Natural and Synthetic Biomedical Polymers

Natural and Synthetic Biomedical Polymers

Natural and Synthetic

Biomedical Polymers

Edited By

Sangamesh G. Kumbar

Cato T. Laurencin

Meng Deng

AMSTERDAM • BOSTON • HEIDELBERG • LONDON • NEW YORK • OXFORD

PARIS • SAN DIEGO • SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO

Elsevier

30 Corporate Drive, Suite 400, Burlington, MA 01803, USA

525 B Street, Suite 1800, San Diego, CA 92101-4495, USA

First edition 2014

Copyright © 2014 Elsevier Inc. All rights reserved.

No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means

electronic, mechanical, photocopying, recording or otherwise without the prior written permission of the publisher.

Permissions may be sought directly from Elsevier's Science & Technology Rights Department in Oxford, UK: phone

(+44) (0) 1865 843830; fax (+44) (0) 1865 853333; email: [email protected]. Alternatively you can submit

your request online by visiting the Elsevier web site at http://elsevier.com/locate/permissions, and selecting Obtaining

permission to use Elsevier material

Notice

No responsibility is assumed by the publisher for any injury and/or damage to persons or property as a matter of products

liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained

in the material herein. Because of rapid advances in the medical sciences, in particular, independent verification of

diagnoses and drug dosages should be made.

Library of Congress Cataloging-in-Publication Data

Natural and synthetic biomedical polymers/edited by Sangamesh Kumbar, Cato Laurencin, Meng Deng. — First edition.

pages cm

Summary: “Polymer scientists have made an extensive research for the development of biodegradable polymers which

could find enormous applications in the area of medical science. Today, various biopolymers have been prepared and

utilized in different biomedical applications. Despite the apparent proliferation of biopolymers in medical science, the

Science and Technology of biopolymers is still in its early stages of development. Tremendous opportunities exist and

will continue to exist for the penetration of biopolymers in every facet of medical science through intensive Research

and Development. Therefore, this chapter addresses different polymerization methods and techniques employed for the

preparation of biopolymers. An emphasis is given to cover the general properties of biopolymers, synthetic protocols and

their biomedical applications. In order to make the useful biomedical devices from the polymers to meet the demands of

medical science, various processing techniques employed for the development of devices have been discussed. Further,

perspectives in this field have been highlighted and at the end arrived at the conclusions. The relevant literature was

collected from different sources including Google sites, books and reviews”— Provided by publisher.

Includes bibliographical references and index.

ISBN 978-0-12-396983-5 (hardback)

1. Biopolymers. 2. Biodegradable plastics. I. Kumbar, Sangamesh, editor of compilation. II. Laurencin, Cato, editor of

compilation. III. Deng, Meng, editor of compilation.

TP248.65.P62N38 2014

610.28—dc23 2014000085

British Library Cataloguing in Publication Data

A catalogue record for this book is available from the British Library

For information on all Elsevier publications

visit our web site at store.elsevier.com

Printed and bound in USA

14 15 16 17 18 10 9 8 7 6 5 4 3 2 1

ISBN: 978-0-12-396983-5

Dedication

Sangamesh G. Kumbar—To my parents

(Mr. and Mrs. G. B. Kumbar), wife Swetha,

and daughter Gauri.

Cato T. Laurencin—To my wife Cynthia,

and my children Ti, Michaela, and Victoria.

