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Sundararajan Madihally

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Principles of Biomedical Engineering
Second Edition
 For a listing of recent titles in the
Artech House Engineering in Medicine and Biology Library,
turn to the back of this book.
Principles of Biomedical Engineering
Second Edition

Sundararajan V. Madihally
Library of Congress Cataloging-in-Publication Data
A catalog record for this book is available from the U.S. Library of Congress.

British Library Cataloguing in Publication Data

A catalog record for this book is available from the British Library.

ISBN-13: 978-1-63081-711-4

Cover design by John Gomes

© 2020 Artech House

685 Canton Street
Norwood, MA 02062

All rights reserved. Printed and bound in the United States of America. No part
of this book may be reproduced or utilized in any form or by any means, elec-
tronic or mechanical, including photocopying, recording, or by any information
storage and retrieval system, without permission in writing from the publisher.
All terms mentioned in this book that are known to be trademarks or service
marks have been appropriately capitalized. Artech House cannot attest to the
accuracy of this information. Use of a term in this book should not be regarded
as affecting the validity of any trademark or service mark.

10 9 8 7 6 5 4 3 2 1
Contents

CHAPTER 1
Introduction 1
1.1 Overview 1
1.2 Roles of Bioengineers 2
1.3 History of Bioengineering 5
1.3.1 Development of Biomedical Imaging 5
1.3.2 Development of Dialysis 9
1.3.3 The Development of the Heart-Lung Machine 14
1.3.4 Other Devices 18
1.4 Sources for Information 19
Problems 20
Selected Bibliography 20

CHAPTER 2
Biotransport 23
2.1 Overview 23
2.2 Fundamental Factors 24
2.2.1 Liquid Compartments 24
2.2.2 Solute Components 28
2.2.3 Components in the Gas Phase 28
2.2.4 Importance of pH 32
2.3 Diffusion-Mediated Transport 36
2.3.1 Free Diffusion 38
2.3.2 Facilitated Diffusion 44
2.3.3 Active Transport 46
2.4 Osmosis-Driven Transport 48
2.4.1 Osmolarity 49
2.4.2 Tonicity 50
2.4.3 Osmotic Pressure 51
2.5 Combined Osmosis and Pressure Gradient-Driven Transport 53
2.6 Transport of Macromolecules 57
Problems 59
References 68

v
vi Contents

CHAPTER 3
Bioelectrical Phenomena 69
3.1 Overview 69
3.2 Membrane Potential 70
3.2.1 Nernst Equation 71
3.2.2 Donnan Equilibrium 73
3.2.3 Goldman Equation 75
3.3 Electrical Equivalent Circuit 77
3.3.1 Cell Membrane Conductance 77
3.3.2 Cell Membrane as a Capacitor 78
3.3.3 Resistance-Capacitance Circuit 81
3.3.4 Action Potential 84
3.4 Principles of Bioelectrodes 87
3.4.1 Electrode-Electrolyte Interface 87
3.4.2 Potential Monitoring Electrodes 91
3.4.3 Amperometric Devices 94
3.4.4 Intracellular Recording of Bioelectricity 97
3.5 Volume Conductors 99
3.5.1 Electric Field 100
3.5.2 Electrical Potential Energy 102
3.5.3 Conservation of Charge 104
3.5.4 Measuring Electrical Activity of Tissues: Example of
Electrocardiogram 109
3.5.5 Biopotential Recording Practicalities 113
Problems 114
References 123
Selected Bibliography 123

CHAPTER 4
Biofluid Flow 125
4.1 Overview 125
4.2 Fluid Flow Characteristics 126
4.2.1 Conservation of Mass 126
4.2.2 Inertial and Viscous Forces 127
4.2.3 Conservation of Momentum 130
4.3 Nonidealities in Biological Systems 139
4.3.1 Oscillatory and Pulsating Flows 139
4.3.2 Alterations in Viscosity 143
4.3.3 Fluid Flow in Microelectromechanical Systems (MEMS) 146
4.4 Conservation of Energy 150
4.4.1 Different Energy Forms 150
4.4.2 Energy Balance in the Body 159
4.4.3 Energy Expenditure Calculations 161
4.5 Fluid Power 163
4.5.1 Power Calculations in a Cardiac Cycle 164
Contents vii

4.5.2 The Efficiency of a Pump 166

4.5.3 Pumps in Series and Parallel 167
4.6 Optimization Principle for Fluid Transport 168
4.6.1 Minimum Work of Circulation 169
Problems 171
References 180
Selected Bibliography 180

CHAPTER 5
Biomechanics 183
5.1 Overview 183
5.2 Conservation of Momentum in Solids 184
5.2.1 Different Forces Acting on the Body 184
5.2.2 Angular Motion 190
5.2.3 Impulse-Momentum Relation 192
5.2.4 Gait Analysis (Motion Analysis) 196
5.3 Ideal Stress-Strain Characteristics 200
5.3.1 Structural Parameters and Material Parameters 200
5.3.2 Axial Stress and Strain 201
5.3.3 Shear Stress 210
5.3.4 Bending 212
5.3.5 Torsion 217
5.4 Nonidealities in Stress-Strain Characterization 219
5.4.1 Failure Under Combined Loading 219
5.4.2 Viscoelastic Characteristics 220
5.4.3 Dynamic Loading 221
5.5 Conservation of Energy in Solids 222
5.5.1 Work-Energy Relation 222
5.5.2 Energy Absorption 225
Problems 227
References 240
Selected Bibliography 241

