Materials Science & Engineering; and Polymer Science The Polymeric Biomaterials 2-Volume Set, Third Edition Dumitriu Popa The Polymeric-Biomaterials 2-Volume Set, Third Edition Structure and Function This volume, Polymeric Biomaterials: Structure and Function, contains 25 authoritative chapters written by experts from around the world. Contributors cover the following topics: • The structure and properties of synthetic polymers including polyesters, polyphosphazenes, and elastomers • The structure and properties of natural polymers such as mucoadhesives, chitin, lignin, and carbohydrate derivatives • Blends and composites—for example, metal–polymer composites and biodegradable polymeric/ceramic composites • Bioresorbable hybrid membranes, drug delivery systems, cell bioassay systems, electrospinning for regenerative medicine, and more Completely revised and expanded, this state-of-the-art reference presents recent developments in polymeric biomaterials: from their chemical, physical, and structural properties to polymer synthesis and processing techniques and current applications in the medical and pharmaceutical fields. Structure and Function Biomaterials have had a major impact on the practice of contemporary medicine and patient care. Growing into a major interdisciplinary effort involving chemists, biologists, engineers, and physicians, biomaterials development has enabled the creation of high-quality devices, implants, and drug carriers with greater biocompatibility and biofunctionality. The fast-paced research and increasing interest in finding new and improved biocompatible or biodegradable polymers have provided a wealth of new information, transforming this edition of Polymeric Biomaterials into a 2-volume set. The Polymeric Biomaterials 2-Volume Set, Third Edition VOLUME 1 Structure and Function VOLUME 1 Founding Editor Severian Dumitriu 9470X VOLUME 1 Editor Valentin Popa Structure and Function VOLUME 1 Polymeric Biomaterials Polymeric Biomaterials: Structure and Function, Volume 1 Polymeric Biomaterials: Medicinal and Pharmaceutical Applications, Volume 2 Structure and Function VOLUME 1 Founding Editor Severian Dumitriu Editor Valentin Popa Boca Raton London New York CRC Press is an imprint of the Taylor & Francis Group, an informa business CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 © 2013 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, an Informa business No claim to original U.S. Government works Version Date: 20120726 International Standard Book Number-13: 978-1-4200-9471-8 (eBook - PDF) This book contains information obtained from authentic and highly regarded sources. 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Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the CRC Press Web site at http://www.crcpress.com Contents Preface...............................................................................................................................................ix Acknowledgments..............................................................................................................................xi Editors............................................................................................................................................. xiii Contributors...................................................................................................................................... xv Chapter 1 Synthesis and Fabrication of Polyesters as Biomaterials..............................................1 Philippe Lecomte and Christine Jérôme Chapter 2 Hydrogels Formed by Cross-Linked Poly(Vinyl Alcohol).......................................... 37 Gaio Paradossi Chapter 3 Development and Evaluation of Poly(Vinyl Alcohol) Hydrogels as a Component of Hybrid Artificial Tissues for Orthopedics Surgery Application......... 57 Masanori Kobayashi Chapter 4 Polyphosphazenes as Biomaterials.............................................................................. 83 Meng Deng, Cato T. Laurencin, Harry R. Allcock, and Sangamesh G. Kumbar Chapter 5 Biodegradable Polymers as Drug Carrier Systems................................................... 135 Abraham J. Domb and Wahid Khan Chapter 6 Bioresorbable Hybrid Membranes for Bone Regeneration....................................... 177 Akiko Obata and Toshihiro Kasuga Chapter 7 Mucoadhesive Polymers: Basics, Strategies, and Future Trends.............................. 193 Andreas Bernkop-Schnürch Chapter 8 Biodegradable Polymeric/Ceramic Composite Scaffolds to Regenerate Bone Tissue............................................................................................................... 221 Catherine Gkioni, Sander Leeuwenburgh, and John Jansen Chapter 9 Amphiphilic Systems as Biomaterials Based on Chitin, Chitosan, and Their Derivatives................................................................................................ 243 Jacques Desbrieres Chapter 10 Biomaterials of Natural Origin in Regenerative Medicine....................................... 271 Vijay Kumar Nandagiri, Valeria Chiono, Piergiorgio Gentile, Franco Maria Montevecchi, and Gianluca Ciardelli v vi Contents Chapter 11 Natural Polymers as Components of Blends for Biomedical Applications...............309 Alina Sionkowska Chapter 12 Metal–Polymer Composite Biomaterials.................................................................. 343 Takao Hanawa Chapter 13 Evolution of Current and Future Concepts of Biocompatibility Testing.................. 377 Menno L.W. Knetsch Chapter 14 Biocompatibility of Elastomers................................................................................. 415 Dominique Chauvel-Lebret, Pascal Auroy, and Martine Bonnaure-Mallet Chapter 15 Preparation and Applications of Modulated Surface Energy Biomaterials.............. 495 Blanca Vázquez, Luis M. Rodríguez-Lorenzo, Gema Rodríguez-Crespo, Juan Parra, Mar Fernández, and Julio San Román Chapter 16 Electrospinning for Regenerative Medicine.............................................................. 539 Toby D. Brown, Cedryck Vaquette, Dietmar W. Hutmacher, and Paul D. Dalton Chapter 17 Polymeric Nanoparticles for Targeted Delivery of Bioactive Agents and Drugs..... 593 Cesare Errico, Alberto Dessy, Anna Maria Piras, and Federica Chiellini Chapter 18 Polymeric Materials Obtained through Biocatalysis................................................ 617 Florin Dan Irimie, Csaba Paizs, and Monica Ioana Tosa Chapter 19 Polymer-Based Colloidal Aggregates as a New Class of Drug Delivery Systems.......659 Cesare Cametti Chapter 20 Photoresponsive Polymers for Control of Cell Bioassay Systems............................. 683 Kimio Sumaru, Shinji Sugiura, Toshiyuki Takagi, and Toshiyuki Kanamori Chapter 21 Lignin in Biological Systems.................................................................................... 709 Valentin I. Popa Chapter 22 Carbohydrate-Derived Self-Crosslinkable In Situ Gelable Hydrogels for Modulation of Wound Healing............................................................................ 739 Lihui Weng, Christine Falabella, and Weiliam Chen vii Contents Chapter 23 Dental and Maxillofacial Surgery Applications of Polymers................................... 783 E.C. Combe Chapter 24 Biomaterials as Platforms for Topical Administration of Therapeutic Agents in Cutaneous Wound Healing................................................................................... 837 Rhiannon Braund and Natalie J. Medlicott Chapter 25 Polymers for Artificial Joints.................................................................................... 851 Masayuki Kyomoto, Toru Moro, and Kazuhiko Ishihara Index............................................................................................................................................... 885 Preface The field of biomaterials has developed rapidly because of the continuous and ever-expanding ­practical needs of medicine and health-care practice. There are currently thousands of medical devices, diagnostic products, and disposables on the market, and the range of applications continues to grow. In addition to traditional medical devices, diagnostic products, pharmaceutical preparations, and health-care disposables, the list of biomaterials applications includes smart delivery ­systems for drugs, tissue cultures, engineered tissues, and hybrid organs. Undoubtedly, biomaterials have had a major impact on the practice of contemporary medicine and patient care, resulting in both saving and improving the quality of lives of humans and animals. Modern biomaterials practice is continuing to develop into a major interdisciplinary effort involving chemists, biologists, engineers, and physicians. It also takes advantage of developments in the traditional, nonmedical materials field, and much progress has been made since the beginning of the research in biomaterials that made possible the creation of a high-quality and much improved variety of devices, implants (permanent or temporary), and drug carrier devices. All of these now display a greater than ever biocompatibility and biofunctionality. The variety of chemical substances used in these materials is currently very broad, and most biomedical applications are associated with various polymers and materials based on them. The pace of research in the field of polymeric biomaterials is so fast that two editions of Polymeric Biomaterials have already been edited by Severian Dumitriu. Due to the interest generated and the success of these books, Severian was working on a third edition. Unfortunately, he passed away before this could be finalized. Many of the scientists who accepted his invitation to cooperate for this new edition agreed to contribute to the book in memory of the contribution that Severian made to the field of polymeric biomaterials. Together with Daniela, his beloved daughter, and Barbara Glunn and Jessika Vakili from Taylor & Francis Group, we decided to continue the work and finalize this book. This book is organized in two volumes consisting of 53 chapters that systematically provide the latest developments in different aspects of polymeric biomaterials. Thus, we can mention contributions to the field of synthesis and applications of polymers such as polyesters, poly(vinyl alcohol), polyphosphazenes, elastomers, bioceramics, blends or composites, enzymatic synthesis, along with natural ones such as mucoadhesives, chitin, chitosan, lignin, carbohydrates derivatives, heparin, etc. Drugs carriers and delivery systems, gene and nucleic acids delivery represent other subjects of some chapters, dealing with both supports (biodegradable and biocompatible) and techniques (nanoparticles, electrospinning, photo- and pH responsive polymers, hydrogels, lipid-core micelles, biomimetic systems, medical devices) aspects. In some cases, biomaterials can be synthesized, modified, and processed by different methods to ensure biocompatibility and biodegradability to be used as membranes, composites, scaffolds, and implants. Some examples of specific utilizations of polymeric biomaterials are presented, such as orthopedic surgery, bone regeneration, wound healing, dental and maxillofacial surgery applications, artificial joints, diabetes, anticancer agents and cancer therapy, modification of living cells, myocardial tissue engineering—repair