© 2006 by Taylor & Francis Group, LLC The Biomedical Engineering Handbook Third Edition Tissue Engineering and Artificial Organs © 2006 by Taylor & Francis Group, LLC The Electrical Engineering Handbook Series Series Editor Richard C. Dorf University of California, Davis Titles Included in the Series The Handbook of Ad Hoc Wireless Networks, Mohammad Ilyas The Avionics Handbook, Cary R. Spitzer The Biomedical Engineering Handbook, Third Edition, Joseph D. Bronzino The Circuits and Filters Handbook, Second Edition, Wai-Kai Chen The Communications Handbook, Second Edition, Jerry Gibson The Computer Engineering Handbook, Vojin G. Oklobdzija The Control Handbook, William S. Levine The CRC Handbook of Engineering Tables, Richard C. Dorf The Digital Signal Processing Handbook, Vijay K. Madisetti and Douglas Williams The Electrical Engineering Handbook, Third Edition, Richard C. Dorf The Electric Power Engineering Handbook, Leo L. Grigsby The Electronics Handbook, Second Edition, Jerry C. Whitaker The Engineering Handbook, Third Edition, Richard C. Dorf The Handbook of Formulas and Tables for Signal Processing, Alexander D. Poularikas The Handbook of Nanoscience, Engineering, and Technology, William A. Goddard, III, Donald W. Brenner, Sergey E. Lyshevski, and Gerald J. Iafrate The Handbook of Optical Communication Networks, Mohammad Ilyas and Hussein T. Mouftah The Industrial Electronics Handbook, J. David Irwin The Measurement, Instrumentation, and Sensors Handbook, John G. Webster The Mechanical Systems Design Handbook, Osita D.I. Nwokah and Yidirim Hurmuzlu The Mechatronics Handbook, Robert H. Bishop The Mobile Communications Handbook, Second Edition, Jerry D. Gibson The Ocean Engineering Handbook, Ferial El-Hawary The RF and Microwave Handbook, Mike Golio The Technology Management Handbook, Richard C. Dorf The Transforms and Applications Handbook, Second Edition, Alexander D. Poularikas The VLSI Handbook, Wai-Kai Chen © 2006 by Taylor & Francis Group, LLC The Biomedical Engineering Handbook Third Edition Edited by Joseph D. Bronzino Biomedical Engineering Fundamentals Medical Devices and Systems Tissue Engineering and Artificial Organs © 2006 by Taylor & Francis Group, LLC The Biomedical Engineering Handbook Third Edition Tissue Engineering and Artificial Organs Edited by Joseph D. Bronzino Trinity College Hartford, Connecticut, U.S.A. A CRC title, part of the Taylor & Francis imprint, a member of the Taylor & Francis Group, the academic division of T&F Informa plc. Boca Raton London New York © 2006 by Taylor & Francis Group, LLC Published in 2006 by CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 © 2006 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 2 1 International Standard Book Number-10: 0-8493-2123-9 (Hardcover) International Standard Book Number-13: 978-0-8493-2123-8 (Hardcover) Library of Congress Card Number 2005044776 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. 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. 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 Tissue engineering and artificial organs / edited by Joseph D. Bronzino. p. cm. -- (The electrical engineering handbook series) Includes bibliographical references and index. ISBN 0-8493-2123-9 (alk. paper) 1. Tissue engineering. 2. Artificial organs. I. Bronzino, Joseph D., 1937- II. Title. III. Series. R857.T55T547 2006 612.028--dc22 2005044776 Visit the Taylor & Francis Web site at and the CRC Press Web site at Taylor & Francis Group is the Academic Division of Informa plc. (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA http://www.taylorandfrancis.com http://www.crcpress.com For permission to photocopy or use material electronically from this work, please access www.copyright.com © 2006 by Taylor & Francis Group, LLC Introduction and Preface During the past five years since the publication of the Second Edition — a two-volume set — of the Biomedical Engineering Handbook, the field of biomedical engineering has continued to evolve and expand. As a result, this Third Edition consists of a three-volume set, which has been significantly modified to reflect the state-of-the-field knowledge and applications in this important discipline. More specifically, this Third Edition contains a number of completely new sections, including: • Molecular Biology • Bionanotechnology • Bioinformatics • Neuroengineering • Infrared Imaging as well as a new section on ethics. In addition, all of the sections that have appeared in the first and second editions have been significantly revised. Therefore, this Third Edition presents an excellent summary of the status of knowledge and activities of biomedical engineers in the beginning of the 21st century. As such, it can serve as an excellent reference for individuals interested not only in a review of funda- mental physiology, but also in quickly being brought up to speed in certain areas of biomedical engineering research. It can serve as an excellent textbook for students in areas where traditional textbooks have not yet been developed and as an excellent review of the major areas of activity in each biomedical engineer- ing subdiscipline, such as biomechanics, biomaterials, bioinstrumentation, medical