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Animal Models in Orthopaedic Research edited by Yuehuei H. An Richard J. Friedman CRC Press Boca Raton London New York Washington, D.C. Published in 1999 by CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 © 1999 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 International Standard Book Number-10: 0-8493-2115-8 (Hardcover) International Standard Book Number-13: 978-0-8493-2115-3 (Hardcover) This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data informa Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com Taylor & Francis Group and the CRC Press Web site at is the Academic Division of Informa pic. http://www.crcpress.com To Kay Q. Kang, M.D. Without her love, inspiration, and suppor t, this book would not have been possible. Yuehuei H. An, M.D. To my wife Vivian, and my daughters Arielle and Leah, for their patience, understanding, love and support. Richard J. Friedman, M.D., FRCS(C) The Editors Yuehuei H. An, M.D. is Associate Professor and Co-director of the Orthopaedic Research Labo- ratory, Department of Orthopaedic Surgery, Medical University of South Carolina, Charleston, SC, and Adjunct Assistant Professor of Bioengineering, Department of Bioengineering, Clemson Uni- versity, Clemson, SC. Dr. An graduated from the Harbin Medical University, Harbin, China, in 1983 and was trained in orthopaedic surgery at Ji Shui Tan Hospital (residency), Beijing, China, and in hand surgery at Sydney Hospital (Clinical Fellow), Sydney, Australia. In 1991, Dr. An joined with Dr. Richard J. Friedman in the Department of Orthopaedic Surgery at the Medical University of South Carolina to establish an Orthopaedic Research Laboratory. Since then, he has been directing and supervising graduate students, research fellows, and residents on numerous orthopaedic research projects. Dr. An has published more than 50 scientific papers and book chapters and presented more than 60 research abstracts. He is an active member of six academic societies, including the Orthopaedic Research Society (USA), Society for Biomaterials (USA), American Society of Biomechanics, and Tissue Engineering Society (USA). Dr. An’s current research interests include repair of bone and cartilage defects using tissue engineering techniques, improving bone or soft tissue ingrowth to implant surfaces, prevention of bacterial adhesion and prosthetic infection, and development of animal models for orthopaedic applications. He enjoys art and created most of the drawings used in his chapters. Richard J. Friedman, M.D., FRCS(C), is Professor and Director of the Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Medical University of South Carolina, Charleston, SC, and Adjunct Professor of Bioengineering, Department of Bioengineering, Clemson University, Clemson, SC. He graduated from the University of Toronto School of Medicine in 1980 and after that was trained in orthopaedic surgery at Johns Hopkins University and Harvard University. Dr. Friedman is the founder and director of the Orthopaedic Research Laboratory at the Medical University of South Carolina. He has published more than 100 scientific papers and book chapters and presented more than 200 research abstracts. In 1994, he editeAd rthroplasty of the Shoulder published by Thieme Medical Publishers, New York, a reference book in human shoulder arthro- plasty. He has been invited as a guest speaker for many national and international academic meetings. He has served as a chairman or member of more than 30 academic or professional committees or meetings and is a member of more than twenty societies or associations. Dr. Friedman’s current research interests include shoulder and elbow surgery, bone and cartilage repair using tissue engineering techniques, bone ingrowth, total joint replacement, orthopaedic biomaterials, and development of animal models for orthopaedic applications. Contributors Yuehuei H. An, M.D., Associate Professor and Co-director, Orthopaedic Research Labora- tory, Department of Orthopaedic Surgery, Medical University of South Carolina, Charles- ton, SC and Adjunct Assistant Professor, Department of Bioengineering, Clemson Uni- versity, Clemson, SC Todd D. Bell, M.D., Orthopaedic Resident, Department of Orthopaedic Surgery, Medical University of South