xi

xiii

Contributors

Aja Aravamudhan Department of Orthopaedic Surgery,

Institute for Regenerative Engineering, Raymond and

Beverly Sackler Center for Biomedical, Biological,

Physical and Engineering Sciences, The University of

Connecticut, Farmington, CT, USA

Brittany L. Banik Department of Bioengineering, The

Pennsylvania State University, PA, USA

Mark R. Battig Department of Bioengineering, College of

Engineering, The Pennsylvania State University, PA, USA

Steve Brocchini UCL School of Pharmacy, University

College London, London, UK

Justin L. Brown Department of Bioengineering, The

Pennsylvania State University, PA, USA

Karen Burg Institute for Biological Interfaces of

Engineering, Clemson, USA

Diane J. Burgess Department of Pharmaceutical Sciences,

School of Pharmacy, University of Connecticut, Storrs,

CT, USA

Sheiliza Carmali UCL School of Pharmacy, University

College London, London, UK

Tram T. Dang Center for Biomedical Engineering,

Department of Medicine, Brigham and Women’s

Hospital, Harvard Medical School, Boston, MA, USA

David H. Koch Institute for Integrative Cancer

Research, Massachusetts Institute of Technology,

Cambridge, MA, USA

Meng Deng Department of Orthopaedic Surgery, Institute

for Regenerative Engineering, Raymond and Beverly

Sackler Center for Biomedical, Biological, Physical and

Engineering Sciences, The University of Connecticut,

Farmington, CT, USA

Abraham (Avi) Domb School of Pharmacy-Faculty

of Medicine, The Hebrew University of Jerusalem,

Jerusalem, ISR

Lakshmi Sailaja Duvvuri Department of Pharmaceutics,

National Institute of Pharmaceutical Education and

Research, Hyderabad, India

Muntimadugu Eameema Department of Pharmaceutics,

National Institute of Pharmaceutical Education and

Research, Hyderabad, India

Jennifer Elisseeff Johns Hopkins School of Medicine,

Translational Tissue Engineering Center, Wilmer Eye

Institute and Department of Biomedical Engineering,

Baltimore, MD, USA

Sahar E. Fard Department of Chemistry, Chemical

Biology, and Biomedical Engineering, Stevens Institute

of Technology, Hoboken, NJ, USA

Bing Gu Department of Pharmaceutical Sciences,

School of Pharmacy, University of Connecticut, Storrs,

CT, USA

Jinshan Guo Department of Bioengineering, Materials

Research Institute, The Huck Institute of The Life sci￾ences, The Pennsylvania State University, PA, USA

Umesh Gupta Department of Pharmaceutical Sciences,

College of Pharmacy, South Dakota State University,

Brookings, SD, USA

Matthew D. Harmon Department of Orthopaedic Surgery,

Department of Material Science and Engineering,

Institute for Regenerative Engineering, Raymond and

Beverly Sackler Center for Biomedical, Biological,

Physical and Engineering Sciences, The University of

Connecticut, Farmington, CT, USA

Markus Heiny Institute for Macromolecular Chemistry,

University of Freiburg, Freiburg, Germany

Anjana Jain Biomedical Engineering Department,

Worcester Polytechnic Institute, Worcester, MA, USA

Roshan James Department of Orthopaedic Surgery,

Institute for Regenerative Engineering, Raymond and

Beverly Sackler Center for Biomedical, Biological,

Physical and Engineering Sciences, The University of

Connecticut, Farmington, CT, USA

Tao Jiang Department of Medicine, Institute for

Regenerative Engineering, Raymond and Beverly

Sackler Center for Biomedical, Biological, Physical and

Engineering Sciences, The University of Connecticut,

Farmington, CT, USA

Ravindra R. Kamble Department of Studies in Chemistry,

Karnatak University, Dharwad, Karnataka, India

Lohitash Karumbaiah Department of Biomedical

Engineering, Georgia Institute of Technology, Atlanta,

Georgia, USA

xiv Contributors

Ali Khademhosseini Center for Biomedical Engineering,

Department of Medicine, Brigham and Women’s

Hospital, Harvard Medical School, Boston, MA, USA

Harvard-MIT Division of Health Sciences and

Technology, Massachusetts Institute of Technology,

Cambridge, MA, USA

Wyss Institute for Biologically Inspired Engineering,

Harvard University, Boston, MA, USA

Wahid Khan Department of Pharmaceutics, National

Institute of Pharmaceutical Education and Research,

Hyderabad, India

School of Pharmacy-Faculty of Medicine, The Hebrew

University of Jerusalem, Jerusalem, ISR

Sangamesh G. Kumbar Department of Orthopaedic

Surgery, Department of Material Science and

Engineering, Department of Biomedical Engineering,

Institute for Regenerative Engineering, Raymond and

Beverly Sackler Center for Biomedical, Biological,

Physical and Engineering Sciences, The University of

Connecticut, Farmington, CT, USA

Cato T. Laurencin University Professor, Albert and Wilda Van

Dusen Distinguished Professor of Orthopaedic Surgery,

Professor of Chemical, Materials and Biomolecular

Engineering; Chief Executive Officer, Connecticut

Institute for Clinical and Translational Science; Director,

The Raymond and Beverly Sackler Center for Biomedical,

Biological, Engineering and Physical Sciences; Director,

Institute for Regenerative Engineering, The University of

Connecticut, Farmington, CT, USA

Paul Lee Department of Chemistry, Chemical Biology,

and Biomedical Engineering, Stevens Institute of

Technology, Hoboken, NJ, USA

Adnan Memic Center for Biomedical Engineering,

Department of Medicine, Brigham and Women’s

Hospital, Harvard Medical School, Boston, MA, USA

Harvard-MIT Division of Health Sciences and

Technology, Massachusetts Institute of Technology,

Cambridge, MA, USA

Center of Nanotechnology, King Abdulaziz University,

Jeddah, Saudi Arabia

Sara K. Murase Departament d’Enginyeria Química,

Universitat Politècnica de Catalunya, Barcelona, ESP

Ahmed A. Nada Department of Orthopaedic Surgery,

Institute for Regenerative Engineering, Raymond and

Beverly Sackler Center for Biomedical, Biological,

Physical and Engineering Sciences, The University of

Connecticut, Farmington, CT, USA

Rajaram K. Nagarale Department of Chemical

Engineering, Indian Institute of Technology Kanpur,

Uttar Pradesh, India

Dianna Y. Nguyen Department of Bioengineering, Materials

Research Institute, The Huck Institute of The Life sci￾ences, The Pennsylvania State University, PA, USA

