Biodegradable Polymers in Clinical Use and Clinical Development E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 1294

Veröffentlichungsjahr: 2011

Beschreibung

This book focuses on biodegradable polymers that are already in clinical use or under clinical development. Synthetic and natural polymers will be included. This excludes polymers that have been investigated and did not reach clinical development.

The purpose of this book is to provide updated status of the polymers that are clinical use and those that are now being developed for clinical use and hopefully will reach the clinic during the next 5 years. The book provides information that of interest to academics and practicing researchers including chemists, biologists and bioengineers and users: physicians, pharmacists.

Leseprobe

CONTENTS

Contributors

Preface

Part I: General

Chapter 1: Biodegradable Polymers in Drug Delivery

1.1 Introduction

1.2 Types of Biodegradable Polymers

1.3 Biodegradation Patterns

1.4 Overview of Different Products Based on Biodegradable Polymers

1.5 Polymer Selection for Biomedical Application

1.6 Future Prospects

References

Part II: Biodegradable Polymers of Natural Origin: Protein-Based Polymers

Chapter 2: Collagen

2.1 Introduction

2.2 Occurrence

2.3 Functions

2.4 Structure

2.5 Types and Properties

2.6 Biosynthesis of Collagen

2.7 Degradation

2.8 Collagen Disorders

2.9 Source

2.10 Clinical Applications of Collagen

References

Chapter 3: Properties and Hemostatic Application of Gelatin

3.1 Introduction

3.2 Gelatin Structure

3.3 Uses of Gelatin

3.4 Manufacturing of Gelatin

3.5 Rheological Properties of Gelatin

3.6 Hemostatic Application of Gelatin

3.7 Conclusion

References

Part III: Biodegradable Polymers of Natural Origin: Polysaccharides

Chapter 4: Chitosan and Its Derivatives in Clinical Use and Applications

4.1 Introduction

4.2 Cationic Nature of Chitosan and Its Implications in Therapeutics

4.3 Safety of Chitosan

4.4 Chemical Modifications of Chitosan

4.5 Hydrophobically Modified Chitosan

4.6 Quaternization of Chitosan

4.7 Clinical Applications of Chitosan and Its Derivatives

4.8 Penetration Enhancers in Vaccine and Drug Delivery

4.9 Gene Delivery Vehicle

4.10 Other Delivery Systems

4.11 Regenerative Medicine

4.12 Hydrogels

4.13 Chitosan as A Coating Material on Drugs

4.14 Biosensor

4.15 Antihyperlipidemic Effect

4.16 Challenges

References

Chapter 5: Clinical Uses of Alginate

5.1 Introduction

5.2 Sources

5.3 Structure

5.4 Alginate Sources and Production

5.5 Procedures for Preparation of Alginate Solution

5.6 Mechanism of Alginate Gelation

5.7 Alginate Gel Preparation

5.8 Clinical Applications, Preclinical Experiments and Possible Future Options for Alginate Implantation

References

Chapter 6: Dextran and Pentosan Sulfate – Clinical Applications

6.1 Dextran

6.2 Pentosan Polysulfate

References

Chapter 7: Arabinogalactan in Clinical Use

7.1 Introduction

7.2 Natural Killer (NK) Cytotoxicity

7.3 Arabinogalactan Proteins (AGPS)

7.4 Medicinal Applications

7.5 Side Effects and Toxicity

7.6 Conclusions

References

Part IV: Biodegradable Polymers of Natural Origin: Polyesters

Chapter 8: Polyhydroxyalkanoate

8.1 Introduction

8.2 Polyhydroxyalkanoate

8.3 Current Applications of PHA

8.4 In Vitro Tissue Response and Degradation

8.5 In Vivo Assessment and Potential Applications

8.6 Clinical Study

8.7 Electrospinning

8.8 Patents

8.9 Outlook

Acknowledgment

References

Part V: Synthetic Biodegradable Polymers

Chapter 9: Lactide and Glycolide Polymers

9.1 Introduction

9.2 Synthesis, Processing, and Properties

9.3 Toxicity and Safety

9.4 Drug Delivery Applications

9.5 Summary

References

Chapter 10: Polyanhydrides-Poly(CPP-SA), Fatty-Acid-Based Polyanhydrides

10.1 Introduction

10.2 Importance of Polyanhydrides

10.3 Types of Polyanhydrides

10.4 Synthesis of Polyanhydrides

10.5 Biocompatibility and Toxicity of Polyanhydrides

10.6 Polyanhydrides and Disease Conditions

References

Chapter 11: Poly(ε-Caprolactone-co-Glycolide): Biomedical Applications of a Unique Elastomer

11.1 Introduction

11.2 Monocryl Suture

11.3 Suture Coatings

11.4 Dermal Tissue Repair

11.5 Buttressing Material

11.6 Summary

References

Chapter 12: Medicinal Applications of Cyanoacrylate

12.1 Introduction

12.2 Current Need in Modern Surgical Approaches

12.3 Important Applications of Cyanoacrylates

12.4 Surgical Applications of Cyanoacrylate Adhesives

12.5 Conclusion

References

Chapter 13: Polyethylene Glycol in Clinical Application and PEGylated Drugs

13.1 Introduction

13.2 Chemistry of PEGylation

13.3 PEGylation Technology and PEGylated Drugs

13.4 Safety and Toxicity Data of PEGylated Drugs

13.5 Clinical Application of PEG

13.6 Conclusions

References

Part VI: Inorganic Polymers

Chapter 14: Calcium-Phosphate-Based Ceramics for Biomedical Applications

14.1 Introduction

14.2 Chemistry

14.3 Toxicity and Safety

14.4 Clinical Applications

14.5 Summary

References

Part VII: Biodegradable Polymers for Emerging Clinical Uses

Chapter 15: Biocompatible Polymers for Nucleic Acid Delivery

15.1 Introduction

15.2 Cationic Polymers

15.3 Synthetic Noncondensing Polymers

15.4 siRNA Delivery Polymers

15.5 Clinical Development of Polymeric Delivery Systems

References

Bibliography

Chapter 16: Biodegradable Polymers for Emerging Clinical Use in Tissue Engineering

16.1 Tissue Engineering

16.2 Biodegradable Polymers Used in Tissue Engineering

16.3 Major Applications of Biodegradable Polymers in Tissue Engineering

16.4 Clinical Applications

16.5 Advances in Discovery of Need-Specific Polymeric Biomaterials and Biomaterial Design

16.6 Conclusion

References

Chapter 17: Injectable Polymers

17.1 Introduction

17.2 Chemistry of In Situ Forming Materials

17.3 Design Considerations for Injectable Materials

17.4 Injectable Polymers in The Clinic and Clinical Development

17.5 Case Study: Chondux

17.6 Conclusion

References

Part VIII: IPR Aspects of Biodegradable Polymers

Chapter 18: Global Patent and Technological Status of Biodegradable Polymers in Drug Delivery and Tissue Engineering

18.1 Introduction

18.2 Methods

18.3 Review of Patents Relating to Polymers in Drug Delivery and Tissue Engineering

18.4 Natural Polymers

18.5 Synthetic Polymers

18.6 Conclusion

References

Index

Copyright © 2011 by John Wiley & Sons, Inc. All rights reserved.

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Library of Congress Cataloging-in-Publication Data:

Biodegradable Polymers in Clinical Use and Clinical Development / edited by Abraham J. Domb, Neeraj Kumar, and Aviva Ezra.

p. cm

Includes index.

ISBN 978-0-470-42475-9 (hardback)

1. Polymers in medicine. 2. Biodegradable plastics. I. Domb, A. J. (Abraham J.), editor of compilation. II. Jain, Jay Prakash. Biodegradable polymers in drug delivery.

R857.P6B537 2011

610.28′4–dc22

2010043471

oBook ISBN: 9781118015810

ePDF ISBN: 9781118015797

ePub ISBN: 9781118015803

CONTRIBUTORS

Khursheed Anwer, EGEN, Inc., Huntsville, Alabama

Parikshit Bansal, Intellectual Property Right (IRR) Cell, Department of Pharmaceutical Management, National Institute of Pharmaceutical Education and Research (NIPER), Punjab, India

Kesaven Bhubalan, Department of Marine Science, Faculty of Maritime Studies and Marine Science, Universiti Malaysia Terengganu, Terengganu, Malaysia

Ravikumar M. Borade, Department of Chemistry, Government Arts and Science College, Aurangabad, Maharashtra, India

Helen Burt, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada

Kevin Cooper, Aruna Nathan, Murty Vyakarnam, Advanced Technologies and Regenerative Medicine, Somerville, NJ.