Carolina, Charleston, SC Sarah A. Bingel, V.M.D., Ph.D., Assistant Professor, Department of Comparative Medicine and Department of Pathology, Medical University of South Carolina, Charleston, SC Earl R. Bogoch, M.D., FRCSC, Associate Professor, Division of Orthopaedic Surgery, Department of Surgery, Director, Wellesley Orthopaedic Research Laboratory, University of Toronto, Toronto, ON, Canada Robert C. Bray, M.D., FRCSC, Orthopaedic Surgeon, University of Calgary, Department of Orthopaedic Surgery, Joint Injury and Arthritis Research Group, Calgary, AB, Canada Frank P. Cammisa, Jr., M.D., Chief, Spine Surgery Service, Division of Orthopaedic Surgery, Hospital for Special Surgery, Cornell Medical College, New York, NY Edgar G. Dawson, M.D., Clinical Professor, Department of Orthopaedic Surgery, UCLA School of Medicine, Los Angeles, CA Masao Deguchi,M .D., Chief of Spine Surgery, Department of Orthopaedic Surgery, Nagano Red Cross Hospital, Nagano, Japan Robert A. Draughn, D.Sc., Professor and Chairman, Department of Materials Science, College of Dental Medicine, Medical University of South Carolina, Charleston, SC Richard T. Fosse, M.R.C.V.S., Associate Director LAR, Rhone Poulenc Rorer, Dagenham Research Centre, Dagenham, Essex, UK. Richard J. Friedman, M.D., FRCSC, Professor and Director, Orthopaedic Research Labo- ratory, Department of Orthopaedic Surgery, Medical University of South Carolina, Charles- ton, SC, and Adjunct Professor, Department of Bioengineering, Clemson University, Clem- son, SC Federico Girardi, M.D., Spine Surgery Fellow, Division of Orthopaedic Surgery, Hospital for Special Surgery, Cornell Medical College, New York, NY Stuart B. Goodman, M.D., Professor, Stanford University Medical Center, Division of Orthopaedic Surgery, Stanford, CA Helen E. Gruber, Ph.D., Senior Scientist and Director of Research Histology, Orthopaedic Research Laboratory, Carolina Medical Center, Charlotte, NC John A. Jansen, D.D.S., Ph.D., Professor and Head, Department of Biomaterials, University of Nijmegen Dental School, Nijmegen, The Netherlands Tokumi Kanemura, M.D., Orthopaedic Surgeon, Department of Orthopaedic Surgery, JR Tokai Hospital, Nagoya University School of Medicine, Nagoya, Japan Linda E. A. Kanim, M.A., Research Associate, University Spine Associates, UCLA School of Medicine, Los Angeles, CA Noriaki Kawakami, M.D., Chief of Orthopaedic Surgery, Department of Orthopaedic Sur- gery, Meijou Hospital, Nagoya University School of Medicine, Nagoya, Japan Donald B. Kimmel, Ph.D., Senior Scientist and Director, Department ofI n vivo Bone Biology, Merck & Co., Inc., West Point, PA Jan Klompmaker, M.D., Registrar, Department of Orthopaedic Surgery, University Hospital Nijmegen, Institute of Orthopaedics, Nijmegen, The Netherlands Martine LaBerge, Ph.D., Associate Professor, Department of Bioengineering, Clemson University, Clemson, SC Martin Lind, M.D., Ph.D., Research Fellow, Orthopaedic Research Laboratory, Aarhus University Hospital Noerrebrogade, Aarhus, Denmark Theodore T. Manson,B .A., Graduate Student, Musculoskeletal Research Center, Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA Kensaku Masuhara, M.D., Associate Professor, Department of Orthopaedic Surgery, Osaka University Medical School, Osaka, Japan Hiromi Matsuzaki, M.D., Associate Professor, Chief of Spine Division, Department of Orthopaedic Surgery, Nihon University Surugadai Hospital, Tokyo, Japan Minoru Matul, M.D., Assistant Professor, Department of Orthopaedic Surgery, Osaka Uni- versity Medical School, Osaka, Japan Jason Jo McDougall, Ph.D., Postdoctoral Fellow, University of Calgary, Joint Injury and Arthritis Research Group, Calgary, AB, Canada Shimpei Miyamoto, M.D., Ph.D., Assistant Professor, Department of Orthopaedic Surgery, Osaka University Medical School, Osaka, Japan Erica L. Moran, B.Sc., Research Associate, Wellesley Orthopaedic Research Laboratory, University of Toronto, Toronto, ON, Canada Katsuya Nakata, M.D., Graduate student, Department of Orthopaedic Surgery, Osaka Uni- versity Medical School, Osaka, Japan Theodore R. Oegema, Jr., Ph.D., Professor, Department of Orthopaedic Surgery, University of Minnesota, Minneapolis, MN Keiro Ono, M.D., Professor Emeritus, Department of Orthopaedic Surgery, Osaka University School of Medicine, Director, Osaka Kosei-nenkin