PROJECT TITLE: POLYMER IN MEDICAL APPLICATION

Kanagesh A/L Manoharan

14989

Chemical Engineering Program

CCB 4423

Polymer Process Engineering

Lecturer: Assoc. Prof. Dr. Zakaria Bin Man

Jan 2015

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ABSTRACT

This project investigates the application of polymer overall in the medical industry with the

recentness application and findings which have been very much a break point in the field. In

recent years, introduction of biodegradable polymer in the field of medical has brought

significant positive changes with little drawbacks due to the recentness of applications. It has

been a big turning point in specified fields such as usage in medical application devices, drug

eluting stents treatments, disposable medical devices, orthopaedic devices, application in tissue

engineering, orthopaedic field, gene delivery. This major impact which drawn a highest

popularity in this medical is due to higher demand nowadays as it has been a safer option

compared to usage of non-biodegradable materials in the field which may bring more hazardous

impact to the patients. Moreover, the higher level of biocompatibility besides the diversified

usage in many field of medical site has been the tremendous choice for physicians yet surgeons

to suggest biodegradable based polymer applications to be implemented for treatment or for

research purpose. Besides that, it can also be divided into synthetic and natural type of

biodegradable polymers depending the source of its origin. To be simplified, this project acts as

the medium to determine the application of biodegradable polymers as a whole in the field of

medical application devices, drug eluting stents treatments, disposable medical devices,

orthopaedic devices, application in tissue engineering, orthopaedic field, gene delivery based on

its recent findings, critical findings, application, advantages and certain drawbacks.

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INTRODUCTION

A biomaterial can be defined as a material intended to interface with biological systems

to evaluate, treat, augment or replace any tissue, organ or function of the body. Biomaterials play

an important role in human health. Biopolymers are the main type of biomaterials. According to

their degradation properties, biopolymers can be further classified into biodegradable and

non-biodegradable biopolymers. Many implants, such as bone substitution materials, some bone

fixing materials, and dental materials, should possess long term stable performance in the body.

In recent years, developments in medical applications, tissue engineering, regenerative

medicine, gene therapy, orthopedic medical field, and controlled drug delivery have promoted

the need of new properties of biomaterials with biodegradability. Biologically derived and

synthetic biodegradable biopolymers have attracted considerable attention.

Given the complexity and the range of applications polymeric biomaterials are currently

used, there is not just one polymeric system available that could be considered as an ideal

biomaterial. This underlines the need for developing a wide range of biodegradable materials

available for implant fabrication that can appropriately match the specific and unique

requirements of each individual medical application.

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Figure 1: Sample types of biodegradable polymers

LITERATURE REVIEW

This chapter discusses about the literature review on the overall project based on previous

research on this study. This will discuss the the general description of biodegradable polymer

and its advantages besides respective application in the medical field by relating it to the

recentness of past study to improvise this overall project.

2.1 Biodegradable Polymers The past two decades have witnessed a significant advance in the biodegradable

polymeric material field. Due to their excellent biocompatibility, biodegradable polymers have

been widely used in biomedical applications, including surgical sutures, bone fixation devices,

vascular grafts, artificial skin, drug delivery systems, gene delivery systems, diagnostic

applications and tissue engineering.

Among the advantages of biodegradable polymer is when the most basic begins with the

physician's or medical expert’s simple desire to have a device that can be used as an implant and

will not require a second surgical intervention for removal (Rezwan, Chen, Blaker, &

Boccaccini, 2006). Besides eliminating the need for a second surgery, the biodegradation may

offer other advantages. For example, a fractured bone that has been fixated with a rigid, non

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Figure 2: Source of biodegradable polymers

biodegradable stainless implant has a tendency for refracture upon removal of the implant. This

is because the stress is caused by the rigid stainless steel, where the bone has not been able to

carry any sufficient load during the healing process. However, an implant prepared from

biodegradable polymer can be engineered to degrade at a rate that will slowly transfer load to the

healing bone (Balint, Cassidy, & Cartmell, 2014).