CHAPTER 6
Biomaterials 243
6.1 Overview 243
6.2 Types of Biomaterials 244
6.2.1 Metals and Alloys 244
6.2.2 Ceramics 246
6.2.3 Polymers 250
6.2.4 Biological Materials 254
6.2.5 Composites 255
6.3 Material Characteristics 256
6.3.1 Mechanical Performance 256
6.3.2 Mechanical Durability 257
viii Contents

6.3.3 Corrosion and Degradation 258

6.3.4 Surface Roughness 260
6.3.5 Sterilization Techniques 262
6.4 Physiological Responses to Biomaterials 264
6.4.1Toxicity Analysis 265
6.4.2Surface Adhesion 266
6.4.3Blood-Material Interactions 273
6.4.4Inflammatory Response 275
6.4.5Infection 277
6.5 Tissue Engineering 279
6.5.1 Material Used in Tissue Regeneration 280
6.5.2 Scaffold Formation Techniques 282
Problems 285
References 287
Selected Bibliography 287

CHAPTER 7
Cellular Engineering 289
7.1 Overview 289
7.2 Cell Culture 290
7.2.1 Microenvironment 290
7.2.2 Proliferation and Differentiation 294
7.2.3 Bioreactors 298
7.2.4 Different Modes of Operation 301
7.3 Characterization and Utilization of Products 305
7.3.1 Purification of Products 305
7.3.2 Soluble Factor Interactions 306
7.3.3 Enzyme-Based Biosensors 320
7.3.4 Antibody-Based Biosensors 324
7.3.5 Nucleic Acid-Based Biosensors 325
7.3.6 Immobilization Strategies 326
7.4 Cellular Processes 330
7.4.1 Cell-Matrix Interactions 331
7.4.2 Cell-Cell Interactions 332
7.4.3 Metabolism 333
7.4.4 Intracellular Degradation 334
7.5 Storage of Cells and Tissues 335
7.5.1 Long-Term Storage of Cells 336
7.5.2 Storage of Tissues 337
7.5.3 Microarray Technology 338
7.6 Bioinformatics 342
Problems 344
References 352
Selected Bibliography 353
Contents ix

CHAPTER 8
Biomedical Imaging 355
8.1 Overview 355
8.2 Properties of Light 356
8.2.1 Electromagnetic Spectrum 356
8.2.2 Energy in an EM Wave 357
8.2.3 Generation of EM Radiation 361
8.3 Interaction of Radiation with Matter 363
8.3.1 Absorption of EM Waves 363
8.3.2 Scattering of EM Waves 364
8.3.3 Transmission Imaging 366
8.4 Basics of Imaging 368
8.4.1 Image Acquisition 368
8.4.2 Digitizing Images 370
8.4.3 The 3-D Image Reconstruction 373
8.4.4 Image Quality 375
8.5 Imaging Devices 377
8.5.1 X-Ray Imaging 377
8.5.2 PET 378
8.5.3 MRI 384
8.5.4 Ultrasound Imaging 392
8.5.5 Optical Coherence Tomography (OCT) 395
8.5.6 Endoscopes 397
8.5.7 Fluorescence Imaging 397
Problems 399
References 401
Selected Bibliography 401

CHAPTER 9
Modeling Complex Systems 403
9.1 Overview 403
9.2 Compartmental Modeling 404
9.2.1 Chemical Compartmental Model 404
9.2.2 The Apparent Volume of Distribution 408
9.2.3 Other Single Compartmental Systems 411
9.2.4 Multicompartmental Models 412
9.3 Special Cases of Compartmental Modeling 419
9.3.1 Modeling Dialysis 419
9.3.2 Cable Theory 424
9.4 Modeling Diffusion-Limited Processes 430
9.4.1 Case 1: Reaction-Diffusion in Cartesian coordinates. 432
9.4.2 Case 2: The Krogh Tissue Cylinder 433
9.4.3 Case 3: A 1-D Radial Diffusion in Spherical Coordinates 436
9.4.4 Case 4: Cell Migration 437
9.4.5 Complex Model Systems 441
x Contents

