long-term studies revealed recurrencerates of up to 92 percent when they were used asa single modality.233,234,264–266

The most promising form of laser therapyseems to be the 585-nm flashlamp-pumpedpulsed-dye laser, which has been effective in re-ducing pruritus, erythema, and the height of ke-loids, with improvement in 57 to 83 percent ofcases.264–268

Laser excision yields the best results whencombined with adjunctive therapy. It is unclear ifthere is truly any variation in results of laser versus

scalpel excision performed in isolation. Prospec-tive, randomized, controlled trials would benefitthe understanding of whether lasers provide morebenefit than scalpel excision.

SteroidsIntralesional steroids often are used for initial

treatment of the keloid. More commonly, they arethe adjunctive treatment of choice periopera-tively, because they are readily available and easilyused. Steroids suppress the inflammatory phase ofwound healing, decrease collagen production bythe fibroblast, and decrease fibroblast prolifera-tion. Triamcinolone acetonide seems to be thesteroid of choice. Studies vary significantly regard-ing the strength of the steroid preparation usedand at what point in the treatment regimen it isadministered. Of the range of dose strengths, 40mg/ml is the most common strength used to treatkeloids. With regard to timing of administration,it is occasionally used preoperatively at one orseveral sessions269,270; this is followed by excisionand further postoperative treatment. Alterna-tively, some physicians use it preoperatively, intra-operatively, postoperatively, or in some combina-tion of the three. No one regimen proved to bemore beneficial. Adverse reactions with the use ofintralesional steroids include localized problems,such as depigmentation, hypopigmentation, epi-dermal atrophy, telangiectasias, and skin necrosis.Occasionally, these changes may be only tempo-rary. Systemic side effects and Cushing’s syndromeare rare and are associated with improper steroiduse.

One of the first studies to report results of tri-amcinolone acetonide injection found that 88 per-cent of keloids (n � 22) injected with steroids re-gressed to varying degrees and that pruritusdisappeared within 3 to 5 days of injections.271 Thebest responses were noted when the injection wasperformed at times of excision and with follow-upvisits. High doses, up to 120 mg, were injected. Com-plications included atrophy, depigmentation, andrecurrence. Currently, most practitioners do not ad-minister such high doses. Monthly doses of approx-imately 12 mg are recommended.270 This modalitycontinues to be a mainstay of treatment. Perioper-ative steroids generally are considered the standardof care, because most controlled studies use this asthe control arm.233,270

Radiation TherapyRadiation therapy has been used to treat ke-

loids since 1906234 and has been successful in erad-


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icating this benign lesion. When used alone, it wasnoted to have a wide range of cure rates, from 15to 94 percent.260 When the lesions are first excisedand subsequently radiated, however, the responserates increase to 33 to 100 percent.260 The resultsof studies performed in the recent past (1974 to1990) have shown that the response rates are evenbetter, from 64 to 98 percent.260 Success seems todepend on the number of rads delivered to thesurgical site and institution of the radiation treat-ment in the immediate postoperative period.

In a retrospective study of 24 patients treatedwith postexcisional superficial radiation therapy,patients had a dosage of 800 to 1200 rads dividedinto one to three doses delivered to the bed of thewound.272 A recurrence rate of 53 percent wasreported, one of the highest in the literature forthis modality.

Controversy abounds regarding the safety ofdelivering radiation to a benign tumor.273 Thereare anecdotal reports regarding the developmentof malignancy after treatment of a keloid withradiation.273 Patients treated with radiation foracne in the past have an increased incidence ofskin cancer, which may develop up to 30 to 40years after the radiation exposure. Currently, ra-diation is no longer used to treat acne. Althoughadequate data are lacking, it is estimated that therisk of developing skin cancer from radiation ex-posures of less than 1000 Gy is low.237 Although thedose administered for the treatment of keloids islow, long-term follow-up is needed to determinethe actual risk for development of malignancy;however, this modality seems to be a highly effec-tive adjunctive measure for eradicating the keloid.