2.2 Medical DevicesSynthetic biodegradable polymers have attracted considerable attention for applications

in medical devices, and will play an important role in the design and function of medical devices.

The general criteria of polymer materials used for medical devices include mechanical properties

and adegradation time appropriate to the medical purpose.

In addition, the materials should not evoke toxic or immune responses, and they should

be metabolized in the body after fulfilling their tasks. According to these requirements, various

synthesized biodegradable polymers have been designed and used. Some synthesized

biodegradable polymers that have been used or show potential in selected fields are summarized

below.

2.1.1 Drug Eluting Stents (DES)DES have been widely used as a default treatment for patients with coronary artery

disease. Biodegradable polymers are always used as a biodegradable and bioresorbable coatings

on stents to control the release of drugs. Studies of some stainless steel stents coated with

sirolimus and PLA, such as Excel (JW Medical System, China), Cura (Orbus Neich, Fort

Lauderdale, Florida) and Supralimus (Sahajanand Medical Technologies, India), showed some

interesting preliminary results (Oka, Ushimaru, Horiishi, Tsuge, & Kitamoto, 2015). In addition,

stents coated with polyurethane as drug control layers were also reported as highly chose by

physicians in prescription.

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Besides being

used as biodegradable coatings, biodegradable polymers are also optimum materials for fully

biodegradable stents because of their suitable properties for controlled drug release and good

mechanical performance to prevent stents from deforming or fracturing. PLLA was used to

prepare a fully degradable stent and an everolimus-PLLA stent (BVS, Abbott Laboratories,IL,

USA), which were under clinical evaluations. Among the advantages are drug eluting stents with

the presents of durable polymer has significantly reduced the risk of late lumen loss besides

playing a major role in minimizing the rate of target lesion and target vessel revascularization

comparable to to bare metal stents. It has been a great progress in the field of drug eluting test

when in the beginning, it had a high level of drawbacks and disadvantages where it had increased

rate of thrombosis besides thicker stent strunts. Hence, it as then evolved to very safe type of

materials where designed with the aim of showing non-inferiority to durable polymer drug

eluting stents and no more such cases have been reported. Besides that, biodegradable polymer

has been very much improved from the earlier application as as this platform has additional

advantages such as lower cost and reduced need for dual antiplatelet treatment.

2.1.2 Disposable Medical Devices In the 21st century, environment factor plays a major concern for all manufacturing

industries. Many disposable medical devices, such as syringes, injection pipes, surgical gloves,

pads, medical absorber, are usually made of non-degradable plastics, resulting in serious

environmental and economic issues. PLA, poly(glycolide), poly[d,l-(lactide-co-glycolide)] and

PCL are all biodegradable. Therefore, they are promising materials for use in disposable medical

devices meeting environmental friendly requirements. These biodegradable polymers have been

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Figure 3: Sample drug eluting stents with polymer application

used to prepare some disposable medical devices and will likely have a widening commercial

application compared to the previous years of using non-environmental based materials.

2.1.3 Orthopedic DevicesIn the 1960s, poly(glycolide) was used to prepare completely biodegradable and

bioresorbable sutures. Since then, poly(glycolide), poly(lactide) and other materials such as

poly(dioxanone), poly(trimethylene carbonate), PCL and poly [d,l-(lactide-co-glycolide)] have

been widely used for medical devices. Orthopedic devices made from biodegradable materials

have advantages over metal or non degradable materials.

They can transfer stress over time to the damaged area as it heals, allowing of the tissues,

and there is no need of a second surgery to remove the implanted devices (Linan et al., 2015).

Many commercial orthopedic fixation devices such as pins and rods for bone fracture fixation,

and screws and plates for maxillofacial repair are made of PLLA, poly(glycolide) and other

biodegradable polymers. However, the research on devices for load-bearing bone repair and

implantable medical devices still has a long way to go as it can be a new findings in this era for a

major transformation.