Problems 442
References 453
Selected Bibliography 453

CHAPTER 10
Ethics and Regulatory Affairs 455
10.1 Overview 455
10.2 Complexities of Bioethics 456
10.2.1 Bioethics in the Context of Ethical Theories 456
10.2.2 The Difference Between Ethics and Law 458
10.2.3 Influence of Religion and Culture 459
10.3 Research Testing 460
10.3.1 The Declaration of Helsinki 460
10.3.2 Belmont Report 460
10.3.3 Institutional Review Board (IRB) 461
10.3.4 Informed Consent 463
10.4 Safety Standards 465
10.4.1 Standards and Guidelines 465
10.4.2 International Electromedical Commission (IEC) 466
10.4.3 ISO 467
10.5 Regulatory Agencies 470
10.5.1 The FDA 470
10.5.2 Device Classification 471
10.5.3 Compliance Requirements 473
   Problems 475
   References 476
   Selected Bibliography 476

About the Author 479

Index 481
 CHAPTER 1

Introduction

1.1 Overview

Bioengineering applies engineering principles and design concepts to medicine and

biology with the intention of improving the overall healthcare of society and par-
ticularly the lives of those with medical impairments. Bioengineering is rooted in the
life sciences, chemistry, mathematics, and physics. Bringing together the knowledge
of problem-solving from many engineering disciplines, bioengineers design medical
instruments, devices, and computational tools and perform population studies or
carry out research to acquire the knowledge needed to solve new problems. Bioengi-
neers play a critical role in developing new products, advancing research, and solv-
ing clinical problems. In cardiology alone, devices such as diagnostic monitors to
measure the electrical activity of the heart (electrocardiographs) as well as systems
to analyze gases in the blood have revolutionized healthcare. Further, pacemakers
and defibrillators help the heart to correct its beating pattern, while lasers and other
instruments are used for surgery.
In general, biomedical scientists observe the natural phenomenon with the in-
tention of enhancing the basic understanding of laws by formulating hypotheses
and testing them. However, bioengineers use established principles and laws to
develop new technologies that are useful to society. For example, bioscientists ex-
plore the phenomena of how cardiac cells function, whereas bioengineers use these
understandings to develop devices that can monitor the activity of cardiac cells and
provide information on their healthiness. While these devices are useful in clinical
care, they also offer new tools to get more insight into biological processes and new
methods of data collection and analysis.
Bioengineering brings together expertise from other engineering disciplines,
such as chemical, electrical, and mechanical engineering, to solve biology and
healthcare problems. Compared with other engineering disciplines, biomedical
engineering is a relatively new field within educational institutions. Many of the
leaders have entered the field of bioengineering with degrees in other engineering
disciplines. Whether bioengineers are involved in designing, testing, or managing
applications, it is collaborative, requiring them to work on teams with physicians,
nurses, technicians, and others involved in the practice of medicine. Bioengineers

1
2 ������������
Introduction

need to know the needs of the basic performance measures in any field. Perform-
ance affects different roles in different ways. As a device developer, one has to
know where to start, how to proceed, and when one has optimized the device
enough. As a device tester, one has to validate whether the device supports expected
workloads. The objective of this book is to provide a basic understanding of those
features based on engineering fundamentals.
In this chapter, some of the roles of bioengineers are introduced first. Then
three examples of device development are given with the intention of introduc-
ing the interdisciplinary nature of bioengineering. Further, the bioengineering com-
munity, which is broad and multidisciplinary, and some of the organizations are
described with the intention of knowing where to look for networking. Finally,
locations where one could search to become updated with recent developments are
given.

1.2 Roles of Bioengineers

Although the fundamental concepts of bioengineering have a significant history, it is

a relatively new discipline relative to other engineering disciplines such as chemical,
civil, electrical, and mechanical engineering. Bioengineers are extensively involved
in developing a number of point-of-care devices that individuals can use at their
comfort locations. Glucose monitors have significantly helped diabetic patients.
Similarly, pregnancy test kits, blood pressure monitoring systems, and various joint
protecting devices have changed the health-care managements. Some of the special-
ized areas in bioengineering are as follows.
Bioinstrumentation (discussed in Chapters 3, 8, and 9) is the application of
electrical measurement (discussed in Chapter 3) and electronics engineering princi-
ples to develop devices used in diagnosis and treatment of disease. Medical imag-
ing and signal processing are part of bioinstrumentation, for example, designing
and development of medical devices such as cardiac pacemakers, defibrillators,
cochlear implants, artificial kidneys, blood oxygenators, joints, arms, and legs.
Examples of instrumentation that have benefited patients include: (1) functional
magnetic resonance imaging that employs computer algorithms to produce detailed
cardiac images without the need for invasive diagnostic procedures, (2) computer-
ized electrocardiograms that allow the diagnosis and treatment of cardiac arrhyth-
mias without open-heart surgery, (3) the application of materials, microprocessors,
and computer and battery technologies, which were used to develop cardiac pace-
makers, and (4) biosensors for detecting and monitoring metabolites and identify-
ing specific genetic materials.
A variety of materials are utilized in the development of various biomedical
devices. Some devices, such as total hip and cochlear implants, are implanted for
a long term. Some devices, such as contact lenses, are used on a regular basis, and
some devices, such as needles and surgical tools, are used for a short term. Materi-
als that are used in biomedical applications typically interact with the body parts or
fluids and should possess unique properties, such as causing no toxic and carcino-
genic effects. This subset which includes metals, alloys, ceramics, polymers, com-
posites, and naturally derived materials such as cotton is referred to as biomaterial
1.2 Roles of Bioengineers 3