Abraham J. Domb, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel

Jennifer H. Elisseeff, Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland

Kalpna Garkhal, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Punjab, India

Samuel Gilchrist, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada

Diana Ickowicz, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel

Ashok E. Jadhav, Organic Chemistry Synthesis Laboratory, Dnyanopasak College, Maharashtra, India

Bhaskar S. Jadhav, Department of Chemistry, Deogiri College, Maharashtra, India

Jay Prakash Jain, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Punjab, India

A. Jayakrishnan, Department of Biotechnology, Indian Institute of Technology, Chennai, India

Bhimrao C. Khade, Organic Chemistry Synthesis Laboratory, Dnyanopasak College, Maharashtra, India

Wahid Khan, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Punjab, India

Kiran R. Kharat, Department of Biotechnology, Deogiri College, Aurangabad, Maharashtra, India

Uma Maheswari Krishnan, Center of Nanotechnology & Advanced Biomaterials, School of Chemical & Biotechnology, SASTRA University, Tamil Nadu, India

Neeraj Kumar, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Punjab, India

Babasaheb A. Kushekar, Department of Chemistry, Deogiri College, Maharashtra, India

Cato T. Laurencin, The University of Connecticut, Farmington, CT.

Wing-Hin Lee, Ecobiomaterial Research Laboratory, School of Biological Sciences, Universiti Sains Malaysia, Malaysia

Kevin Letchford, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada

Kevin W.-H. Lo, The University of Connecticut, Farmington, CT.

Qing Lv, The University of Connecticut, Farmington, CT.

Norman A. Marcus, Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland

Anupama Mittal, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Punjab, India

Lakshmi Nair, The University of Connecticut, Farmington, CT.

Amos Nussinovitch, Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel

Udi Nussinovitch, Department of Medicine B, Chaim Sheba Medical Center, Tel Hashomer, Israel

Ramu Parthasarathy, Department of Biotechnology, Indian Institute of Technology, Chennai, India

Rajendra P. Pawar, Department of Chemistry, Deogiri College, Aurangabad, Maharashtra, India

David Plackett, Risø National Laboratory for Sustainable Energy, Technical University of Denmark, Roskilde, Denmark

Archana A. Sawale, Department of Chemistry, Viva College, Virar (W), Dist. Thane, Maharashtra, India

Swaminathan Sethuraman, Center of Nanotechnology & Advanced Biomaterials, School of Chemical & Biotechnology, SASTRA University, Tamil Nadu, India

Anders Södergard, Abo Akademi Univerisity, Laboratory of Polymer Technology, Turku, Finland

Jeff Sparks, EGEN, Inc., Huntsville, Alabama

Teerapol Srichana, Drug Delivery System Excellence Center, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hatyai, Songkla, Thailand

Anuradha Subramanian, Center of Nanotechnology & Advanced Biomaterials, School of Chemical & Biotechnology, SASTRA University, Tamil Nadu, India

Kumar Sudesh, Ecobiomaterial Research Laboratory, School of Biological Sciences, Universiti Sains Malaysia, Malaysia

Tan Suwandecha, Drug Delivery System Excellence Center, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hatyai, Songkla, Thailand

Sumangala B. Tathe, Organic Chemistry Synthesis Laboratory, Dnyanopasak College, Maharashtra, India

Jalinder Totre, Institute for Drug Research, School of Pharmacy, The Hebrew University, Jerusalem, Israel

Shimon A. Unterman, Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland

Kirthanashri Srinivasan Vasanthan, Center of Nanotechnology & Advanced Biomaterials, School of Chemical & Biotechnology, SASTRA University, Tamil Nadu, India

Shalini Verma, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Punjab, India

Deepak Yadav, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Punjab, India

Wubante Yenet, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Punjab, India

PREFACE

The use of biodegradable polymers has been increasing in recent years, specifically toward various biomedical applications as these materials not only serve the desired purpose but also get eliminated from the body due to their biodegradable nature. Ideally, a material should possess specific physical, chemical, biological, functional, biomechanical, and degradation properties that fit a particular biomedical application. Biodegradable polymers have been used as surgical aids, extended-release drug carriers, and as scaffolds for tissue engineering, to name a few applications. Traditional biodegradable medical devices such as orthopaedic pins and nails, fixation plates, suture nets, filaments, and hemostatic sponges, have been used for decades with few modifications. However, recent advances in drug delivery, tissue engineering, gene therapy, and medical devices have resulted in an increased need for biopolymers with tailored properties. It should be noted that introducing new polymeric devices or drug delivery systems requires extensive clinical development, which may take several years and involve a significant financial investment. Thus, the trend has been to rely on varying compositions and modifications of clinically used biodegradable polymers. Considering the importance of such an area, this new reference text, Biodegradable Polymers in Clinical Use and Clinical Development, focuses on biodegradable polymers and their importance in biomedical research and presents their clinical status and development scenario along with their patent landscape. This book has been divided into eight parts based on different types of biodegradable polymers and their applications. Every attempt has been made to exclude the polymers that have not yet reached clinical application.

Part I provides a brief overview of different classes of biodegradable polymers elaborated upon in the book with an emphasis on drug delivery, detailing their key features and degradation patterns. Polymer selection criteria for specific biomedical applications have also been discussed. Additionally, an overview of different products based on biodegradable polymers is provided.

There are two major classes of biodegradable polymers, i.e. natural and synthetic, where natural polymers can be further classified based on their source of generation. Natural polymers are discussed in Parts II through IV. Part II discusses two main protein-based polymers of natural origin, namely, collagen and gelatin. The chapters focus on detailing their structure, occurrence, types, properties, manufacturing processes, degradation, and clinical applications.

Part III focuses on polysaccharide-based polymers of natural origin. A chapter on chitosan and its derivatives highlights its role as biosensor, permeation enhancer, delivery vehicle, tissue-engineering scaffold, and wound-healing material. Another chapter focuses on various sources, clinical applications, preclinical experiments, and possible future options for alginates. Furthermore, dextran, pentosan sulphate, and arabinogalactans are detailed in terms of their occurrence, structure, biochemistry, chemical nature, pharmacokinetics, side effects and toxicity, and medicinal applications.

Polyhydroxyalkanoates are discussed in Part IV, focusing on their production, characterization, and current applications in the medical field. Results from in vitro and in vivo efficacy studies are highlighted along with insights on toxicity and biocompatibility. Also, a patent landscape is provided.

Furthermore, Part V details important synthetic biodegradable polymers used in clinical settings. A chapter is dedicated specifically to the use of lactide and glycolide polymers and their copolymers in drug delivery applications, detailing their synthesis, processing, and properties vis-a-vis toxicity and safety considerations. Another chapter discusses the use of polyanhydrides in localized delivery with special attention to their degradability behavior, toxicological profile, uses in different disease conditions, and recent advances in the medical field. Also, synthesis, physicochemical characteristics, and biomedical applications of poly(ε-caprolactone-co-glycolide) copolymers and their applications as monocryl sutures, suture coatings, dermal tissue repair agents, and buttressing materials are detailed. This part also includes chapters on polycyanoacrylates and PEGylation technology, PEGylated drugs, chemistry, safety and toxicity of PEGylation, and applications of PEG at the clinical level and in the market.

Part VI deals with biomedical applications of calcium phosphate-based ceramics where synthesis, characterization, and properties of calcium phosphate materials are discussed. Moreover, the biocompatibility and toxicity profiles are reviewed along with a summary on some of the clinical results and commercially available calcium phosphate products.

Emerging clinical uses of biodegradable polymers are dealt with in Part VII, where a chapter focuses on polymers described for nucleic acid delivery, showing promising in vivo activity. A description of the structural design, physicochemical properties, and preclinical evaluation of different polymeric carriers and progress in clinical development is also provided. A separate chapter has been added focusing on applications of biodegradable polymers in tissue engineering, with a major focus on clinical applications thereof. The chapter compiles biodegradable polymer-based products currently under clinical trials or in the market for tissue engineering applications and also discusses the advances in discovery of need-specific polymeric biomaterials and biomaterial design.

