Tissue Engineering. Series Editor- Anthony Atala, MD Children's Hospital, Boston

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2 Tissue Engineering Series Editor- Anthony Atala, MD Children's Hospital, Boston Editorial Advisory Board Jeffrey Hubbell, PhD California Institute of Technology Robert S. Langer, ScD Massachusetts Institute of Technology Antonios G. Mikos, PhD Rice University Joseph P. Vacanti, MD Children's Hospital, Boston Forthcoming TItles in the Series Encapsulated Cell Technology and Therapeutics R. Lanza and W. L. Chick, eds. Wound Healing and Tissue Engineering 1. O. Hollinger and D. M. Toriumi, eds.

3 Synthetic Biodegradable Polymer Scaffolds Anthony Atala David 1. Mooney Editors Joseph P. Vacanti Robert Langer Associate Editors Birkhauser Boston Basel Berlin

4 Anthony Atala Department of Surgery Children's Hospital and Harvard Medical School Boston, MA David J. Mooney University of Michigan, Ann Arbor 3074 Herbert Dow Building Ann Arbor, MI Joseph P. Vacanti Department of Surgery Children's Hospital Boston, MA Robert Langer Department of Chemical Engineering Massachusetts Institute of Technology Cambridge, MA Library of Congress CataJoging-in-Publication Data Synthetic biodegradable polymer scaffolds / Anthony Atala and David 1. Mooney, editors: Joseph P. Vacanti and Robert Langer, associate editors. p. cm. - (Tissue engineering) Includes bibliographical references and index. ISBN -13: e-isbn -13: DOl: / Polymers in medicine-biodegradation. 2. Tissue culture. 3. Animal cell biotechnology. I. Atala, Anthony, II. Mooney, David 1., III. Series. R857.P6S '5-dc CIP Printed on acid-free paper 1997 Birkhauser Boston Copyright is not claimed for works of U.S. Government employees. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without prior permission of the copyright owner. The use of general descriptive names, trademarks, etc. in this publication even if the former are not Merchandise Marks Act, may accordingly be used freely by anyone. While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Permission to photocopy for internal or personal use of specific clients is granted by Birkhauser Boston for libraries and other users registered with the Copyright Clearance Center (Ccq, provided that the base fee of $6.00 per copy, plus $0.20 per page is paid directly to CCC, 222 Rosewood Drive, Danvers, MA 01923, U.S.A. Special requests should be addressed directly to Birkhauser Boston, 675 Massachusetts Avenue, Cambridge, MA 02139, U.S.A. COVER PHOTOS-Left: Polyglycolic acid polymer scaffold with urothelial cells implanted in vivo and retrieved at 30 days shows cell layering and spatial orientation similar to that of normal urothelium. Reduced from X100. Center: Polyglycolic acid polymer without cells. Reduced from X200. Right: Formation of composite multilayered sheet-like structures lining tube obtained from cell-polymer implant consisting of urothelial and smooth muscle cells. Reduced from X200. Courtesy of Anthony Atala, Harvard Medical School, Boston. ISBN-13: Typeset by Northeastern Graphic Services, Inc., Hackensack, NJ

5 List of Contributors Anthony Atala, MD, Director, Laboratory for Tissue Engineering, Division of Urology and Department of Surgery, Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA Ronnda Bartel, PhD, Advanced Tissue Sciences, Inc., N. Torrey Pines Road, La Jolla, CA Rebekah D. Bostrom, BA, Cox Laboratory for Biomedical Engineering, Institute of Biosciences and Bioengineering and Department of Chemical Engineering, Rice University, P.o. Box 1892, Houston, TX Linda G. Braddon, PhD, Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA Yilin Cao, MD, PhD, Laboratory for Tissue Engineering, Department of Anesthesiology, University of Massachusetts Medical Center, 55 Lake Avenue North, S2-751, Worcester, MA Beverly E. Chaignaud, MD, Department of Surgery, Enders 1161,320 Longwood Avenue, Children's Hospital, Boston, MA Jeffrey A. Hubbell, PhD, California Institute of Technology, Mail Code , Pasadena, CA Clemente Ibarra, MD, Laboratory for Tissue Engineering, Department of Anesthesiology, University of Massachusetts Medical Center, 55 Lake Avenue North, S2-751, Worcester, MA William H. Kitchens, JD, Arnall Golden & Gregory, 2800 One Atlantic Center, 1201 West Peachtree Street, Atlanta, GA, Robert Langer, ScD, Department of Chemical Engineering, Massachusetts Institute of Technology, Room B25-342, 77 Massachusetts Avenue, Cambridge, MA 02139

