`
`
`
`HANDBOOK
`
`Editor—in—Chief
`
`JOSEPH D. BRONZINO
`
`Trinity College .
`Hartford, Connecticut
`
`cm: PRESS
`
`@ IEEE mass
`
`A CRC Handbook Published in Cooperation with IEEE Press
`
`Petitioner Apple Inc. – Ex. 1019, cover p. 1
`Petitioner Apple Inc. — Ex. 1019, cover p. 1
`APPLE 1013
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`1
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`1
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`APPLE 1013
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`Library of Congress Cataloging-in-Publication Data
`
`The biomedical engineering handbook / editor-in-chief, Joseph-D. Bronzino.
`p.
`cm. — (The electrical engineering handbook series)
`Includes bibliographical references and index.
`ISBN 0-8493-8346-3
`l. Biomedical engineering—Handbooks, manuals, etc.
`Joseph D., 1937— .
`II. Series.
`[DNLM:
`l. Biomedical Engineering—handbooks. QT 29 8615 1995]
`R856.15.BS6
`1995
`6 l 0 '.28—d620
`‘ DNLM/DLC
`
`I. Bronzino,
`
`For Library of Congress
`
`’
`
`95—6294
`CIP
`
`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 valid-
`ity of all materials or for the consequences of their use.
`Neither this book not any part may be reproduced or transmitted in any form or by any means, electronic or
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`© 1995 by CRC Press, Inc.
`
`No claim to original U.S. Government works
`International Standard Book Number 0-8493-8346-3
`Library of Congress Card Number 95-6294
`Printed in the United States ofAmerica 1 2 3 4 5 6 7 8 9 0
`Printed on acid-free paper
`
`Petitioner Apple Inc. – Ex. 1019, cover p. 2
`Petitioner Apple Inc. — Ex. 1019, cover p. 2
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`2
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`
`Introduction
`
`
`In the 20th century, technological innovation has progressed at such an accelerated pace that it has
`permeated almost every facet of our lives This is especially true in the field of medicine and the de—
`livery of health care services. Today, in most developed countries, the modern hospital has emerged
`as the center of a technologically sophisticated health care system serviced by an equally technolog—
`ically sophisticated staff.
`V
`.
`With almost continual technological innovation driving 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 en—
`gineering. In the process, biomedical engineers have become actively involved in the design, devel-
`opment, and utilization of materials, devices (such as ultrasonic lithotripsy, pacemakers, etc.), and
`techniques (such as signal and image processing, artificial intelligence, etc.) for clinical research, as
`well as the diagnosis and treatment of patients. Thus many biomedical engineers now serve as mem—
`bers of health care delivery teams seeking new solutions for the difficult health care problems con—
`fronting our society. The purpose of this handbook is to provide a central core ofknowledgefrom those
`fields encompassed by the discipline of biomedical engineering. Before presenting this detailed infor-
`mation, 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
`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 prac-
`tices, in which specialized physicians and nurses located within the hospital provide critical diag-
`nostic 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
`
`iii
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`Petitioner Apple Inc. – Ex. 101(cid:28), p. (cid:76)(cid:76)(cid:76)
`Petitioner Apple Inc. — Ex. 1019, p. iii
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`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, the 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 a 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.
`However, the most significant innovation for clinical medicine was the development ofx-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 process, x-ray machines became commonplace in most urban hospitals. Separate de-
`partments of radiology were established, and their influence spread to other departments through-
`out the hospital. By the 19303, 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 di-
`agnosis of a wide variety of diseases and injuries. Moreover, since x—ray machines were too cum-
`bersome 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 ofhealth care services became essential because ofmany
`other important technological innovations appearing on the medical scene. However, hospitals re-
`mained institutions to dread, and it was not until the introduction ofsulfanilamide in the mid—19305
`and penicillin in the early 19405 that the main danger of hospitalization, i.e., cross—infection among
`patients, was significantly reduced. With these new drugs in their arsenals, surgeons were permitted
`to perform their operations without prohibitive morbidity and mortality due to infection. Further-
`more, even though the different blood groups and their incompatibilitywere discovered in 1900 and
`sodium citrate was used in 1913 to prevent clotting, full development of blood banks was not prac-
`tical until the 19305, 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 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 lung and heart vessels and
`valves), were developed. As a result, accurate diagnosis of congenital and acquired heart disease
`(mainly valve disorders due to rheumatic fever) became possible, and a new era of cardiac and vas-
`cular 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 ef-
`forts, 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 funda—
`mental unit of the central nervous system—the neuron—as well as to monitor various phys-
`iologic 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.