and reconstruction, and bioartificial organs. Publishing this book was accomplished with the contributions of renowned scientists from all over the world. They are all experts in their particular field of biomaterials research and have made high-level contributions to various fields of research. We are very grateful to these scientists for their willingness to contribute to this reference work as well as for their engagement. Without their commitment and enthusiasm, it would not have been possible to compile such a book. ix x Preface I am also grateful to the publisher for recognizing the demand for such a book, for taking the risk to bring out such a book, and for realizing the excellent quality of the publication. I would like to thank Daniela for her inestimable help and assistance. I dedicate this book to memory of Severian, one of my best friends. Last but not least, I would like to thank my family for their patience. I sincerely apologize for the many hours I spent in the preparation of this book, which kept me away from them. This book is a very useful tool for many scientists, physicians, pharmacists, engineers, and other experts in a variety of disciplines, both in academe and industry. It may not only be useful for research and development but may also be suitable for teaching. This book has a companion CD that contains color figures as noted at the applicable text figures. Valentin I. Popa Acknowledgments My father was passionate about polymeric biomaterials. He was very happy when this project was planned with Taylor & Francis Group. He had worked tirelessly toward this. He would have loved to have seen this book published, but destiny willed otherwise. I am extremely grateful to Professor Popa for accepting to serve as the editor, to all the authors for their precious contributions, and to the staff at Taylor & Francis Group. The positive response from the authors to pursue their contribution to this book was amazing and is testimony of their appreciation for the scientific contribution that my father made to the field of polymeric biomaterials. I trust the book is of great quality and reflects the efforts and dedication that have been put into it by my father and all the contributors. My small contribution to this book is dedicated to the memory of my parents, Severian and Maria, for their unconditional love and for being the best teachers ever. And to finish on a positive note, I want to cite one quote of Dr. Seuss that I particularly like: “Don’t cry because it’s over. Smile because it happened”. Daniela Dumitriu xi Editors Severian Dumitriu (deceased) was a research professor, Department of Chemical Engineering, University of Sherbrooke, Quebec, Canada. He edited several books, including Polymeric Biomaterials, second edition, Polysaccharides in Medicinal Applications, and Polysaccharides: Structural Diversity and Functional Versatility (all three titles were published by Taylor & Francis Group [previously Marcel Dekker]), and authored or coauthored over 190 professional papers and book chapters in the fields of polymer and cellulose chemistry, polyfunctional initiators, and bioactive polymers. He also held 15 international patents. Professor Dumitriu received his BSc (1959) and MS (1961) in chemical engineering and his PhD (1971) in macromolecular chemistry from the Polytechnic Institute of Jassy, Romania. Upon completing his doctorate, he worked with Professor G. Smets at the Catholic University of Louvain, Belgium, and was a research associate at the University of Pisa, Italy; the Hebrew University Medical School, Jerusalem, Israel; and the University of Paris, South France. Valentin I. Popa earned his BSc and MSc in chemical engineering (1969) and PhD in the field of polysaccharide chemistry (1976) from Polytechnic Institute of Iasi, Romania. He was awarded the Romanian Academy Prize for his contributions in the field of seaweed ­chemistry (1976). He has published more than 500 papers in the following fields: wood chemistry and biotechnology, biomass complex processing, biosynthesis and biodegradation of natural compounds, allelochemicals, bioadhesives, and bioremediation. He is also the author or coauthor of 37 books or book chapters. Dr. Popa holds six patents and has been involved in many Romanian and European research projects as scientific manager. He was visiting scientist or visiting professor at Academy of Sciences (Seoul, Korea, 1972), Technical University of Helsinki (Finland, 1978), Institute of Biotechnology (Vienna, Austria, 1995), Research Institute for Pulp and Paper (Braila, Romania, 1976), “Petru Poni” Institute of Macromolecular Chemistry (Iasi, Romania, 1985, 1986), Université de Sherbrooke and University McGill (Canada, 2003), STFI–Packforsk (now known as Innventia, Stockholm, Sweden, 2008), and Institute of Wood Chemistry (Riga, Latvia, 2009). Dr. Popa is a member of the International Lignin Institute, International Association of Scientific Papermakers, International Academy of Wood Science, Romanian Academy for Technical Sciences, and American Chemical Society. He is also a professor of wood chemistry and biotechnology in “Gheorghe Asachi” Technical University of Iasi, PhD supervisor (30 students defended their theses), and editor-inchief of Cellulose Chemistry and Technology. xiii Contributors Harry R. Allcock Department of Chemistry The Pennsylvania State University University Park, Pennsylvania Pascal Auroy Université d’Auvergne Clermont-Ferrand, France Andreas Bernkop-Schnürch Institute of Pharmacy University of Innsbruck Innsbruck, Austria Martine Bonnaure-Mallet UFR Odontologie Equipe de Microbiologie EA 1254 Université Européenne de Bretagne Rennes, France Rhiannon Braund School of Pharmacy University of Otago Dunedin, New Zealand Toby D. Brown Institute for Health and Biomedical Innovation Queensland University of Technology Brisbane, Queensland, Australia Cesare Cametti Department of Physics University of Rome “La Sapienza” and CNR-INFM-SOFT Rome, Italy Dominique Chauvel-Lebret Université Européenne de Bretagne UFR d’Odontologie-UMR CNRS 6226 Sciences Chimiques de Rennes-UR1, CHU-pole d’Odontologie et de chirurgie Buccale Rennes, France Weiliam Chen Department of Surgery Division of Wound Healing and Regenerative Medicine School of Medicine New York University New York, New York Federica Chiellini Laboratory of Bioactive Polymeric Materials for Biomedical and Environmental Application (BIOLab) Department of Chemistry and Industrial Chemistry University of Pisa Pisa, Italy Valeria Chiono Department of Mechanical and Aerospace Engineering Politecnico di Torino Torino, Italy Gianluca Ciardelli Department of Mechanical and Aerospace Engineering Politecnico di Torino Torino, Italy E.C. Combe School of Dentistry University of Minnesota Minneapolis, Minnesota Paul D. Dalton Institute for Health and Biomedical Innovation Queensland University of Technology Brisbane, Queensland, Australia Meng Deng Institute for Regenerative Engineering Raymond and Beverly Sackler Center for Biological, Physical and Engineering Sciences The University of Connecticut Storrs, Connecticut xv xvi Jacques Desbrieres Department of Physics and Chemistry of Polymers Pau and Adour Countries University Pau, France Alberto Dessy Laboratory of Bioactive Polymeric Materials for Biomedical and Environmental Application (BIOLab) Department of Chemistry and Industrial Chemistry University of Pisa Pisa, Italy Abraham J. Domb Faculty of Medicine School of Pharmacy Institute of Drug Research The Hebrew University of Jerusalem Jerusalem, Israel Cesare Errico Laboratory of Bioactive Polymeric Materials for Biomedical and Environmental Application (BIOLab) Department of Chemistry and Industrial Chemistry University of Pisa Pisa, Italy Christine Falabella Department of Biomedical Engineering Stony Brook University State University of New York New York, New York Mar Fernández Institute for Health and Biomedical Innovation Queensland University of Technology Kelvin Grove, Queensland, Australia Piergiorgio Gentile Department of Mechanical and Aerospace Engineering Politecnico di Torino Torino, Italy Contributors Catherine Gkioni Department of Periodontology and Biomaterials Radboud University Nijmegen Medical Center Nijmegen, the Netherlands Takao Hanawa Institute of Biomaterials and Bioengineering Tokyo Medical and Dental University Tokyo, Japan Dietmar W. Hutmacher Institute for Health and Biomedical Innovation Queensland University of Technology Brisbane, Queensland, Australia Florin Dan Irimie Department of Biochemistry and Biochemical Engineering “Babeş-Bolyai” University Cluj-Napoca, Romania Kazuhiko Ishihara Department of Materials Engineering and Department of Bioengineering School of Engineering The University of Tokyo Tokyo, Japan John Jansen Department of Periodontology and Biomaterials Radboud University Nijmegen Medical Center Nijmegen, the Netherlands Christine Jérôme Center for Education and Research on Macromolecules University of Liège Liège, Belgium Toshiyuki Kanamori National Institute of Advanced Industrial Science and Technology Tsukuba, Japan Toshihiro Kasuga Graduate School of Engineering Nagoya Institute of Technology Nagoya, Japan xvii Contributors Wahid Khan Institute of Drug Research (IDR) School of Pharmacy-Faculty of Medicine The Hebrew University of Jerusalem Jerusalem, Israel Menno L.W. Knetsch Department of Biomedical Engineering/Biomaterials Science Maastricht University Maastricht, the Netherlands Masanori Kobayashi Department of Biomedical Engineering Daido University Nagoya, Japan Sangamesh G. Kumbar Department of Orthopaedic Surgery, Chemical, Materials and Biomolecular Engineering Institute for Regenerative Engineering Raymond and Beverly Sackler Center for Biological, Physical and Engineering Sciences The University of Connecticut Storrs, Connecticut Masayuki Kyomoto Department of Materials Engineering School of Engineering and Science for Joint Reconstruction Graduate School of Medicine The University of Tokyo and Research Department Kyocera Medical Corporation Tokyo, Japan Cato T. Laurencin Connecticut Institute for Clinical and Translational Science and Institute for Regenerative Engineering Raymond and Beverly Sackler Center for Biological, Physical and Engineering Sciences The University of Connecticut Storrs, Connecticut Philippe Lecomte Center for Education and Research on Macromolecules University of Liège Liège, Belgium Sander Leeuwenburgh Department of Periodontology and Biomaterials Radboud University Nijmegen Medical Center Nijmegen, the Netherlands Natalie J. Medlicott School of Pharmacy University of Otago Dunedin, New Zealand Franco Maria Montevecchi Department of Mechanical and Aerospace Engineering Politecnico di Torino Torino, Italy Toru Moro Science for Joint Reconstruction Graduate School of Medicine The University of Tokyo Tokyo, Japan Vijay Kumar Nandagiri Department of Mechanical and Aerospace Engineering Politecnico di Torino Torino, Italy Akiko Obata Graduate School of Engineering Nagoya Institute of Technology Nagoya, Japan Csaba Paizs Department of Biochemistry and Biochemical Engineering “Babeş-Bolyai” University Cluj-Napoca, Romania Gaio Paradossi Department of Chemical Sciences and Technologies University of Rome Tor Vergata Rome, Italy xviii Juan Parra Institute for Health and Biomedical Innovation Queensland University