Pressure TherapyPressure therapy is effective in the treatment

of hypertrophic scars and keloids, especially afterburn injury. This therapeutic strategy is used incombination with other treatment modalities(e.g., silicone gels or sheets to enhance the pres-sure treatment). Maximum benefit is achieved bywearing the pressure appliance for 18 to 24 hoursper day for at least 4 to 6 months.233,274,275 Goodresponse rates were seen in 90 to 100 percent ofpatients treated with keloid excision followed bypressure therapy, especially when the keloid waslocated on the earlobe.233,274,275 The amount ofpressure delivered should be between 24 and 30mmHg, to avoid decreased peripheral blood cir-culation. Pressure earrings have been developedfor postoperative use on keloids involving the ear-lobe. Intralesional verapamil combined with 6

months of pressure therapy used after keloid ex-cision resulted in a 55 percent cure rate.276

Magnetic DisksChang et al.35 treated 47 patients (91 auricles)

with “hypertrophic scarring of the earlobe” (ke-loids) with compressive therapy using magneticdisks after surgical excision. With a mean fol-low-up of 18.1 months, they had only one recur-rence 13 months after surgery. This was treatedwith additional disk compression for 3 months.Thirty-one of the 47 patients complained of painwith the disk therapy. The pain was treated byreducing the compression intensity, by attachinga silicone gel sheet to the magnetic disk, or byreducing the amount of time patients had to wearthe disk. The authors offer no explanation for whythe magnetic disks work, except that they are aform of compression therapy.

CryosurgerySerial cryotherapy treatments using spray or

contact methods have traditionally been useful formanaging hypertrophic scars and keloids.Zouboulis et al.277 introduced an intralesional nee-dle cryosurgery device for both hypertrophic scarsand keloids The authors advocate this method asmore effective for treating deeper parts of scarsand keloids than spray or contact methods, re-quiring fewer treatments. Twelve lesions were fro-zen with a cryoneedle inserted along the long axisof the lesion; the needle was connected to a liquidnitrogen source. They found an average 51 per-cent reduction in lesion volume, with significantlyimproved subjective (pain, itching) and objective(hardness, color) ratings. Pretreatment and post-treatment histologic analysis demonstrated im-proved scar organization after needle cryosurgery.

InterferonInterferons interfere with fibroblasts’ ability to

synthesize collagen. Specifically, IFN-�-2b normal-izes the collagen and glycosaminoglycan of thekeloid.233 Complications with IFN-�-2b injectioninclude flu-like symptoms, headache, fever, andmyalgias. These symptoms may be tolerable withthe prophylactic administration of acetamino-phen. In a retrospective study, Berman andFlores307 found that the recurrence rate with pos-texcisional use of IFN-�-2b (18.7 percent) was su-perior to that for excision alone (51.1 percent)and for postexcisional steroid (triamcinolone) in-jections (58.4 percent). IFN-�-2b was injected intothe wound at a dosage of 1 million U in 0.1 ml per


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linear centimeter per treatment. Twelve of the 16patients treated with IFN were reinjected 1 weeklater with 5 million U. Follow-up was only 7 monthson average, but the differences were statisticallysignificant. Conejo-Mir et al.278 achieved a 3-year 0percent recurrence rate with the combination ofcarbon dioxide laser excision and IFN-�-2b injec-tions for earlobe keloids. IFN-�-2b seems to beeffective in decreasing the keloid recurrence rate.In a recent, smaller prospective study,37 of 13 ke-loids treated with postoperative intralesional IFN-�-2b, seven recurred (54 percent). In contrast, 26keloids treated with triamcinolone (controlgroup) had a 15 percent recurrence rate.

IFN-� is believed to work in manner similar toIFN-�-2b. There have been several anecdotal re-ports regarding the benefits of IFN-� in treatingkeloids. More recently, a pilot study examined thetreatment of keloids with this modality.279 In aplacebo-controlled, randomized, double-blindstudy, patients with two keloids had one keloidrandomized to excision and postoperative pla-cebo injections and the other to IFN-� injections.In the experimental group, patients were given aseries of 10 injections of 10 �g of IFN-�. Only sevenpatients were enrolled in the study, three of whomdropped out at the 1-year follow-up examination.Experimental and control groups had uniformlypoor results, with an approximate 75 percent re-currence rate. Because of the small sample size,conclusions could not be drawn.

