`
`
`
`HANDBOOK
`
`Editor-in-Chief
`JOSEPH D. BRONZINO
`Trinity College |
`Hartford, Connecticut
`
`CRC PRESS
`
`&IEEE PRESS
`
`A CRC Handbook Published in Cooperation with IEEE Press
`
`Petitioner Apple Inc. – Ex. 1019, cover p. 1
`Petitioner Apple Inc. — Ex. 1019, coverp. 1
`APPLE 1013
`
`1
`
`1
`
`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.— (Theelectrical engineering handbookseries)
`Includes bibliographical references and index.
`ISBN 0-8493-8346-3
`1. Biomedical engineering—Handbooks, manuals, etc.
`Joseph D.,1937— .
`ILSeries.
`[DNLM:_1. Biomedical Engineering—handbooks. QT 29 B615 1995]
`R856.15.B86
`1995
`610°.28—dc20
`~ DNLM/DLC
`
`1, 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 referencesare listed. Reasonable efforts have been made
`to publish reliable data and information,but the authorand the publisher cannot assumeresponsibility for the valid-
`ity of all materials or for the consequencesoftheir use.
`Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or
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`Reporting Service is ISBN 0-8493-8346-3/95/ $0.00+ $.50. Thefee is subject to change withoutnotice. For organiza-
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`Direct all inquiries to CRC Press,Inc., 2000 Corporate Blvd. N.W., Boca Raton, Florida 33431.
`
`© 1995 by CRC Press,Inc.
`
`Noclaim to original U.S. Government works
`International Standard Book Number0-8493-8346-3
`Library of Congress Card Number 95-6294
`Printed in the United States ofAmerical 234567890
`Printed on acid-free paper
`
`Petitioner Apple Inc. – Ex. 1019, cover p. 2
`Petitioner Apple Inc. — Ex. 1019, coverp. 2
`
`2
`
`

`

`
`
`Introduction
`
`In the 20th century, technological innovation has progressed at such an accelerated pace that it has
`permeatedalmosteveryfacet of ourlives. Thisis especially true in the field of medicine andthe 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 sophisticatedstaff.
`,
`With almost continual technological innovation driving medical care, engineering professionals
`have becomeintimately 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 becomeactively 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 treatmentof patients. Thus many biomedical engineers now serve as mem-
`bers of health care delivery teams seeking new solutions forthe difficult health care problems con-
`fronting our society. The purposeof this handbookis 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
`ofpatients.
`
`Evolution of the Modern Health Care System
`Before 1900, medicine hadlittle 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 currentcrisis in the availability of health
`care professionals. Although the costs of obtaining medicaltraining wererelatively 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 wastypically the site
`for treatment and recuperation, andrelatives and neighbors constituted an able and willing nursing
`staff. Babies were delivered by midwives, and thoseillnesses not cured by home remedies wereleft
`to run their natural, albeit frequentlyfatal, course. The contrast with contemporary health care prac-
`tices, in which specialized physicians and nurses located within the hospital provide critical diag-
`nostic andtreatmentservices,is dramatic.
`Thechangesthat have occurred within medicalscience originated in the rapid developments that
`tookplace in the applied sciences (chemistry, physics, engineering, microbiology, physiology, phar-
`macology,etc.) at the turn of the century. This process of developmentwas characterized by intense
`
`iti
`
`Petitioner Apple Inc. – Ex. 101(cid:28), p. (cid:76)(cid:76)(cid:76)
`Petitioner Apple Inc. — Ex. 1019,p.tit
`
`3
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`