of Technology Kelvin Grove, Queensland, Australia Anna Maria Piras Laboratory of Bioactive Polymeric Materials for Biomedical and Environmental Application (BIOLab) Department of Chemistry and Industrial Chemistry University of Pisa Pisa, Italy Valentin I. Popa Department of Natural and Synthetic Polymers Faculty of Chemical Engineering and Environmental Protection “Gheorghe Asachi” Technical University of Iasi Iasi, Romania Gema Rodríguez-Crespo Institute for Health and Biomedical Innovation Queensland University of Technology Kelvin Grove, Queensland, Australia Luis M. Rodríguez-Lorenzo Institute for Health and Biomedical Innovation Queensland University of Technology Kelvin Grove, Queensland, Australia Julio San Román Institute for Health and Biomedical Innovation Queensland University of Technology Kelvin Grove, Queensland, Australia Contributors Alina Sionkowska Faculty of Chemistry Nicolaus Copernicus University Torun, Poland Shinji Sugiura National Institute of Advanced Industrial Science and Technology Tsukuba, Japan Kimio Sumaru National Institute of Advanced Industrial Science and Technology Tsukuba, Japan Toshiyuki Takagi National Institute of Advanced Industrial Science and Technology Tsukuba, Japan Monica Ioana Tosa Department of Biochemistry and Biochemical Engineering “Babeş-Bolyai” University Cluj-Napoca, Romania Cedryck Vaquette Institute for Health and Biomedical Innovation Queensland University of Technology Brisbane, Queensland, Australia Blanca Vázquez Institute for Health and Biomedical Innovation Queensland University of Technology Kelvin Grove, Queensland, Australia Lihui Weng Department of Radiology University of Minnesota Minneapolis, Minnesota 1 Synthesis and Fabrication of Polyesters as Biomaterials Philippe Lecomte and Christine Jérôme CONTENTS 1.1 1.2 1.3 Introduction...............................................................................................................................1 Step-Growth Polymerization.....................................................................................................2 Ring-Opening Polymerization of Cyclic Esters........................................................................3 1.3.1 Anionic Polymerization.................................................................................................4 1.3.2 Coordination Polymerization.........................................................................................6 1.3.3 Metal-Free Ring-Opening Polymerization....................................................................8 1.3.4 Enzymatic Ring-Opening Polymerization.................................................................. 13 1.3.5 Polymerization of Substituted and Functionalized Cyclic Esters................................ 14 1.4 Radical Ring-Opening Polymerization of Cyclic Ketene Acetals..........................................25 1.5 Macromolecular Engineering of Aliphatic Polyesters.............................................................26 1.5.1 Copolymerization........................................................................................................26 1.5.2 Modification of the Architecture................................................................................. 27 1.6 Conclusions..............................................................................................................................28 Acknowledgments.............................................................................................................................28 References.........................................................................................................................................28 1.1 INTRODUCTiON Nowadays, biomaterials are produced from a wide range of polymers. Among them, biodegradable and biocompatible aliphatic polyesters occupy a key position. Their chemical structure can be easily modified, which allows the tailoring of important properties such as bioadherence, mechanical properties, and kinetics of biodegradation. Aliphatic polyesters are thus widely used in biomedical applications as implants, as scaffolds in tissue engineering, and as carriers for drug delivery. This chapter aims at reviewing the most important techniques used for the synthesis of aliphatic polyesters in biomedical applications. The simplest approach relies on step-growth polymerization (Figure 1.1, routes a and b). Nevertheless, the control imparted to the polymerization is limited by this technique, and the synthesis of high molar mass polyesters is difficult. These drawbacks can be tackled by implementing another technique, the ring-opening polymerization of cyclic esters (Figure 1.1, route c). Under appropriate conditions, this polymerization is living and enables the synthesis of controlled high molar mass aliphatic polyesters. The chemical structure of the chainends can be controlled and it is thus possible to functionalize them on demand. Besides, aliphatic polyesters are produced by the ring-opening polymerization of cyclic esters at the industrial scale. Moreover, the livingness of the ring-opening polymerization of cyclic esters opens up the possibility to prepare various architectures such as star-shaped, comb-shaped, hyperbranched polymers and networks. The versatility of the ring-opening polymerization of cyclic esters thus allows fine tailoring of the properties of aliphatic polyesters in view of biomedical applications. A very important section of this chapter will thus be dedicated to this technique. It must be noted that other polymerization 1 2 Polymeric Biomaterials: Structure and Function, Volume 1 O HO R OH + HO O R OH O HO R O OH O a b c R O O O R O n d R FigURE 1.1 Main techniques for the synthesis of aliphatic polyesters. techniques were investigated even though they were not so popular. In this regard, special attention will be paid to the ring-opening polymerization of cyclic ketene acetals (Figure 1.1, route d). For biomedical applications, it is mandatory that aliphatic polyesters exhibit a very high purity and are not contaminated by potentially toxic impurities. Unfortunately, usual polymerization techniques are based on catalysts and initiators made up of toxic metals such as tin and aluminum, especially as far as the ring-opening polymerization of cyclic esters is concerned. Special attention will thus be paid to the recent advances in the implementation of polymerization processes based on less toxic metals or, even better, on metal-free processes. 1.2 STEP-GROWTH POLYMERiZATiON A straightforward approach for the synthesis of aliphatic polyesters is based on the step-growth polymerization of a mixture of diacids and diols or, more directly, of hydroxy acids, by implementing an esterification reaction. This technique allows the synthesis of a very wide range of aliphatic polyesters because of the easy synthesis of various diols, diacids, and hydroxy acids. Some of these can even be obtained from renewable resources, and bio-based aliphatic polyesters can then be ­produced. Step-growth polymerization has been in use for a long time, and hence we will not develop further the theory of polycondensation. It is just worth noting that, recently, Kricheldorf revised the concept of kinetically controlled (Kricheldorf and Schwarz 2003) and thermodynamically controlled (Kricheldorf 2003) step-growth polymerization. The main limitation of all step-growth polymerizations remains the difficult synthesis of high molar masses. Indeed, the synthesis of high molar mass polyesters by step-growth polymerization requires to reach high conversions very close to 100% and to stay close to the ideal 1/1 stoichiometry between alcohol and acid functions. The synthesis of polyhydroxyalkanoates (PHAs) by step-growth polymerization is a naturally occurring process (Lu et al. 2009). These aliphatic polyesters are produced by microorganisms as an intracellular reserve of carbon storage compounds and energy (Lu et al. 2009). Poly(3-(R)hydroxybutyrate) (PHB) is a typical example, but PHAs with a huge variety of chemical structures can be synthesized from a very wide range of hydroxyalkanoates. The potential of PHAs has been assessed for several biomedical applications such as controlled release, tissue engineering, surgical sutures, and wound dressings (Williams et al. 1999). The limitations of step-growth polymerization urged chemists to search for more efficient techniques for the synthesis of high molar mass aliphatic polyesters with a fine control of the chemical structure and the molar mass. This goal was achieved by implementing the ring-opening polymerization of cyclic esters, as will be shown in the next section. 3 Synthesis and Fabrication of Polyesters as Biomaterials 1.3 RiNg-OPENiNg POLYMERiZATiON Of CYCLiC ESTERS Ring-opening polymerization is a very popular technique to synthesize aliphatic polyesters in view of biomedical applications. The main reason for its success lies in the very easy synthesis of aliphatic polyesters with high and controlled molar masses (Stridsberg et al. 2002, Penczek et al. 2007). The main limitation remains, for the time being, the scarcity of cyclic esters, despite the recent progresses being made in the last few years, especially compared to diacids, diols, and hydroxyacids used in step-growth polymerization. The ring-opening polymerization of cyclic esters has been in use for a long time. van Natta et al. (1934) already reported in 1934 the ring-opening polymerization of ɛ-caprolactone (ɛCL). Nowadays, polylactide (PLA) and poly(ɛ-caprolactone) (PCL) are produced at the industrial scale (Figure 1.2). PCL is a semicrystalline biodegradable and biocompatible polyester (Tm = 60°C; Tg = −60°C) (Woodruff and Hutmacher 2010). Nevertheless, the degradation of PCL is slow, making it suitable in the field of drug delivery applications for long-term applications (Sinha et al. 2004). PLA and copolymers of lactide and glycolide (PLGA) have the advantage to be more hydrophilic than PCL and thus to degrade faster. Polylactide contains a chiral center (R or S), and its properties depend on tacticity. It is indeed well known that isotactic PLA is semicrystalline, whereas atactic PLA is amorphous. Semicrystalline PLA exhibits interesting mechanical properties but at the expense of biodegradability. Isotactic PLLA is synthesized by the polymerization of enantiomerically pure l-lactide, whereas atactic PLLA is obtained from a racemic mixture of l- and d-lactides. The ring-opening polymerization of ɛCL and LA is carried out at the industrial level. Interestingly enough, PLA is a bio-based polyester produced from agricultural renewable resources such as starch, whereas biodegradable PCL is produced from oil. Although ɛCL, GA, and LA are very important monomers, other cyclic esters can be polymerized by ring-opening depending on their size. First, there is an important question to determine whether a cyclic ester can be polymerized or not. The answer to this question can be found by considering thermodynamic data. According to the microreversibility rule, there is a competition between polymerization and depolymerization. Table 1.1 shows the values of the enthalpy (ΔHp) and entropy (ΔSp) of polymerization, the monomer concentration at equilibrium ([M]eq), and the ceiling temperature (Tc) (Duda et al. 2005). Table 1.1 shows that the polymerization of low-membered cyclic esters is an enthalpy-driven process (Penczek et al. 2000, Duda et al. 2005). The release of the ring strain is obviously a key parameter in favor of polymerization. Nevertheless, the behavior of five-membered lactones is completely different, as shown by the high-ceiling temperature, because depolymerization is faster than polymerization. Although the ring-opening polymerization of γBL is difficult, it is possible to O O O O n Poly(ε-caprolactone) (PCL) ε-Caprolactone O R O O O O R R n O R = H: glycolide R = Me: lactide R = H: polyglycolide (PGA) R = Me: polylactide (PLA) FigURE 1.2 Polymerization of ɛ-caprolactone (ɛCL) and lactide (LA) and glycolide (GA). 