(discussed in Chapter 6). Understanding the properties, possible interactions with

blood, sterilization approaches, and manufacturing capabilities of these materials
is vital in the design and development of various devices. The selection of appropri-
ate material to place in the human body may be one of the most difficult tasks faced
by the biomedical engineer. Specialists in biomaterials could be involved in design-
ing and developing novel prosthetic devices, such as implantable insulin pumps
or improved cochlear implants designing and synthesizing novel biomaterials for
tissue regeneration and/or determination of the mechanical, transport of nutrients
(discussed in Chapter 2), and biocompatibility properties.
Biomechanics (discussed in Chapter 5) deals with the application of traditional
mechanics to biological or medical problems. A better understanding of the forces
and their effects on the human body is essential to get more insight into the func-
tioning of various body parts, the effect of load and overload on specific structures,
and biomaterial that could be utilized in prosthetic development. One example is
the biomechanical analyses during the impact of automobiles that can be utilized
to develop safety devices such as airbags, seatbelts, and helmets. Other applications
of biomechanics include designing prosthetic components, improving athletic per-
formance and rehabilitation engineering, developing tools for persons with physi-
cal disabilities.
Cellular engineering (discussed in Chapter 7) involves solving biomedical prob-
lems at the cellular and subcellular levels utilizing the molecular nature of building
blocks of the body such as cells, proteins, carbohydrates, fatty acids, and nucleic
acids. Cells can be cultured in large quantities outside the body, which can be uti-
lized to relate function and disease occurrence, to regenerate an artificial tissue,
to detect a biological signal, to test the toxicity of a chemical, or to collect cell-
derived products for use as therapeutic molecules. One of the successful cellular
engineerings is the development of devices that help in reducing risk in bone mar-
row transplantation and other cellular therapies to treat various diseases. One can
play a significant role in the production of new vaccines from cloned cells and the
development of other therapeutic proteins from monoclonal antibodies.
Clinical engineering is the application of technology to healthcare in hospitals
or in the industry. The clinical engineer is a member of the healthcare team in a
hospital along with physicians, nurses, and other hospital staff. Clinical engineers
are responsible for testing, repairing, and maintaining proper and safe operating
condition, the hospital’s diagnostic and therapeutic equipment. Sometimes clinical
engineers provide pre-purchase evaluations of new technology and equipment, re-
search equipment issues for physicians and administrative staff, and assist clinical
departments with service contract analysis, negotiations, and management. Clini-
cal engineers also work in medical product development industry, contributing to
product design or sales and support. Primarily their job is to ensure that new prod-
ucts meet the demands of medical practice.
Medical imaging (Chapter 8) involves the development of various imaging
techniques that can be utilized in a clinical setting and basic physiology and bi-
ology research. Non-invasive imaging modalities provide information regarding
functional processes or anatomy of some of the internal organs. Imaging tech-
niques such as magnetic resonance imaging (MRI), X-ray computed tomography
(CT) and positron emission tomography (PET) have become important tools for
4 ������������
Introduction

the early detection of disease, the understanding of basic molecular aspects of living
organisms and the evaluation of medical treatment. Often, these images can be ob-
tained with minimal or completely noninvasive procedures, making them less pain-
ful and more readily repeatable than invasive techniques. With the incorporation of
the digital scan converters in real-time instruments, the computer has assumed an
expanding role in diagnostic imaging. Imaging for medical and biological purposes
has expanded tremendously due to advances in instrumentation, and computa-
tional mechanisms. Bioengineers play a critical role in designing, constructing, and/
or analyzing medical imaging systems.
Rehabilitation engineering, as defined in the Rehabilitation Act of 1973 by the
United States government, means the systematic application of engineering sciences
to design, develop, adapt, test, evaluate, apply, and distribute technological solu-
tions to problems confronted by individuals with disabilities in functional areas,
such as mobility, communications, hearing, vision, and cognition, and in activities
associated with employment, independent living, education, and integration into
the community. Rehabilitation engineers are involved in prosthetics, the develop-
ment of home, workplace and transportation modifications and the design of assis-
tive technology that enhances seating and positioning, mobility, and communica-
tion. Rehabilitation engineers are also developing hardware and software computer
adaptations and cognitive aids to assist people with cognitive difficulties. These
careers require additional training beyond the bachelor’s degree in bioengineering.
Modeling complex systems (discussed in Chapter 9) deals with developing
mathematical expressions to understand various physiological events, processes,
and functions. In conjunction with experimentation, one could develop quantifi-
able information. For example, when a contrast agent is developed for improving
the resolution of a biomedical image, understanding its half-life in the body and
clearance characteristics is critical to its use. Many compartmental models are used
in such studies and similar strategies can be explored for conduction of electrical
signals by neurons. Bioengineering creates knowledge from the molecular to the
organ systems levels. Modeling complex systems play a significant role in

•• Development and implementation of computational models of physiological

systems;
•• Development of new diagnostic procedures, particularly those requiring en-
gineering analyses to determine parameters that are not directly accessible to
measurements;
•• Development of artificial intelligence-based strategies for decision making,
such as a computer-based system for managing the care of patients or for
diagnosing diseases;
•• Design of computer systems to monitor patients during surgery or in inten-
sive care.