Imiquimod is a relatively new agent, an im-mune response modifier that indirectly acts tostimulate innate and cell-mediated immune path-ways, thereby enhancing the body’s natural abilityto heal.280 Along with inducing and activating nat-ural killer cells, macrophages, and Langerhanscells, imiquimod also induces the local synthesisand release of cytokines, including IFN-�, IFN- �,TNF-�, and IL-1, IL-6, IL-8, and IL-12, when top-ically applied.281 A variety of case reports and clin-ical studies have documented recent successes as-sociated with the use of imiquimod and itsantiviral, antitumor, and immunoregulatory prop-erties, especially in conditions in which interfer-ons have also been used successfully in treatment.Berman and Kaufman282 examined the effects oftopical application of imiquimod 5% cream aftersurgical excision of 13 keloids from 12 patients.Imiquimod 5% cream was applied nightly directlyto the suture line and to the surrounding areabeginning on the day of the surgery and continu-ing for a total of 8 weeks. At 24 weeks, no recur-rence of keloidal growth was noted among the 11keloids of the 10 patients who completed the

study, a recurrence rate lower than those previ-ously reported in the literature for surgery alone.

Silicone Gel SheetsThe mechanism of action of silicone gel sheet-

ing, also known as hydrocolloid dressing, is notfully known. Scar hydration is facilitated by thepresence of this occlusive dressing. Hydrocolloiddressings have been deemed safe for treatingwounds in the initial stages of healing.283 Siliconegel probably acts as an impermeable membranethat keeps the skin hydrated.37 In vitro experi-ments have shown that silicone is inert and doesnot affect fibroblast function or survival; however,enhanced keratinocyte hydration alters growthfactor secretion, which in turn affects fibroblastfunction and collagen production.284 The clinicaleffects of silicone gel do not appear to be medi-ated by changes in pressure, temperature, or tissueoxygenation.37 In an animal study, no detrimentaleffect was found when silicone gel sheets werecompared with Nu-Gauze dressings in the imme-diate postoperative period. Histologic examina-tion of the wounds revealed no evidence of sili-cone leakage into the tissues. Prevention orimprovement of keloids was not addressed in thestudy. In human trials, topical silicone gel was usedto treat 22 keloids in 18 patients, with an 86 per-cent significant objective response rate.285 Siliconegel sheets may reduce recurrence rates after ex-cision. It is a benign intervention that does notincrease the rate of recurrence, and it may beuseful as an adjunctive measure.

A brief summary of keloid treatments is shownin the Table 12.286–299 The reader should be awarethat most of the studies include a mixture of pa-tients with keloidal scars and hypertrophic scars,and they are rarely discussed separately.

Practical GuidancePrevention is the best keloid therapy.

Proposals259 for prevention include avoidingnonessential cosmetic surgery in keloid-formingpatients, closing wounds with minimal tension,using cuticular, monofilament, synthetic perma-nent sutures in an effort to decrease tissue re-action, avoiding Z-plasties or any wound-length-ening techniques, and avoiding, as often aspossible, making incisions that cross joints andfollow skin creases.259

Despite a broad range of therapeutic possibil-ities, there is no universally effective treatment forkeloids. A few treatment options, such as cortico-steroid injections and perhaps compression, are


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used as monotherapy. Polytherapy or a “shotgunapproach” is used most often, and specific treat-ments are chosen on a patient-by-patient basis.237

For example, although injected triamcinolone isconsidered to be efficacious as a first-line therapy,silicone gel sheets may be more useful in childrenand others who cannot tolerate the pain of othertherapies.300

FUTURE WOUND-HEALING THERAPIESGene therapy is the future for wound-healing

strategies. Current research is aimed at insertinggrowth factor genomes into the wound. Petrie et

al.301 have written an excellent review of gene ther-apy in wound healing, and it is recommended tothe reader who wants more detailed information.

Inserting the desired genome can be accom-plished through several different vehicles: bio-logic (viral) techniques, chemical methods via cat-ionic liposomes, and physical insertion.

Viral TechniquesMany different viruses have been tried in gene

therapy. There are four popular virus types: ret-roviruses, adenoviruses, adenoassociated viruses,and herpes simplex virus. The principles behind

Table 12. Comparison of Treatment Modalities and Results*

Treatment No. of Patients Results

5-FU � steroids (intralesional)286 10 All subjects showed significant flattening compared with control for all treatment arms.The most flattening was observed in the steroid treatment group, followed by steroid �5-FU, 5-FU alone, and PDL treatment. Scar texture was better with PDL treatment.