4 Polymeric Biomaterials: Structure and Function, Volume 1 TABLE 1.1 Thermodynamics for the Polymerization of Cyclic Esters Monomer βPL γBL LA GA VL εCL Ring Size Monomer Polymer States ΔHp (kJ/mol) ΔSp (J/mol K)p [M]eq (mol/L) Tc (K) 4 5 6 6 6 7 1c 1c 88 11 Lc 1c −82.3 5.1 −22.9 −13.8 −27.4 −28.8 −74 −29.9 −41 −45 −65 −53.9 3.9 × 10−10 3.3 × 10−3 5.5 × 10−2 2.5 3.9 × 10−1 5.3 × 10−2 1112 −171 914 520 — 534 TABLE 1.2 Nomenclature of Cyclic Esters Ring Size βPL γBL δVL LA GA εCL 4 5 6 6 6 7 IUPAC Name Usual Name oxetan-2-one dihydrofuran-2(3H)-one tetrahydro-2H-pyran-2-one lactide glycolide oxepan-2-one β-propionolactone γ-butyrolactone δ-valerolactone 3,6-dimethyl-1,4-dioxane-2,5-dione 1,4-dioxane-2,5-dione ε-caprolactone obtain low molar mass oligomers under suitable conditions and also to copolymerize γBL with other cyclic esters (Penczek et al. 2000). It is worth noting that lactide, caprolactone, and glycolide are not the names recommended by IUPAC. Table 1.2 shows the usual and official names for several cyclic esters. For the sake of simplicity, the usual names will be mentioned in this review to avoid confusion. So many initiators and catalysts have been used for the ring-opening polymerization of cyclic esters for the last few years that it is impossible to list all. This review will thus focus on the most popular processes with special attention being paid to the livingness and kinetics of polymerization, and the contamination of aliphatic polyesters by toxic residues not tolerated in the frame of biomedical applications. 1.3.1 ANIONIC POLYMERIZaTION Metal alkoxides are nucleophilic species prone to initiate the ring-opening polymerization of cyclic esters. Polymerization takes place usually by the cleavage of the acyl-oxygen bond. Figure 1.3 shows the initiation and propagation steps in the case of polymerization of ɛCL. O O R O – + RO O O O O Initiation O – Propagation FigURE 1.3 Anionic ring-opening polymerization of ɛCL. RO O 5 n 5 O – O 5 Synthesis and Fabrication of Polyesters as Biomaterials The mechanism shown in Figure 1.3 assumes that polymerization is living and takes place only by initiation and propagation reactions according to Szwarc (1956), which means that no ­termination and transfer reactions are present. This view is unfortunately oversimplified because termination and transfer reactions are often observed. Indeed, anionic species are deactivated by traces of water or by other protic substances, which is nothing but a termination reaction. It is thus necessary to perform these anionic polymerizations with carefully purified monomers under strictly anhydrous conditions. Besides, although metal alkoxides react as nucleophiles, they react also as bases. For instance, potassium tert-butoxide reacts with ɛCL to form the corresponding potassium enolate. Transfer reactions by transesterification reactions are commonly observed and are at the origin of loss of control of polymerization (Figures 1.4 and 1.5). Indeed, alkoxides are often too reactive to be selective, and they can react not only with the ester functions of monomers but also with the ester functions present all along the polymer chains. Depending upon whether alkoxide and ester are located on the same chain or not, transesterification reaction can be intramolecular or intermolecular. Intramolecular transesterification reactions result in a decrease of the molar mass and in the formation of cyclic oligomers (Figure 1.4). Conversely, intermolecular transesterification does not result in a decrease of the number-average molar mass but rather results in the reshuffling of the length of chains and thus in the modification of the polydispersity index (Figure 1.5). For the sake of simplicity, the mechanism of ɛCL is shown in Figures 1.4 and 1.5, but it can be extended to other cyclic esters as well. Special attention has to be paid to the four-membered lactones because of their unusual behavior. Indeed, polymerization of β-lactones by the mechanism based on the cleavage of the acyl-oxygen bond is disfavored, which was accounted for by stereo-electronic effects (Coulembier et al. 2006a). Another mechanism based on the scission of the alkyl-oxygen bond is then observed (Figure 1.6). O O O O 5 n O O– O 5 Cyclic oligomer 5 m + O O FigURE 1.4 Intramolecular transesterification reactions during the polymerization of ɛCL. O O O – O O + 5 n O O O 5 5 m 5 p O O O O O 5 n 5 O O FigURE 1.5 + 5 p 5 m O O Intermolecular transesterification reactions during the polymerization of ɛCL. O O R FigURE 1.6 – O O R O O– O– Ring-opening polymerization of β-lactones by cleavage of the alkyl-oxygen bond. 5 n O– 6 Polymeric Biomaterials: Structure and Function, Volume 1 R O O O– O n + R O R R=H, Me O– O OH O n + O R Intramolecular elimination reaction O RHC O– FigURE 1.7 Transfer reaction for the polymerization of β-lactones. Interestingly enough, ring-opening affords a carboxylate anion rather than an alkoxide. This polymerization can thus also be initiated by carboxylic salts even though they are less nucleophilic than alkoxides (Penczek 2007). It is worth noting that another transfer reaction mechanism shown in Figure 1.7 is reported as far as β-lactones are concerned (Penczek 2007). 1.3.2 COORDINaTION POLYMERIZaTION Anionic metal alkoxides are too reactive to be selective and transfer transesterification reactions are very difficult to get rid of, at the expense of control of polymerization. In order to improve the control of polymerization, it is mandatory to use less reactive initiators. This can be achieved by playing with steric and electronic effects (Lecomte and Jérôme 2004). The use of cumbersome ligands is the first possible route to obtain more selective species. The most common approach relies on the use of less electrophilic metals. The works of Teyssié and coworkers who used bimetallic μ-oxo-alkoxides as initiators have to be mentioned (Hamitou et al. 1973, Ouhadi et al. 1976). Since then, a wide range of transition metals have been investigated. Aluminum alkoxides occupy a key position because of the very good control imparted to the polymerization of cyclic esters. Commercially available aluminum triisopropoxide is a widely used aluminum alkoxide. Firstly, the three alkoxide bonds initiate polymerization. Nevertheless, the behavior of aluminum triisopropoxide is complicated due to its aggregation in solution. Indeed, aluminum isopropoxide exists as a mixture of trimers (A3) and tetramers (A4; Ropson et al. 1995). As long as polymerization of ɛCL is carried out by aluminum isopropoxide in toluene at 0°C, only A3 is prone to initiate polymerization. The interconversion of A4 into A3 is slow compared to the kinetics of polymerization, and A4 does not initiate polymerization under these conditions. Conversely, polymerization of lactide is carried out at a higher temperature, typically at 70°C. The interconversion of A4 into A3 is faster, and all species initiate polymerization. It is thus very important to take into account the equilibrium between A3 and A4 species to determine the theoretical molar mass on the basis of the monomer-to-initiator molar ratio. Last but not least, it is worth ­noting that aluminum alkoxides can be prepared in the laboratory by the reaction of any alcohol with ­triethylaluminum or aluminum isopropoxide (Dubois et al. 1989). The mechanism of polymerization is quite similar to that of anionic polymerization. Nevertheless, one has to take into account the coordination of the metal with oxygen atoms. The mechanism shown in Figure 1.8 is referred in the state of the art as the coordination–insertion mechanism. Firstly, the alkoxide (RO-M) coordinates with the carbonyl of the cyclic ester, followed by the nucleophilic addition of the alkoxide onto the electrophilic C=O bond. Thereafter, ring-opening takes place by an elimination reaction, resulting in the cleavage of the acyl-oxygen bond and in the formation of a new alkoxide. The initiator can contain one functional group, provided it is tolerated by aluminum alkoxide species (Dubois et al. 1989). 7 Synthesis and Fabrication of Polyesters as Biomaterials M O O RO M O O R O R O O OM + O O O M O O 5 5 O n OR M O O OR M O O OR n FigURE 1.8 Coordination–insertion mechanism for the ring-opening polymerization of cyclic esters. During the propagation of the ring-opening polymerization of cyclic esters initiated by aluminum alkoxides, aggregation can again take place depending upon stereoelectronic factors, as shown by NMR spectroscopy and kinetic studies (Duda and Penczek 1991). For instance, during the polymerization of ɛCL, the three-arm growing species is a unimer when initiated by A3 and is a trimer when initiated by Et2AlOR (Ropson et al. 1995). Although aluminum alkoxides exerted an excellent control to the polymerization of cyclic esters, they are suspected to be involved in Alzheimer’s disease. Moreover, catalytical remnants are very difficult to withdraw and these toxicity issues are thus a huge limitation for biomedical applications. Many researchers used tin(II) bis-(2-ethylhexanoate), also commonly referred to as tin octoate, instead of aluminum alkoxides because of its recognition by the American Food and Drug Administration (FDA). Another reason for the popularity of tin(II) bis-(2-ethylhexanoate) is its lower sensitivity to water and other impurities. It is thus easier to achieve polymerization in laboratories or in industry. Nevertheless, it was found that tin(II) bis-(2-ethylhexanoate) is also cytotoxic and should ideally be avoided for the synthesis of biomaterials. Tin(II) bis-(2-ethylhexanoate) does not contain any alkoxide bond, and the mechanism remained unclear for a long time and several proposals were reported. In 1998, Penczek and coworkers reported that tin alkoxides are formed in the polymerization medium by the reaction of tin(II) bis(2-ethylhexanoate) with traces of water or with any other protic impurities. Polymerization thus takes place by the usual coordination–insertion mechanism at least as long as it is carried out in THF at 80°C (Kowalski et al. 1998). This proposal was substantiated by kinetic measurements (Kowalski et al. 1998, 2000a), analysis of the chain-ends by MALDI-TOF (Kowalski et al. 2000b), and proton-trapping agent experiments (Majerska et al. 2000). It is worth noting that other tin-based initiators are also used. Hedrick and coworkers proposed to use tin trifluoromethanesulfonate to improve the kinetics of polymerization (Möller et al. 2000). Another possibility relies on the use of Sn(II) alkoxides (Duda et al. 2000, Kowalski et al. 2000c) and Sn(IV) alkoxides (Kricheldorf and Eggerstedt 1998, Kricheldorf et al. 2001, Kricheldorf 