Additionally, clinical use and applications of various injectable polymers of both natural and synthetic origin are discussed and offer insight into the underlying chemistry and design of in situ forming materials. The relevant design considerations affecting material properties and functionality are described along with highlights of possible future trends in the field.

Part VIII discusses the aspects of biodegradable polymers relating to intellectual property rights. It was felt that inclusion of patent database search would be useful to researchers in giving an overview of the technological developments and innovations that have taken place on a global level. This section may serve as a useful guide and reference chapter for research as it gives an overview of the innovations and technological challenges, and it also supplies a global map of the players involved, that is, industry and academia working on the applications of biodegradable polymers in drug delivery and tissue engineering.

Given the history of research and development in the applications and use of biodegradable polymers, it seems certain that new modifications in existing polymers and a wide variety of new polymers used in drug delivery and other biomedical applications will emerge in the coming years. The readers of this text are expected to have a broad base of backgrounds ranging from the basic sciences to more applied disciplines. Keeping this in mind, each section is planned such that it provides an overview of the specific subject and also goes into a detailed discussion with extensive references. With these details, the book will be valuable to both novices and experts. We trust that this in-depth coverage shall assist recent inductees to the subject of biodegradable polymers for various biomedical applications.

Lastly, and most importantly, the editors are thankful to all the internationally recognized authors who have played a vital role in making this book a reality through their contributions.

PART I

GENERAL

CHAPTER 1

BIODEGRADABLE POLYMERS IN DRUG DELIVERY

JAY PRAKASH JAIN,1 WUBEANTE YENET AYEN,1 ABRAHAM J. DOMB,2 and NEERAJ KUMAR1

1Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab, India

2Institute for Drug Design, Medicinal Chemistry, School of Pharmacy - Faculty of Medicine, The Hebrew University, Jerusalem, Israel

CONTENTS

1.1 Introduction

1.2 Types of Biodegradable Polymers

1.3 Biodegradation Patterns

1.4 Overview of Different Products Based on Biodegradable Polymers

1.5 Polymer Selection for Biomedical Application

1.6 Future Prospects

References

1.1 INTRODUCTION

Polymers have become an indispensible part of daily life. Biodegradable polymers are of special interest because they do not accumulate in nor harm the environment and thus can be considered “green” [1–3]. The use of biodegradable polymers has increased in the vast array of application, but it is staggering in its use in biomedical applications. A whole new genera of “polymer therapeutics” has developed because of the wide applicability of these polymers, which includes but is not limited to their function in pharmacological uses, mechanical support, mechanical barrier, artificial tissue/organs, preparation of produrgs, and as carriers for cells, drugs, and the like [4–15] with and without targeting. These functions can also be executed by nonbiodegradable devices, but such devices would permanently remain in biological tissues if not removed surgically. Because of the inherent difficulty in retrieving small-scale devices from tissues, it is advantageous to use biodegradable polymers that would naturally degrade and disappear in tissues over a desired period of time [16, 17].

In addition, the most important criteria for polymers that should be considered is their toxicological profiles. The polymer and any of its degradation products should not invoke any unacceptable toxicity and immune response. General criteria for selecting a polymer for use as a degradable biomaterial are to match the mechanical properties and the degradation rate to the needs of the application, shelf life/stability, processability, cost, and the like [1, 2, 18].

Biodegradable polymers can be either natural or synthetic. In general, synthetic polymers offer greater advantages over natural ones as they can be tailored to give a wider range of possibilities with a variety of properties. Some of the natural polymers have functional groups suitable for applications such as tissue engineering and are less prone to produce toxic effects. However, the presence of such functional groups and contaminants present in the material of natural origin may produce undesirable immunoligcal effects [19–21]. On the other hand, synthetic polymers are available with a wide range of chemical linkages that can greatly affect their degradation and other derived properties. To obtain an intermediate property, two or more polymers can be blended or chemically linked (copolymerized) [1, 22]. This latter approach has basically attracted a lot of attention because of the possibility of generating polymers with desired properties without limitations such as phase separation.

To date, due to the versatility of polymeric materials, specifically biodegradable ones, they are rapidly replacing other biomaterial classes, such as metals, alloys, and ceramics for use in biomedical applications. In 2003, the sales of polymeric biomaterials exceeded $7 billion, accounting for almost 88% of the total biomaterial market for that year [8]. The global market for biodegradable polymers increased from 409 million pounds in 2006 to an estimated 541 million pounds by the end of 2007. It should reach an estimated 1203 million pounds by 2012, a compound annual growth rate (CAGR) of 17.3% [23, 24].

This chapter provides a brief overview of different classes of polymers with their key features. Different degradation patterns affect the release of entrapped molecules as well as other derived properties, and these patterns are also discussed in this chapter. There are various successful products in clinical practice, and the number of such products is ever increasing and at a faster rate from the past few decades. Several products are discussed in this chapter with their major properties; however, the focus is on drug delivery systems available on the market. A general decision tree, based upon these properties, for the selection of material is also given, which could be of help in selecting polymers for a particular end use. Finally, the future of the polymeric biomaterial is briefly discussed.

1.2 TYPES OF BIODEGRADABLE POLYMERS

Biodegradable polymers can be divided in two major classes of natural and synthetic origin. However, the properties of polymers in these classes vary widely and give a selection of individual polymers for individual requirements. Most of the polymers utilized for biomedical application are listed in Table 1.1 with their chemical structure, properties, major applications, and marketed product. The properties given are those for the particular type of polymer; however, customarily copolymers are employed to achieve a hybrid of individual properties. Because of constant advancements the list is ever increasing and many new copolymers as well as polymers are entering the panorama of biodegradable polymers for biomedical application.

TABLE 1.1 Biomedical Applications of Polymers

Most of properties required for use as a biomaterial are fulfilled by many natural polymers, for example, polysaccharides and protein derivatives and synthetic polymers (e.g., polyesters, polyanhydride, and polyorthoesters). However, when biomedical applications are considered, the requirement diversifies in terms of mechanical strength required, degradation time, surface properties, physicochemical parameters, degree of crosslinking, presence of functional group for modification and tagging, and so forth. Some of the applications such as bone grafting and bone repair, in addition to biocompatibility, require purely mechanical function. Hence polymers that can withstand load and have long degradation time are suitable for these applications [25–27]. Some applications such as surgical dressings, sutures, and the like require varying strength and degradation time, which usually depends on the type of tissue and the type of injury. In tissue engineering application growth factors are considered vital for rapid healing of the tissue and generating more biofuncational tissue. Hence, the strategy is to mimic matrix and provide the necessary information or signaling for cell attachment, proliferation, and differentiation to meet the requirement of dynamic reciprocity for tissue engineering [28–34]. Natural polymers in this regard are conceived better than noninformational synthetic polymers [20, 35]. However, the flip side of natural polymers is that even though they are available in ample quantity, they suffer from some limitations such as immunogenecity, difficulty in processing, a potential risk of transmitting origin related/associated pathogens, and batch-to-batch variability [36, 37]. Synthetic polymers on the other hand can be produced in a reproducible manner with better quality control. This particular fact is more important when these are used as carriers for bioactives where reproducible delivery is required from the carrier, as the change in the in vivo release of the bioactive carrier can change the course of the treatment. Choice among the synthetic polymers is again based on the individual application; however, when it comes to drug delivery, time of release is one of the most important characteristic, which not only determines the type of polymer but also the shape and size of the carrier device [38–40].

