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INTRODUCTION
TO BIOMEDICAL
ENGINEERING
Second Edition


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This is a volume in the
ACADEMIC PRESS SERIES IN BIOMEDICAL ENGINEERING
J O S E P H B R O N Z I N O , SE R I E S E D I T O R
Trinity College—Hartford, Connecticut


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INTRODUCTION
TO BIOMEDICAL
ENGINEERING
Second Edition
John D. Enderle
University of Connecticut

Storrs, Connecticut

Susan M. Blanchard
Florida Gulf Coast University
Fort Myers, Florida

Joseph D. Bronzino
Trinity College
Hartford, Connecticut

Amsterdam Boston Heidelberg London New York Oxford
Paris San Diego San Francisco Singapore Sydney Tokyo


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Elsevier Academic Press
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525 B Street, Suite 1900, San Diego, California 92101-4495, USA
84 Theobald’s Road, London WC1X 8RR, UK
This book is printed on acid-free paper.
Copyright ß 2005, Elsevier Inc. All rights reserved.
No part of this publication may be reproduced or transmitted in any form or by any means, electronic or
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permission in writing from the publisher.
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also complete your request on-line via the Elsevier homepage (), by selecting ‘‘Customer
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Library of Congress Cataloging-in-Publication Data
Introduction to biomedical engineering / edited by John D. Enderle, Joseph
D. Bronzino, and Susan M. Blanchard. —2nd ed.
p. ;cm.
Includes biographical references and index.
ISBN 0-12-238662-0
1. Biomedical engineering.
[DNLM: 1. Biomedical Engineering. QT 36 I615 2005] I. Enderle, John D.
( John Denis) II. Bronzino, Joseph D., III. Blanchard, Susam M.
R856.I47 2005
610’.28—dc22

2004030223

British Library Cataloguing in Publication Data
A catalogue record for this book is available from the British Library
ISBN: 0-12-238662-0
For all information on all Elsevier Academic Press publications visit our Web site at www.books.elsevier.com
Printed in the United States of America
05 06 07 08 09 10 9 8 7 6 5 4 3 2 1


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This book is dedicated to our families



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Enderle / Introduction to Biomedical Engineering 2nd ed. Final Proof

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CONTENTS

PREFACE xiii
CONTRIBUTORS TO THE FIRST EDITION xv
CONTRIBUTORS TO THE SECOND EDITION xix

1

BIOMEDICAL ENGINEERING:
A HISTORICAL PERSPECTIVE 1
1.1 Evolution of the Modern Health Care System 2
1.2 The Modern Health Care System 10
1.3 What Is Biomedical Engineering? 17
1.4 Roles Played by Biomedical Engineers 23
1.5 Professional Status of Biomedical Engineering 24
1.6 Professional Societies 26
Exercises 28
References and Suggested Reading 29


2

MORAL AND ETHICAL ISSUES
2.1

31

Morality and Ethics: A Definition of Terms

33
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CONTENTS

2.2
Two Moral Norms: Beneficence and Nonmaleficence 40
2.3
Redefining Death 41
2.4
The Terminally Ill Patient and Euthanasia 45
2.5
Taking Control 49
2.6
Human Experimentation 49
2.7

Definition and Purpose of Experimentation 51
2.8
Informed Consent 53
2.9
Regulation of Medical Device Innovation 59
2.10 Marketing Medical Devices 61
2.11 Ethical Issues in Feasibility Studies 63
2.12 Ethical Issues in Emergency Use 65
2.13 Ethical Issues in Treatment Use 68
2.14 The Role of the Biomedical Engineer in the FDA Process 69
Exercises 70
Suggested Reading 71

3

ANATOMY AND PHYSIOLOGY

73

3.1 Introduction 74
3.2 Cellular Organization 76
3.3 Tissues 92
3.4 Major Organ Systems 94
3.5 Homeostasis 119
Exercises 121
Suggested Reading 125

4

BIOMECHANICS


127

4.1 Introduction 128
4.2 Basic Mechanics 131
4.3 Mechanics of Materials 151
4.4 Viscoelastic Properties 159
4.5 Cartilage, Ligament, Tendon, and Muscle
4.6 Clinical Gait Analysis 169
4.7 Cardiovascular Dynamics 186
Exercises 207
Suggested Reading 209