Hospital, Osaka, Japan Donald L. Pruitt, M.D., Hand Surgeon, Alabama Orthopaedic Clinics, Mobile, Alabama, USA Warren K. Ramp, Ph.D., Senior Scientist, Orthopaedic Research Laboratory, Carolina Medical Center, Charlotte, NC. Harvinder S. Sandhu, M.D., Division of Orthopaedic Surgery, Hospital for Special Surgery, Cornell Medical College, New York, NY Alison C. Smith, D.V.M., Associate Professor, Department of Comparative Medicine and Division of Cardiology, Medical University of South Carolina, Charleston, SC Yong Song, M.D., Research Assistant, Stanford University Medical Center, Division of Orthopaedic Surgery, Stanford, CA Audrey A. Stasky, B.A., Senior Laboratory Technician, Orthopaedic Research Laboratory, Carolina Medical Center, Charlotte, NC Dale R. Sumner, Ph.D., Professor and Chairman, Department of Anatomy, Professor, Depart- ment of Orthopaedic Surgery, Rush Medical College, Rush-Presbyterian-St. Luke’s Med- ical Center, Chicago, IL M. Michael Swindle, D.V.M., Professor and Chairman, Department of Comparative Medi- cine and Department of Surgery, Medical University of South Carolina, Charleston, SC Thomas M. TYirner, D.V.M., Assistant Professor, Department of Orthopaedic Surgery, Rush Medical College, Rush-Presbyterian-St. Luke’s Medical Center, Chicago, IL Robert M. Urban, Research Administrator, Department of Orthopaedic Surgery, Rush Med- ical College, Rush-Presbyterian-St. Luke’s Medical Center, Chicago, IL René P. H. Veth, M.D., Professor and Chairman, Department of Orthopaedic Surgery, Uni- versity Hospital Nijmegen, Institute of Orthopaedics, Nijmegen, The Netherlands Denise M. Visco, Ph.D., Research Fellow, Merck Research Laboratories, Department of Pharmacology, Merck & Co., Inc., Rahway, NJ Tracy M. Vogrin, B.Sc., Graduate Student, Musculoskeletal Research Center, Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA Ken Wakabayashi, M.D., Assistant Professor, Department of Orthopaedic Surgery, Nihon University Surugadai Hospital, Tokyo, Japan Savio L.-Y. Woo, Ph.D., A. B. Ferguson Professor and Director, Musculoskeletal Research Center, Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA Kazuo Yonenobu, M.D., Associate Professor, Department of Orthopaedic Surgery, Osaka University Medical School, Osaka, Japan Franklin A. Young, Jr., D.Sc., Professor, Department of Materials Science, College of Dental Medicine, Medical University of South Carolina, Charleston, SC Preface Research using animal models provides important knowledge of pathological conditions that even- tually can lead to the development of more effective clinical treatment of diseases in both humans and animals. This book covers most of the major animal models used in studies of biomaterials and orthopaedic disorders. It is to be used as a reference book and is primarily directed towards surgeons, investigators, research fellows, graduate students, or anyone working in the field of orthopaedic or biomaterial research. It is intended to serve as a basis for a literature search before embarking on a detailed research project. It is possible that other scientists or physicians in areas unrelated to orthopaedic or biomaterial research may also find this material useful as a source of reference, or as a tool to expedite their research. This book is an outgrowth of the editors’ own quest for information about animal research methodology in orthopaedic and biomaterial research and, more importantly, represents tremendous support from the orthopaedic and biomaterial research communities. The 11 chapters written by the editors are a combination of knowledge gained from personal experience and the research literature. The remaining 20 chapters are contributions from 45 well-known experts in their fields of interest from throughout the world. The book has 31 chapters and is divided into eight major parts. Part I is a general discussion about the care and use of laboratory animals and experimental designs in orthopaedic research. Part II describes the most commonly used evaluation methods in orthopaedic animal research. Detailed descriptions of common animal models used in orthopaedic research are given in Parts III-VIII. The book is designed to be concise as well as inclusive and more practical than theoretical. The text is simple and straightforward. Appropriate numbers