2004). Penczek and coworkers reported that the polymerization of lactide, initiated by Sn(OBu)2, is under control in a range of molar masses up to 106 g/mol (Duda et al. 2000, Kowalski et al. 2000c). Nevertheless, whatever the tin derivative used to initiate polymerization, toxicity remains an issue. Albertsson and coworkers proposed a smart approach to extract tin derivatives (Stjerndahl et al. 2007). They initiated the polymerization of cyclic esters by tin(IV) alkoxides before adding 1,2-ethanedithiol to the polymerization medium to afford a sulfur-containing dibutyltin derivative, which can be extracted because of its high solubility in organic solvents. For example, this process allowed synthesizing a sample of PCL contaminated by only 23 ppm of tin residues (Stjerndahl et al. 2007). If ring-opening polymerization can be carried out in bulk and in organic solvents, supercritical carbon dioxide is also a valuable medium. The technology based on supercritical carbon dioxide is 8 Polymeric Biomaterials: Structure and Function, Volume 1 particularly interesting in the field of biomaterials because of the remarkable extraction properties of this medium with the prospect to purify aliphatic polyesters. Ring-opening polymerization of ɛCL in supercritical carbon dioxide was first reported by Mingotaud and coworkers (Mingotaud et al. 1999, 2000). Then, Jérôme and coworkers observed that tin(IV) alkoxides initiate the controlled ring-opening polymerization of ɛCL in supercritical CO2 (Stassin et al. 2001). Slow kinetics was accounted for by the reversible reaction of tin alkoxides and carbon dioxide (Stassin and Jérôme 2002). PCL is not soluble in supercritical carbon dioxide, and the polymerization of ɛCL is thus heterogeneous. Nevertheless, in the presence of a suitable surfactant, nanoparticles can be obtained (Stassin and Jérôme 2004). Last but not least, supercritical CO2 was used to withdraw quantitatively unconverted monomer and metallic remnants. The issues related to the toxicity of tin and aluminum derivatives urged researchers to initiate the polymerization of cyclic esters by alkoxides based on less toxic metals. In this regard, bismuth (Kim et al. 2004), magnesium (Shueh et al. 2004, Yu et al. 2005b), and calcium (Zhong et al. 2001, Westerhausen et al. 2003) alkoxides are reported. The mechanism remains the usual coordination– insertion mechanism. The kinetics and control of polymerization depend on the nature of the metal and on its ligands. So many metallic derivatives have been used to initiate or catalyze the ring-opening polymerization of cyclic esters that it is almost impossible to list all. Among these derivatives, zinc octoate (Libiszowki et al. 2002, Kowalski et al. 2007), aluminum acetyl acetonate (Kowalski et al. 2007), scandium trifluoromethanesulfonate (Möller et al. 2000, Nomura et al. 2000), and scandium trifluoromethanesulfonimide [Sc(NTf2)3] (Oshimura and Takasu 2010) can be mentioned. Special attention has to be paid to lanthanides alkoxides (Metal = Er, Sm, Dy, La) as initiators because of the very fast kinetics of polymerization (McLain and Drysdale 1992). Shen et al. (1996) showed that the increase of steric hindrance of the ligand disfavors transesterification reactions. Yasuda and coworkers polymerized ɛCL by SmOEt(C5Me5)2(OEt2), [YOMe(C5H5)2]2, and YOMe(C5Me5)2(THF) (Yamashita et al. 1996). In 1996, yttrium isopropoxide was obtained “in situ” by the reaction of isopropanol and yttrium tris(2,6-di-tert-butylphenolate (Stevels et al. 1996a,b). Then, a similar approach was implemented by Jérôme and Spitz who synthesized Y(OiPr)3 (Martin et al. 2000, 2003a) and Nd(OiPr)3 (Tortosa et al. 2001) by the reaction of isopropanol with Y[N(SiMe3)2]3 and Nd[N(SiMe3)2]3, respectively. In 2003, the polymerization of ɛ-caprolactone was carried out by La(OiPr)3 (Save et al. 2002) and M(BH4)3(THF)3 (M = Nd, La, Sm) (Guillaume et al. 2003, Palard et al. 2005). Cyclic esters other than ɛCL can be polymerized by the same family of lanthanide alkoxides (Yamashita et al. 1996). Last but not least, Jérôme and coworkers grafted yttrium isopropoxide onto a porous silica surface (Martin et al. 2003b,c). Two methods of immobilization were reported. Firstly, the hydroxyl groups located on the surface of silica were allowed to react with an excess of Y[N(SiMe3)2]3 into silylamido groups, which were finally allowed to react with 2-propanol to obtain yttrium alkoxides. Secondly, Y[N(SiMe3)2]3 was made to react with less than three equivalents of 2-propanol into an yttrium alkoxide, which was then grafted onto the surface. Hamaide and coworkers supported alkoxides based on other metals (Al, Zr, Sm, and Nd) onto silica and alumina (Miola-Delaite et al. 2000). 1.3.3 METaL-FREE RING-OpENING POLYMERIZaTION Aluminum and tin alkoxides being too toxic for biomedical applications, chemists investigated original metal-free processes for the ring-opening polymerization of cyclic esters. Their strategy relies on the initiation of the polymerization by nucleophilic species such as alcohols and amines. Nevertheless, these species are in general not nucleophilic enough to react with cyclic esters. Nevertheless, there are exceptions to this general rule. For instance, highly reactive β-lactones are polymerized by nucleophilic amines in the absence of any catalyst. Polymerization initiated by tertiary amines is known as zwitterionic polymerization in the literature (Löfgren et al. 1995). The mechanism shown in Figure 1.9 is based on the reaction of tertiary amines and cyclic esters 9 Synthesis and Fabrication of Polyesters as Biomaterials O O O + R΄ R΄ N R΄ R΄ O– N+ R΄ O O R΄ O– R΄ N+ O O O n R΄ R΄ Zwitterion FigURE 1.9 Zwitterionic polymerization of pivalolactone. H O O n H+ O H RO O O R + O _H+ n OH n FigURE 1.10 Ring-opening polymerization of cyclic esters catalyzed by acids and initiated by alcohols. with a zwitterionic species made up of an ammonium cation and a carboxylate anion. Interestingly enough, Kricheldorf et al. (2005) mentioned the possibility that chain extension takes place by stepgrowth polycondensation at least at some stage of polymerization. As a rule, alcohols and amines are in general not nucleophilic enough to react with cyclic esters and the reaction has thus to be catalyzed. In order to do so, two main strategies might be implemented. They rely on the activation of either the monomer or the initiator. Last but not least, some processes combine both mechanisms of activation. Cyclic esters can be activated by either acids or nucleophiles to allow their reaction with alcohols and amines in the frame of a polymerization process. As far as acids are concerned as catalysts, the mechanism of ring-opening polymerization relies on the activation of cyclic esters by protonation of the exocyclic oxygen of cyclic diesters, which facilitates the reaction with the nucleophilic species, that can be the initiator during initiation or the hydroxyl-end capped chain during propagation (Figure 1.10). Polymerization takes place by the scission of the oxygen-acyl bond. In 2000, an example of ring-opening polymerization of ɛCL and δVL was reported by Endo and coworkers by using alcohol as an initiator and HCl.Et2O as a catalyst (Shibasaki et al. 2000). Polymerization was under control but the molar mass did not exceed 15,000 g/mol. It is worth noting that, later on, Jérôme and coworkers reported that molar masses up to 50,000 g/mol were obtained as far as PVL was polymerized (Lou et al. 2002a). Recently, the process was extended to a wider range of acids. Trifluoromethanesulfonic is an efficient catalyst for the controlled ring-opening polymerization of lactide (Bourissou et al. 2005) and ɛ-caprolactone (Basko and Kubisa 2006). Later, Bourrissou showed that trifluoromethanesulfonic acid can be substituted for less acidic methanesulfonic acid for the polymerization of ɛCL (Gazeau-Bureau et al. 2008). Polymerization of δVL was catalyzed by trifluoromethanesulfonimide according to Kakuchi et al. (2010). Interestingly enough, polymerization was under control and various functionalized alcohols were used as initiators. Very recently, Takasu and coworkers extended this strategy to nonafluorobutanesulfonimide for the polymerization of ɛCL (Oshimura et al. 2011). Interestingly enough, organic catalysts such as lactic acid (Casas et al. 2004, Persson et al. 2006), citric acid (Casas et al. 2004), fumaric acid (Sanda et al. 2002, Zeng et al. 2005), and amino acids (Casas et al. 2004) were also used. In addition, the acid catalyst can be supported on silica (Wilson and Jones 2004). Amino acids exhibit a particular behavior because they both catalyze and initiate polymerization (Liu and Liu 2004). In the absence of any nucleophilic species such as an alcohol, the only nucleophilic species remaining in the system is the cyclic ester. This is the typical case of cationic ring-opening polymerization of cyclic esters, which has been in use for a long time. The cationic polymerization can be catalyzed not only by Bronsted acids but also by alkylating agents, acylating agents, and Lewis acids. 10 Polymeric Biomaterials: Structure and Function, Volume 1 O C O + O O O O + C O + O R O O R 5 + R n FigURE 1.11 Mechanism for cationic ring-opening polymerization based on the reaction of the endocyclic oxygen. For instance, in 1984, Penczek reported the cationic polymerization of ɛCL and βPL by acylating agents (Hofman et al. 1984). For a long time it was accepted that cationic ring-opening polymerization mediated by alkylating agents takes place by the mechanism shown in Figure 1.11, which is based on the reaction of the cation with the endocyclic oxygen followed by the cleavage of the acyloxygen bond. In 1984, Penczek (Hofman et al. 1984) and Kricheldorf et al. (1986) proposed that the cation reacts with the exocyclic oxygen rather than the endocyclic oxygen to afford a dialkoxycarbocationic species, which finally reacts by cleavage of the alkyl-oxygen bond (Figure 1.12). It is worth noting that both mechanisms shown in Figures 1.12 and 1.13 are observed when acylating agents are used (Slomkowski et al. 1985). In recent years, the ring-opening polymerization of cyclic esters by nucleophilic catalysts has emerged as a very promising process under the impulse given by the group of Hedrick (Kamber et al. 2007). Table 1.3 shows several nucleophiles known to activate cyclic esters and thus prone to catalyze the ring-opening polymerization of cyclic esters initiated by alcohols by the mechanism shown in Figure 1.13. Among nucleophilic species, N-heterocyclic carbenes (Table 1.3, entries 1–7), amines (Table 1.3, entries 8–11), and phosphines (Table 1.3, entries 12–17) can be mentioned. Depending upon the cyclic ester that has to be polymerized, the nucleophilic catalyst must be carefully selected because its nucleophilicity and thus the kinetics of this ring-opening is influenced by steric and electronic effects. Interestingly enough, polymerization is under control. Although this approach is very promising, more work is needed to assess the impact of these catalysts on the biocompatibility of aliphatic polyesters. Another mechanism relies on the activation of the initiator. Bases that are able to activate nucleophilic alcohols and catalyze the ring-opening polymerization of cyclic esters are shown in Table 1.4. TBD and DBU catalyze