5

REHABILITATION ENGINEERING AND
ASSISTIVE TECHNOLOGY 211
5.1

Introduction

212

163


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CONTENTS

5.2 The Human Component 218
5.3 Principles of Assistive Technology Assessment 224
5.4 Principles of Rehabilitation Engineering 227
5.5 Practice of Rehabilitation Engineering and Assistive Technology
Exercises 243
Suggested Reading 252

6

BIOMATERIALS

255

6.1
6.2
6.3
6.4
6.5
6.6
6.7

Materials in Medicine: From Prosthetics to Regeneration 256
Biomaterials: Properties, Types, and Applications 258
Lessons from Nature on Biomaterial Design and Selection 276
Tissue–Biomaterial Interactions 281
Guiding Tissue Repair with Bio-Inspired Biomaterials 290

Safety Testing and Regulation of Biomaterials 296
Application-Specific Strategies for the Design and Selection of
Biomaterials 301
Exercises 310
Suggested Reading 311

7

TISSUE ENGINEERING

313

7.1
7.2
7.3
7.4
7.5
7.6

What Is Tissue Engineering? 314
Biological Considerations 331
Physical Considerations 360
Scaling Up 382
Implementation of Tissue Engineered Products 386
Future Directions: Functional Tissue Engineering and the
‘‘-Omics’’ Sciences 390
7.7 Conclusions 393
7.8 Glossary 393
Exercises 395
Suggested Reading 400


8

BIOINSTRUMENTATION
8.1
8.2
8.3
8.4
8.5
8.6

403

Introduction 404
Basic Bioinstrumentation System 407
Charge, Current, Voltage, Power, and Energy
Resistance 415
Linear Network Analysis 425
Linearity and Superposition 432

408

239


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CONTENTS


8.7
The´venin’s Theorem 436
8.8
Inductors 439
8.9
Capacitors 442
8.10 A General Approach to Solving Circuits Involving
Resistors, Capacitors, and Inductors 446
8.11 Operational Amplifiers 455
8.12 Time-Varying Signals 468
8.13 Active Analog Filters 474
8.14 Bioinstrumentation Design 484
Exercises 487
Suggested Reading 504

9

BIOMEDICAL SENSORS

505

9.1 Introduction 506
9.2 Biopotential Measurements 508
9.3 Physical Measurements 513
9.4 Blood Gases and pH Sensors 527
9.5 Bioanalytical Sensors 536
9.6 Optical Biosensors 539
Exercises 545
Suggested Reading 548


10

BIOSIGNAL PROCESSING

549

10.1 Introduction 550
10.2 Physiological Origins of Biosignals 551
10.3 Characteristics of Biosignals 554
10.4 Signal Acquisition 557
10.5 Frequency Domain Representation of Biological Signals 562
10.6 Linear Systems 584
10.7 Signal Averaging 597
10.8 Wavelet Transform and Short-Time Fourier Transform 605
10.9 Artificial Intelligence Techniques 612
Exercises 619
Suggested Reading 624

11

BIOELECTRIC PHENOMENA
11.1
11.2

Introduction 628
History 629

627



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CONTENTS

11.3 Neurons 637
11.4 Basic Biophysics Tools and Relationships 642
11.5 Equivalent Circuit Model for the Cell Membrane 653
11.6 Hodgkin–Huxley Model of the Action Potential 664
11.7 Model of the Whole Neuron 680
Exercises 684
Suggested Reading 690

12

PHYSIOLOGICAL MODELING 693
12.1
Introduction 694
12.2
Compartmental Modeling 698
12.3
An Overview of the Fast Eye Movement System 723
12.4
Westheimer Saccadic Eye Movement Model 728
12.5
The Saccade Controller 735

12.6
Development of an Oculomotor Muscle Model 738
12.7
A Linear Muscle Model 751
12.8
A Linear Homeomorphic Saccadic Eye Movement Model 757
12.9
A Truer Linear Homeomorphic Saccadic Eye Movement Model 763
12.10 System Identification 773
Exercises 788
Suggested Reading 797

13

GENOMICS AND BIOINFORMATICS

799

13.1 Introduction 800
13.2 Core Laboratory Technologies 804
13.3 Core Bioinformatics Technologies 812
13.4 Conclusion 828
Exercises 829
Suggested Reading 830

14

COMPUTATIONAL CELL BIOLOGY AND COMPLEXITY
14.1 Computational Biology 834
14.2 The Modeling Process 835