6 vi List of Contributors Hanmin Lee, MD, Department of Surgical Research, 1155 Enders, Children's Hospital, 320 Longwood Avenue, Boston, MA Kam W. Leong, PhD, Department of Biomedical Engineering, The Johns Hopkins University, School of Medicine, Baltimore, MD Jonathan Mansbridge, PhD, Advanced Tissue Sciences, Inc., N. Torrey Pines Road, La Jolla, CA John E. Mayer Jr., MD, Department of Cardiac Surgery, Children's Hospital, 300 Longwood Avenue, Boston, MA Antonios G. Mikos, PhD, T.N. Law Associate Professor, Cox Laboratory for Biomedical Engineering, Institute of Biosciences and Bioengineering and Department of Chemical Engineering, Rice University, P.o. Box 1892, Houston, TX David 1. Mooney, PhD, Departments of Biologic and Materials Sciences and Chemical Engineering, The University of Michigan, Ann Arbor, MI Gail K. Naughton, PhD, Advanced Tissue Sciences Inc., N. Torrey Pines Road, La Jolla, CA Robert M. Nerem, PhD, Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA Patrea L. Pabst M.S., JD, Arnall Golden & Gregory LLP, 2800 One Atlantic Center, 1201 West Peachtree Street, Atlanta, GA Dror Seliktar, MS, Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA Toshiharu Shin'oka, MD, Department of Surgical Research, Enders 1155, 320 Longwood Avenue, Children's Hospital, Boston, MA Charles A. Vacanti, MD, Laboratory for Tissue Engineering, Department of Anesthesiology, University of Massachusetts Medical Center, 55 Lake Avenue North, S2-751, Worcester, MA Joseph P. Vacanti, MD, Department of Surgery, Enders 1161,320 Longwood Avenue, Children's Hospital, Boston, MA Jennifer L. West, PhD, Department of Bioengineering, Rice University, Houston, TX Wai Hung Wong, PhD, Departments of Biologic and Materials Sciences and Chemical Engineering, The University of Michigan, Ann Arbor, MI Thierry Ziegler, PhD, Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA

7 Contents Series Preface Anthony Atala... ix Preface David Mooney and Anthony Atala.... xi Introduction 1. The History of Tissue Engineering Using Biodegradable Synthetic Polymer Scaffolds and Cells Beverly E. Chaignaud, Robert S. Langer, and Joseph P. Vacanti Legal Issues Involved in Tissue Engineering Patrea L. Pabst FDA Regulation of Tissue Engineering William H. Kitchens Fundamentals of Biodegradable Polymer Scaffolds 4. Synthesis and Properties of Biodegradable Polymers used as Synthetic Matrices for Tissue Engineering Wai Hung Wong and David Mooney Bioactive Polymers Jennifer L. West and Jeffrey A. Hubbell Applications 6. Drug Delivery Related to Tissue Engineering Kam W. Leong

8 viii Contents 7. Tissue Engineering in the Epithelial System Gail Naughton, Ronnda Bartel and Jonathan Mansbridge Tissue Engineering in the Genitourinary System Anthony Atala Tissue Engineering and the Vascular System Robert M. Nerem, Linda S. Braddon, Dror Seliktar, and Thierry Ziegler New Frontiers in Tissue Engineering: Tissue Engineered Heart Valves Toshiharu Shin'oka and John E. Mayer Jr Tissue Engineering Cartilage and Bone Yilin Cao, Clemente Ibarra and Charles A. Vacanti Tissue Engineering of Bone Rebekah D. Bostrom and Antonios G. Mikos Tissue Engineering of the Liver Hanmin Lee and Joseph P. Vacanti Index

9 Series Preface This body of work represents the first volume of a book series covering the field of tissue engineering. Tissue engineering, which refers to a category of therapeutic or diagnostic products and processes which are based upon a combination of living cells and biomaterials, was defined as a field only a few years ago (1988). Tissue engineering is an inherently interdisciplinary field, combining bioengineering, life sciences and clinical sciences. The definition of this area of work as the field of tissue engineering brought together scientists from multiple backgrounds who already were working toward the achievement of similar goals. Why a book series exclusively devoted to tissue engineering? The field of tissue engineering is heterogeneous. The cells involved in tissue engineering can be autologous, allogeneic or xenogeneic. The biomaterials utilized can be either naturally occurring, synthetic or a combination of both. The application of the technology can be either for acute or permanent purposes. An attempt to cover the field of tissue engineering in a single volume, with the degree of detail necessary for individuals with different scientific backgrounds and disciplines, would be a difficult task to accomplish, particularly when this field is just emerging and changing rapidly. Therefore, addressing different technologies within the field of tissue engineering, in a comprehensive manner, is the main mission of this series of volumes. A stellar group of scientists has been brought together to form the editorial board of the series. The distinguished members of the editorial board are some of the current leaders in the field, and all share the same goals of making this series of volumes the "Bible" in regards to all technologies within the field of tissue engineering. The first volume of the series is dedicated to the technology involving synthetic biodegradable polymers as extracellular matrices. This area was chosen as the subject of the first volume due to the wide applicability of the technology to many areas in the clinical sciences. Today, health care costs for millions of Americans who suffer tissue loss or end-stage organ failure exceed $400 billion per year. Tissue engineering holds the promise of deliv-