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`Petitioner Apple Inc. – Ex. 101(cid:28), p. (cid:76)(cid:89)
`Petitioner Apple Inc. — Ex. 1019, p. iV
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`4. Diagnostic ultrasound based on sonar technologybecame 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
`cardiac assist devices, such as artificial heart valves and artificial blood vessels, and the artifi—
`cial 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 inten-
`sive care units, and to provide sophisticated statistical diagnoses of potential diseases corre-
`lated with specific sets of patient symptoms.
`8. Development of the first computer-based medical instrument, the computerized axial to—
`mography scanner, revolutionized clinical approaches to noninvasive diagnostic imaging
`procedures, which now include magnetic resonance imaging and positron emission tomog—
`raphy as well.
`
`The impact of these discoveries and many others has been profound. The health care system con—
`sisting primarily of the “horse and buggy” physician is gone forever, replaced by a technologically
`sophisticated clinical staff operating primarily in “modern” hospitals designed to accommodate the
`new medical technology. This evolutionary process continues, with advances in biotechnology and
`tissue engineering altering the very nature of the health care delivery system itself.
`
`The Field of Biomedical Engineering
`
`Today, many of the problems confronting health professionals are of extreme interest to engineers
`because they involve the design and practical application of medical devices and systems—processes
`that are fundamental to engineering practice. These medically related design problems can range
`from very complex large-scale constructs, such as the design and implementation of automated clin-
`ical laboratories, multiphasic screening facilities (i.e., centers that permit many clinical tests to be
`conducted), and hospital information systems, to the creation of relatively small and “simple” de-
`vices, such as recording electrodes and biosensors, that may be used to monitor the activity of spe-
`cific physiologic processes in either a research or clinical setting. They encompass the many com-
`plexities of remote monitoring and telemetry, including the requirements of emergency vehicles,
`operating rooms, and intensive care units. The American health care system, therefore, encompasses
`many problems that represent challenges to certain members of the engineering profession called
`biomedical engineers.
`
`Biomedical Engineering: A Definition
`
`Although what is included in the field of biomedical engineering is considered by many to be quite
`clear, there are some disagreements about its definition. For example, consider the terms biomedical
`engineering, bioengineering, and clinical (or medical) engineering which have been defined in Pacela’s
`Bioengineering Education Directory [Quest Publishing Co., 1990]. While Pacela defines bioengineer—
`ing as the broad umbrella term used to describe this entire field, bioengineering is usually defined as
`a basic research—oriented activity closely related to biotechnology and genetic engineering, i.e., 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 im-
`provement 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 quality of human life, the
`potential of this specialty is difficult to imagine. Consider the following activities of bioengineers:
`
`Petitioner Apple Inc. – Ex. 101(cid:28), p. (cid:89)
`Petitioner Apple Inc. — Ex. 1019, p. V
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`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
`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
`
`In reviewing the above-mentioned terms, however, biomedical engineering appears to have the
`most comprehensive meaning. Biomedical engineers apply electrical, mechanical, chemical, optical,
`and other engineering principles to understand, modify, or control biologic (i.e., human and ani-
`mal) 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 hos-
`pital or clinic, they are more properly called clinical engineers.