Mehdi Nikkhah Center for Biomedical Engineering,

Department of Medicine, Brigham and Women’s

Hospital, Harvard Medical School, Boston, MA, USA

Harvard-MIT Division of Health Sciences and

Technology, Massachusetts Institute of Technology,

Cambridge, MA, USA

Meera Parthasarathy School of Chemical & Biotechnology,

SASTRA University, Centre for Nanotechnology &

Advanced Biomaterials, Thanjavur, Tamil nadu, India

Omathanu Perumal Department of Pharmaceutical

Sciences, College of Pharmacy, South Dakota State

University, Brookings, SD, USA

Jordi Puiggalí Departament d’Enginyeria Química,

Universitat Politècnica de Catalunya, Barcelona, ESP

Walid P. Qaqish Department of Biomedical Engineering,

The University of Akron, Akron, Ohio, USA

Daisy M. Ramos Department of Orthopaedic Surgery,

Department of Material Science and Engineering,

Institute for Regenerative Engineering, Raymond and

Beverly Sackler Center for Biomedical, Biological,

Physical and Engineering Sciences, The University of

Connecticut, Farmington, CT, USA

Department of Chemical, Materials and Biomedical

Engineering, University of Connecticut, CT, USA

Dina Rassias Biomedical Engineering Department,

Worcester Polytechnic Institute, Worcester, MA, USA

Tarun Saxena Department of Biomedical Engineering,

Georgia Institute of Technology, Atlanta, Georgia, USA

Swaminathan Sethuraman Centre for Nanotechnology

& Advanced Biomaterials, School of Chemical &

Biotechnology, Sastra University, Thanjavur, India

Kush N. Shah Department of Biomedical Engineering,

The University of Akron, Akron, Ohio, USA

Venkatram Prasad Shastri Hermann Staudinger Haus,

University of Freiburg, Freiburg, DEU

Namdev B. Shelke Department of Orthopaedic Surgery,

Institute for Regenerative Engineering, Raymond and

Beverly Sackler Center for Biomedical, Biological,

Physical and Engineering Sciences, The University of

Connecticut, Farmington, CT, USA

Anuradha Subramaniam Centre for Nanotechnology &

Advanced Biomaterials, Sastra University, Thanjavur,

India

Contributors xv

Xiaoyan Tang Department of Orthopaedic Surgery,

Department of Material Science and Engineering,

Institute for Regenerative Engineering, Raymond and

Beverly Sackler Center for Biomedical, Biological,

Physical and Engineering Sciences, The University of

Connecticut, Farmington, CT, USA

Shalumon Kottappally Thankappan Department

of Orthopaedic Surgery, Institute for Regenerative

Engineering, Raymond and Beverly Sackler Center for

Biomedical, Biological, Physical and Engineering Sciences,

The University of Connecticut, Farmington, CT, USA

Katelyn Tran Department of Chemistry, Chemical Biology,

and Biomedical Engineering, Stevens Institute of

Technology, Hoboken, NJ, USA

Richard T. Tran Department of Bioengineering, Materials

Research Institute, The Huck Institute of The Life sci￾ences, The Pennsylvania State University, PA, USA

Chandra M. Valmikinathan Global Surgery Group,

Johnson and Johnson, Somerville, NJ, USA

Yong Wang Department of Bioengineering, College of

Engineering, The Pennsylvania State University, PA, USA

Iwen Wu Department of Biomedical Engineering, Johns

Hopkins University; Translational Tissue Engineering

Center, Wilmer Eye Institute

Jonathan Johannes Wurth Institute for Macromolecular

Chemistry, University of Freiburg, Freiburg, Germany;

BIOSS – Centre for Biological Signalling Studies,

University of Freiburg, Freiburg, Germany

Zhiwei Xie Department of Bioengineering, Materials

Research Institute, The Huck Institute of The Life sci￾ences, The Pennsylvania State University, PA, USA

Jian Yang Department of Bioengineering, Materials

Research Institute, The Huck Institute of The Life sci￾ences, The Pennsylvania State University, PA, USA

Yuan Yin Biomedical Engineering Department, Worcester

Polytechnic Institute, Worcester, MA, USA

Xiaojun Yu Department of Chemistry, Chemical Biology,

and Biomedical Engineering, Stevens Institute of

Technology, Hoboken, NJ, USA

Yang H. Yun Dept. of Biomedical Engineering, University

of Akron, Akron, OH, USA

I am truly delighted to write the foreword for Natural and

Synthetic Biomedical Polymers edited by well-established

leaders and pioneers in the field, Professors Dr. Kumbar,

Dr. Laurencin, and Dr. Deng. This book should prove

extremely useful as a reference source for all those working

in the fields of polymer chemistry and physics, biomaterial

science, tissue engineering, drug delivery, and regenerative

medicine. Polymeric materials are routinely used in clinical

applications, ranging from surgical sutures to drug-eluting

devices to implants. In particular, implants and drug delivery

devices fabricated using biodegradable polymers provide the

significant advantage of being degraded and/or resorbed after

they have served their function. Yet, biomedical polymers

must satisfy several design criteria, including physical,

chemical, biomechanical, biological, and degradation

properties when serving as an active implant material.