`

`interdisciplinary cross-fertilization, which provided an environmentin 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
`measuretheelectrical 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 andelectrical
`measurement techniques.
`Newdiscoveries in medical sciences followed one anotherlike intermediates in a chain reaction.
`However, the most significant innovation for clinical medicine was the developmentofx-rays. These
`“new kindsof 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 bonefractures anddislocations,
`and in the process, x-ray machines became commonplace in most urban hospitals. Separate de-
`partmentsof radiology were established, andtheir influence spread to other departments through-
`out the hospital. By the 1930s, x-ray visualization of practically all organ systems of the body had
`been madepossible through the use of barium salts and a wide variety of radiopaque materials.
`X-ray technology gave physicians a powerful toolthat,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 membersofsociety.
`For economicreasons,the centralization ofhealth care services becameessential because ofmany
`other important technological innovations appearing on the medical scene. However,hospitals re-
`mainedinstitutions to dread, andit was not until the introduction ofsulfanilamide in the mid-1930s
`and penicillin in the early 1940s that the main dangerof hospitalization,i.e., cross-infection among
`patients, was significantly reduced. With these new drugsin their arsenals, surgeons were permitted
`to perform their operations withoutprohibitive morbidity and mortality due to infection. Further-
`more, even thoughthedifferent blood groupsand their incompatibility.were discovered in 1900 and
`sodium citrate was used in 1913 to preventclotting, full developmentof blood banks was notprac-
`tical until the 1930s, when technology provided adequate refrigeration. Until that time, “fresh”
`donors were bled andthe blood transfused while it wasstill warm.
`Once these surgical suites were established, the employmentof specifically designed pieces of
`medical technology assisted in further advancing the development of complex surgical procedures.
`For example, the Drinker respirator was introduced in 1927andthefirst 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 andinto the
`heart with the injection of radiopaque dyefor 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 newera ofcardiac and vas-
`cular surgery was established.
`Following World WarII, technological advances were spurred on by efforts to develop superior
`weapon systemsand establish habitats in space and onthe ocean floor. As a by-product oftheseef-
`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. Advancesin solid-state electronics madeit possible to map the subtle behaviorof the funda-
`mental unit of the central nervous system—the neuron—aswell as to monitorvarious phys-
`iologic parameters, such as the electrocardiogram,ofpatients in intensive care units.
`2. New prosthetic devices became a goal of engineers involved in providing the disabled with
`tools to improve their quality oflife.
`3. Nuclear medicine—an outgrowth of the atomic age—emerged as a powerful andeffective
`approachin detecting and treating specific physiologic abnormalities.
`
`iv
`
`Petitioner Apple Inc. – Ex. 101(cid:28), p. (cid:76)(cid:89)
`Petitioner Apple Inc. — Ex. 1019, p. iv
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`4
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`