Frequently, these specialized areas are interdependent. For example, the design
of an artificial hip is greatly aided by studies on anatomy, bone biomechanics, gait
analysis, and biomaterial compatibility. The forces that are applied to the hip can
be considered in the design and material selection for the prosthesis. �
1.3 History of Bioengineering 5

1.3 History of Bioengineering

Bioengineering has evolved into a field of its own as a result of contributions from
a number of disciplines. From the historical perspective, the revolutionary changes
that have occurred in biology and medicine have depended on new methods that
are the result of fundamental discoveries in many different fields. A number of
individuals with expertise in different disciplines would collaborate in solving a
problem related to bioengineering. Major contributions of bioengineering includ-
ing hip joint replacement, artificial articulated joint, magnetic resonance imaging,
heart pacemaker, arthroscopy, heart-lung machine, angioplasty, bioengineered skin,
time-release drug capsules, and kidney dialysis have evolved through successful col-
laborations between medical practitioners and many disciplines including physics,
mathematics, chemistry, computer sciences, and engineering. Significant improve-
ments in computational tools and information technologies have already played a
greater role in the emergence of telemedicine. The number of medical device estab-
lishments registered at the United States-Food and Drug Administration (FDA) was
nearly 11,000 in 2004. To understand the interdisciplinary nature of bioengineer-
ing, the history behind three significant contributions are described below.

1.3.1 Development of Biomedical Imaging

Various medical imaging modalities provide complementary windows through
which most of the organs and their functions can be visualized. It began many
centuries ago with the discovery of various fundamental concepts in physics, biol-
ogy, and chemistry. In 1668, Antoni van Leeuwenhoek (Dutch scientist and builder
of microscopes) confirmed the discovery by Marcello Malpighi (Italian anatomist)
of capillary systems using a simple magnifying lens. He demonstrated how the red
corpuscles circulated through the capillaries of a rabbit’s ear and the web of a
frog’s foot. In 1674, Leeuwenhoek gave the first description of red blood corpuscles
(RBC). He then discovered the motion of bacteria (he referred them as animalcules),
and sperm cells. In 1729, Stephen Gray (British pensioner) distinguished conductors
of electricity from nonconductors. In 1750, Benjamin Franklin (best known as an
American politician) defined positive and negative electricity. In 1800, Alessandro
Volta (Italian physicist) constructed the first electrical battery. In 1827, Georg S.
Ohm (German physicist) formulated Ohm’s law, stating the relation between elec-
tric current, electromotive force, and resistance. Michael Faraday, a British physicist
and chemist, and Joseph Henry, an American scientist, discovered electromagnetic
induction (i.e., refined the science of electromagnetism to make it possible to design
practical electromagnetic devices). In 1873, James C. Maxwell, a Scottish math-
ematician and theoretical physicist, published his famous four equations describ-
ing electrical and magnetic phenomena in the book “Treatise on Electricity and
Magnetism.” In 1893, Joseph J. Thomson, the British physicist widely recognized
for discovering electrons, published a supplementary volume to Maxwell’s treatise,
describing in detail the passage of electricity through gases. Further, he developed
the cathode-ray tubes with the help of some graduate students.
6 ������������
Introduction