5-FU286 10 All subjects showed significant flattening compared with control for all treatment arms.The most flattening was observed in the steroid treatment group, followed by steroid �5-FU, 5-FU alone, and PDL treatment. Scar texture was better with PDL treatment.

Bleomycin287 13 Compete flattening, 42.8%Cryosurgery � steroid

(intralesional)28858 Complete regression, 70.6%; improvement, 13.7%; recurrence, 15.5%

Cryotherapy289 93 (38 HS, 55 KS) 61.3% had excellent or good results, 29% had poor response, 9.7% had no responseIFN-� (monotherapy)307 10 All 10 scars flattened, five out of 10 flattened greater than 50% of original heightIFN-2�-2b (monotherapy)291 22 Only three out of 22 patients (14%) showed a reduction in size; nine patients withdrew

from study (seven because of pain)IFN-2�-2b � surgery308 124 Recurrence was 18% after surgery and postoperative IFN treatment compared with 51%

of patients treated with surgery � triamcinoloneIFN-2�-2b � surgery278 30 33% recurrence rate after IFN � laser excision; 19% recurrence rate after IFN � surgeryImiquimod282 13 keloids in 12

patients5% cream was applied to surgical scar after keloid was excised. At 24 weeks, there was no

recurrence in 11 keloids of the 10 patients who completed the study.Laser265 (77 with Argon, 5

with CO2)82 55% excellent or good improvement (softening, flattening, lack of

progression/recurrence), 11% poorPulsed dye laser267 16 Effective in reducing pruritus and erythema and flattening scar in 57-83%Pulsed dye laser292 10 All subjects showed significant flattening compared with control for all treatment arms.

The most flattening was observed in the steroid treatment group, followed by steroid �5-FU, 5-FU alone, and PDL treatment. Scar texture was better with PDL treatment.

Radiation (postsurgical)293 393 Cosmetic results excellent in 92%, favorable in 6%; only a 2.4% recurrenceRadiation (postsurgical)272 24 Irradiation given after keloid excised; 54% recurrence at 24 monthsRadiation (postsurgical)294 147 KS 32.7% total recurrence rate within 18 months; the highest (41.7%) over high tension

areas (chest wall, scapular region, upper limb) versus a 13.5% recurrence at lowtension areas (neck, earlobes, lower limb)

Silicone295 94 (80 HS, 14 KS) Overall, 84% were “greatly improved,” 11% were “somewhat improved,” and 5% had noimprovement. Silicone “greatly improved” scar in 92.5% of hypertrophic scars and35.7% of keloidal scars. “Somewhat improved” were 6.25% of hypertrophic scars and35.7% of keloids. “No improvement” was seen in 1.25% of hypertrophic and 28.8% ofkeloidal scars.

Silicone296 46 Excellent, 13%; good, 47.8%; fair, 26; poor, 13%Steroids (intralesional) after

excision30958 (21 HS, 37 KS) No recurrence, 93.1%; partial recurrence, 5.2%; full recurrence, 1.7%

Steroids (intralesional)286 10 All subjects showed significant flattening compared with control for all treatment arms.The most flattening was observed in the steroid treatment group, followed by steroid �5-FU, 5-FU alone, and PDL treatment. Scar texture was better with PDL treatment.

Surgery � silicone � verpamil298 22 Complete result, 54%; partial result, 36%; absence of results, 9%Surgery � silicone298 22 Complete result, 0; partial result, 18%; absence of results, 82%Verapamil (intralesional) �

excision23822 Verapamil was injected intralesionally and into the donor site (when skin graft was used)

after excision of keloid with W-plasty. At 2-year follow-up, there were two recurrences(9%) (recurrent keloids were smaller than the originals), and four (18%) hadhypertrophic-appearing scars; one patient developed a keloid at the skin donor site.

5-FU, 5-fluorouracil; HS, hypertrophic scar; KS, keloidal scar; PDL, pulsed dye laser.*Nearly all of the above studies contain a mixture of hypertrophic and keloid scars. When differences were noted by the author, those differenceswere included in the table. Otherwise, both types of scar were treated equally.