the ring-opening polymerization of cyclic esters (Table 1.4, entries 1, 2). R O R+ + R O C+ O O O O O O O C+ O FigURE 1.12 Mechanism for cationic ring-opening polymerization based on the reaction of the exocyclic oxygen. O Nu + O O + Nu FigURE 1.13 Activation of cyclic esters by nucleophiles. O– 5 R O OH RO 5 OH 11 Synthesis and Fabrication of Polyesters as Biomaterials TABLE 1.3 Nucleophilic Catalysts for the Ring-Opening Polymerization of Lactones Entry Organocatalyst 1 N 2 N 3 N C C N N N C 4 N 5 Initiator Reference l-lactide εCL βBL rac-lactide meso-lactide εCL δVL EtOH, pyrenebutanol EtOH, pyrenebutanol EtOH, pyrenebutanol — — PhCH2OH PhCH2OH Connor et al. (2002) βBL δVL εCL εCL PhCH2OH PhCH2OH PhCH2OH PhCH2OH Nyce et al. (2003) l-lactide MeOH, pyrenebutanol, PEO-OH pyrenebutanol Coulembier et al. (2005) Dove et al. (2006) Dove et al. (2006) Nyce et al. (2003) Nyce et al. (2003) N C Ph N Ph Monomer C N N 6 βBL Ph N N Coulembier et al. (2006b) l-lactide — Connor et al. (2002) rac-lactide meso-lactide — — Dove et al. (2006) rac-lactide meso-lactide — — Dove et al. (2006) OR 7 Ph Ph N 7 C Ph Me H Ph N C Ph 8 N N N H Ph Me N Lactide EtOH, PhCH2OH Nederberg et al. (2001) Lactide EtOH, PhCH2OH Nederberg et al. (2001) Lactide Pyrenebutanol Pratt et al. (2006) and Lohmeijer et al. (2006) Lactide Pyrenebutanol Lohmeijer et al. (2006) DMAP 9 N N 10 N N N MTBD 11 N N DBU (continued) 12 Polymeric Biomaterials: Structure and Function, Volume 1 TABLE 1.3 (continued) Nucleophilic Catalysts for the Ring-Opening Polymerization of Lactones Entry 12 13 14 15 Organocatalyst Monomer PBu3 PPhMe2 PPh3 Initiator Reference Lactide Lactide Lactide Lactide PhEtOH PhEtOH PhEtOH PhEtOH Myers et al. (2002) Myers et al. (2002) Myers et al. (2002) Myers et al. (2002) Lactide PhEtOH Myers et al. (2002) Lactide PhEtOH Myers et al. (2002) Lactide PhEtOH Myers et al. (2002) P P 16 Et P Et Fe Et P Et 17 Pipr2 Fe Pipr2 18 PCy2 PCy2 Fe The mechanism is pseudoanionic and is based on the activation of the alcohol by attracting the ­proton. Phosphazene bases are also prone to catalyzing the ring-opening polymerization of cyclic esters (Zhang et al. 2007a). In particular, 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydrdro-1,3,2-diazaphosphorine (BEMP) is efficient (Table 1.4, entry 3). It is worth noting that BEMP exhibits a higher basicity (pKBH+ = 27.6) compared to DBU (pK BH+ = 24.3) and MTBD (pK BH+ = 25.4). As long as a dimeric phosphazene is used to catalyze the polymerization of racemic lactide (Table 1.4, entry 4), isotactic polylactide is obtained (Zhang et al. 2007b). Several catalysts have the ability to activate both the monomer and the initiator at the same time (Table 1.5). 1,5,7-Triazabicyclo[4.4.0]dec-5-ene (TBD) is an efficient organocatalyst for the ring-opening polymerization of cyclic esters initiated by alcohols (Table 1.5, entry 1), and the polymerization takes place by dual activation of both the monomer and the initiator. The activation of the monomer can take place either by an acyl transfer mechanism or by a mechanism based on hydrogen bonding. This last mechanism was preferred as far as the polymerization of l-lactide is concerned (Chuma et al. 2008). As long as 1,8-diaza[5.4.0]bicycloundec-7-ene (DBU) and N-methylated TBD (MTBD) were used as catalysts instead of TBD, the polymerization of lactide was slower. Polymerization of CL and VL did not take place. Indeed, these experimental data can be easily understood if one takes into account that these catalysts can only activate the alcohol but not cyclic esters (Lohmeijer et al. 2006). However, a possible trick to overcome this issue relies on the addition of a thiourea activating cyclic esters by hydrogen 13 Synthesis and Fabrication of Polyesters as Biomaterials TABLE 1.4 Basic Catalysts for the Ring-Opening Polymerization of Lactones Entry Organocatalyst 1 Monomer N Initiator Reference Lactide 1-Pyrenebutanol Pratt et al. (2006) and Lohmeijer et al. (2006) Lactide 1-Pyrenebutanol Lohmeijer et al. (2006) l-lactide δVL εCL 1-Pyrenebutanol 1-Pyrenebutanol 1-Pyrenebutanol Zhang et al. (2007a) Zhang et al. (2007a) Zhang et al. (2007a) l-lactide 1-Pyrenebutanol Zhang et al. (2007a) N N MTBD 2 N N DBU 3 N Et2N N P N tBu 4 N N P N N N P N tBu N bonding (Table 1.5, entry 2). Interestingly enough, both catalytical species can be combined in a single molecule. Indeed, Hedrick and coworkers reported that the polymerization of cyclic esters is efficiently catalyzed by 1-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(dimethylamino)cyclohexyl]thiourea with a very good control of the molecular parameters (Table 1.5, entry 3; Dove et al. 2005). Polymerization takes place also in the presence of both 1-[3,5-bis(trifluoromethyl) phenyl]-3-cyclohexylthiourea and N,N-dimethylcyclohexanamine (Table 1.5, entry 4; Dove et al. 2005). Whenever only one of these is present, no polymer was obtained, in agreement with a dual activation mechanism. 1.3.4 ENZYMaTIC RING-OpENING POLYMERIZaTION Enzymes are very promising nontoxic catalysts for the preparation of biomaterials. They are green catalysts obtained from renewable resources and are easily separated from polyesters. Among enzymes, lipases are known to catalyze the hydrolysis reaction of esters. Chemists used these natural enzymes to catalyze the reverse reaction, for example, the esterification reaction. The ring-opening polymerization of cyclic esters can be catalyzed by lipases as independently discovered in 1993 by the groups of Kobayashi (Uyama and Kobayashi 1993) and Knani et al. (1993). Since then, a wide variety of cyclic esters of different size were polymerized. Several reviews have been published on this topic (Gross et al. 2001, Varma et al. 2005, Albertsson and Srivastava 2008, Kobayashi and Makino 2009). Among the different lipases, Candida antarctica (lipase CA, CALB or Novozym 435) is widely used. An alcohol can purposely be added in the reaction medium to initiate polymerization. The course of polymerization is influenced by water. 14 Polymeric Biomaterials: Structure and Function, Volume 1 TABLE 1.5 Dual Catalysts for the Ring-Opening Polymerization of Lactones Entry Organocatalyst 1 N N N TBD 2 CF3 N N 3 S + N H F3C DBU Reference Lactide δVL εCL Pyrenebutanol Pyrenebutanol Pyrenebutanol Pratt et al. (2006) Lohmeijer et al. (2006) Lohmeijer et al. (2006) δVL εCL Pyrenebutanol Pyrenebutanol Lohmeijer et al. (2006) Lohmeijer et al. (2006) Lactide Pyrenebutanol Dove et al. (2005) Lactide Pyrenebutanol Dove et al. (2005) rac N H N H F3C Initiator N H CF3 S Monomer NMe2 4 CF3 S F3C N H + N H NMe2 Indeed, a minimum amount of water needs to be bound to the surface of the enzyme to maintain its conformational flexibility and catalytic activity (Gross et al. 2001). Nevertheless, water also initiates this polymerization. The synthesis of high molar mass aliphatic polyesters by enzymatic ring-opening polymerization is thus difficult because it is not possible to carry out polymerization in strictly anhydrous conditions. In terms of the control of polymerization, enzymatic polymerization cannot compete with coordination or organocatalytic polymerization. Nevertheless, enzymatic polymerization has some practical interests. Polymerization proceeds under mild conditions in terms of pH, temperature, and pressure and can be carried out in bulk, in organic media, and even in supercritical carbon dioxide (Takamoto et al. 2001, Loeker et al. 2004). Moreover, enzymes are able to catalyze the ring-opening polymerization of large-membered cyclic esters, which are very difficult to polymerize by chemical catalysts and initiators such as metal alkoxides and organocatalysts (Duda et al. 2002). The mechanism of enzymatic polymerization is based on the activation of the monomer and is very similar to the one already shown for nucleophilic organocatalysts. Briefly, a complex is formed between the enzyme and cyclic esters. The hydroxyl group of a serine residue of the active site of the enzyme reacts with cyclic esters affording an activated open form of the monomer. This activated intermediate then reacts with an alcohol, which can be the initiator or a hydroxyl-end capped chain. This mechanism is summarized in Figure 1.14. 1.3.5 POLYMERIZaTION Of SUBsTITUTED aND FUNCTIONaLIZED CYCLIC EsTERs Although PCL, PLA, and PGA are widely used for biomedical applications, it is highly desirable to synthesize a wider range of aliphatic polyesters in view of the development of novel biomedical applications. Two main routes were investigated for this application: the first one relies on the direct 15 Synthesis and Fabrication of Polyesters as Biomaterials O Lipase Lipase-OH O Lipase/OH complex O n R n OH OR OH – Lipase-OH FigURE 1.14 O O n OH Enzymatic polymerization of cyclic esters. chemical modification of aliphatic polyesters, and the second one is based on the synthesis and polymerization of substituted and/or functionalized cyclic esters. The direct functionalization of aliphatic polyesters is the most straightforward route. Vert and coworkers functionalized PCL by a two-step process. Firstly, the metallation of PCL was carried out by lithium diisopropylamide in order to obtain a poly(enolate), which was then reacted with any electrophile such as naphthoyl chloride (Ponsart et al. 2000), benzylchloroformate (Ponsart et al. 2000), acetophenone (Ponsart et al. 2000), benzaldehyde (Ponsart et al. 2000), carbon dioxide (Gimenez et al. 2001), tritiated water (Ponsart et al. 2001), α-bromoacetoxy-ω-methoxy-poly(ethylene oxide) (Ponsart et al. 2002), and iodine (Nottelet et al. 2006; Figure 1.15). This approach is very simple, and many functionalized PCL can be synthesized just by changing the nature of the electrophile. Moreover, the absence of any potentially toxic catalyst is a huge advantage. Unfortunately, this strategy is very touchy because degradation of aliphatic polyesters by nucleophilic enolates always takes place at a significant level. Under optimized conditions, degradation can only be limited. Although the process was extended to the functionalization of PLA, degradation is even more difficult to limit, this polymer being more sensitive than PCL. Moreover, the content of functionalization is quite low (<30%) even under optimized conditions. O 4 O x LDA OLi 4 O x Cl H MeI Cl Ph O 4 O FigURE 1.15 O O 4 x HO OBn O O O O Ph O 4 x O O OBn Functionalization of PCL according to Vert and coworkers. 