A significant change occurred in 1895 when Wilhelm C. Roentgen, a German

physicist, accidentally discovered that a cathode-ray tube could make a sheet of
paper coated with barium platinocyanide glow, even when the tube and the paper
were in separate rooms. Roentgen decided that the tube must be emitting some sort
of penetrating rays. He named them X for unknown. Shortly afterward, Roentgen
found that if he aimed the X-rays through Mrs. Roentgen’s hand at a chemically
coated screen, he could see the bones in the hand clearly on the screen. The first
radiograph of human anatomy was reported using his wife’s left hand. In 1896,
Henry Becquerel, a French scientist, discovered that the X-rays were emitted from
uranium ore. Further, he found out that another new type of radiation was being
spontaneously emanated without the salts of uranium had to be illuminated: radia-
tion (referred to as radioactivity), which could pass through metal foils and darken
a photographic plate. Two of his students, Pierre and Marie Curie, traced the radia-
tion to the element radium.
In 1905, Robert Kienböck, a German radiologist known for identifying Kien-
böck disease, used strips of silver bromide photographic paper to estimate the
amount of radiation to which patients were exposed in radiation therapy. Over the
next few decades, X-rays grew into a widely used diagnostic tool. Within the first
year after the announcement of the discovery of X-rays, many papers and books on
X-rays were published. By the 1930s, X-rays were being used to visualize most or-
gan systems using radio-opaque materials. With the developments in photography,
various films were developed. In 1932, DuPont produced cellulose nitrate and cel-
lulose acetate films that could be used for X-rays. However, with the development
of electron imaging and processing in the television industry, processing biomedical
images were also developed. Much of the early work on improving the image qual-
ity had its ultimate objective with the application of electron imaging to the prob-
lem of television camera tubes. The concept of image intensification by cascading
stages was suggested independently by a number of workers in the field during the
same period. In 1951, Russell H. Morgan and Ralph E. Sturm, radiologists from
Johns Hopkins University, constructed a brightness intensifier for X-rays with an
image intensification tube similar to the tube used in television cameras.
In the meantime, Karl T. Dussik, an Austrian neurologist, reported in 1942 the
first use of diagnostic ultrasound (acoustic energy with a frequency above human
hearing, that is, 20,000 Hertz), although high-frequency sound wave was discov-
ered in late 1780. In the late 1940s, George D. Ludwig (American scientist) system-
atically started evaluating ultrasound, for diagnostic purposes. Ludwig reported
that echo patterns could sometimes be confusing, and multiple reflections from
soft tissues could make test results difficult to interpret. Later, Ludwig collaborated
with physicist Richard H. Bolt, the director of the Acoustics Laboratory at the
Massachusetts Institute of Technology (MIT), neurosurgeon H. Thomas Ballan-
tine, Jr., and physicist Theodor F. Hueter from Siemens Electromedical Laborato-
ries in Erlangen, Germany, to work on ultrasound propagation characteristics in
mammalian tissues. This research concluded that ultrasonograms suffered from a
high level of noise problems. However, along with the advancements of SONAR
(Sound Navigation and Ranging) in the metal industry, research into using ultra-
sound for diagnostic purposes continued. In 1968, Stuart Campbell, a British ob-
1.3 History of Bioengineering 7

stetrician and gynecologist, published an improved method of ultrasonic imaging

which became standard practice in the examination of the fetus during pregnancy.
Based on nuclear magnetic resonance phenomenon pioneered in the 1930s by
Isidor I. Rabi, an American physicist, and Felix Bloch and Edward M. Purcell,
American scientists, magnetic resonance imaging (MRI) was developed as a new
way of taking pictures of the body’s interior. MRI relies on a strong magnetic field
and a radio signal that together trigger atoms in the body to send out radio signals
of different frequency (discussed in Chapter 9). In 1964, a major improvement in
the quality of the signal was achieved by using the concept of Fourier transform
developed by Jean Baptiste Joseph Fourier, a French mathematician, in 1822. In
1971, Raymond V. Damadian, an American researcher, showed that nuclear mag-
netic relaxation time of tissues and tumors differed, motivating scientists to use
MRI to study disease. Later, Damadian also built the MRI machine that was ap-
proved by the U.S. Food and Drug Administration (FDA).
The science of medical imaging grew slowly with incremental improvements in
the X-ray technique. All the images lacked spatial information. In the early 1970s,
discovery of computerized tomography (CT) or computerized axial tomography
(CAT) by many researchers including Godfrey N. Hounsfield, a British engineer,
Allan M. Cormack, a physicist, Paul C. Lauterbur, an American chemist, and Peter
Mansfield, a British physicist, revolutionized medical diagnosis with the opportu-
nity of a new imaging option. Hounsfield built an instrument that combined an
X-ray machine and a computer. A series of X-ray images from various angles were
combined with the computer using certain principles of algebraic reconstruction
to build a three-dimensional (3-D) image of that part of the body. Small detectors
inside the scanner measured the amount of X-rays that make it through the part
of the body being studied. The computer receives this information to create several
individual images called slices. These images were stored, viewed on a monitor,
or printed on film. Physicians could then instruct the computer to display two-
dimensional (2-D) slices from any angle and at any depth.
Lauterbur applied magnetic field gradients in all three dimensions to create
magnetic resonance images via CAT-scan projection-reconstruction technique, bor-
rowed from CT scanning. The 3-D models of organs were created by stacking the
individual slices together. Mansfield showed how the radio signals could be math-
ematically analyzed and images could be generated extremely fast, which made it
possible to develop a useful imaging technique. Richard R. Ernst, a Swiss physical
chemist, realized that one could use switched magnetic field gradients with chang-
ing time, which led to the basic reconstruction method for MRI. In the early 1980s,
MRI was developed as a new way of taking pictures of the body’s interior (Figure
1.1(a)). Many scientists over the next two decades developed MRI into a robust
technology of obtaining sophisticated images without using surgery. Developments
in magnet technology led to designs that increased both patient acceptance and the
range of potential applications. The development of superconducting electromag-
nets that produce high magnetic field systems has made it possible to obtain better-
quality images. Another major improvement in MRI is the development of open
MRI (Figure 1.1(b)), making it possible for people with claustrophobia to get the
scans without fear. However, open MRI utilizes low-field resistive electromagnets
or permanent magnets and the quality of the image obtained is lower than enclosed
8 ������������
Introduction