2.2 Drug delivery and control releaseBiodegradable polymers with reactive groups or responsive characteristics have been

widely investigated for applications drug delivery and control release. Biodegradable polymers,

such as poly(-malic acid),with reactive pendant carboxyl groups, can produce and conjugate

drugs via ester or amide bonds to form a biodegradable macromolecular prodrug to reduce the

side-effects of free drugs. Drugs can be released via the degradation of biodegradable polymers.

The poly(-malic acid)/amide/DOX conjugate showed much lower cytotoxic activity than free

DOX and poly(-malic acid)/amide/DOX conjugate (Singhal, Small, Cosgriff-Hernandez,

Maitland, & Wilson, 2014).

Academician and past reseachers reported a poly(ethylene glycol)-block-poly(l-lactide-

co-2-methyl-2-carboxyl-propylene carbonate)/Dtxl (PEG-b-P(LA-co-MCC/Dtxl)) conjugate

[56]. The poly(ethylene glycol)-block-poly(l-lactideco-2-methyl-2-carboxyl-propylene

carbonate/docetaxel (PEG-b-P(LA-co-MCC)/Dtxl) conjugate showed high cytotoxic activity

against HeLa cancer cells.

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2.3 Tissue EngineeringTissue engineering is an interdisciplinary field that applies the principles of engineering

and life sciences towards the development of biological substitutes used to restore, maintain or

improve tissue functions. The main purpose of tissue engineering is to overcome the lack of

tissue donors and the immune repulsion between receptors and donors. In the process of tissue

engineering, cells are cultured on a scaffold to form a natural tissue, and then the formed tissue is

implanted in the defect part in the patients as what mentioned by (Qazi, Rai, & Boccaccini,

2014). In some cases, a scaffold or a scaffold with cells is implanted in vivo directly, and the

host’s body works as a bioreactor to construct new tissues. A successful tissue engineering

implant largely depends on the role played by three-dimensional porous scaffolds. The ideal

scaffolds should be biodegradable and bioabsorbable to support the replacement of new tissues.

In addition, the scaffolds must be biocompatible without inflammation or immune reactions and

possess proper mechanical properties to support the growth of new tissues.

Table 1: Compilation of Type of Polymer and Its Application in Tissue Engineering

Polymer Application in Aspect of Tissue Engineering

Polyanhydrides Bone tissue engineering

Polyurethane Vascular tissue engineering

Polyelectroactive materials Bone tissue engineering

Polyphosphoester Nerve tissue engineering

Poly(propylene fumarate) Bone tissue engineering

Polyesterurathane Genitourinary tissue engineering

Synthetic biopolymers such as PLLA, PCL, PGA,poly(glycolide) and poly[d,l-(lactide-

co-glycolide)] have excellent biocompatibility and good mechanical properties and have been

licensed by FDA for in vivo applications, so they have been the most widely used materials for

tissue engineering scaffolds. Considerable research has been carried out about PLLA, PCL,

PGA, poly(glycolide) and poly[d,l-(lactide-co-glycolide)] used in bone tissue engineering,

cartilage tissue engineering, cardiovascular tissue engineering, arterial replacement, heart valve

tissue engineering , small intestine tissue engineering, nerve regeneration tissue engineering,

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engineering of dermal substitutes for skin regeneration, ligament replacement, genitourinary

tissue engineering and other fields (Rezwan et al., 2006). Other synthetic polymers such as

polyanhydride, polyurethane, polyelectroactive materials, PPE polycarbonate,poly(ester amide),

poly(amino acid) biodegradable hydrogels polyesterurathane, poly(propylene fumarate) are also

biodegradable and have shown many potential applications in tissue engineering. Table 1 lists

the application or potential applications of these biodegradable polymers in tissue engineering.