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creating a recombinant viral vector involve delet-ing essential parts of the viral genome to renderviral replication defunct and inserting the gene ofinterest. The transgene inserted is limited by thepackaging capacity of the vector. Although theendogenous viral promoter may be able to drivethe expression of the inserted gene, this process isusually optimized by cloning the target gene un-der the control of a more powerful promoter se-quence, such as the cytomegalovirus promoter.Two complications of retroviral vectors limit theiruse. One is the theoretical risk of inducing neo-plastic transformation in the target cell—an eventtermed insertional mutagenesis—which could oc-cur should the viral genome integrate in proximityto a cellular proto-oncogene, driving its produc-tion, or by disrupting a tumor suppressor gene.The other complication is the risk of generating areplication-competent virus, as evidenced by re-ports of several outbreaks of wild-type virus fromrecombinant virus–producing cell lines.302

Cationic LiposomesCationic liposomes are lipid bilayer spheres

that are rendered cationic (positively charged)and associate in a noncovalent fashion with neg-atively charged DNA to form liposome-DNA com-plexes. The rationale for coating nucleic acid withlipids is to allow highly negatively charged nucleicacid molecules to traverse the plasma membraneof the target cell. Lipofection is the term used torefer to gene transfer by this mechanism. It in-volves the addition of the complexes to the targetcells, following which the molecules adsorb to thecell membrane and deliver the bound DNA. Theadvantages of lipofection include repeated appli-cation, lack of toxicity, and ability to carry largeamounts of DNA. Although currently used in 13percent of all gene therapy clinical trials, lipofec-tion is limited by a low rate of stable integrationinto the target cell and a lack of specificity.301

Physical Insertion MethodsThere are several methods of physically deliv-

ering the plasmid DNA directly into the cell301:direct injection using a hypodermic needle, mi-croseeding, particle-mediated transfer (using agene gun), and electroporation.

Direct Injection Using a Hypodermic NeedleDirect injection involves injecting naked plas-

mid DNA solution directly into the target tissue toenable transgene expression. It is a desirablemode of transfection because it is versatile and can

be used for plasmid DNA solution and liposome-DNA complexes. It has a lower incidence of effectsexhibited by some viral vectors, such as elicitationof an adverse immune response and insertionalmutagenesis. This technique has the disadvantageof low levels of transfection.303

MicroseedingMicroseeding is a technique for in vivo gene

transfer. A plasmid DNA solution of choice is de-livered directly to the target cells of the skin by aset of oscillating solid microneedles driven by amodified tattooing device. Because no specialpreparation is required, recombinant viral vectorscan be delivered efficiently. No foreign material isdeposited, as can occur with particle-mediatedgene transfer, and microseeding has a muchhigher transfection efficiency compared with sin-gle injection, possibly because the DNA is deliv-ered by smaller, finer solid microneedles.

Particle-Mediated Transfer (Gene Gun)Particle-mediated gene transfer involves bom-

barding cells and tissues with particles or micro-particles coated with DNA. The microparticles arecomposed of gold or tungsten and are 1 to 5 �min diameter. The particles are coated with theDNA of interest and loaded into a device knownas the gene gun before being accelerated by aforce (either an electrical discharge or high-pres-sure helium) that drives the particles into the tar-get cell, where the DNA dissociates from the par-ticles and is expressed. Advantages of thistechnique include its broad spectrum for beingable to transfect a wide variety of target tissues invivo and in vitro, including skin, liver, pancreas,kidney, muscle, and cornea, and the high loadingcapacity of the microparticles, which permits theintroduction of multiple genes. Limitations in-clude a relatively low level of transfection, esti-mated in monolayer culture as being 3 to 15 per-cent. EGF,304 PDGF,305 and TGF-�306 are amongthe growth factors that have been delivered byparticle-mediated gene transfer, and all have beenshown to accelerate the wound-healing response.

ElectroporationThe principle of electroporation rests on the

ability of electrical field pulses to create pores in thecell membrane. Cells suspended in a medium con-taining plasmid DNA and treated with electrical fieldpulses take up and express DNA from the medium.


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SUMMARYSuccessful wound management requires a

thorough understanding of wound healing andthe factors that influence it.

George Broughton, II, M.D., Ph.D.Department of Plastic Surgery

University of Texas Southwestern Medical Center5323 Harry Hines Boulevard

Dallas, Texas [email protected]

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