4 x O O x 16 Polymeric Biomaterials: Structure and Function, Volume 1 The important limitations of the process shown in Figure 1.15 prompted chemists to investigate a less direct approach based on the synthesis and polymerization of functionalized cyclic esters (Lou et al. 2003). For that sake, two strategies can be applied. The first one relies on the insertion of the functional group inside the ring, and the second one is based on the substitution of the cyclic ester by a pendent functionalized group. Table 1.6 shows the conditions used for the polymerization of cyclic esters bearing, inside the ring, functional groups such as an ether (Table 1.6, entries 1–3), a protected amine (Table 1.6, entries 4,5), an unsaturation (Table 1.6, entries 6,7), a ketone (Table 1.6, entry 8), and an amide (Table 1.6, entries 9–12) are present. Table 1.7 shows cyclic esters bearing a substituent, functionalized or not. As functional groups, aromatics (Table 1.7, entry 1), chloride (Table 1.7, entries 2,3), bromide (Table 1.7, entries 4–6), iodide (Table 1.7, entry 7), alkyne (Table 1.7, entries 8, 9), alkene (Table 1.7, entries 10–15), and epoxide (Table 1.7, entry 16) can be mentioned. Cyclic esters reported in Tables 1.6 and 1.7 are usually polymerized by tin and aluminum alkoxides. It is worth noting that 6,7-dihydro-2(3H)-oxepinone is an unusual case because this monomer can be polymerized by another mechanism, the ring-opening metathesis polymerization (ROMP) process by using the Schrock’s catalyst (Figure 1.16; Lou et al. 2002c). In terms of chemoselectivity, enzymes are appealing catalysts because they tolerate a wide range of functional groups and even epoxides (Table 1.7, entry 16). Unfortunately, tin and aluminum alkoxides are less tolerant and do not tolerate the presence of alcohols, carboxylic acids, and epoxides. Noteworthily, ketones are tolerated by tin (IV) alkoxides but not by aluminum alkoxides for reasons which still remain unclear (Latere et al. 2002). This issue was overcome by protecting these functional groups prior to polymerization. Table 1.8 shows lactones substituted by protected ketones (Table 1.8, entry 1), alcohols (Table 1.8, entries 2–6), diols (Table 1.8, entry 7), carboxylic acids (Table 1.8, entries 8–15), and amines (Table 1.8, entries 16–19). The choice of the protection group is essential for the success of this strategy. One the one hand, the protected functional groups have to be stable enough to avoid any degradation prior to polymerization and to allow obtaining the monomer in a very high purity, which is a prerequisite to achieve polymerization, at least as far as sensitive initiators are concerned, such as aluminum alkoxides. On the other hand, the protection group has to be removed after polymerization under conditions that prevent degradation from occurring. For this reason, benzylic alcohols and carboxylic esters are widely used because they can be deprotected under neutral conditions rather than in acidic conditions. As a rule, these two conditions are contradictory and it is not always that easy to find a satisfactory compromise between the stability of the monomer and the easy deprotection. Many of the cyclic esters shown in Tables 1.6 through 1.8 are chiral and possess at least one chiral carbon (R or S). Although the stereoselective polymerization of lactide (Zhong et al. 2004) and β-butyrolactone (Amgoune et al. 2006, Carpentier 2010) is reported in the literature, the stereoselectivity of their polymerization is in general not discussed and racemic mixtures are polymerized. Obviously, more attention should be paid to these aspects in the future because stereoselective polymerization allows the synthesis of aliphatic polyesters with different tacticities, and thus of different properties. Last but not least, it must be noted that substituted cyclic esters can sometimes be expensive because their synthesis can require several steps from commercially available compounds at the expense of the global yield, which can be low. It is beyond the scope of this chapter to describe all the syntheses of these functionalized cyclic esters, and the reader is invited to read the references given in Tables 1.6 through 1.8. Another limitation relies on the necessity to synthesize a new cyclic ester for any new functional aliphatic polyester. The functionalization of aliphatic polyesters opens up new avenues in the field of biomaterials. The presence of functional groups allows modifying the biodegradation rate by changing the crystallinity and hydrophilicity or by adding functional groups such as carboxylic acids prone to catalyze the degradation. Interestingly enough, pH-sensitive aliphatic polyesters can be obtained by grafting carboxylic acids or amines along aliphatic polyesters. These groups can be under a neutral or an 17 Synthesis and Fabrication of Polyesters as Biomaterials TABLE 1.6 Ring-Opening of Cyclic Monoesters Functionalized inside the Ring Entry Monomer 1 O Initiator Bu2SnO, Sn(Oct)2 O Reference Al(OiPr)3 Mathisen and Albertsson (1989) and Mathisen et al. (1989) Löfgren et al. (1994) Et3Al, H2O Shirahama et al. (1993, 1996) Zn(II) l-lactate Al (OiPr)3 Kricheldorf and Damrau (1998) and Raquez et al. (2000) ROH/Sn(Oct)2 Trollsas et al. (2000) DBU Kudoh et al. (2009) Al(OiPr)3 Lou et al. (2001) Al(OiPr)3 Schrock’s catalyst Lou et al. (2002b) Lou et al. (2002c) O 2 O O Me 3 R O O O O 4 O O N O CF3 5 O O N 6 O Ph O 7 O O (continued) 18 Polymeric Biomaterials: Structure and Function, Volume 1 TABLE 1.6 (continued) Ring-Opening of Cyclic Monoesters Functionalized inside the Ring Entry Monomer 8 O Initiator Reference l-Phenyl-2-propanol, Sn(Oct)2 Latere et al. (2002) Feng et al. (1999a, 2000) Feng et al. (1999a,b) O Porcine pancreatic lipase lipase type XIII from Pseudomonas species lipase from Pseudomonas cepacia lipase type VII from Candida rugosa porcine pancreatic lipase O porcine pancreatic lipase Feng et al. (2000) O porcine pancreatic lipase Feng et al. (2000) O O 9 O O 10 N O O 11 12 Feng et al. (1999b) Feng et al. (2000) N O O Feng et al. (1999a,b) N O O O N ionic form depending upon the pH and their pKa, which affects their solubility in water. Another application relies on the use of these functional groups for the covalent grafting of biologically active molecules, drugs, targeting units, and other functional groups. For that sake, very efficient reactions have to be used under nondegrading conditions. It is not very easy to find a reaction that meets these criteria (Lecomte et al. 2006). Recently, it turned out that the click copper-catalyzed alkyne-azyde Huisgen’s cycloaddition reaction (CuAAC) is particularly efficient (Parrish et al. 2005, Riva et al. 2007, Lecomte et al. 2008) in the presence of limited degradation (Lecomte et al. 2008). Moreover, the reaction can take place in water and in organic solvents. Nevertheless, the use of copper salts as catalysts is a severe limitation for biomedical applications. Although they are not as efficient as the CuAAC reaction, several other metal-free reactions have been used such as the esterification reaction between alcohols and carboxylic acids (Renard et al. 2003, Parrish and Emrick 2004), the ring-opening of epoxides by thiols (Lou et al. 2002b), the thiol-ene reaction (Rieger et al. 2005), and the coupling of ketones and oxyamines (Taniguchi et al. 2005, van Horn et al. 2008). 19 Synthesis and Fabrication of Polyesters as Biomaterials TABLE 1.7 Ring-Opening Polymerization of Functionalized Cyclic Esters Entry Monomer 1 O Initiator Reference 4-tBu-C6H4-CH2OH, Sn(Oct)2 Simmons and Baker (2001) Sn(Oct)2 Al(OiOr)3 Pyridine, Et3N CF3CO2H Liu et al. (1999) Liu et al. (1999) Liu et al. (1999) Liu et al. (1999) 2,2-Dibutyl-2-stanna-1,3dioxepane Lenoir et al. (2004) Al(OiPr)3 Mecerreyes et al. (1999) Al(OiPr)3 Detrembleur et al. (2000) Al(OiPr)3 (copolymerization with εCL) Wang et al. (2005) O O O 2 Cl O O 3 O Cl O 4 O O O O Br 5 O O Br 6 Br O O (continued) 20 Polymeric Biomaterials: Structure and Function, Volume 1 TABLE 1.7 (continued) Ring-Opening Polymerization of Functionalized Cyclic Esters Entry 7 Monomer O I Initiator Reference MeOH, Sn(Oct)2 El Habnouni et al. (2009) EtOH, Sn(OTf)2 Parrish et al. (2005) 4-tBu-C6H4-CH2OH, Sn(Oct)2 Jiang et al. (2008) Al(OiPr)3 Mecerreyes et al. (2000a) PhCH2OH, Sn(Oct)2 Mecerreyes et al. (2000b) MeO-[Y] (copolymerization with βBL) Ajellal et al. (2009) O 8 O O 9 O O O O 10 O O O O 11 O O 12 O O 21 Synthesis and Fabrication of Polyesters as Biomaterials TABLE 1.7 (continued) Ring-Opening Polymerization of Functionalized Cyclic Esters Entry Monomer 13 Initiator O Reference PhCH2OH, Sn(Oct)2 Leemhuis et al. (2008) 2,2-Dibutyl-2-stanna-1,3dioxepane (block copolymerization with εCL) Li et al. (2006) Novozym 435 Veld et al. (2007) Novozym 435 Veld et al. (2007) O O O 14 O O O O 15 O O O 16 O O O O CH3(CF3)2OC O N Mo CMe2Ph OC(CF3)2CH3 O ROMP FigURE 1.16 Polymerization of 6,7-dihydro-2(3H)-oxepinone by ROMP. O n 22 Polymeric Biomaterials: Structure and Function, Volume 1 TABLE 1.8 Ring-Opening Polymerization of Cyclic Esters Bearing Protected Functional Groups Entry Monomer 1 O Initiator Reference Al(OiPr)3 Tian et al. (1997) Sn(Oct)2 (copolymerization with δVL and a dilactone) Pitt et al. (1987) Al(OiPr)3 (copolymerization with εCL and TOSUO) Stassin et al. (2000) ROH, Sn(Oct)2 Trollsas et al. (2000) O O O 2 O O TBDMSO 3 O O Et3SiO 4 O O PhCH2O 5 O Leemhuis et al. (2006) N O O O Zn iPrOH, O 6 OBn O O O O iPrOH, O Leemhuis et al. (2006) N OBn Zn 23 Synthesis and Fabrication of Polyesters as Biomaterials TABLE 1.8 (continued) Ring-Opening Polymerization of Cyclic Esters Bearing Protected Functional Groups Entry Monomer 7 O Initiator Reference ROH, Sn(Oct)2 Trollsas et al. (2000) ROH, Sn(Oct)2 Trollsas et al. (2000) ROH, Sn(Oct)2 Trollsas et al. (2000) Al(OiPr)3 (copolymerization with εCL) Lecomte et al. (2000) Tetraethylammonium benzoate Bizzari et al. (2002) O O O O O Ph 8 O O O OBn 9 O O O OtBn 10 O O O OTBDMS 11 O O O OBn (continued) 24 Polymeric Biomaterials: Structure and Function, Volume 1 TABLE 1.8 (continued) Ring-Opening Polymerization of Cyclic Esters Bearing Protected Functional Groups Entry 12 Monomer Initiator O Reference Tetraethylammonium benzoate Barbaud et al. (2004) PEO-OH, Sn(Oct)2 Mahmud et al. (2006) PhCH2OH, Sn(Oct)2 Gerhardt et al. (2007) Al(OiPr)3, Sn(Oct)2, Et2zn Kimura et al. (1988) Tetrabutylammonium acetate Flétier et al. (1990) iPrOH, Sn(Oct)2 Blanquer et al. (2010) O OBn O 13 O O OBn O 14 O O O O n O 15 OBn n = 1,2 O O O O O 16 O O O TrN 17 O O O HN OBn O 25 Synthesis and Fabrication of Polyesters as Biomaterials TABLE 1.8 (continued) Ring-Opening Polymerization of Cyclic Esters Bearing Protected Functional Groups Entry 18 Monomer Initiator O Reference Sn(Oct)2 (copolymerization with εCL) Yan et al. (2010) PhCH2OH, Sn(Oct)2 Gerhardt et al. (2007) O HN OBn O 19 O O H N O OBn 4 O O 1.4 RADiCAL RiNg-OPENiNg POLYMERiZATiON Of CYCLiC KETENE ACETALS Although the ring-opening polymerization of cyclic esters is a very widely used technique to prepare aliphatic polyesters, special attention has to be paid to a less common process based on the ring-opening polymerization of cyclic ketene acetals (Bailey 1985, Sanda and Endo 2001, Agarwal 2010). For instance, the polymerization of ɛCL and 2-methylidene-1,3-dioxepane affords an aliphatic polyester with the same chemical structure. Nevertheless, the polyester obtained from ɛCL is semicrystalline and the polyester obtained from 2-methylidene-1,3-dioxepane is completely amorphous due to a high degree of branching (Jin and Gonsalves 1997, Undin et al. 2010). The degradation rate of amorphous polymers being faster compared to semicrystalline polymers, the synthesis of amorphous aliphatic polyesters is promising in terms of biomedical applications. The mechanism of the polymerization of 2-methylidene-1,3-dioxepane is shown in Figure 1.17. Radicals add onto the double bond to afford a new radical. This radical rearrange by ring-opening of the ketal into a new radical, which then propagate. The new C=O double bond is approximately more stable than 50 kcal than the starting C=C double bond. This energy gain, combined with the release of the ring-strain, is the driving force of polymerization (Bailey 1985). Another possible mechanism is the direct radical polymerization without any ring-opening (Figure 1.18). The polymerization selectivity (ring-opening versus direct polymerization) depends on several parameters such as ring size, substituents, and temperature. As far as the seven-membered cyclic acetal 2-methylene-1,3-dioxepane is concerned, polymerization takes place with 100% of ring-opening at room temperature (Bailey et al. 1982). Conversely, ring-opening is accompanied by direct vinyl polymerization whenever five- and six-membered cyclic acetals are polymerized (Bailey 1985). It is also worth noting that the presence of substituents can affect the selectivity of polymerization. Indeed, substituents able to stabilize the radical formed after the ring-opening step disfavor the direct vinyl polymerization. For instance, polymerization of 2-methylidene-4-phenyl1,3-dioxolane is fully selective with 100% ring-opening, whereas polymerization of unsubstituted five-membered cycles is usually not selective (Bailey 1985). 