Moreover, synthesized biodegradable polymers have been used to prepare nano

composites in tissue engineering to combine advantages of different materials together. Polymer/

bioceramic composites such as PLLA/hydroxyapatite and PLLA/bioactive glass nanocomposites

have been widely studied in bone tissue engineering. Other inorganic based biodegradable

polymer composites such as carbon nano-tube based composites are also used in tissue

engineering.

2.4 Gene DeliveryGene delivery has great potential for treating various human diseases. Recently, nonviral

vectors have been proposed as safer alternatives to viral vectors for gene delivery. However,

many carriers are non-degradable and the risk arises of accumulation in the body, especially after

repeated administration . Furthermore, most of cationic polymers show high cytotoxicity because

of adverse interactions between the cationic polymers and the membranes when the gene carriers

cross certain barriers to enter the cells.

Recently, some research has evaluated non-degradable polymers with biodegradable

polycations via hydrolyzable linkers as gene carriers which is much safer and induced trust in

donor and receiver. This has been a great boost as it proves the success in this field based on the

implementation of biodegradable polymers.

2.5 Orthopaedic FieldSince synthetic biodegradable polymer based medical implants eliminate the need for a

second surgical intervention to remove the device, their use reduces the total treatment time of

the patient, halves the number of operations required during the care process. It also prevents

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refracture occurring upon removal of a metal based implant, from the sudden implementation of

load, previously caused by the implant, back to the bone. Using the engineering technical

properties, the biodegradable implant is mainly visualized to achieve predictable degradation

which provides progressive bone loading, leading to better bone healing and a reduction in the

risk of refracture (Armentano, Dottori, Fortunati, Mattioli, & Kenny, 2010). Biodegradable

devices can be used as a foundation for drug delivery, so that the degradation rate allows for the

optimal release of the drug or agent to further assist the healing process as mentioned above. As

the benefits of biodegradable medical implants become more widely known and acceptable to

the orthopedic surgeon, demand is expected to grow rapidly relative to the growth rate of the

orthopedics market. Inion, a rapidly growing company focused on the development of novel

biodegradable medical implants, has received FDA 510(k) clearance of its Trinion Meniscus

Screw for use in knee cartilage repair. Trinion screws are used for the fixation of longitudinal

vertical meniscus lesions, where the knee cartilage has torn. Inion products use a combination of

four polymers--trimethylene carbonate (TMC), L-polylactic acid (LPLA), D, L-polylactic acid

(DLPLA), and polyglycolic acid (PGA). Of these biodegradable polymers, highly crystalline

LPLA and PGA homopolymers have the highest strength and stiffness (Balint et al., 2014).

LPLA is a slow-degrading hydrophobic polymer, that takes more than 24 months to fully

biodegrade, whereas PGA is more hydrophilic and biodegrades faster, within 6-12 months. By

combining (co-polymerizing) LPLA and PGA monomers in varying proportions, Inion has

extended the range of polymer properties.

SUMMARY

Biodegradable polymer has played wide range of role in the medical field whether it

relates to the medical application and for the future research works. It has been a paradigm shift

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in the medical field in this modern era to use biodegradable polymer as part and parcel of daily

used appliances besides incorporating them in humans to curb diseases and be a new type of

resistance vaccine for physical sickness.

In terms of medical devices, polymers are very much encouraged to be non toxic released

and its human friendly. It is very much indeed for the mechanical properties and the respective

degradation time to fulfill the medical purpose. There are 3 main aspects of medical devices

highlighted in this project work which are Drug Eluting Stents (DES), Disposable Medical

Devices, and Orthopedic Devices. DES is very much linked with coronary artery disease

treatment. They are always used as a biodegradable and bioresorbable coatings on stents to

control the release of drugs. Disposable medical devices made up of biodegradable polymer is

another aspect of medical devices which have been introduced to replace non biodegradable

polymer in order to fulfill the environmental friendly requirements. In the orthopedic devices

biodegradable polymer called poly(glycolide) was used to prepare completely biodegradable and

bioresorbable sutures which can transfer stress over time to the damaged area as it heals,

allowing of the tissues, and there is no need of a second surgery to remove the implanted

devices.