14.3 Bionetworks 846
14.4 Introduction to Complexity Theory
Exercises 852
Suggested Readings 854

849

833


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15

CONTENTS

RADIATION IMAGING

857

15.1 Introduction 858
15.2 Emission Imaging Systems 859
15.3 Instrumentation and Imaging Devices
15.4 Radiographic Imaging Systems 882
Exercises 902
Suggested Reading 904


16

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MEDICAL IMAGING

876

905

16.1 Introduction 906
16.2 Diagnostic Ultrasound Imaging 908
16.3 Magnetic Resonance Imaging (MRI) 940
16.4 Comparison of Imaging Modes 969
Exercises 972
Suggested Reading 975

17

BIOMEDICAL OPTICS AND LASERS

977

17.1 Introduction to Essential Optical Principles 979
17.2 Fundamentals of Light Propagation in Biological Tissue 985
17.3 Physical Interaction of Light and Physical Sensing 997
17.4 Biochemical Measurement Techniques Using Light 1006
17.5 Fundamentals of Photothermal Therapeutic Effects of Lasers 1015
17.6 Fiber Optics and Waveguides in Medicine 1026

17.7 Biomedical Optical Imaging 1033
Exercises 1039
Suggested Reading 1042

Appendix 1045
Index 1085


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PREFACE

The purpose of the second edition remains the same as the first edition: that is, to
serve as an introduction to and overview of the field of biomedical engineering. Many
chapters have undergone major revision from the previous edition with new endof-chapter problems added. Some chapters were combined and some chapters
were eliminated completely, with several new chapters added to reflect changes
in the field.
Over the past fifty years, as the discipline of biomedical engineering has evolved, it
has become clear that it is a diverse, seemingly all-encompassing field that includes
such areas as bioelectric phenomena, bioinformatics, biomaterials, biomechanics,
bioinstrumentation, biosensors, biosignal processing, biotechnology, computational
biology and complexity, genomics, medical imaging, optics and lasers, radiation
imaging, rehabilitation engineering, tissue engineering, and moral and ethical issues.
Although it is not possible to cover all of the biomedical engineering domains in this
textbook, we have made an effort to focus on most of the major fields of activity in
which biomedical engineers are engaged.

The text is written primarily for engineering students who have completed differential equations and a basic course in statics. Students in their sophomore year or
junior year should be adequately prepared for this textbook. Students in the biological
sciences, including those in the fields of medicine and nursing, can also read and
understand this material if they have the appropriate mathematical background.
Although we do attempt to be fairly rigorous with our discussions and proofs, our
ultimate aim is to help students grasp the nature of biomedical engineering. Therefore, we have compromised when necessary and have occasionally used less rigorous
mathematics in order to be more understandable. A liberal use of illustrative examples
amplifies concepts and develops problem-solving skills. Throughout the text,
MATLAB1 (a matrix equation solver) and SIMULINK1 (an extension to MATLAB1
xiii


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PREFACE

for simulating dynamic systems) are used as computer tools to assist with problem
solving. The Appendix provides the necessary background to use MATLAB1 and
SIMULINK1. MATLAB1 and SIMULINK1 are available from:
The Mathworks, Inc.
24 Prime Park Way
Natick, Massachusetts 01760
Phone: (508) 647-7000
Email:

WWW: {extend}

Chapters are written to provide some historical perspective of the major developments in a specific biomedical engineering domain as well as the fundamental principles that underlie biomedical engineering design, analysis, and modeling procedures
in that domain. In addition, examples of some of the problems encountered, as well as
the techniques used to solve them, are provided. Selected problems, ranging from
simple to difficult, are presented at the end of each chapter in the same general order
as covered in the text.
The material in this textbook has been designed for a one-semester, two-semester,
or three-quarter sequence depending on the needs and interests of the instructor.
Chapter 1 provides necessary background to understand the history and appreciate
the field of biomedical engineering. Chapter 2 presents the vitally important chapter
on biomedically-based morals and ethics. Basic anatomy and physiology are provided
in Chapter 3. Chapters 4-10 provide the basic core biomedical engineering areas:
biomechanics, rehabilitation engineering, biomaterials, tissue engineering, bioinstrumentation, biosensors, and biosignal processing. To assist instructors in planning the
sequence of material they may wish to emphasize, it is suggested that the chapters on
bioinstrumentation, biosensors, and biosignal processing should be covered together
as they are interdependent on each other. The remainder of the textbook presents
material on biomedical technology (Chapters 12-17).
A website is available at that provides an
errata and extra material.