`
`Activities of Biomedical Engineers
`
`The breadth of activity of biomedical engineers is significant. The field has moved significantly from
`being concerned primarily with the development of medical devices in the 19503 and 19605 and to
`include a more wide-ranging set of activities. As illustrated below, the field of biomedical engineer—
`ing now includes many new career areas, 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 biomed-
`ical 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 infor-
`matics and artificial intelligence)
`'
`Medical imaging, i.e., the graphic display of anatomic detail or physiologic function
`The creation of new biologic products (i.e., biotechnology and tissue engineering)
`
`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 diseases
`Design of closed-loop control systems for drug administration
`
`o o '
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`vi
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`Petitioner Apple Inc. – Ex. 101(cid:28), p. (cid:89)(cid:76)
`Petitioner Apple Inc. — Ex. 1019, p. vi
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`- Modeling of the physiologic 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 the-
`oretical, 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 in-
`terdisciplinary 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 chem—
`istry 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 identifi—
`cation of the problems and needs of our present health care system that can be solved using exist-
`ing engineering technology and systems methodology. Consequently, the field of biomedical engi-
`neering offers hope in the continuing battle to provide high-quality health care at a reasonable cost;
`and if properly directed toward solving problems related to preventive medical approaches, ambu—
`latory care services, and the like, biomedical engineers can provide the tools and techniques to make
`our health care system more effective and efficient.
`
`Joseph D. Bronzino
`Editor—in-Chief
`
`vii
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`Petitioner Apple Inc. – Ex. 101(cid:28), p. (cid:89)(cid:76)(cid:76)
`Petitioner Apple Inc. — Ex. 1019, p. Vii
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`7
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`The Discipling of ngmedical Engineering
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`
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`Petitioner Apple Inc. – Ex. 101(cid:28), p. (cid:89)(cid:76)(cid:76)(cid:76)1
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`8
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`52
`
`Optical Sensors
`
`‘
`
`Yitzhak Mendelson
`Worcester Polytechnic Institute
`
`52.1 Instrumentation ...................................... 765
`LightSource - Optical Element - Photodetectors - Signal Processing
`52.2 Optical Fibers ......................................... 766
`Probe Configurations ' Optical Fiber Sensors - Indicator—Mediated
`Transducers
`
`52.3 General Principles of Optical Sensing ..................... 767
`Evanescent Wave Spectroscopy Surface Plasmon Resonance
`52.4 Applications ......................................... 769
`Oximetry- Blood Gases ' Glucose Sensors - Immunosensors
`I
`
`Optical methods are among the oldest and best-established techniques for sensing biochemical
`analytes. Instrumentation for optical measurements generally consists of a light source, a number
`of optical components to generate a light beam with specific characteristics and to direct this light
`to some modulating agent, and a photodetector for processing the optical signal. The central part
`of an optical sensor is the modulating component, and a major part of this chapter will focus on
`how to exploit the interaction of an analyte with optical radiation in order to obtain essential
`biochemical information.
`
`The number of publications in the field of optical sensors for biomedical applications has grown
`significantly during the past two decades. Numerous scientific reviews and historical perspectives
`have been published, and the reader interested in this rapidly growing field is advised to consult these
`sources for additional details. This chapter will emphasize the basic concept of typical optical sensors
`intended for continuous in vivo monitoring of biochemical variables, concentrating on those
`sensors which have generally progressed beyond the initial feasibility stage and reached the promis-
`ing stage of practical development or commercialization.
`Optical sensors are usually based on optical fibers or on planar waveguides. Generally, there are
`three distinctive methods for quantitative optical sensing at surfaces:
`
`1. The analyte directly affects the optical properties 'of a waveguide, such as evanescent waves
`(electromagnetic waves generated in the medium outside the optical waveguide when light
`is reflected from within) or surface plasmons (resonances induced by an evanescent wave in
`a thin film deposited on a waveguide surface).
`2. An optical fiber is used as a plain transducer to guide light to a remote sample and return
`light from the sample to the detection system. Changes in the intrinsic optical properties of
`the medium itself are sensed by an external spectrophotometer.
`3. An indicator or chemical reagent placed inside, or on, a polymeric support near the tip of the
`optical fiber is used as a mediator to produce an observable optical signal. Typically, conven-
`tional techniques, such as absorption spectroscopy and fluorimetry, are employed to measure
`changes. in the optical signal.