imaging, etc. Finally, it can serve as the “bible” for practicing biomedical engineering professionals by covering such topics as a historical perspective of medical technology, the role of professional societies, the ethical issues associated with medical technology, and the FDA process. Biomedical engineering is now an important vital interdisciplinary field. Biomedical engineers are involved in virtually all aspects of developing new medical technology. They are involved in the design, development, and utilization of materials, devices (such as pacemakers, lithotripsy, etc.) and techniques (such as signal processing, artificial intelligence, etc.) for clinical research and use; and serve as members of the health care delivery team (clinical engineering, medical informatics, rehabilitation engineering, etc.) seeking new solutions for difficult health care problems confronting our society. To meet the needs of this diverse body of biomedical engineers, this handbook provides a central core of knowledge in those fields encompassed by the discipline. However, before presenting this detailed information, it is important to provide a sense of the evolution of the modern health care system and identify the diverse activities biomedical engineers perform to assist in the diagnosis and treatment of patients. Evolution of the Modern Health Care System Before 1900, medicine had little to offer the average citizen, since its resources consisted mainly of the physician, his education, and his “little black bag.” In general, physicians seemed to be in short © 2006 by Taylor & Francis Group, LLC supply, but the shortage had rather different causes than the current crisis in the availability of health care professionals. Although the costs of obtaining medical training were relatively low, the demand for doctors’ services also was very small, since many of the services provided by the physician also could be obtained from experienced amateurs in the community. The home was typically the site for treatment and recuperation, and relatives and neighbors constituted an able and willing nursing staff. Babies were delivered by midwives, and those illnesses not cured by home remedies were left to run their natural, albeit frequently fatal, course. The contrast with contemporary health care practices, in which specialized physicians and nurses located within the hospital provide critical diagnostic and treatment services, is dramatic. The changes that have occurred within medical science originated in the rapid developments that took place in the applied sciences (chemistry, physics, engineering, microbiology, physiology, phar- macology, etc.) at the turn of the century. This process of development was characterized by intense interdisciplinary cross-fertilization, which provided an environment in which medical research was able to take giant strides in developing techniques for the diagnosis and treatment of disease. For example, in 1903, Willem Einthoven, a Dutch physiologist, devised the first electrocardiograph to measure the electrical activity of the heart. In applying discoveries in the physical sciences to the analysis of the biologic process, he initiated a new age in both cardiovascular medicine and electrical measurement techniques. New discoveries in medical sciences followed one another like intermediates in a chain reaction. How- ever, the most significant innovation for clinical medicine was the development of x-rays. These “new kinds of rays,” as their discoverer W.K. Roentgen described them in 1895, opened the “inner man” to medical inspection. Initially, x-rays were used to diagnose bone fractures and dislocations, and in the pro- cess, x-ray machines became commonplace in most urban hospitals. Separate departments of radiology were established, and their influence spread to other departments throughout the hospital. By the 1930s, x-ray visualization of practically all organ systems of the body had been made possible through the use of barium salts and a wide variety of radiopaque materials. X-ray technology gave physicians a powerful tool that, for the first time, permitted accurate diagnosis of a wide variety of diseases and injuries. Moreover, since x-ray machines were too cumbersome and expensive for local doctors and clinics, they had to be placed in health care centers or hospitals. Once there, x-ray technology essentially triggered the transformation of the hospital from a passive receptacle for the sick to an active curative institution for all members of society. For economic reasons, the centralization of health care services became essential because of many other important technological innovations appearing on the medical scene. However, hospitals remained insti- tutions to dread, and it was not until the introduction of sulfanilamide in the mid-1930s and penicillin in the early 1940s that the main danger of hospitalization, that is, cross-infection among patients, was signi- ficantly reduced. With these new drugs in their arsenals, surgeons were able to perform their operations without prohibitive morbidity and mortality due to infection. Furthermore, even though the different blood groups