Several natural and synthetic degradable polymers have been

developed and are used clinically today. However, a wide

range of new polymers, as well as modifications to existing

polymers, are constantly being developed and applied

to meet on-going and evolving challenges in biomedical

applications. For example, polymeric nanostructures,

implants, scaffolds, and drug delivery devices are allowing

unprecedented manipulation of cell-biomaterial interactions,

promotion of tissue regeneration, targeting of therapies, and

combined diagnostic and imaging modalities.

This timely book provides a well-rounded and articulate

summary of the present status of natural and synthetic

biomedical polymers, their structure and property rela￾tionships, and their biomedical applications including

regenerative engineering and drug delivery. Polymers that

are both synthetic and natural in origin have been widely

used as biomaterials for a variety of biomedical applications

and greatly impacted the advancement of modern medicine.

In this regard, 23 concise and comprehensive chapters are

prepared by experts in their fields from different parts of

the world. The chapters encompass numerous topics that

appear prominently in the modern biomaterials literature

and cover a wide range of traditional synthetic, natural, and

semi-synthetic polymers and their applications. In my opin￾ion, this book presents an excellent overview of the sub￾ject that will appeal to a broad audience and will serve as

a valuable resource to those working in the fields of poly￾mer science, tissue engineering, regenerative medicine, or

drug delivery. I believe that this textbook will be a welcome

addition to personal collections, libraries, and classrooms

throughout the world.

Kristi S. Anseth

Professor, Department of Chemical

and Biological Engineering,

University of Colorado

Foreword

xvii

1

Natural and Synthetic Biomedical Polymers

Copyright © 2014 Elsevier Inc. All rights reserved.

Chapter 1

1.1 INTRODUCTION

Polymers are the most versatile class of biomaterials,

being extensively used in biomedical applications such

as contact lenses, pharmaceutical vehicles, implantation,

artificial organs, tissue engineering, medical devices,

prostheses, and dental materials [1–3]. This is all due to

the unique properties of polymers that created an entirely

new concept when originally proposed as biomaterials.

For the first time, a material performing a structural ap￾plication was designed to be completely resorbed and be￾come weaker over time. This concept was applied for the

first time with catgut sutures successfully and, later, with

arguable results, on bone fixation, ligament augmenta￾tion, plates, and pins [4,5].

Current research on new and improved biodegradable

polymers is focused on more sophisticated biomedical appli￾cations to solve the patients' problems with higher efficacy

and least possible pains. One example is tissue engineering,

wherein biodegradable scaffolds seeded with an appropri￾ate cell type provide a substitute for damaged human tissue

while the natural process of regeneration is completed [6,7].

Another important application of biodegradable polymer

Chapter Outline

1.1 Introduction 1

1.2 Types of Polymerization 2

1.2.1 Addition Polymerization 2

1.2.2 Condensation Polymerization 3

1.2.3 Metathesis Polymerization 4

1.3 Techniques of Polymerization 4

1.3.1 Solution Polymerization 5

1.3.2 Bulk (Mass) Polymerization 5

1.3.3 Suspension Polymerization 5

1.3.4 Precipitation Polymerization 6

1.3.5 Emulsion Polymerization 6

1.4 Polymers: Properties, Synthesis, and Their Biomedical

Applications 6

1.4.1 Polycaprolactone 6

1.4.2 Polyethylene Glycol 7

1.4.3 Polyurethane 7

1.4.4 Polydioxanone or Poly-p-Dioxanone 8

1.4.5 Polymethyl Methacrylate 9

1.4.6 Polyglycolic Acid or Polyglycolide 9

1.4.7 Polylactic Acid or Polylactide 10

1.4.8 Polylactic-co-Glycolic Acid 11

1.4.9 Polyhydroxybutyrate 12

1.4.10 Polycyanoacrylates 13

1.4.11 Polyvinylpyrrolidone 13

1.4.12 Chitosan 13

1.4.13 Gelatin 14

1.4.14 Carrageenan 15

1.4.15 Hyaluronic Acid 17

1.4.16 Xanthan Gum 18

1.4.17 Acacia Gum 18

1.4.18 Alginate 19

1.5 Processing of Polymers for Biomedical Devices 19

1.5.1 Fabrication of Polymer Films 19

1.5.1.1 Solution Casting 20

1.5.1.2 Melt Pressing 20

1.5.1.3 Melt Extrusion 20

1.5.1.4 Bubble Blown Method 21

1.5.2 Spinning Industrial Polymers 21

1.5.2.1 Solution Spinning 22

1.5.3 Fabrication of Shaped Polymer Objects 24

1.5.3.1 Compression Molding 24

1.5.3.2 Injection Molding 25

1.5.3.3 Reaction Injection Molding 25

1.5.3.4 Blow Molding 25

1.5.3.5 Extrusion Molding 26

1.5.4 Calendaring 26

1.6 Future Perspectives 27

1.7 Conclusions 27

Mahadevappa Y. Kariduraganavar*

, Arjumand A. Kittur†

, Ravindra R. Kamble*

*

Department of Studies in Chemistry, Karnatak University, Dharwad, India

†

Department of Chemistry, SDM College of Engineering & Technology, Dharwad, India

Polymer Synthesis and Processing

2 Natural and Synthetic Biomedical Polymers

is in the gene therapy that provides a safer way of gene

delivery than use of viruses as vectors [8,9].