26 Polymeric Biomaterials: Structure and Function, Volume 1 O R + O R R R C O O O O O O O O O C C O FigURE 1.17 Polymerization of 2-methylidene-1,3-dioxepane. R R R + O O O C Ringopening O O O O C O R O O O C O Direct polymerization O R C O FigURE 1.18 O O Polymerization of six-membered cyclic ketene acetals. This technique of polymerization is not very popular because of its poor selectivity and the very difficult synthesis and purification of cyclic ketene acetals with moderate or even low yields. 1.5 MACROMOLECULAR ENgiNEERiNg Of ALiPHATiC POLYESTERS The properties of aliphatic polyesters have to be tailored on demand to develop novel biomedical applications. The previous sections of this review dealt with the main processes of polymerization and the examples given were limited to homopolymerizations. It was already shown that the functionalization of aliphatic polyesters is a first tool allowing the extension of the range of their properties. A second possible approach is based on copolymerization or in the modification of the architecture in the frame of macromolecular engineering. 1.5.1 COpOLYMERIZaTION The simplest technique of copolymerization is the polymerization of a mixture of, at least, two comonomers. The distribution of the two comonomers in the final polymer depends on their reactivity ratios. As far as copolymerization is random, the so-obtained copolyesters exhibit averaged properties of the corresponding homopolymers. The sequential polymerization of comonomers provides block copolymers, provided that the polymerization is living. In this review, it was shown that a plethora of initiators and catalysts allows the ring-opening polymerization of cyclic esters to be living. Accordingly, the literature reports a large number of examples dealing with the synthesis of block copolymers by this technique. Interestingly enough, block copolymers exhibit brand new properties compared to the corresponding homopolymers, and thus not just averaged properties as is the case for random copolymers. In many examples, the ring-opening polymerization of cyclic esters is just used to synthesize one block and the other block is obtained by another technique. Synthesis and Fabrication of Polyesters as Biomaterials 27 For example, PCL-b-PEO diblock copolymers are synthesized by successive polymerization of ethylene oxide and ɛCL (Kim et al. 2004, Bednarek and Kubisa 2005). These polymers are amphiphilic, PEO being soluble in water, which is not in the case of PCL. The self-association of these amphiphilic copolymers in water affords micelles or hollow spheres, which are used as drug carriers in drug delivery applications. It is worth recalling that PEO is not biodegradable but is biocompatible and bioresorbable provided its molar mass is low enough. A plethora of other works describes examples of fully degradable block copolyesters synthesized by ring-opening polymerization. 1.5.2 MODIfICaTION Of THE ARCHITECTURE The synthesis of aliphatic polyesters with various architectures is achieved by using the ­ring-­opening polymerization of cyclic esters, this technique being living under appropriate conditions. A first example is given by star-branched polyesters, which show particular properties such as lower melt viscosities, lower crystallinity, and smaller hydrodynamic volume. Interestingly enough, star-shaped copolyesters contain a higher number of chain-ends compared to linear polymers. Whenever chemists desire to graft a drug, a targeting unit, or a probe, the use of star-shaped polyesters rather than linear polyesters is thus an easy trick to increase their number. Two main techniques allow synthesizing star-shaped copolyesters. In the frame of the arm-first technique, living chains are coupled onto multifunctional (>3) electrophiles (Tian et al. 1994). Conversely, the initiation of the ring-opening polymerization by multifunctional initiators is known as the core-first technique. The most usual conditions are based on the initiation of the polymerization of cyclic esters by polyols in the presence of tin octoate (Trollsas et al. 1998, Lang et al. 2002, Kricheldorf 2004, Choi et al. 2005). Another approach less commonly used relies on the initiation of the polymerization by a spirocyclic initiator (Kricheldorf and Lee 1996, Li et al. 2008). Finally, the arm-first and core-first techniques can be combined to synthesize star-shaped copolymers in order to increase further the range of properties of star-shaped copolymers (Van Butsele et al. 2006, Riva et al. 2011). Graft polymers are other examples of polymers with a branched architecture (Dai et al. 2009). These polymers can be synthesized by three main methods. The polymerization of chains end-capped by a polymerizable unit, i.e., a macromonomer, is known as the “grafting through approach.” The “grafting onto” process is based on the coupling of chains functionalized at one chain-end onto a backbone bearing several complementary functions. The last process, the “grafting from” technique, relies on the initiation of the polymerization by a macroinitiator bearing several initiating units. Hyperbranched aliphatic polyesters are obtained by the polymerization of ABx inimers made up of an initiator and a polymerizable group. Typical examples are lactones substituted by unprotected alcohols (Liu et al. 1999a, Trollsas et al. 1999, Tasaka et al. 2001, Yu et al. 2005a, Parzuchowski et al. 2006). The crystallinity, biodegradation rate, and the mechanical properties of biomaterials made up of aliphatic polyesters can be modified by implementing cross-linking reactions. For instance, Hedrick and coworkers reported the cross-linking of PCL bearing pendant acrylates (Mecerreyes et al. 2001). An intramolecular cross-linking takes place under diluted conditions and nanoparticles are then prepared. As far as the cross-linking is carried out at higher concentration, intermolecular cross-linking affords three-dimensional networks. The cross-linking can be carried out in the presence of radicals (Mecerreyes et al. 2001) or photochemically (Riva et al. 2007, Vaida et al. 2008). The cross-linking of linear or star-shaped aliphatic polyesters bearing an unsaturation at least at two chain-ends is also possible (Turunen et al. 2001, Kweon et al. 2003). The cross-linking can be carried out by processes based exclusively on ring-opening polymerization. In this respect, Albertsson and coworkers reported on the ring-opening polymerization of tetrafunctional bis-(ɛ-caprolactones) (Palmgren et al. 1997, Albertsson et al. 2000). Other cross-linking agents are made up of other polymerizable heterocycles, such as bis-carbonates (Grijpma et al. 1993) or lactones substituted by epoxides (Lowe et al. 2009). All these processes are based on the ring-opening polymerization ­technique. Nevertheless, networks can also be obtained by the polycondensation of comonomers, one of them being at least trifunctional (Kricheldorf and Fechner 2002, Theiler et al. 2010). 28 Polymeric Biomaterials: Structure and Function, Volume 1 Finally, the cross-linking can be carried out by the coupling of telechelic polymers with polyesters bearing along the chains the complementary functional groups. Several coupling reactions are reported for that sake such as the Michael addition of amines onto acrylates (Theiler et al. 2010), the coupling of ketones and oxyamines (van Horn and Wooley 2007), the click copper(II) catalyzed azide-alkyne cycloaddition (Zednik et al. 2008), and the esterification reaction (Kricheldorf and Fechner 2001, Kricheldorf 2004, Theiler et al. 2010). Finally, it is worth noting that other examples of architectures such as macrocycles (Li et al. 2006, Jeong et al. 2007, Lang et al. 2002, Hiskins and Grayson 2009, Misaka et al. 2009, Xie et al. 2009) can be found in the literature. Nevertheless, their impact on the field of biomaterial is quite limited and they will not be reported in this review. As far as macrocycles are concerned, the lack of applications as biomaterials can be accounted for by their difficult synthesis even though some recent progresses have been made in this field (Laurent and Grayson 2009). 1.6 CONCLUSiONS The importance of biodegradable and biocompatible aliphatic polyesters as biomaterials and as environmentally friendly thermoplastics prompted researchers to develop efficient processes for their synthesis, mainly by step-growth polymerization and ring-opening polymerization of cyclic esters. Nowadays, owing to the impressive progresses achieved in this field, it is possible to synthesize ­aliphatic polyesters with high and controlled molar masses, to control the functionalities at the chain-ends and to graft functional groups all along the chains. The architecture of aliphatic ­polyesters can also be modified on demand in the frame of macromolecular engineering. Remarkably, ring-­opening polymerization can be carried out by a very wide range of polymerization techniques such as anionic, cationic, coordination, organocatalytic, enzymatic, and radical polymerizations. The synthesis of aliphatic polyesters can thus be considered as a mature field. Currently, the challenge for a chemist remains to develop efficient processes for the synthesis of ultrapure aliphatic polyesters, thus noncontaminated by toxic catalytical residues. In this regard, tin(II) bis-(2-ethylhexanoate) is still widely used despite its known toxicity and very difficult extraction. Obviously, more work needs to be done despite the very important progresses being reported in the last few years. In the future, special attention will have to be paid to implement green processes, for instance, by avoiding organic solvents and to the synthesis of a wider range of biobased aliphatic polyesters from new monomers produced from renewable resources. ACkNOWLEDgMENTS CERM is indebted to the “Belgian Science Policy” for general support in the frame of the “Interuniversity Attraction Poles Programme (IAP 6/27)—Functional Supramolecular Systems.” P.L. is research associate by the “Fonds National pour la Recherche Scientifique” (FRS-FNRS). REfERENCES Agarwal, S. 2010. Chemistry, chances and limitations of the radical ring-opening polymerization of cyclic ketene acetals for the synthesis of degradable polyesters. Polym. Chem. 1: 953–954. Ajellal, N., C.M. Thomas, and J.F. Carpentier. 2009. 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