Usually, polymers having higher hydrophobicity sustain the release of bioactive for longer times; however, it is not always the requirement since sometimes instant release is required upon triggered by the external stimuli, which may be present at the target site [41–49]. In this type of case, polymers with functional groups are suitable so that targeting moieties can be attached. On the other hand, if the polymer is the only governing factor for the release of bioactives, then predictable release is of considerable importance. If the system releases the active moiety in a zero-order pattern at a predetermined rate, then it is considered ideal in terms of release kinetics from the system [11, 50–52]. Surface-eroding polymers are considered to follow zero-order release kinetics and release rate differs depending on the type of polymer/monomer. However, surface-eroding polymers have very labile links, thus often not a suitable candidate for nanoscopic carriers, and thus polyesters are preferred and used most widely for this purpose [51, 53–55]. Polyesters can sustain the release for a longer time, and moreover they have very well established safety and disposition profiles from a clinical point of view, and this can be well appreciated in a number of products approved by the Food and Drug Administration (FDA) [56–62]. Of the many polyesters poly(lactic-co-glycolic acid) (PLGA) is more widely utilized because of the ratio and molecular weight of the blocks and/or of the whole polymer, which can be varied flexibly to give a wide variety of properties for diverse biomedical applications.

1.3 BIODEGRADATION PATTERNS

Similar to the production and properties of biodegradable polymers equally important is their degradation, and it is of utmost significance when it comes to biomedical applications. The polymer should degrade and/or be disposed off completely in a predictable manner from the body, unless it is to perform some permanent function. The degradation products generated should not cause any adverse effect at the site of use or on any other body organs/functions. Usually, the polymer matrix begins to degrade by hydrolytic and/or enzymatic attack. Each reaction results in the scission of a molecule, slowly reducing the weight of the matrix until the entire material has been digested.

Degradation of the polymer occurs through the process of chain cleavage [271] while erosion is the sum of all processes that lead to the loss of mass from a polyanhydride matrix [272, 273]. Erosion of the polymer matrices depends on processes such as the rate of degradation, swelling, porosity, and ease of diffusion of oligomers and monomers from the matrices [271]. Considering the diffusion of water into the polymer matrix the degradation process can be divided into bulk and surface-eroding polymer (Fig. 1.1). In a bulk erosion process polymer mass is lost uniformly throughout the matrix, and the erosion rate is dependent on the volume of the polymer rather than its thickness. Consequently, the lifetime of polymer disks of different thicknesses is the same. In contrast, surface-eroding systems display material loss from the outside to the inside of the matrix, so that the erosion rate is dependent on the surface area of the polymer rather than its volume. The lifetime of surface-eroding polymers is dependent on the thickness of the polymer disk, and so thicker samples have a longer lifetime. In the case of controlled drug delivery applications, a surface-eroding device is the better option for drug release [274–276].

FIGURE 1.1 Erosion patterns in polymeric matrices. (a) Bulk erosion and (b) surface erosion. In bulk erosion, degradation of the matrix occurs throughout the matrix simultaneously with solubilization of oligomers in the surrounding media and drug release occurs by diffusion, which is a concentration-dependent phenomenon. On the other hand, surface erosion occurs from the front of the device, which continuously moves to the core of the device. As these types of polymers are made up of very hydrophobic monomers they do not allow aqueous media to penetrate the core; moreover, the oligomers usually deposit on the device itself and further hinder the release of entrapped bioactives. As a particular volume of the device is exposed to the environment, release occurs in zero-order fashion. These surface-eroding polymers have very labile hydrolytic bonds, thus usually not suitable for sustaining the release in nanoscopic carriers.

In general biodegradation of the polymers is affected by following factors:

Chemical nature: Type of linkage between the monomersWater solubility and permeability of polymer: Hydrophlic/hydrophobicMethod of chain scission: Hydrolytic/enzymaticMechanism of hydrolysis: Noncatalytic/pH catalytic/autocatalyticWater solubility and diffusion of degradation products: Hydrophlic/hydrophobic—slow/fastMolecular weight and polydispersity: Low/medium/highMolecular level assembly: Crystalline/amorphousGlass transition temperature: High/lowMorphology of device: Size/shape/dimensions/surface-to-volume ratioPorosity before and during degradation: Low/medium/highAdditives: Drug/modifiers/stabilizersMethod of sterilization: Moist heat/irradiation/otherSite of application: Local (site)/systemic

All these factors affect the overall degredation rate and lifetime of the polymer. However, the basic governing factor is the chemical nature of the backbone and the hydrophilicity/hydrophobicity of the polymer [277–279]. Polymers that are hydrophilic or not so hydrophobic to diffusion of surrounding aqueous media into the matrix degrade all over the matrix and are called bulk-degrading polymers. Polymers that have very hydrophophobic bone as well as hydrolytically nonlabile bonds are very slow degrading polymers, whereas polymers with hydrophobic monomers but labile linkage, which do not allow water to penetrate, erode from the surface only are called surface-degrading polymers. However, these monomers are so hydrophobic that they do not diffuse away from matrix and keep on depositing on the matrix, thus overall the mass of the device does not reduce significantly. Moreover, they hinder and sustain the diffusion of entrapped bioactive molecules. Natural polymers are usually hydrophilic and undergo bulk degradation [19–21, 35]. Enzymatic degradation is a major contributor in their degradation process, whereas few synthetic polymers undergo enzymatic degradation such as polyesters. Polymers that are substrate for enzymatic degradation are considered better for biomedical applications as they are excreted readily form the body. Hydrophilicity is a major determinant in the time of degradation: the more hydrophilic the polymer, the faster is the degradation when other factors are kept constant. The solubility of the degradation product is another important parameter that governs their removal from the body. Lower molecular weight of the oligomers and their higher aqueous solubility lead to faster degradation and excretion from the body. Some of the oligomers, as in the case of polyanhydrides, are very hydrophobic and deposit on the polymer matrix itself and, in turn, making the degradation slow. Some degradation products have an autocatalytic effect on the chain scission [280–284]. The catalytic effect is usually because of a change in pH by degradation products in microenvironments, which can cause either acid or base catalysis. Free radical generation during degradation also catalyzes the chain scission in some polymers. Solubility of the degradation product in changed pH can also change the course of degradation as their diffusion away from the matrix is increased. Increase in the molecular weight is usually proportional, though not directly, to the degradation time [285–290]. It is just not because the number of bonds to be broken are more; it also increases the hydrophobicity of the device and makes hydrolysis proportionally slower.

Increase in molecular weight distribution on the other hand usually increases degradation rate as there are more free groups for the chain scission reaction, and if the free groups are hydrophilic, then they ingress water more readily into the device, which thus increases degradation. Only a few polymers occur in completely crystalline form, and they have long-range order in their molecular arrangement, thus making penetration of the water difficult. Because of higher lattice energy, they degrade slowly as compared to their amorphous counterparts. Semicrystalline polymers have an intermediate degradation period, depending on the degree of crystallinity [291–297]. Among amorphous polymers, the glass transition temperature (Tg) is the factor that dictates the degradation behavior. Polymers with higher Tg, in the same class, usually have a higher molecular weight, thus naturally will require a longer time to degrade. On the other hand, high Tg also means that the polymer is stable in that particular molecular configuration, which may be because of forces such as hydrogen bonding and hydrophobic interaction, in turn making polymer degradation slower. Crystallinity and Tg also determine the polymer fragmentation and crumpling of the polymer device, thus affecting degradation. As the size of the device increases, the time required for complete degradation of the device also increases, but the effect is more pronounced in the case of a surface-degrading polymer as compared to a bulk-degrading polymer where degradation takes place throughout the matrix.

Shapes or factors that make surface-to-volume ratios high also have varied effects on polymers with different degradation patterns, as an increase in surface area exposes more surface to the hydrolytic media and thus enhances the degradation process more in the case of heterogonous degradation [53, 298–301]. Porosity is one of the factors that increase the surface-to-volume ratio, thus affecting the degradation similarly. For formulating particular devices, additives are included in the polymer, and it also undergoes some processes to make the device suitable for application. Additives that include a drug can make the polymer more hydrophobic or more hydrophilic and can change the degradation profile accordingly. In practice, two or more polymers are chemically linked (copolymer) or blended to achieve particular degradation or some other derived properties. Processing such as application of heat, pressure, and sterilization can modify the polymer’s physical and more importantly chemical properties to further affect the degradation [302–306]. Generally, all these stresses lead to a decrease in molecular weight, but, occasionally, it can also give rise to a phenomenon such as crosslinking, and may thereby hamper the degradation rate. Finally, location or the site of application in the body of the polymer also affects its degradation by secondary effects such as blood flow, movement of the device, load on the device, hardness of the tissue, and the like. If the device is in an environment that causes faster removal of degradation product, it can cause an increased degradation rate in the case of surface-degrading polymers. On the other hand, a balance effect can be in the case of bulk-degrading polymers as autocatalysis will be reduced at one hand but better sink conditions for degredants on the other hand, which reduces matrix mass will be faster. Conditions that subject the polymer to pH conditions and enzymes favorable to the degradation, then naturally polymer disappearance from the body will be faster, and such a case, for example, could be the presentation of large nanoparticles made up of polyesters in a liver microtonal condition.