Figure 1.1 MRI. (a) MAGNETOM Symphony whole body imaging system. (b) MAGNETOM C!, an
open MRI. (Courtesy of Siemens Medical Solutions, Malvern, Pennsylvania.)

systems. Another development in 1990 was that Seiji Ogawa, a Japanese biophysi-
cist who worked for AT&T’s Bell Laboratories, reported that deoxygenated hemo-
globin, when placed in a magnetic field, would increase the strength of the field in
its vicinity, while oxygenated hemoglobin would not. This led to the development
of functional MRI (fMRI), which allows capturing the images of an organ in action
or study functions of that organ. The number of MRI scans performed increases
each year, as does the number of people with implanted cardiac devices. In 2007,
there were approximately 30 million MRI scans conducted in the United States and
that number continues to grow. It is estimated that more than 200,000 patients
annually in the United States have to forego an MRI scan because they have a
pacemaker due to the risks involved, including interference with the pacemaker op-
eration, damage to system components, lead or pacemaker dislodgement, heating
of the lead tips, and unintended cardiac stimulation. MRI scans allow physicians
to make a wide range of health diagnoses by viewing highly detailed images of
internal organs, blood vessels, muscle, joints, tumors, areas of infection, and more.
Other techniques such as positron emission tomography (PET) and single pho-
ton emission computed tomography (SPECT) have also been developed for use
in biomedical imaging. Further, substantial improvements in optics hardware and
the development of increasingly sensitive electronic imaging sensors have paved
the way for the use of light microscopy-based techniques in biomedical imaging.
Combined with time-lapse imaging, novel developments have provided powerful
tools in unraveling the complex processes underlying the basic building blocks of
life. Although there is no perfect imaging method through which everything in the
body can be visualized, various medical imaging techniques provide complemen-
tary windows through which many tissues and organs can be visualized. The new
imaging techniques can produce information about the anatomical structure that is
linked to functional data.
There have also been significant developments in sophisticated algorithms for
extracting structural and functional volumetric information from raw measure-
ments (computed imaging) and for processing, visualizing, and analyzing the image
1.3 History of Bioengineering 9

data. Novel imaging methods can provide comprehensive views of the human body
in greater depth and detail while becoming less expensive, faster, and less invasive.
For example, innovations in the performance of the computer system used to con-
trol data acquisition and image processing are increasing the speed of MRI data
acquisition and opening up new possibilities in real-time imaging. Most of the
images are constructed using computers from a collection of digital data; image
quality depends on the power of the computer and the caliber of its software, and
there is a significant opportunity for improvement in both. A biomedical engineer
may spend his or her day designing electrical circuits and computer software for
medical instrumentations.

1.3.2 Development of Dialysis

The kidneys are vital organs in maintaining the balance of several key electrolytes
in the body (including common salt, sodium chloride), eliminating liquid wastes
from the body, and filtering over 400 gallons of blood daily. When the kidneys
are not functioning correctly, pathological conditions are caused by the accumula-
tion of waste products. The body swells, and if there are no intervention, death
results. Acute and chronic kidney failure is an illness that is as old as humanity
itself and can lead to death if untreated for several days or weeks. In early Rome
and later in the Middle Ages, treatments for uremia (Greek for urine poisoning, or
“urine in the blood”) included the use of hot baths and sweating therapies. Since
an individual can only last a short time with total kidney failure, dialysis was devel-
oped as a method of keeping a person alive until a suitable organ donor could be
located. The current procedures for the treatment of kidney failure include hemo-
dialysis and peritoneal dialysis, developed on the principles of osmosis, diffusion,
and ultrafiltration (separation based on the size of the particles). Hemodialysis is
a more frequently prescribed type than peritoneal dialysis. The treatment involves
circulating the patient’s blood outside of the body through a dialysis circuit (Figure
1.2(a)). Two needles are inserted into the patient’s vein, or access site, and are at-
tached to the dialysis circuit, which consists of plastic blood tubing, a filter known
as a dialyzer, and a dialysis machine that monitors and maintains blood flow and
administers dialysate. The dialysate is a chemical bath that is used to draw waste
products out of the blood. In peritoneal dialysis, the patient’s abdominal lining (or
peritoneum) acts as a blood filter. A catheter is surgically inserted into the patient’s
abdomen. During treatment, the catheter is used to fill the abdominal cavity with
dialysate. Waste products and excess fluids move from the bloodstream into the di-
alysate solution. After waiting, depending on the treatment method, the waste-filled
dialysate is drained from the abdomen and replaced with clean dialysate.
Development of dialyzers began nearly two centuries ago (1831) when Thomas
Graham, a Scottish chemist, described a procedure that he called dialysis to remove
solute from a solvent (or purify the blood in case of kidney failure). Using parch-
ment as a membrane, Graham demonstrated that urea can be removed from urine.
Osmosis (described in Chapter 2) and dialysis became popular as methods used in
chemical laboratories that allowed the separation of dissolved substances or the
removal of water from solutions through semipermeable membranes. The blood
was spread across the membrane (a thin layer formed between objects and organs)
10 ������������
Introduction