Recently, an implant prepared from biodegradable poly￾mer played a tremendous beneficial role in replacing the

stainless steel implant during the surgery [10]. This has

not necessitated a second surgical event for the removal. In

addition to this, the biodegradation may offer other advan￾tages. For example, a fractured bone, fixated with a rigid,

nonbiodegradable stainless steel implant, has a tendency for

refracture upon removal of the implant. The bone does not

carry sufficient load during the healing process, since the

load is mainly carried by the rigid stainless steel. However,

an implant prepared from biodegradable polymer can be en￾gineered to degrade at a rate that will slowly transfer load

to the healing bone [11]. Another exciting application for

which biodegradable polymers offer tremendous applica￾tions is the basis for the drug delivery, either as drug de￾livery system alone or in conjunction with functioning as

a medical device. In orthopedic applications, the delivery

of a polymer-bound morphogenic protein may be used to

speed up the healing process after a fracture or delivery of

an antibiotic may help to prevent osteomyelitis following

surgery [12–14]. Biodegradable polymers also make pos￾sible targeting of drugs into sites of inflammation or tumors.

Prodrugs with macromolecular carriers have also been used

for such purposes. The term prodrug has been coined to

describe a harmless molecule, which undergoes a reaction

inside the body to release the active drug. Polymeric pro￾drugs are obtained by conjugating biocompatible polymeric

molecules with appropriate drugs. Such macromolecular

conjugate accumulates positively in tumors, since the per￾meability of cell membranes of tumor cells is higher than

that of normal cells [1,15,16].

Polymers used as biomaterials can be naturally occur￾ring and synthetic or combination of both. Natural poly￾mers are abundant, usually biodegradable, and offer good

biocompatibility [11,17]. The biocompatibility of a poly￾mer depends on the specific adsorption of protein to the

polymer surface and the subsequent cellular interactions.

These interactions with the surrounding medium are gov￾erned mostly by the distribution of functional groups on

the surface of biomaterial. Several useful biocompatible

polymers of microbial origin are being produced from

natural sources by fermentation processes. They are non￾toxic and truly biodegradable [18]. Biodegradation is

usually catalyzed by enzymes and may involve both hy￾drolysis and oxidation. Aliphatic chains are more flexible

than aromatic ones and can easily fit into the active sites

of enzymes, and hence, they are easier to biodegrade.

Crystallinity hinders polymer degradation. Irregularities

in chain morphology prevent crystallization and favor

degradation [19].

Considering the significance and relevance of biode￾gradable polymers in the area of medical science, we have

made an attempt to discuss the different polymerizations and

their techniques employed for the preparation of polymers,

synthetic methods of both natural and synthetic polymers

including their properties and biomedical applications. At

the end of the chapter, the methods of polymer processing

for the preparation of films, objects, and fibers have also

been discussed.

1.2 TYPES OF POLYMERIZATION

Polymerizations are generally classified according to the

types of reactions involved in the synthesis [20,21]. There

are mainly three types of polymerizations.

1.2.1 Addition Polymerization

In this polymerization process, the addition polymers

are prepared from monomers without the loss of small

molecules. Usually, unsaturated monomers such as ole￾fins, acetylenes, aldehydes, or other compounds undergo

addition polymerization. It is also called chain-growth

polymerization since reactions are known to proceed

in a stepwise fashion by way of reactive intermedi￾ates. The process of polymerization is usually exother￾mic by 8-20 kcal/mol since a π-bond in the monomer

is converted to a sigma bond in the polymer. The reac￾tion quickly leads to a polymer with very high molecu￾lar weight. The most common and thermodynamically

favored chemical transformations of olefins are the addi￾tion reactions. Generally, these polymers can be prepared

using bulk, solution, suspension, and emulsion polymer￾ization techniques. Sometimes cross-linking can also be

achieved using monomers with two double bonds.

Many well-known thermoplastics are the addition-type

polymers. Figure 1.1 illustrates some addition polymeriza￾tion processes.

The properties and biomedical applications of some

of the important addition polymers are given in Table 1.1

[22,23].

nCH2=CH2 CH2CH2

nCH2=CHCN CH2CHCN

nCH2=CHPh CH2CHPh

nCH2=C CH2C

n

n

n

n

CH3

CH3

CH3

CH3

a Polyethylene

Polystyrene

Polyacrylonitrile

Polyisobutylene

b

c

d

FIGURE 1.1 Common examples of addition polymerization.

Chapter | 1 Polymer Synthesis and Processing 3

1.2.2 Condensation Polymerization

It is a process in which two different monomers join to￾gether by the elimination of small molecules like water, am￾monia, methanol, and HCl. It is also known as step-growth

polymerization. The type of end product resulting from a

condensation polymerization is dependent on the number of

functional end groups of the monomer that can react. The

monomers that are involved in condensation polymeriza￾tion are not the same as those in addition polymerization.