1.4 OVERVIEW OF DIFFERENT PRODUCTS BASED ON BIODEGRADABLE POLYMERS

Over the past four decades controlled-release polymer technology has impacted virtually every branch of medicine, including oncology, ophthalmology, pulmonary, pain medicine, endocrinology, cardiology, orthopedics, immunology, neurology, and dentistry, with several examples of these systems in clinical practice today (Table 1.2). Several controlled-release formulations based on biodegradable polymers have been approved and marketed where the polymer matrix can be formulated as microspheres, nanospheres, injectable gel, or implant.

TABLE 1.2 Marketed Controlled-Release Formulations Based on Biodegradable Polymers

1.5 POLYMER SELECTION FOR BIOMEDICAL APPLICATION

Polymers, both synthetic and those derived from a natural origin, are a promising class of biomaterials that can be engineered to meet specific end-use requirements if proper selection is made based on their biomedical application. Polymers can be selected according to key device characteristics, such as mechanical resistance, degradability, permeability, solubility, and transparency, in which all can influence manufacturing characteristics and performance of device. Moreover, it requires a thorough understanding of the surface and bulk properties of the polymer that can give the desired chemical, interfacial, mechanical, and biological functions. The choice of polymer in addition to its physicochemical properties is dependent on the need for the extensive biomedical characterization and specific preclinical tests to prove its safety. Hence, its selection must be carefully tailored in order to provide the combination of chemical, interfacial, mechanical, and biological functions necessary for the manufacturing of biomaterials.

In general, there are varieties of polymer attributes to be considered when selecting a biodegradable polymer for biomedical application [371–373]:

Regulatory and Toxicology Status

One of the most critical considerations is the regulatory requirement for a particular application. If an application requires a rapid development and commercialization, then the polymer selection will most likely be made from among those that have already received regulatory approval, for instance, polyesters.

Polymer (Monomer or Copolymer) Composition

Whether to use homopolymers consisting of a single monomeric repeat unit or copolymers containing multiple monomer species has to be considered before a decision is made of which polymer to be used. If copolymers are to be used, then the relative ratio of the different monomers may be manipulated to change polymer physicochemical properties including bulk hydrophilicity, morphology, structure, and the extent of drug–polymer interactions (e.g., drug solubility in the polymer). Ultimately, these properties will all influence the performance of the drug delivery system, for instance, via changes to the relative rates of mass transport and the degradation rate of both the polymer and the device.

Thermal Properties

The thermal attributes of the polymer, as described by the glass transition temperature (Tg) and the melting temperature (Tm), can also affect the mass transport rates through the polymer as well as the polymer processing characteristics and the stability of the device at the end. Below the glass transition temperature, the polymer will exist in an amorphous, glassy state. When exposed to temperatures, above Tg, the polymer will experience an increase in free volume that permits greater local segmental chain mobility along the polymer backbone. Consequently, the mass transport through the polymer is faster at temperatures above Tg. Often, the polymer processing, such as extrusion or high shear mixing, is performed above Tg. On the other hand, the greatest stability during the storage of a polymer device may be obtained at temperatures below Tg, where solute diffusion is much slower and more subtle changes in polymer properties are reduced.

Ionization

The presence of charged groups on a polymer can also influence the physicochemical properties of the polymer, the device, and the drug release pattern from the device. The number and density of ionized groups along the polymer backbone, on the side-chain groups, or at the terminal end groups of the polymer chains can all vary the extent of polymer–polymer and polymer–drug interactions. As drug delivery systems, the polymer properties can affect the performance of the drug delivery system as ionizable groups can affect drug solubility in the polymer and, correspondingly, the release rate from the polymer.

Molecular Weight and Molecular Weight Distribution

Molecular weight of a monodisperse or polydisperse polymer is expressed in terms of its relative molar mass, which is related to the degree of polymerization and relative molecular mass of the repeat unit. The properties that have enabled polymers to be used in a diversity of biomedical applications derive almost entirely from their long-chain macromolecular nature. We are concerned about molecular weight and its distribution in polymer selection because many physicochemical properties of polymers are influenced by the length of the polymer chain, including viscosity, the glass transition temperature, mechanical strength, and the like and, consequently, the use of polymers in various biomedical applications will be affected.

Molecular Architecture

An important microstructural feature determining polymer properties is the polymer architecture. Molecular architecture of polymers can be described as linear polymers, branched polymers, crosslinked network polymers, and the like. The simplest polymer architecture is a linear chain: a single backbone without branches. A related unbranching architecture is a ring polymer. A branched polymer is composed of a main chain with one or more short or long substituent side chains or branches. Special types of branched polymers include star polymers, comb polymers, brush polymers, ladders, and dendrimers among others. Branching of polymer chains affects the ability of chains to slide past one another by altering intermolecular forces, in turn affecting bulk physical properties of polymers. Long-chain branches may increase polymer strength, toughness, and the glass transition temperature due to an increase in the number of entanglements per chain. Different representative polymer architectures are shown in Figure 1.2.

FIGURE 1.2 Types of molecular architectures of polymers.

Polymer Morphology

Polymer morphology generally refers to the arrangement of chains in space and the microscopic ordering of many polymer chains and described as amorphous, semicrystalline, and crystalline structures that can affect the manufacturing characteristics and performance. There are some polymers that are completely amorphous, although the morphology of most polymers is semicrystalline. That is, they form mixtures of small crystals and are amorphous in combination with the tangled and disordered surrounding crystalline material and melt over a range of temperatures instead of at a single melting point. In most polymers the combination of crystalline and amorphous structures forms a material with advantageous properties of strength and stiffness so that manufacturing characteristics and performance can be tailored as desired. Different polymer morphologies are shown in Figure 1.3.

FIGURE 1.3 Types of molecular arrangement of polymeric chains in crystal lattice.

In general, when the polymer selection is made, it has to fulfill the following end-use requirements:

The mechanical properties must match the application. For instance, in tissue engineering application, it should remain sufficiently strong until the surrounding tissue has healed.The degradation time must match the time required for biomedical application.It does not invoke a toxic response upon in vivo degradation.It is metabolized in the body after fulfilling its purpose into nontoxic constituents that can be easily eliminated.It is easily processable in the final product form with an acceptable shelf life and easily sterilized.

1.6 FUTURE PROSPECTS

Biodegradable materials are highly desired for most biomedical applications in vivo, such as transient implants, drug delivery carriers, and tissue engineering scaffolds. Biodegradable polymers remain the most versatile and promising class of biomaterials that can be engineered to meet specific end-use requirements in biomedical application. Given the importance of biodegradable polymers in the various biomedical applications, the currently available polymers need to be further improved by altering their surface and bulk properties in order to provide the desired functions necessary for manufacturing of new and improved biomaterials, for instance, the generation of stimuli-responsive polymeric biodegradable materials. Stimuli-responsive biomaterials resembling natural living tissues that undergo changes in physicochemical properties in response to a variety of physical, chemical, and biological stimuli are attracting increasing interest because of their potential application in biomedical fields. Hence, biomedical systems that are both biodegradable and stimuli responsive have therefore been studied intensively and significant progress in this field has been achieved. Although biodegradable stimuli-responsive materials are highly attractive for biomedical applications, most such materials are currently at a developmental research stage. Additionally, single stimulus-responsive property limits the practical applications of these materials. To achieve more favorable applications for these materials, further efforts are still necessary, especially for developing multi-stimuli-responsive functions of materials and improving the stimuli-responsive properties of such materials in a biological environment. Bearing in mind the great prospect of these biodegradable stimuli-responsive materials, there is great hope in the future for the development of stimuli-responsive polymers or systems that could be reliably employed in biomedical applications for further clinical practices.