`
`764
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`o—amssqs—3/95/so.ou+s.so
`o 1995 by CRC Press, Inc.
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`Petitioner Apple Inc. – Ex. 101(cid:28), p. 764
`Petitioner Apple Inc. — Ex. 1019, p. 764
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`Optical Sensors
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`52.1 Instrumentation
`
`The actual implementation of instrumentation designed to interface with optical sensors will vary
`greatly depending on the type of optical sensor used and its intended application. A block diagram
`of a generic instrument is illustrated in Fig. 52.1. The basic building blocks of such an instrument
`are the light source, various optical elements, and photodetectors.
`
`Light Source
`
`A wide selection of light sources are available for optical sensor applications. These include; highly
`coherent gas and semiconductor diode lasers, broad spectral band incandescent lamps, and narrow—
`band, solid-state, light—emitting diodes (LEDs). The important requirement of a light source is
`obviously good stability. In certain applications, for example in portable instrumentation, LEDs
`have significant advantages over other light sources because they are small and inexpensive, con—
`sume low power. produce selective wavelengths, and are easy to work with. In contrast, tungsten
`lamps produce a broader range of wavelengths, higher intensity, and better stability but require a _
`sizable power supply and can cause heating problems inside the apparatus.
`
`Optical Elements
`
`Various optical elements are used routinely to manipulate light in optical instrumentation. These
`include lenses, mirrors, light choppers, .beam splitters, and couplers for directing the light from the
`light source into the small aperture of a fiber optic sensor or a specific area on a waveguide surface
`and collecting the light from the sensor before it is processed by the photodetectot. For wavelength
`selection, optical filters, prisms, and diffraction gratings are the most common components used to
`provide a narrow bandwidth of excitation when a broadwidth light source is utilized.
`
`Photodetectors
`
`In choosing photodetectors for optical sensors, a number of factors must be considered. These
`include sensitivity, detectivity, noise, spectral response, and response time. Photomultipliers and
`
`
`
`FIGURE 52.1 General diagram representing the basic building blocks ofan optical instrument
`for optical sensor applications.
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`Petitioner Apple Inc. – Ex. 101(cid:28), p. 765
`Petitioner Apple Inc. — Ex. 1019, p. 765
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`Biomedical Sensors
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`semiconductor quantum photodetectors, such as photoconductors and photodiodes, are both suit-
`able. The choice, however, is somewhat dependent on the wavelength region of interest. Generally,
`both give adequate performance. Photodiodes are usually more attractive because of the compact—
`ness and simplicity of the circuitry involved.
`Typically, two photodetectors are used in optical instrumentation because it is often necessary to
`include arseparate reference detector to track fluctuations in source intensity and temperature. By
`taking a ratio between the two detector readings, whereby a part of the light that is not affected by
`the measurement variable is used for correcting any optical variations in the measurement system,
`a more accurate and stable measurement can be obtained.
`
`Signal Processing
`Typically, the signal obtained from a photodetector provides a voltage or a current proportional to
`the measured light intensity. Therefore, either simple analog computing circuitry (e.g., a current-
`to-voltage converter) or direct connection to a programmable gain voltage stage is appropriate.
`Usually, the output frdm a photodetector is connected directly to a preamplifier before it is applied
`to sampling and analog—to—digital conversion circuitry residing inside a computer.
`Quite often two different wavelengths of light are utilized to perform a specific measurement. One
`wavelength is usually sensitive to changes in the species being measured, and the other wavelength
`is unaffected by changes in the analyte concentration. In this manner, the unaffected wavelength is
`used as a reference to compensate for fluctuations in instrumentation over time. In other applica-
`tions, additional discriminations, such as pulse excitation or electronic background subtraction
`utilizing synchronized lock—in amplifier detection, are useful, allowing improved selectivity and
`enhanced signal—to—noise ratio.