They have two main characteristics: these monomers have

functional groups like OH, NH2

, or COOH instead of

double bonds and each monomer has at least two reactive

sites. In this process, high molecular weight can be attained

only at high conversions. Most of the reactions have high

ΔEa

and hence heating is usually required.

Monomers with only one reactive group terminate a

growing chain and thus give end products with a lower mo￾lecular weight. Linear polymers are created using monomers

with two reactive end groups, and monomers with more than

two end groups give three-dimensional polymers that are

cross-linked. Dehydration synthesis often involves joining

monomers with an OH group and a freely ionizable H on

either end (such as a hydrogen from the NH2

in nylon or

proteins). Normally, two or more different monomers are

used in the reaction. The bonds between the hydroxyl group,

the hydrogen atom, and their respective atoms break form￾ing water from the hydroxyl and hydrogen and the polymer.

Polyester is created through ester linkages between

monomers, which involve the functional groups like car￾boxyl and hydroxyl (an organic acid and an alcohol mono￾mer). Nylon is another common condensation polymer,

which can be prepared by reacting diamines with carboxyl

derivatives. In this example, the derivative is a dicarboxylic

acid, but buta-diacyl chlorides are also used. Another ap￾proach used is the reaction of difunctional monomers with

one amine and one carboxylic acid group on the same mol￾ecule. An example of condensation polymerization is given

in Figure 1.2.

The carboxylic acids and amines link to form peptide

bonds, also known as amide groups. Proteins are the con￾densation polymers made from amino acid monomers.

Carbohydrates are also condensation polymers made

from sugar monomers such as glucose and galactose.

Condensation polymerization is occasionally used to form

simple hydrocarbons. This method, however, is expensive

and inefficient, so the addition polymer of ethene, i.e., poly￾ethylene, is generally used. Condensation polymers, unlike

addition polymers, may be biodegradable. The peptide or

ester bonds between monomers can be hydrolyzed by acid

catalysts or bacterial enzymes breaking the polymer chain

into smaller pieces. The most commonly known condensa￾tion polymers are proteins and fabrics such as nylon, silk,

or polyester.

As before, a water molecule is removed, and an amide

linkage is formed. An acid group remains on one end of

the chain, which can react with another amine monomer.

Similarly, an amine group remains on the other end of the

chain, which can react with another acid monomer. Thus,

monomers can continue to join by amide linkages to form

a long chain. Because of the type of bond that links the

monomers, this polymer is called a polyamide. The poly￾mer made from these two six-carbon monomers is known

as nylon 6,6 (Figure 1.3).

Similarly, a carboxylic acid monomer and an alcohol

monomer can join together to form an ester linkage fol￾lowed by a loss of water molecule. The monoester thus

TABLE 1.1 Properties and Biomedical Uses of Some Common Addition Polymers

Polymer Name(s) Properties Biomedical Uses

Polyethylene low density (LDPE) Soft, waxy solid Films, blood bags

Polyethylene high density (HDPE) Rigid, translucent solid Hip joints

Polyvinyl chloride (PVC) Strong rigid solid Reinforcement of artery

Polytetrafluoroethylene (PTFE, Teflon) Resistant, smooth solid Heart pumps, reinforcement of

artery and blood vessels

Polymethyl methacrylate (PMMA, Lucite, and Plexiglas) Hard, transparent solid Contact lenses, heart pumps

NH2

N

H

N

H

n HOOC R COOH + n H2N + R 2H2O

R

O O

R

FIGURE 1.2 An example of condensation polymerization.

4 Natural and Synthetic Biomedical Polymers

formed reacts with another monoester and subsequent reac￾tions yield polyethylene terephthalate (PET). The reaction

scheme is shown in Figure 1.4.

Since the monomers are joined by ester linkages, the re￾sulting polymer is called polyester. The polycondensation

can be achieved in melt, solution, and at interfacial bound￾ary between two liquids in which the respective monomers

are dissolved. It is a slow step addition process and molecu￾lar weight is >1,00,000 and highly dependent on monomer

stoichiometry. The addition of little amount of tri- or multi￾functional monomers develops extensive cross-linking.

1.2.3 Metathesis Polymerization

Olefin metathesis can be used for the synthesis of polymer,

wherein carboncarbon double bond in an olefin is broken

and then rearranged in a statistical fashion to form poly￾mer. In other polymerization processes, once vinyl mono￾mer is converted into polymer, the carboncarbon double

bond does not remain in the polymer backbone. However,

in metathesis polymerization, the carboncarbon double

bond remains in the polymer backbone chain and such

polymers are called polyalkenamers [24]. The mechanism

of metathesis polymerization is illustrated in Figure 1.5.

The commonly accepted mechanism for the olefin me￾tathesis reaction was proposed by Chauvin. It involves a

[2+2] cycloaddition reaction between transition metal al￾kylidene complex and the olefin to form an intermediate

metallocyclobutane. This metallocycle then breaks up in the

opposite fashion to afford a new alkylidene and new olefin.