REFERENCES

1. Gunatillake, P., R. Mayadunne, and R. Adhikari. Recent developments in biodegradable synthetic polymers. Biotechnol. Annu. Rev. 2006;12:301–347.

2. Pachence, J. M., M. P. Bohrer, J. Kohn, L. Robert, and V. Joseph. Biodegradable polymers. In Principles of Tissue Engineering, 3rd ed. Academic: Burlington, 2007, pp. 323–339.

3. Scott, G. “Green” polymers. Polym. Degrad. Stab. 2000;68(1):1–7.

4. Tuzlakoglu, K. and R. L. Reis. Biodegradable polymeric fiber structures in tissue engineering. Tissue Eng. Part B Rev. 2009;15(1):17–27.

5. Chiellini, F., A. M. Piras, C. Errico, and E. Chiellini. Micro/nanostructured polymeric systems for biomedical and pharmaceutical applications. Nanomed, 2008;3(3):367–393.

6. Heller, J. Biodegradable polymers in controlled drug delivery. Crit. Rev. Ther. Drug Carrier Syst. 1984;1(1):39–90.

7. Ratcliffe, A. Tissue engineering of vascular grafts. Matrix Biol. 2000;19(4):353–357.

8. Ju, X. J., R. Xie, L. Yang, and L. Y. Chu. Biodegradable “intelligent” materials in response to physical stimuli for biomedical applications. Expert Opin. Ther. Pat. 2009;19(4):493–507.

9. Gunja, N. J. and K. A. Athanasiou. Biodegradable materials in arthroscopy. Sports Med. Arthrosc. 2006;14(3):112–119.

10. Chitkara, D., A. Shikanov, N. Kumar, and A. J. Domb. Biodegradable injectable in situ depot-forming drug delivery systems. Macromol. Biosci. 2006;6(12):977–990.

11. Commandeur, S., H. M. van Beusekom, and W. J. van der Giessen. Polymers, drug release, and drug-eluting stents. J. Interv. Cardiol. 2006;19(6):500–506.

12. Friedman, J. A., A. J. Windebank, M. J. Moore, R. J. Spinner, B. L. Currier, and M. J. Yaszemski. Biodegradable polymer grafts for surgical repair of the injured spinal cord. Neurosurgery 2002;51(3):742–751; discussion 751–752.

13. Piskin, E. Biodegradable polymeric matrices for bioartificial implants. Int. J. Artif. Organs 2002;25(5):434–440.

14. Gaspar, R. S. and R. Duncan. Polymeric carriers: Preclinical safety and the regulatory implications for design and development of polymer therapeutics. Adv. Drug Deliv. Rev. 2009;61(13):1220–1231.

15. Kiick, K. L. Materials science. Polymer therapeutics. Science 2007;317(5842):1182–1183.

16. Benagiano, G., H. Gabelnick, and M. Farris. Contraceptive devices: Subcutaneous delivery systems. Expert Rev. Med. Devices 2008;5(5):623–637.

17. Dash, A. K. and G. C. Cudworth II. Therapeutic applications of implantable drug delivery systems. J. Pharmacol. Toxicol. Methods. 1998;40(1):1–12.

18. Nair, L. S. and C. T. Laurencin. Biodegradable polymers as biomaterials. Prog. Polym. Sci. 2007;32(8–9):762–798.

19. Malafaya, P. B., G. A. Silva, and R. L. Reis. Natural-origin polymers as carriers and scaffolds for biomolecules and cell delivery in tissue engineering applications. Adv. Drug Deliv. Rev. 2007;59(4–5):207–233.

20. Dang, J. M. and K. W. Leong. Natural polymers for gene delivery and tissue engineering. Adv. Drug Deliv. Rev. 2006;58(4):487–499.

21. Stacey, M. In Natural & Synthetic Polymers an Introduction, Vol. 17. H. I. Bolker (ed.). Marcel Dekker: New York, 1976, pp. 456–456.

22. Reinert, K. H., J. P. Carbone, J. Sven Erik, and F. Brian. Synthetic polymers. In Encyclopedia of Ecology. Academic: Oxford, 2008, pp. 3461–3472.

23. Thompson, H. Biomaterials: We have the technology. 2005 (cited September 2009); available from: http://www.devicelink.com/mddi/archive/05/05/024.html.

24. Schlechter, M. Biodegradable polymers (PLS025B). 2005 (cited September 2009); available from: http://www.bccresearch.com/report/PLS025B.html.

25. Navarro, M., A. Michiardi, O. Castano, and J. A. Planell. Biomaterials in orthopaedics. J. R. Soc. Interface 2008;5(27):1137–1158.

26. Holland, T. A. and A. G. Mikos. Biodegradable polymeric scaffolds. Improvements in bone tissue engineering through controlled drug delivery. Adv. Biochem. Eng. Biotechnol. 2006;102:161–185.

27. Liu, X. and P. X. Ma. Polymeric scaffolds for bone tissue engineering. Ann. Biomed. Eng. 2004;32(3):477–486.

28. Borenstein, J. T., G. Yogesh, T. Osamu, and Z. Hans. Tissue engineering. In Comprehensive Microsystems. 2008, Elsevier: Oxford, 2008, pp. 541–583.

29. Carlos Rodríguez-Cabello, J., J. Reguera, A. Girotti, M. Alonso, and A. M. Testera. Developing functionality in elastin-like polymers by increasing their molecular complexity: The power of the genetic engineering approach. Prog. Polym. Sci. 2005;30(11):1119–1145.

30. El-Amin, S. F., H. H. Lu, Y. Khan, J. Burems, J. Mitchell, R. S. Tuan, and C. T. Laurencin. Extracellular matrix production by human osteoblasts cultured on biodegradable polymers applicable for tissue engineering. Biomaterials 2003;24(7):1213–1221.

31. Ma, P. X. Biomimetic materials for tissue engineering. Adv. Drug Deliv. Rev. 2008;60(2):184–198.

32. Pêgo, A. P., A. A. Poot, D. W. Grijpma, and J. Feijen. Biodegradable elastomeric scaffolds for soft tissue engineering. J. Control. Release 2003;87(1–3):69–79.

33. Sheridan, M. H., L. D. Shea, M. C. Peters, and D. J. Mooney. Bioabsorbable polymer scaffolds for tissue engineering capable of sustained growth factor delivery. J. Control. Release 2000;64(1–3):91–102.

34. van Dijkhuizen-Radersma, R., L. Moroni, A. v. Apeldoorn, Z. Zhang, D. Grijpma, B. Clemens van, T. Peter, L. Anders, H. Jeffrey, F. W. David, C. Ranieri, D. d. B. Joost, and S. Jérôme. Degradable polymers for tissue engineering. In Tissue Engineering. Academic: Burlington, 2008, pp. 193–221.

35. Gomes, M., H. Azevedo, P. Malafaya, S. Silva, J. Oliveira, G. Silva, R. Sousa, J. Mano, R. Reis, B. Clemens van, T. Peter, L. Anders, H. Jeffrey, F. W. David, C. Ranieri, D. d. B. Joost, and S. Jérôme. Natural polymers in tissue engineering applications. In Tissue Engineering. Academic: Burlington, 2008, pp. 145–192.

36. Lee, S.-H. and H. Shin. Matrices and scaffolds for delivery of bioactive molecules in bone and cartilage tissue engineering. Adv. Drug Deliv. Rev. 2007;59(4–5):339–359.

37. Malafaya, P. B., G. A. Silva, and R. L. Reis. Natural-origin polymers as carriers and scaffolds for biomolecules and cell delivery in tissue engineering applications. Adv. Drug Deliv. Rev. 2007;59(4–5):207–233.

38. Deng, J. S., L. Li, Y. Tian, M. Meisters, H. C. Chang, D. Stephens, S. Chen, and D. Robinson. The relationship between structures and in vitro properties of a polyanhydride implant containing gentamicin sulfate. Pharm. Dev. Technol. 2001;6(4):541–549.

39. Dittrich, M., P. Solich, L. Opletal, A. J. Hunt, and J. D. Smart. 20-Hydroxyecdysone release from biodegradable devices: The effect of size and shape. Drug Dev. Ind. Pharm. 2000;26(12):1285–1291.