`
`
`52.2 Optical Fibers
`
`Several types of biomedical measurements can be made by using either plain optical fibers as a
`remote device for detecting changes in the spectral properties of tissue and blood or optical fibers
`tightly coupled to Various indicator-mediated transducers. The measurement relies either on direct
`illumination of a sample through the endface of the fiber or by excitation of a coating on the side
`wall surface through evanescent wave coupling. In both cases, sensing takes place in a region out-
`side the optical fiber itself. Light emanating from the fiber end is scattered or fluoresced back into
`the fiber, allowing measurement-of the returning light as an indication of the optical absorption or
`fluorescence of the sample at the fiber optic tip.
`_
`Optical fibers are based on the principle of total internal reflection. Incident light is transmitted
`through the fiber if it strikes the cladding at an angle greater than the so—called critical angle, so that
`it is totally internally reflected at the core/cladding interface. A typical instrument for performing fiber
`optic sensing consists of a light source, an optical coupling arrangement, the fiber optic light guide
`with or without the necessary sensing medium incorporated at the distal tip, and a light detector.
`A variety of high— quality optical fibers are'available commercially for biomedical sensor applica—
`tions, depending on the analytic wavelength desired. These include plastic, glass, and quartz fibers
`which cover the optical spectrum from the UV through the Visible to the near IR region. On one
`hand, plastic optical fibers have a larger aperture and are strong, inexpensive, flexible, and easy to
`work with but have poor UV transmission below 400 nm. On the other hand, glass and quartz fibers
`have low attenuation and better transmission in the UV but have small apertures, are fragile, and
`present a potential risk in in vivo applications.
`
`Probe Configurations
`
`There are many different ways to implement fiber optic sensors. Most fiber optic chemical sensors
`employ either a single-fiber configuration, where light travels to and from the sensing tip in one
`
`I
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`Petitioner Apple Inc. – Ex. 101(cid:28), p. 766
`Petitioner Apple Inc. — Ex. 1019, p. 766
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`fiber, Or a double—fiber configuration, where separate optical fibers are used for illumination and
`detection. A single fiber optic configuration offers the most compact and potentially least expensive
`implementation. However, additional challenges in instrumentation are involved in separating the
`illuminating signal from the composite signal returning for processing.
`The design of intravascular catheters require special considerations related to the sterility and bio-
`compatibility of the sensor. For example, intravascular fiberoptic sensors must be sterilizable and
`their material nonthrombogenic and resistant to platelet and protein deposition. Therefore, these
`catheters are typically made of materials covalently bound with heparin or antiplatelet agents. The
`catheter is normally introduced into the jugular vein via a peripheral cut-down and a slow heparin
`flush is maintained until it is removed from the blood.
`
`Optical Fiber Sensors
`
`Advantages cited for fiber optic sensors include their small size and low cost. In contrast to electri-
`cal measurements, where the difference of two absolute potentials must be measured, fiber optics
`are self—contained and do not require an external reference signal. Because the signal is optical, there
`is no electrical risk to the patient, and there is no direct interference from surrounding electric or
`magnetic fields. Chemical analysis can be performed in real-time with almost an instantaneous
`response. Furthermore, versatile sensors can be developed that respond to multiple analytes by
`utilizing multiwavelength measurements.
`Despite these advantages, optical fiber sensors exhibit several shortcomings. Sensors with immo—
`bilized dyes and other indicators have limited long—term stability, and their shelf life degrades over
`time. Moreover, ambient light can interfere with the optical measurement unless optical shielding
`or special time-synchronous gating is performed.
`
`Indicator-Mediated Transducers
`
`Only a limited number of biochemical analytes have an intrinsic optical absorption that can be
`measured with sufficient selectivity directly by spectroscopic methods. Other species, particularly
`hydrogen, oxygen, carbon dioxide, and glucose, which are of primary interest in diagnostic applica—
`tions, are not susceptible to direct photometry. Therefore, indicator-mediated sensors have been
`developed using specific reagents that are properly immobilized on the surface of an optical sensor.
`The