If this process is repeated, eventually, an equilibrium mix￾ture of olefins will be obtained.

The following are the two different types of metathesis

polymerization [25]:

(a) Acyclic diene metathesis (ADMET) polymerization

(b) Ring-opening metathesis polymerization (ROMP)

(a) ADMET polymerization ADMET starts with an acy￾clic diene such as 1,5-hexadiene and ends up in a

polymer with a double bond in the backbone chain

and ethylene as a by-product. The reaction is shown

in Figure 1.6.

(b) ROMP In this polymerization, a cyclic olefin such as

cyclopentene is used to make a polymer that does not

have cyclic structures in its backbone and therefore

it is called ROMP. Similarly, norbornene is polymer￾ized by ROMP to get polynorbornene (Figure 1.7).

Using ROMP, molecules like endo-dicyclopentadiene

can also be polymerized to get a polymer with a cy￾clic olefin in a pendant group and the product is called

polydicyclopentadiene. This is used to make big things

in one piece. This can also undergo vinyl polymeriza￾tion to give a cross-linked thermoset material.

1.3 TECHNIQUES OF POLYMERIZATION

Based on the different methods of preparation, the

polymerization techniques can be classified broadly into

Adipic acid Hexamethylene diamine

Nylon 6,6

NH2

n H2N

O

O

O

O

HO n OH +

H

N

N

H

FIGURE 1.3 Preparation of nylon 6,6 as an example of condensation polymerization.

O

HO

O

O O

O

O O

O

O

O n

O

O

O

OH

HO

HO

O

OH

−H2O

Terephthalic acid

Monoester

Polyethylene terephthalate

Polymerization

Ethylene glycol

OH

FIGURE 1.4 Preparation of polyethylene terephthalate as an example of

condensation polymerization.

Chapter | 1 Polymer Synthesis and Processing 5

homogeneous and heterogeneous [26–28]. For homoge￾neous process, the diluted or pure monomers are added

directly to one another and the reaction occurs in the me￾dia created when mixing the reactants. With heterogeneous

process, a phase boundary exists, which acts as an inter￾phase where the reaction occurs.

1.3.1 Solution Polymerization

It is an industrial polymerization technique, wherein a

monomer is dissolved in a nonreactive solvent that contains

a catalyst. In this method, both the monomer and the result￾ing polymer are soluble in the solvent. The heat released

during the reaction is absorbed by the solvent and thus re￾duces the reaction rate. Once the maximum or desired con￾version is reached, excess solvent is to be removed in order

to obtain the pure polymer. The products obtained by this

method are relatively low molecular weights because of the

possibility of chain transfer. This process is suitable for the

production of wet polymers since the removal of excess sol￾vent is difficult and also the solvent is occluded and firmly

traps the polymer. Therefore, this polymerization technique

is applied when solutions of polymers are required (for

ready-made use) for technical applications such as lacquers,

adhesives, and surface coatings.

This process is used in the production of sodium poly￾acrylate, a superabsorbent polymer and neoprene used in

disposable diapers and wetsuits, respectively. The polymers

produced using this method are generally polyacrylonitrile

(PAN), polyacrylic acid, and polytetrafluoroethylene.

1.3.2 Bulk (Mass) Polymerization

Bulk polymerization occurs within the monomer itself. The

reaction is catalyzed by additives such as initiator and trans￾fer agents under the influence of heat or light. Since this

polymerization process is highly exothermic, it is difficult

to control and hence the polymer obtained is generally of

nonuniform molecular mass distribution. However, molec￾ular-weight distribution can be easily changed by the use of

chain transfer agent. The temperature and pressure can also

be varied to control the properties of the final polymer. If

the polymer is insoluble in its monomer, it is obtained as a

powdery or porous solid. Since the recipe contains primarily

the monomers, the polymer formed is usually pure. This is

suitable for liquid (or liquefiable) monomers, which can be

carried in batch or continuous mode. The product obtained

has higher optical clarity, which is suitable for casting es￾pecially for clear products (e.g., polymethyl methacrylate

(PMMA) films). Low-molecular-weight polymers can also

be prepared by this method for adhesives, plasticizers, and

lubricants.

1.3.3 Suspension Polymerization

It is a heterogeneous radical polymerization process. Step￾growth polymers such as polyesters are manufactured us￾ing this technique. In this polymerization, the monomer

containing initiator, modifier, etc., is dispersed in a solvent

(generally water) by vigorous stirring. The monomer and

initiator are insoluble in the liquid phase, so they form beads

within the liquid matrix. A suspension agent such as PVA or

methyl cellulose is usually added to stabilize the monomer

droplets and hinder monomer drops from coming together.

The reaction mixture usually has a volume ratio of monomer

to liquid phase of 0.10-0.50. A major advantage is that heat

transfer is very efficient and the reaction is therefore easily

controlled. The reactions are usually carried out in a stirred

tank reactor that continuously mixes the solution using tur￾bulent pressure or viscous shear forces. The stirring action

helps to keep the monomer droplets separated and creates

R

R

MLn

MLn LnM

R R R  R

R

R R 

FIGURE 1.5 Mechanism of metathesis polymerization.