40. Park, E.-S., M. Maniar, and J. Shah. Water uptake in to polyanhydride devices: Kinetics of uptake and effects of model compounds incorporated, and device geometry on water uptake. J. Control. Release 1996;40(1–2):55–65.

41. Ju, X. J., R. Xie, L. Yang, and L. Y. Chu. Biodegradable “intelligent” materials in response to chemical stimuli for biomedical applications. Expert Opin. Ther. Pat. 2009;19(5):683–696.

42. Bawa, P., V. Pillay, Y. E. Choonara, and L. C. du Toit. Stimuli-responsive polymers and their applications in drug delivery. Biomed. Mater. 2009;4(2):22001.

43. Meng, F., Z. Zhong, and J. Feijen, Stimuli-responsive polymersomes for programmed drug delivery. Biomacromolecules 2009;10(2):197–209.

44. Onaca, O., R. Enea, D. W. Hughes, and W. Meier. Stimuli-responsive polymersomes as nanocarriers for drug and gene delivery. Macromol. Biosci. 2009;9(2):129–139.

45. Mendes, P. M. Stimuli-responsive surfaces for bio-applications. Chem. Soc. Rev. 2008;37(11):2512–2529.

46. Stoop, R. Smart biomaterials for tissue engineering of cartilage. Injury 2008;39(Suppl 1):S77–87.

47. Dayananda, K., C. He, D. K. Park, T. G. Park, and D. S. Lee. pH- and temperature-sensitive multiblock copolymer hydrogels composed of poly(ethylene glycol) and poly(amino urethane). Polymer 2008;49(23):4968–4973.

48. Qiu, Y. and K. Park. Environment-sensitive hydrogels for drug delivery. Adv. Drug Deliv. Rev. 2001;53(3):321–339.

49. Sershen, S. and J. West, Implantable, polymeric systems for modulated drug delivery. Adv. Drug Deliv. Rev. 2002;54(9):1225–1235.

50. Iconomopoulou, S. M., J. K. Kallitsis, and G. A. Voyiatzis. Incorporation of small molecular weight active agents into polymeric components. Recent Pat. Drug Deliv. Formul. 2008;2(2):94–107.

51. Jain, J. P., S. Modi, A. J. Domb, and N. Kumar. Role of polyanhydrides as localized drug carriers. J. Control. Release 2005;103(3):541–563.

52. Park, J. H., M. Ye, and K. Park. Biodegradable polymers for microencapsulation of drugs. Molecules 2005;10(1):146–161.

53. Gopferich, A. and J. Tessmar. Polyanhydride degradation and erosion. Adv. Drug Deliv. Rev. 2002;54(7):911–931.

54. Jain, J. P., D. Chitkara, and N. Kumar. Polyanhydrides as localized drug delivery carrier: An update. Expert Opin. Drug Deliv. 2008;5(8):889–907.

55. Tamada, J. and R. Langer. The development of polyanhydrides for drug delivery applications. J. Biomater. Sci. Polym. Ed. 1992;3(4):315–353.

56. Bala, I., S. Hariharan, and M. N. Kumar. PLGA nanoparticles in drug delivery: The state of the art. Crit. Rev. Ther. Drug Carrier Syst. 2004;21(5):387–422.

57. Campolongo, M. J. and D. Luo. Drug delivery: Old polymer learns new tracts. Nat. Mater. 2009;8(6):447–448.

58. Dhiman, N., M. Dutta, and G. K. Khuller. Poly (dl-lactide-co-glycolide) based delivery systems for vaccines and drugs. Indian J. Exp. Biol. 2000;38(8):746–752.

59. Jain, R., N. H. Shah, A. W. Malick, and C. T. Rhodes. Controlled drug delivery by biodegradable poly(ester) devices: Different preparative approaches. Drug Dev. Ind. Pharm. 1998;24(8):703–727.

60. Jain, R. A. The manufacturing techniques of various drug loaded biodegradable poly(lactide-co-glycolide) (PLGA) devices. Biomaterials 2000;21(23):2475–2490.

61. Mundargi, R. C., V. R. Babu, V. Rangaswamy, P. Patel, and T. M. Aminabhavi. Nano/micro technologies for delivering macromolecular therapeutics using poly(d,l-lactide-co-glycolide) and its derivatives. J. Control. Release 2008;125(3):193–209.

62. Vert, M. Aliphatic polyesters: Great degradable polymers that cannot do everything. Biomacromolecules 2005;6(2):538–546.

63. Coombes, A. G., S. C. Rizzi, M. Williamson, J. E. Barralet, S. Downes, and W. A. Wallace. Precipitation casting of polycaprolactone for applications in tissue engineering and drug delivery. Biomaterials 2004;25(2):315–325.

64. Dhanaraju, M. D., D. Gopinath, M. R. Ahmed, R. Jayakumar, and C. Vamsadhara. Characterization of polymeric poly(ε-caprolactone) injectable implant delivery system for the controlled delivery of contraceptive steroids. J. Biomed. Mater. Res. A 2006;76(1):63–72.

65. Huatan, H., J. H. Collett, D. Attwood, and C. Booth. Preparation and characterization of poly(ε-caprolactone) polymer blends for the delivery of proteins. Biomaterials 1995;16(17):1297–1303.

66. Jia, W., Y. Gu, M. Gou, M. Dai, X. Li, B. Kan, J. Yang, Q. Song, Y. Wei, and Z. Qian. Preparation of biodegradable polycaprolactone/poly(ethylene glycol)/polycaprolactone (PCEC) nanoparticles. Drug Deliv. 2008;15(7):409–416.

67. Juni, K. and M. Nakano. Poly(hydroxy acids) in drug delivery. Crit. Rev. Ther. Drug Carrier Syst. 1987;3(3):209–232.

68. Luciani, A., V. Coccoli, S. Orsi, L. Ambrosio, and P. A. Netti. PCL microspheres based functional scaffolds by bottom-up approach with predefined microstructural properties and release profiles. Biomaterials 2008;29(36):4800–4807.

69. Mei, L., H. Sun, and C. Song. Local delivery of modified paclitaxel-loaded poly(ε-caprolactone)/pluronic F68 nanoparticles for long-term inhibition of hyperplasia. J. Pharm. Sci. 2009;98(6):2040–2050.

70. Sheikh, F. A., N. A. Barakat, M. A. Kanjwal, S. Aryal, M. S. Khil, and H. Y. Kim. Novel self-assembled amphiphilic poly(ε-caprolactone)-grafted-poly(vinyl alcohol) nanoparticles: Hydrophobic and hydrophilic drugs carrier nanoparticles. J. Mater. Sci. Mater. Med. 2009;20(3):821–831.

71. Zhu, K. J., Y. Li, H. L. Jiang, H. Yasuda, A. Ichimaru, K. Yamamoto, P. Lecomte, and R. Jerome. Preparation, characterization and in vitro release properties of ibuprofen-loaded microspheres based on polylactide, poly(ε-caprolactone) and their copolymers. J. Microencapsul. 2005;22(1):25–36.

72. Ashammakhi, N. and P. Rokkanen. Absorbable polyglycolide devices in trauma and bone surgery. Biomaterials 1997;18(1):3–9.

73. Hutmacher, D., M. B. Hurzeler, and H. Schliephake. A review of material properties of biodegradable and bioresorbable polymers and devices for GTR and GBR applications. Int. J. Oral. Maxillofac. Implants 1996;11(5):667–678.

74. Lu, J. M., X. Wang, C. Marin-Muller, H. Wang, P. H. Lin, Q. Yao, and C. Chen. Current advances in research and clinical applications of PLGA-based nanotechnology. Expert Rev. Mol. Diagn. 2009;9(4):325–341.

75. Miller, N. D. and D. F. Williams. The in vivo and in vitro degradation of poly(glycolic acid) suture material as a function of applied strain. Biomaterials 1984;5(6):365–368.

76. Pulapura, S. and J. Kohn. Trends in the development of bioresorbable polymers for medical applications. J. Biomater. Appl. 1992;6(3):216–250.

77. Shum, A. W. T. and A. F. T. Mak. Morphological and biomechanical characterization of poly(glycolic acid) scaffolds after in vitro degradation. Polym. Degrad. Stab. 2003;81(1):141–149.