and their incompatibility were discovered in 1900 and sodium citrate was used in 1913 to prevent clotting, full development of blood banks was not practical until the 1930s, when technology provided adequate refrigeration. Until that time,“fresh” donors were bled and the blood transfused while it was still warm. Once these surgical suites were established, the employment of specifically designed pieces of medical technology assisted in further advancing the development of complex surgical procedures. For example, the Drinker respirator was introduced in 1927 and the first heart–lung bypass was done in 1939. By the 1940s, medical procedures heavily dependent on medical technology, such as cardiac catheterization and angiography (the use of a cannula threaded through an arm vein and into the heart with the injection of radiopaque dye) for the x-ray visualization of congenital and acquired heart disease (mainly valve disorders due to rheumatic fever) became possible, and a new era of cardiac and vascular surgery was established. Following World War II, technological advances were spurred on by efforts to develop superior weapon systems and establish habitats in space and on the ocean floor. As a by-product of these efforts, © 2006 by Taylor & Francis Group, LLC the development of medical devices accelerated and the medical profession benefited greatly from this rapid surge of technological finds. Consider the following examples: 1. Advances in solid-state electronics made it possible to map the subtle behavior of the fundamental unit of the central nervous system — the neuron — as well as to monitor the various physiological parameters, such as the electrocardiogram, of patients in intensive care units. 2. New prosthetic devices became a goal of engineers involved in providing the disabled with tools to improve their quality of life. 3. Nuclear medicine — an outgrowth of the atomic age — emerged as a powerful and effective approach in detecting and treating specific physiologic abnormalities. 4. Diagnostic ultrasound based on sonar technology became so widely accepted that ultrasonic studies are now part of the routine diagnostic workup in many medical specialties. 5. “Spare parts” surgery also became commonplace. Technologists were encouraged to provide car- diac assist devices, such as artificial heart valves and artificial blood vessels, and the artificial heart program was launched to develop a replacement for a defective or diseased human heart. 6. Advances in materials have made the development of disposable medical devices, such as needles and thermometers, as well as implantable drug delivery systems, a reality. 7. Computers similar to those developed to control the flight plans of the Apollo capsule were used to store, process, and cross-check medical records, to monitor patient status in intensive care units, and to provide sophisticated statistical diagnoses of potential diseases correlated with specific sets of patient symptoms. 8. Developmentof thefirstcomputer-basedmedicalinstrument,thecomputerizedaxialtomography scanner, revolutionized clinical approaches to noninvasive diagnostic imaging procedures, which now include magnetic resonance imaging and positron emission tomography as well. 9. A wide variety of new cardiovascular technologies including implantable defibrillators and chemically treated stents were developed. 10. Neuronal pacing systems were used to detect and prevent epileptic seizures. 11. Artificial organs and tissue have been created. 12. The completion of the genome project has stimulated the search for new biological markers and personalized medicine. The impact of these discoveries and many others has been profound. The health care system of today consists of technologically sophisticated clinical staff operating primarily in modern hospitals designed to accommodate the new medical technology. This evolutionary process continues, with advances in the physical sciences such as materials and nanotechnology, and in the life sciences such as molecular biology, the genome project and artificial organs. These advances have altered and will continue to alter the very nature of the health care delivery system itself. Biomedical Engineering: A Definition Bioengineering is usually defined as a basic research-oriented activity closely related to biotechnology and genetic engineering, that is, the modification of animal or plant cells, or parts of cells, to improve plants or animals or to develop new microorganisms for beneficial ends. In the food industry, for example, this has meant the improvement of strains of yeast for fermentation. In agriculture, bioengineers may be concerned with the improvement of crop yields by treatment of plants with organisms to reduce frost damage. It is clear that bioengineers of the future will have a tremendous impact on the qualities of human life. The potential of this specialty is difficult to imagine. Consider the following activities of bioengineers: • Development of improved species of plants and animals for food production • Invention of new medical diagnostic tests for diseases • Production of synthetic vaccines from clone cells © 2006 by Taylor & Francis