of tables, diagrams, line figures, and photographs are used to make the contents more vivid. The appendices include a list of periodicals and publications related to orthopaedic research, laboratory animals, and procurement sources. Full bibliographies at the end of each chapter guide readers to more detailed information on the subject. A book of this length cannot possibly discuss every animal model that has ever been produced in orthopaedic research, but it is felt that the major models and their applications have been included. Yuehuei H. An Richard J. Friedman Foreword Research is at the heart of progress in orthopaedic surgery as it is in all other fields of medicine. The products of research have changed the face of orthopaedics and have provided for millions of human beings the chance of enjoying active and productive lives. Research encompasses a broad range of activities, but it should always begin with a burning question that will lead to the development of one or more hypotheses and the need to test them experimentally. For that purpose, there are a number of methods available to the investigator. They includine vitro experiments, the use of cadaveric material, computer models, physical models, and clinical databases. Animal models are an integral part of the process and, as such, are frequently used in orthopaedic research. However, prior to their application there are some fundamental issues that must be addressed. Is the animal experiment truly necessary or can the questions be answered using other methods? Experimental work requiring the use of living creatures can never be taken lightly. An enormous controversy surrounds us regarding the ethical issues involved. Thus, the use of animal models for subjects that are important to mankind can only be justified when there is no other viable alternative. Experiments in animals when justified and properly planned and executed have been essential in the acquisition of new knowledge. Animal models have allowed us to understand the natural history of disease, to develop new and improved surgical techniques, and to predict the effect of a given treatment or surgical procedure. They have been critical in the development and in the evaluation of implants, one of the basic elements of modem orthopaedics. Animal models play a crucial role in biocompatibility evaluation, which is the most fundamental basis of knowledge necessary in the biomaterials field. Tissue engineering and the use of new technologies based on molecular biology developments require animal experiments. And the list can goes on and on. In every aspect of orthopaedic research, the use of animal models constitutes an essential step that leads to the eventual application of newly acquired information to the human patient. This work then addresses a very important subject and one that to my knowledge has not been covered in such a comprehensive manner in any other book or publication. There are a number of features that make this book unique in addition to the subject and the depth in which it has been addressed. The editors have played a very active role in the conception and in the execution of the project. Of the 31 chapters that comprise the book, 11 were written by the editors themselves. This is unusual and reflects on the one hand their expertise and knowledge of the subject and, on the other, the level of their commitment. The book is divided into eight parts. The first two deal with principles of detailed method- ology. The other six address the use of models for specific purposes. Given the nature of the musculoskeletal system, a broad picture needs to be considered. Bone, cartilage, joint replace- ment, ligaments and tendons, spinal conditions and microsurgical techniques are included with chapters that address in detail the use of animal models in most areas of related research. I particularly enjoyed Part One of the book, including all its five chapters, which by themselves represent in my judgment a major contribution. The ethical issues involved are presented in a very objective light, taking into account the concerns of the orthopaedic research community as well as those of animal rights advocates. This is a topic with which all investigators should be very familiar.

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