Figure 1.2 Hemodialysis. (a) Flow loop of the hemodialysis. (b) Components in the hollow-fiber
dialyzer.

that allowed wastes to pass into a balanced fluid while replenishing substances
would pass from the fluid into the blood. In 1855, Adolf Fick, a German physiolo-
gist, published a quantitative description of the diffusion process. However, it was
Albert Einstein, 50 years later, who derived those empirically defined diffusion laws
using the thermodynamics of the theory of Brownian molecular motion.
In 1912, John Jacob Abel, an American biochemist and pharmacologist, was
investigating byproducts in the blood. He needed a device to extract these materi-
als from the blood. With his colleagues Benjamin Turner and Leonard Rowntree,
Abel built the first functioning dialysis machine. This machine circulated blood
through 8-mm tubing made of colloidin (nitrocellulose) membrane, immersed in a
salt (saline)-dextrose (a type of naturally occurring sugar) solution, coiled around
a rotating drum encased in a glass jacket. Urea (a compound found in urine) and
other toxins passed out into the solution and oxygen passed into the blood. Abel
called the process “vividiffusion.” In 1913, they “dialyzed” anesthetized animals
by directing the blood outside the body and through tubes with semipermeable
membranes. Before Abel could route the animals’ blood through the dialyzer, the
blood’s ability to clot or coagulate had to be at least temporarily restricted using
hirudin, the anticoagulant element in the saliva of leeches.
Georg Haas, a German physician, performed the first dialysis treatment involv-
ing humans in 1924. Haas also used a collodion membrane and hirudin as the anti-
coagulant similar to Abel but built dialyzers in a variety of models and sizes. When
and how much Haas knew about Abel’s research group are not known because of
the confusion surrounding World War I. By 1928, Haas had dialyzed an additional
six patients, none of whom survived, likely because of their critical condition and
1.3 History of Bioengineering 11

the insufficient effectiveness of the dialysis treatment. Nevertheless, the use of hiru-
din often led to massive complications arising from allergic reactions since the sub-
stance was insufficiently purified and originated in a species distant from humans.
In the end, Haas used heparin, which was first isolated in dog livers by Jay McLean,
an American researcher, in 1916. Heparin caused substantially fewer complications
than hirudin, even when it was insufficiently purified, and it could be produced in
larger amounts. Heparin became and remains the anticoagulant of choice, with
the development of better separation technologies in the 1930s. In 1923, the use
of intact living peritoneum (abdominal lining) was a good dialyzing surface, and
Georg Ganter, a German clinical investigator, reported the first use of peritoneal
dialysis in clinical therapy. Subsequently, Heinrich Necheles, a German physician,
modified his extracorporeal (meaning apparatus carrying the blood outside the
body) device by compressing tubes of a peritoneal membrane between screens of
metal mesh, which reduced the enclosed blood volume and increased the effective
surface area. However, due to issues with sterility, peritoneal membranes suffered
from an increased incidence of infection. Another development in the 1930s was
commercial production of cellophane (regenerated cellulose acetate) in large quan-
tities as tubing for sausage casing, which replaced colloidin membranes due to its
better performance and mechanical stability. Later, cuprophane (cuprammonium
cellulose) membranes replaced cellophane due to its better permeability properties.
Willem J. Kolff, a Dutch physician, secured success in 1945 when he treated
a 67-year-old patient with acute kidney failure for a week, which allowed the pa-
tient to be released with normal kidney function. The patient died at the age of
73 years from an illness unrelated to kidney failure. Although Kolff had unsuc-
cessfully treated 16 previous patients in a series of experiments, this success was
the first major breakthrough in the treatment of patients with kidney disease. The
success is attributed to the technical improvements in the actual equipment used for
the treatment. Kolff’s device consisted of a rotating wooden drum around which
a new membrane made of cellophane was wrapped. Blood was taken from the
artery propelled through the tubing when the drum rotated (using the principle
of Archimedes’ screw). The drum containing blood-filled tubes were partially im-
mersed in an electrolyte solution known as dialysate. As the membranous tubes
passed through the bath, the uremic toxins would pass into this rinsing liquid due
to diffusion (described in Chapter 2) and osmosis. Blood was returned to the vein,
largely cleared of urea and unknown toxic substances.
In 1947, Nils Alwall, a Swedish engineer, published a scientific work describing
a modified dialyzer that could better combine the necessary processes of dialysis
and ultrafiltration than the traditional Kolff kidney. The cellophane membranes
used in the dialyzer could withstand higher pressure because of their positioning
between two protective metal grates. All of the membranes were in a tightly closed
cylinder so that the necessary pressure need not be derived with the blood flow but
could rather be achieved using lower pressure in the dialysate. However, due to
its alleged lack of compatibility with blood (described in Chapter 6), membranes
made from unmodified cellulose lost their market share. They have been replaced
by modified cellulosic and synthetic dialysis membranes that show better compati-
bility with blood than unmodified cellulose membranes. Leonard T Skeggs, Jr., and
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