Catalyst

n

+ CH2= CH2

FIGURE 1.6 The reaction of acyclic diene metathesis polymerization.

n

n

FIGURE 1.7 The reaction of ring-opening metathesis polymerization.

6 Natural and Synthetic Biomedical Polymers

a more uniform suspension, which leads to a more narrow

size distribution of the final polymer beads. The beads look

like pearls, hence the name pearl polymerization. This po￾lymerization is not applicable to tacky polymers such as

elastomers due to the tendency of agglomerations.

This process is used in the production of many commer￾cial resins, including polyvinyl chloride (PVC), a widely

used plastic; styrene resins including polystyrene, expanded

polystyrene, and high-impact polystyrene; and PAN and

PMMA.

1.3.4 Precipitation Polymerization

It is a heterogeneous polymerization process that begins

initially as a homogeneous system in the continuous

phase where the monomer and the initiator are com￾pletely soluble, but upon initiation, the formed polymer

is insoluble and thus precipitates. The precipitated poly￾mer can be separated in the form of a gel or powder by

centrifugation or simple filtration. The degree of polym￾erization is high as there is no problem in heat dissipa￾tion. Polyvinyl esters and polyacrylic esters are obtained

commercially using hydrocarbons as solvents. PAN is

prepared using water as solvent.

1.3.5 Emulsion Polymerization

It is a type of radical polymerization in which the liquid

monomer is dispersed in an insoluble liquid leading to an

emulsion. The most common type of emulsion polym￾erization is an oil-in-water emulsion, wherein droplets of

monomer (the oil) are emulsified (with surfactants) in a

continuous phase of water. Water soluble polymers, such

as certain polyvinyl alcohols or hydroxyethyl celluloses,

can also be used to act as emulsifiers/stabilizers. The po￾lymerization takes place in the latex particles that form

spontaneously in the first few minutes of the process. These

latex particles are typically 100 nm in size and are made of

many individual polymer chains. The particles are stopped

from coagulating with each other because each particle is

surrounded by the surfactant (soap); the charge on the sur￾factant repels other particles electrostatically. When water￾soluble polymers are used as stabilizers instead of soap, the

repulsion between particles arises as these water-soluble

polymers form a hairy layer around a particle that repels

other particles, because pushing particles together would

involve in compressing these chains. Since polymer mol￾ecules are contained within the particles, the viscosity of

the reaction medium remains close to that of water and is

not dependent on molecular weight. Emulsion polymeriza￾tions are designed to operate at high conversion of mono￾mer to polymer. This can result in significant chain transfer

to polymer. For dry (isolated) polymers, water removal is an

energy-intensive process.

Emulsion polymerization technique is used to manufac￾ture several commercially important polymers. Many of these

polymers are used as solid materials and must be isolated from

the aqueous dispersion after polymerization. In other cases, the

dispersion itself is the end product. A dispersion resulting from

the emulsion polymerization technique is often called latex

(especially if derived from a synthetic rubber) or an emulsion

(even though emulsion strictly speaking refers to a dispersion

of an immiscible liquid in water).

1.4 POLYMERS: PROPERTIES, SYNTHESIS,

AND THEIR BIOMEDICAL APPLICATIONS

Under this section, general properties, different synthetic

methods, and biomedical applications of the most com￾monly used polymers are discussed.

1.4.1 Polycaprolactone

It is biodegradable polyester with a low melting point

around 60°C and a glass transition temperature of about

−60 °C. Polycaprolactones (PCLs) impart good water, oil,

solvent, and chlorine resistance to the polyurethanes (PUs)

produced. It is commonly used in the manufacture of spe￾cialty PUs. PCL is degraded by hydrolysis of its ester link￾ages in physiological conditions and has therefore received

a great deal of attention for use as an implantable biomate￾rial. It is especially interesting for the preparation of long￾term implantable devices, owing to its degradation, which is

even slower than that of polylactide.

This polymer is often used as an additive for resins

to improve their processing characteristics and their end￾use properties (e.g., impact resistance). Being compat￾ible with a range of other materials, PCL can be mixed

with starch to lower its cost and increase biodegradabil￾ity or it is also added as a polymeric plasticizer to PVC.

PCL was approved by the Food and Drug Administration

(FDA) in specific applications used in the human body

as a drug delivery device and surgical suture (sold under

the brand name Monocryl) [29–31]. It is being investi￾gated as a scaffold for tissue repair via tissue engineer￾ing and guided bone regeneration membrane. It has been

used as the hydrophobic block of amphiphilic synthetic

block copolymers used to form the vesicle membrane of

polymersomes. In odontology or dentistry (as compos￾ite named Resilon), it is used as a component of night

guards (dental splints) and in root canal filling. It per￾forms like gutta-percha, has the same handling proper￾ties, and for retreatment purposes may be softened with

heat or dissolved with solvents like chloroform. The ma￾jor difference between the PCL-based root canal filling

material (Resilon and Real Seal) and gutta-percha is that

the PCL-based material is biodegradable but the gutta￾percha is not.