Group, LLC The world of biomedical engineering Biomechanics Medical & biological analysis Biosensors Clinical engineering Medical & bioinformatics Rehabilitation engineering Physiological modeling Bionanotechnology Biomedical instrumentation Neural engineering Tissue engineering Biotechnology Biomaterials Medical imaging Prosthetic devices & artificial organs FIGURE 1 The world of biomedical engineering. • Bioenvironmental engineering to protect human, animal, and plant life from toxicants and pollutants • Study of protein–surface interactions • Modeling of the growth kinetics of yeast and hybridoma cells • Research in immobilized enzyme technology • Development of therapeutic proteins and monoclonal antibodies Biomedical engineers, on the other hand, apply electrical, mechanical, chemical, optical, and other engineering principles to understand, modify, or control biologic (i.e., human and animal) systems, as well as design and manufacture products that can monitor physiologic functions and assist in the diagnosis and treatment of patients. When biomedical engineers work within a hospital or clinic, they are more properly called clinical engineers. Activities of Biomedical Engineers The breadth of activity of biomedical engineers is now significant. The field has moved from being concerned primarily with the development of medical instruments in the 1950s and 1960s to include a more wide-ranging set of activities. As illustrated above, the field of biomedical engineering now includes many new career areas (see Figure 1), each of which is presented in this handbook. These areas include: • Application of engineering system analysis (physiologic modeling, simulation, and control) to biologic problems • Detection, measurement, and monitoring of physiologic signals (i.e., biosensors and biomedical instrumentation) • Diagnostic interpretation via signal-processing techniques of bioelectric data • Therapeutic and rehabilitation procedures and devices (rehabilitation engineering) • Devices for replacement or augmentation of bodily functions (artificial organs) • Computer analysis of patient-related data and clinical decision making (i.e., medical informatics and artificial intelligence) © 2006 by Taylor & Francis Group, LLC • Medical imaging, that is, the graphic display of anatomic detail or physiologic function • The creation of new biologic products (i.e., biotechnology and tissue engineering) • The development of new materials to be used within the body (biomaterials) Typical pursuits of biomedical engineers, therefore, include: • Research in new materials for implanted artificial organs • Development of new diagnostic instruments for blood analysis • Computer modeling of the function of the human heart • Writing software for analysis of medical research data • Analysis of medical device hazards for safety and efficacy • Development of new diagnostic imaging systems • Design of telemetry systems for patient monitoring • Design of biomedical sensors for measurement of human physiologic systems variables • Development of expert systems for diagnosis of disease • Design of closed-loop control systems for drug administration • Modeling of the physiological systems of the human body • Design of instrumentation for sports medicine • Development of new dental materials • Design of communication aids for the handicapped • Study of pulmonary fluid dynamics • Study of the biomechanics of the human body • Development of material to be used as replacement for human skin Biomedical engineering, then, is an interdisciplinary branch of engineering that ranges from theoretical, nonexperimental undertakings to state-of-the-art applications. It can encompass research, development, implementation, and operation. Accordingly, like medical practice itself, it is unlikely that any single person can acquire expertise that encompasses the entire field. Yet, because of the interdisciplinary nature of this activity, there is considerable interplay and overlapping of interest and effort between them. For example, biomedical engineers engaged in the development of biosensors may interact with those interested in prosthetic devices to develop a means to detect and use the same bioelectric signal to power a prosthetic device. Those engaged in automating the clinical chemistry laboratory may collaborate with those developing expert systems to assist clinicians in making decisions based on specific laboratory data. The possibilities are endless. Perhaps a greater potential benefit occurring from the use of biomedical engineering is identification of the problems and needs of our present health care system that can be solved using existing engineering technology and systems methodology. Consequently, the field of biomedical engineering offers hope in the continuing battle to provide high-quality care at a reasonable cost. If properly directed toward solving problems related to preventive medical approaches, ambulatory care services, and the like, biomedical engineers can provide the tools and techniques to make our health care system more effective and efficient; and in the process, improve the quality of life for all. Joseph D. Bronzino Editor-in-Chief