ACKNOWLEDGEMENTS
Many people have helped us in writing this textbook. Well deserved credit is due to
the many contributors who provided chapters and worked under a very tight timeline.
Special thanks go to our publisher, Elsevier, especially for the tireless work of the
editors, Christine Minihane and Shoshanna Grossman. In addition, we appreciate the
work of Karen Forster, the project manager, and Kristin Macek, who supervised the
production process.
A great debt of gratitude is extended to Joel Claypool, the editor of the first edition
of the book and Diane Grossman from Academic Press. From an initial conversation

over coffee in Amsterdam in 1996 to publication in 2000 required a huge effort.


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CONTRIBUTORS TO THE
FIRST EDITION

Susan M. Blanchard
Florida Gulf Coast University
Fort Myers, Florida

Joseph D. Bronzino
Trinity College
Hartford, Connecticut

Stanley A. Brown
Food and Drug Administration
Gaithersburg, Maryland

Gerard Cote´
Texas A&M University
College Station, Texas

Roy B. Davis III
Shriners Hospital for Children
Greenville, South Carolina


John D. Enderle
University of Connecticut
Storrs Connecticut
xv


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CONTRIBUTORS TO THE FIRST EDITION

Robert J. Fisher
University of Massachusetts
Amherst, Massachusetts

Carol Lucas
University of North Carolina
Chapel Hill, North Carolina

Amanda Marley
North Carolina State University
Raleigh, North Carolina

Yitzhak Mendelson
Worcester Polytechnic Institute

Worcester, Massachusetts

Katharine Merritt
Food and Drug Administration
Gaithersburg, Maryland

H. Troy Nagle
North Carolina State University
Raleigh, North Carolina

Joseph Palladino
Trinity College
Hartford, Connecticut

Bernhard Palsson
University of California at San Diego
San Diego, California

Sohi Rastegar
National Science Foundation
Arlington, Virginia

Daniel Schneck
Virginia Polytechnic Institute & State University
Blacksburg, Virginia

Kirk K Shung
Pennsylvania State University
University Park, Pennsylvania


Anne-Marie Stomp
North Carolina State University
Raleigh, North Carolina

Andrew Szeto
San Diego State University
San Diego, California


Enderle / Introduction to Biomedical Engineering 2nd ed. Final Proof

CONTRIBUTORS TO THE FIRST EDITION

LiHong Wang
Texas A&M University
College Station, Texas

Steven Wright
Texas A&M University
College Station, Texas

Melanie T. Young
North Carolina State University
Raleigh, North Carolina

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CONTRIBUTORS TO THE
SECOND EDITION

Susan M. Blanchard
Florida Gulf Coast University
Fort Myers, Florida

Joseph D. Bronzino
Trinity College
Hartford, Connecticut

Stanley A. Brown
Food and Drug Administration
Gaithersburg, Maryland

Gerard Cote´
Texas A&M University
College Station, Texas

Charles Coward
Drexel University
Philadelphia, Pennsylvania


Roy B. Davis
Shriners Hospital for Children
Greenville, South Carolina
xix


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CONTRIBUTORS TO THE SECOND EDITION