78. Gupta, B., N. Revagade, and J. Hilborn. Poly(lactic acid) fiber: An overview. Prog. Polym. Sci. 2007;32(4):455–482.

79. Hyon, S. H., Biodegradable poly(lactic acid) microspheres for drug delivery systems. Yonsei Med. J. 2000;41(6):720–734.

80. Miyajima, M., A. Koshika, J. i. Okada, and M. Ikeda. Mechanism of drug release from poly(-lactic acid) matrix containing acidic or neutral drugs. J. Control. Release 1999;60(2–3):199–209.

81. Saulnier, B., S. Ponsart, J. Coudane, H. Garreau, and M. Vert. Lactic acid-based functionalized polymers via copolymerization and chemical modification. Macromol. Biosci. 2004;4(3):232–237.

82. Steendam, R., M. J. van Steenbergen, W. E. Hennink, H. W. Frijlink, and C. F. Lerk. Effect of molecular weight and glass transition on relaxation and release behaviour of poly(-lactic acid) tablets. J. Control. Release 2001;70(1–2):71–82.

83. Tsuji, H. Poly(lactide) stereocomplexes: Formation, structure, properties, degradation, and applications. Macromol. Biosci. 2005;5(7):569–597.

84. Wang, S., W. Cui, and J. Bei. Bulk and surface modifications of polylactide. Anal. Bioanal. Chem. 2005;381(3):547–556.

85. Barham, P. J., P. Barker, and S. J. Organ. Physical properties of poly(hydroxybutyrate) and copolymers of hydroxybutyrate and hydroxyvalerate. FEMS Microbiol. Lett. 1992;103(2–4):289–298.

86. Chen, C., C. H. Yu, Y. C. Cheng, P. H. F. Yu, and M. K. Cheung. Biodegradable nanoparticles of amphiphilic triblock copolymers based on poly(3-hydroxybutyrate) and poly(ethylene glycol) as drug carriers. Biomaterials 2006;27(27):4804–4814.

87. Martin, D. P. and S. F. Williams. Medical applications of poly-4-hydroxybutyrate: A strong flexible absorbable biomaterial. Biochem. Eng. J. 2003;16(2):97–105.

88. Pouton, C. W. and S. Akhtar. Biosynthetic polyhydroxyalkanoates and their potential in drug delivery. Adv. Drug Deliv. Rev. 1996;18(2):133–162.

89. van der Walle, G. A., G. J. de Koning, R. A. Weusthuis, and G. Eggink. Properties, modifications and applications of biopolyesters. Adv. Biochem. Eng. Biotechnol. 2001;71:263–291.

90. Cai, Z.-Y., D.-A. Yang, N. Zhang, C.-G. Ji, L. Zhu, and T. Zhang. Poly(propylene fumarate)/(calcium sulphate/[β]-tricalcium phosphate) composites: Preparation, characterization and in vitro degradation. Acta Biomater. 2009;5(2):628–635.

91. Fisher, J. P., D. Dean, and A. G. Mikos. Photocrosslinking characteristics and mechanical properties of diethyl fumarate/poly(propylene fumarate) biomaterials. Biomaterials 2002;23(22):4333–4343.

92. Haesslein, A., H. Ueda, M. C. Hacker, S. Jo, D. M. Ammon, R. N. Borazjani, J. F. Kunzler, J. C. Salamone, and A. G. Mikos. Long-term release of fluocinolone acetonide using biodegradable fumarate-based polymers. J. Control. Release 2006;114(2):251–260.

93. He, S., M. J. Yaszemski, A. W. Yasko, P. S. Engel, and A. G. Mikos. Injectable biodegradable polymer composites based on poly(propylene fumarate) crosslinked with poly(ethylene glycol)-dimethacrylate. Biomaterials 2000;21(23):2389–2394.

94. Jayabalan, M., K. T. Shalumon, and M. K. Mitha. Injectable biomaterials for minimally invasive orthopedic treatments. J. Mater. Sci. Mater. Med. 2009;20(6):1379–1387.

95. Kempen, D. H., L. Lu, C. Kim, X. Zhu, W. J. Dhert, B. L. Currier, and M. J. Yaszemski. Controlled drug release from a novel injectable biodegradable microsphere/scaffold composite based on poly(propylene fumarate). J. Biomed. Mater. Res. A 2006;77(1):103–111.

96. Kim, C. W., R. Talac, L. Lu, M. J. Moore, B. L. Currier, and M. J. Yaszemski. Characterization of porous injectable poly-(propylene fumarate)-based bone graft substitute. J. Biomed. Mater. Res. A 2008;85(4):1114–1119.

97. Mistry, A. S., Q. P. Pham, C. Schouten, T. Yeh, E. M. Christenson, A. G. Mikos, and J. A. Jansen. In vivo bone biocompatibility and degradation of porous fumarate-based polymer/alumoxane nanocomposites for bone tissue engineering. J. Biomed. Mater. Res. A 2009;92(2):451–462.

98. Wang, S., L. Lu, and M. J. Yaszemski. Bone-tissue-engineering material poly(propylene fumarate): Correlation between molecular weight, chain dimensions, and physical properties. Biomacromolecules 2006;7(6):1976–1982.

99. Yaszemski, M. J., R. G. Payne, W. C. Hayes, R. Langer, and A. G. Mikos. In vitro degradation of a poly(propylene fumarate)-based composite material. Biomaterials 1996;17(22):2127–2130.

100. Bai, W., D. Chen, Z. Zhang, Q. Li, D. Zhang, and C. Xiong. Poly(para-dioxanone)/inorganic particle composites as a novel biomaterial. J. Biomed. Mater. Res. B Appl. Biomater. 2009;90(2):945–951.

101. Hutmacher, D. W., J. C. Goh, and S. H. Teoh, An introduction to biodegradable materials for tissue engineering applications. Ann. Acad. Med. Singapore 2001;30(2):183–191.

102. Li, M.-X., R.-X. Zhuo, and F.-Q. Qu. Study on the preparation of novel functional poly(dioxanone) and for the controlled release of protein. React. Funct. Polym. 2003;55(2):185–195.

103. Lin, H. L., C. C. Chu, and D. Grubb. Hydrolytic degradation and morphologic study of poly-p-dioxanone. J. Biomed. Mater. Res. 1993;27(2):153–166.

104. Saito, N., N. Murakami, J. Takahashi, H. Horiuchi, H. Ota, H. Kato, T. Okada, K. Nozaki, and K. Takaoka. Synthetic biodegradable polymers as drug delivery systems for bone morphogenetic proteins. Adv. Drug Deliv. Rev. 2005;57(7):1037–1048.

105. Song, C. X., X. M. Cui, and A. Schindler. Biodegradable copolymers based on p-dioxanone for medical application. Med. Biol. Eng. Comput. 1993;31(Suppl):S147–151.

106. Vogt, S., S. Berger, I. Wilke, Y. Larcher, J. Weisser, and M. Schnabelrauch. Design of oligolactone-based scaffolds for bone tissue engineering. Biomed. Mater. Eng. 2005;15(1–2):73–85.

107. Wang, X.-L., K.-K. Yang, Y.-Z. Wang, D.-Y. Wang, and Z. Yang. Crystallization and morphology of a novel biodegradable polymer system: Poly(1,4-dioxan-2-one)/starch blends. Acta Mater. 2004;52(16):4899–4905.

108. Kluin, O. S., H. C. van der Mei, H. J. Busscher, and D. Neut. A surface-eroding antibiotic delivery system based on poly-(trimethylene carbonate). Biomaterials 2009;30(27):4738–4742.

109. Papenburg, B. J., S. Schüller-Ravoo, L. A. M. Bolhuis-Versteeg, L. Hartsuiker, D. W. Grijpma, J. Feijen, M. Wessling, and D. Stamatialis. Designing porosity and topography of poly(1,3-trimethylene carbonate) scaffolds. Acta Biomater. 2009;5(9):3281–3294.

110. Timbart, L., M. Y. Tse, S. C. Pang, O. Babasola, and B. G. Amsden. Low viscosity poly(trimethylene carbonate) for localized drug delivery: Rheological properties and in vivo degradation. Macromol. Biosci. 2009;9(8):786–794.