Besides medical devices, there are 4 other aspects of medical applications where

biodegradable has a huge role. They are drug delivery and control release, tissue engineering and

gene delivery besides orthopedic field usage. Drug delivery and control release have the role of

biodegradable polymer where it can conjugate drugs via ester or amide bonds to form a

biodegradable macromolecular pro-drug to reduce the side-effects of free drugs. In tissue

engineering, they are certain biodegradable polymers which are polyanhydrides for bone tissue

engineering, polyurethane for vascular tissue engineering and polyelectroactive materials for

bone tissue engineering. For gene delivery, non-degradable polymers with biodegradable

polycations via hydrolyzable linkers as gene carriers which is safer than non-biodegradable

polymers. From the orthopedic medical field, it can be mentioned that biodegradable polymers

application also prevents refracture occurring upon removal of a metal based implant. Besides

that it has basically proven that it is very much more safer to and less hazardous impact due to

removal impact. Moreover, it has been very popular in the knee repair cartilage issue to use

biodegradable based polymer among those are Trinion Meniscus Screw.

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As a conclusion, biodegradable polymers have better advantages compared to non-

biodegradable polymers in the medical field usage. It is mainly supported by vast diversity in

their applications in medical field due to its special properties of its nature. Continuous study and

research with different combination of biodegradable polymers will bring a great paradigm shift

in the industry to a higher level of greater inventions for mankind benefits.

REFERENCES

Armentano, I., Dottori, M., Fortunati, E., Mattioli, S., & Kenny, J. M. (2010). Biodegradable polymer matrix nanocomposites for tissue engineering: A review. Polymer Degradation and Stability, 95(11), 2126-2146. doi: 10.1016/j.polymdegradstab.2010.06.007

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Balint, Richard, Cassidy, Nigel J., & Cartmell, Sarah H. (2014). Conductive polymers: Towards a smart biomaterial for tissue engineering. Acta Biomaterialia, 10(6), 2341-2353. doi: 10.1016/j.actbio.2014.02.015

Linan, L. Z., Nascimento Lima, N. M., Filho, R. M., Sabino, M. A., Kozlowski, M. T., & Manenti, F. (2015). Pilot-scale synthesis and rheological assessment of poly(methyl methacrylate) polymers: Perspectives for medical application. Mater Sci Eng C Mater Biol Appl, 51, 107-116. doi: 10.1016/j.msec.2015.02.038

Oka, Chiemi, Ushimaru, Kazunori, Horiishi, Nanao, Tsuge, Takeharu, & Kitamoto, Yoshitaka. (2015). Core–shell composite particles composed of biodegradable polymer particles and magnetic iron oxide nanoparticles for targeted drug delivery. Journal of Magnetism and Magnetic Materials, 381, 278-284. doi: 10.1016/j.jmmm.2015.01.005

Qazi, T. H., Rai, R., & Boccaccini, A. R. (2014). Tissue engineering of electrically responsive tissues using polyaniline based polymers: a review. Biomaterials, 35(33), 9068-9086. doi: 10.1016/j.biomaterials.2014.07.020

Rezwan, K., Chen, Q. Z., Blaker, J. J., & Boccaccini, A. R. (2006). Biodegradable and bioactive porous polymer/inorganic composite scaffolds for bone tissue engineering. Biomaterials, 27(18), 3413-3431. doi: 10.1016/j.biomaterials.2006.01.039

Singhal, P., Small, W., Cosgriff-Hernandez, E., Maitland, D. J., & Wilson, T. S. (2014). Low density biodegradable shape memory polyurethane foams for embolic biomedical applications. Acta Biomater, 10(1), 67-76. doi: 10.1016/j.actbio.2013.09.027

FIGURE REFERENCES

http://www.intechopen.com/books/integrated-waste-management-volume-i/environmental-friendly-biodegradable-polymers-and-composites

http://www.mdpi.com/1999-4923/6/2/249/htm

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