Robert Dennis
University of North Carolina
Chapel Hill, North Carolina

John D. Enderle
University of Connecticut
Storrs, Connecticut

Monty Escabı´
University of Connecticut
Storrs, Connecticut

R.J. Fisher
University of Massachusetts
Amherst, Massachusetts

Liisa Kuhn
University of Connecticut Health Center

Farmington, Connecticut

Carol Lucas
University of North Carolina
Chapel Hill, North Carolina

Jeffrey Mac Donald
University of North Carolina
Chapel Hill, North Carolina

Amanda Marley
North Carolina State University
Raleigh, North Carolina

Randall McClelland
University of North Carolina
Chapel Hill, North Carolina

Yitzhak Mendelson
Worcester Polytechnic Institute
Worcester, Massachusetts

Katharine Merritt
Food and Drug Administration
Gaithersburg, Maryland

Spencer Muse
North Carolina State University
Raleigh, North Carolina


H. Troy Nagle
North Carolina State University
Raleigh, North Carolina


Enderle / Introduction to Biomedical Engineering 2nd ed. Final Proof 5.2.2005

CONTRIBUTORS TO THE SECOND EDITION

Banu Onaral
Drexel University
Philadelphia, Pennsylvania

Joseph Palladino
Trinity College
Hartford, Connecticut

Bernard Palsson
University of California at San Diego
San Diego, California

Sohi Rastegar
National Science Foundation
Arlington, Virginia

Lola Reid
University of North Carolina
Chapel Hill, North Carolina

Kirk K. Shung

Pennsylvania State University
University Park, Pennsylvania

Anne-Marie Stomp
North Carolina State University
Raleigh, North Carolina

Tom Szabo
Boston University
Boston, Massachusetts

Andrew Szeto
San Diego State University
San Diego, California

LiHong Wang
Texas A&M University
College Station, Texas

Stephen Wright
Texas A&M University
College Station, Texas

Melanie T. Young
North Carolina State University
Raleigh, North Carolina

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1

BIOMEDICAL
ENGINEERING:
A HISTORICAL
PERSPECTIVE
Joseph Bronzino PhD, PE

Chapter Contents
1.1 Evolution of the Modern Health Care System
1.2 The Modern Health Care System
1.3 What Is Biomedical Engineering?
1.4 Roles Played by Biomedical Engineers
1.5 Professional Status of Biomedical Engineering
1.6 Professional Societies
1.6.1 American Institute for Medical and Biological Engineering (AIMBE)
1.6.2 IEEE Engineering in Medicine and Biology Society (EMBS)
1.6.3 Biomedical Engineering Society (BMES)
Exercises
References and Suggested Reading

At the conclusion of this chapter, students will be able to:
&


&

&

Identify the major role that advances in medical technology have played in the
establishment of the modern health care system.
Define what is meant by the term biomedical engineering and the roles biomedical
engineers play in the health care delivery system.
Explain why biomedical engineers are professionals.

1


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CHAPTER 1

BIOMEDICAL ENGINEERING: A HISTORICAL PERSPECTIVE

In the industrialized nations, technological innovation has progressed at such an
accelerated pace that it is has permeated almost every facet of our lives. This is
especially true in the area of medicine and the delivery of health care services.
Although the art of medicine has a long history, the evolution of a technologically
based health care system capable of providing a wide range of effective diagnostic and
therapeutic treatments is a relatively new phenomenon. Of particular importance in
this evolutionary process has been the establishment of the modern hospital as the
center of a technologically sophisticated health care system.

Since technology has had such a dramatic impact on medical care, engineering
professionals have become intimately involved in many medical ventures. As a result,
the discipline of biomedical engineering has emerged as an integrating medium for
two dynamic professions, medicine and engineering, and has assisted in the struggle
against illness and disease by providing tools (such as biosensors, biomaterials, image
processing, and artificial intelligence) that can be utilized for research, diagnosis, and
treatment by health care professionals.
Thus, biomedical engineers serve as relatively new members of the health care
delivery team that seeks new solutions for the difficult problems confronting modern
society. The purpose of this chapter is to provide a broad overview of technology’s
role in shaping our modern health care system, highlight the basic roles biomedical
engineers play, and present a view of the professional status of this dynamic field.

1.1

EVOLUTION OF THE MODERN HEALTH CARE SYSTEM
Primitive humans considered diseases to be ‘‘visitations,’’ the whimsical acts of
affronted gods or spirits. As a result, medical practice was the domain of the witch
doctor and the medicine man and medicine woman. Yet even as magic became an
integral part of the healing process, the cult and the art of these early practitioners
were never entirely limited to the supernatural. These individuals, by using their
natural instincts and learning from experience, developed a primitive science based
on empirical laws. For example, through acquisition and coding of certain reliable
practices, the arts of herb doctoring, bone setting, surgery, and midwifery were
advanced. Just as primitive humans learned from observation that certain plants and
grains were good to eat and could be cultivated, so the healers and shamans observed
the nature of certain illnesses and then passed on their experiences to other
generations.
Evidence indicates that the primitive healer took an active, rather than a simply
intuitive interest in the curative arts, acting as a surgeon and a user of tools. For

instance, skulls with holes made in them by trephiners have been collected in various
parts of Europe, Asia, and South America. These holes were cut out of the bone with
flint instruments to gain access to the brain. Although one can only speculate the
purpose of these early surgical operations, magic and religious beliefs seem to be the
most likely reasons. Perhaps this procedure liberated from the skull the malicious
demons that were thought to be the cause of extreme pain (as in the case of migraine)
or attacks of falling to the ground (as in epilepsy). That this procedure was carried out