10 x Series Preface ering new and less expensive solutions to the medical field. Although the field is young, multiple clinical trials are in progress already. Certainly within the area of tissue engineering, what was considered science fiction only a few years ago has now become a reality. Thus, this series is dedicated to engineers, life scientists, clinicians and other individuals involved in tissue engineering, both in industry and academia, who are striving to advance the field for the benefit of mankind. Anthony Atala, M.D. Series Editor

11 Preface Broadly described, the emerging field of tissue engineering includes studies in areas as diverse as synthesis of new polymers, studies of signal transduction and gene regulation in cultured cells, and immunology issues related to transplantation. This book does not aspire to cover all of the diverse issues relevant to tissue engineering; rather, it focuses on approaches to engineering new tissues using synthetic biodegradable polymers as extracellular matrices. These synthetic matrices are utilized to: 1) deliver transplanted cells to a desired anatomic location and/or control the ingrowth of host cells into the new tissue, 2) create potential space for tissue development, and 3) guide the process of tissue formation. Both naturally-derived (e.g., collagen) and synthetic polymers (e.g., polylactic acid) have been utilized to fabricate these matrices. Naturally-derived materials must be isolated from human, animal, or plant tissue, which typically results in high costs and large batch-to-batch variations. In addition, these materials typically exhibit a very limited range of properties and are often difficult to process. Synthetic polymers, in contrast, are both cheaply produced and reproducible, and they can be readily processed into a variety of matrices with desirable macro- and microstructures. Biodegradable polymers are attractive materials because they can be designed to erode once they accomplish their function, resulting in the formation of a completely natural tissue with no permanent synthetic element. Thus, many difficulties commonly associated with the permanent implantation of synthetic materials (e.g., infection and chronic inflammation) may be avoided. This first volume in the Tissue Engineering series was developed not only to bring together an accessible collection of polymer, cellular, and tissue studies, but also to introduce important legal issues in engineering tissues with synthetic biodegradable polymers. Included are chapters on the synthesis and properties of these polymers, their application to engineering a variety of tissue types, and relevant FDA and patent issues. This text will serve as a useful reference to researchers and clinicians already involved in

12 xii Preface the field as they seek guidance on potential new materials or applications, and to students or beginning researchers who need an overview of the field. This book begins with a history of tissue engineering in order to place the current state of the field in a historical perspective. The introductory chapters (Chapters 1-3) present this history and discuss legal issues which will be critical to this emerging industry. A valuable overview of patent and other intellectual property issues leads into a discussion of FDA regulatory strategies. The next section (Chapters 4-5) examines the fundamentals of biodegradable polymer scaffolds: Chapter 4 reviews the synthesis and properties of those synthetic polymers presently utilized in the field, as well as the numerous other polymers that could be useful in the future; Chapter 5 examines a critical area of research-the synthesis of biologically active polymers. The last section (Chapters 6-13) details the wide variety of applications for these polymers in different systems. Chapter 6 describes how these polymers can be utilized for drug delivery, and the remaining chapters describe engineering in epithelial tissue, urologic tissue, vascular structures, cartilage, bone, and liver. We acknowledge the authors for their outstanding efforts in achieving concise, yet comprehensive, overviews of their topics. David 1. Mooney and Anthony Atala Note added in proof: Regarding Chapter 3-FDA Regulation of Tissue Engineering As this book went to press, the U.S. Food and Drug Administration on February 28, 1997 proposed a new regulatory framework for human cellular and tissue-based products. The proposal provides a tiered approach to regulation with increasing degrees of government oversight as the potential risk increases. Tissues that do not undergo extensive processing will be subject to infectious disease screening and testing and to requirements aimed at preventing contamination and preserving integrity and function, but will not need FDA review or marketing approval. FDA, however, will require approval of human testing and premarket approval based on a demonstration of safety and effectiveness for tissues that are processed extensively (i.e., their biological or functional characteristics have been manipulated), used for purposes other than their normal function, or combined with devices, drugs or other biologics. Technologies such as somatic cell therapy and gene therapy will be in this category as will stem cell therapy in patients not closely related to the cell donor. Because this proposal supplements and in some instances deviates from previous guidance that was available at the time this chapter was written, the reader is encouraged to review this new FDA proposal as well. William H. Kitchens