`4, Diagnostic ultrasound basedon sonartechnology became so widely accepted that ultrasonic
`studies are nowpart of the routine diagnostic workup in many medicalspecialties.
`5. “Spare parts”surgery also became commonplace. Technologists were encouraged to provide
`cardiac assist devices, suchas artificial heart valves andartificial blood vessels, andthe artifi-
`cial heart program waslaunched to develop a replacementfora defective or diseased human
`heart.
`6. Advances in materials have made the developmentof disposable medical devices, such as
`needles and thermometers,as well as implantable drug delivery systems,a reality.
`7. Computers similar to those developed to controltheflight 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. Developmentofthefirst 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-
`raphyas well.
`
`The impactof these discoveries and manyothers has been profound.Thehealth 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 engineeringaltering the very nature ofthe health care delivery systemitself.
`
`The Field of Biomedical Engineering
`
`Today, many of the problems confronting health professionals are of extreme interest to engineers
`because they involvethe design andpractical 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 automatedclin-
`ical laboratories, multiphasic screeningfacilities (i.e., centers that permit manyclinical tests to be
`conducted), and hospital information systems, to the creation ofrelatively small and “simple” de-
`vices, such as recordingelectrodes and biosensors, that may be used to monitorthe activity of spe-
`cific physiologic processes in either a research orclinical setting. They encompass the many com-
`plexities of remote monitoring and telemetry, including the requirements of emergencyvehicles,
`operating rooms, and intensive care units. The American health care system, therefore, encompasses
`many problemsthat represent challenges to certain members of the engineering profession called
`biomedical engineers.
`
`Biomedical Engineering: A Definition
`Although whatis includedin thefield of biomedical engineering is considered by manyto be quite
`clear, there are some disagreements aboutits definition. For example, consider the terms biomedical
`engineering, bioengineering, andclinical (or medical) engineering which have been defined in Pacela’s
`Bioengineering Education Directory {Quest Publishing Co., 1990]. While Pacela defines bicengineer-
`ing as the broad umbrella term used to describethis entirefield, bioengineering is usually defined as
`a basic research-orientedactivity closely related to biotechnology and genetic engineering,i.e., the
`modification of animal or plantcells, or parts of cells, to improve plants or animals or to develop
`new microorganismsfor beneficial ends. In the food industry, for example, this has meant the im-
`provementofstrainsofyeast for fermentation.In agriculture, bioengineers may be concerned with
`the improvementofcrop yields by treatmentof plants with organisms to reduce frost damage.It is
`clear that bioengineers of the future will have a tremendous impacton the quality ofhumanlife, the
`potential ofthis specialty is difficult to imagine. Consider the followingactivities of bioengineers:
`
`Petitioner Apple Inc. – Ex. 101(cid:28), p. (cid:89)
`Petitioner Apple Inc. — Ex. 1019, p. v
`
`5
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`

`

`*
`
`°
`
`Developmentof 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 plantlife from toxicants and
`pollutants
`Study of protein-surface interactions
`Modelingofthe growth kinetics of yeast and hybridomacells
`Research in immobilized enzyme technology
`Developmentof 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 treatmentof patients. When biomedical engineerswork within a hos-
`pital or clinic, they are more properlycalled clinical engineers.
`
`Activities of Biomedical Engineers
`The breadth ofactivity of biomedical engineersis significant. The field has movedsignificantly from
`being concerned primarily with the development of medical devices in the 1950s and 1960s and to
`include a more wide-rangingsetofactivities. As illustrated below,the field of biomedical engineer-
`ing now includes many newcareerareas, 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 (.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 andclinical decision making(i.e., medical infor-
`matics and artificial intelligence)
`:
`Medical imaging,i.e., the graphic display of anatomic detail or physiologic function
`Thecreation 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 modelingof the function of the human heart
`Writing software for analysis of medical research data
`Analysis of medical device hazardsfor safety andefficacy
`Development of new diagnostic imaging systems
`Design of telemetry systems for patient monitoring
`Design of biomedical sensors for measurement of human physiologic systems variables
`Developmentof expert systems for diagnosis of diseases
`Design of closed-loop control systems for drug administration
`
`vi
`
`Petitioner Apple Inc. – Ex. 101(cid:28), p. (cid:89)(cid:76)
`Petitioner Apple Inc. — Ex. 1019, p. vi
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`6
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`

`- Modeling ofthe physiologic systems of the human body
`* Design of instrumentation for sports medicine
`* Developmentof new dental materials
`* Design of communication aids for the handicapped
`* Study of pulmonaryfluid dynamics
`+ Study of the biomechanicsof the human body
`+ Developmentof 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 encompassresearch,
`development, implementation, and operation. Accordingly,like medicalpracticeitself, it is unlikely
`that any single person can acquire expertise that encompassestheentirefield. Yet, because of the in-
`terdisciplinary nature ofthis activity, there is considerable interplay and overlappingofinterest and
`effort between them. For example, biomedical engineers engagedin the developmentof biosensors
`may interact with those interested in prosthetic devices to develop a meansto detect and use the
`same bioelectric signal to powera prosthetic device. Those engaged in automatingtheclinical chem-
`istry laboratory may collaborate with those developing expert systemsto assist clinicians in making
`decisions based onspecific laboratory data. The possibilities are endless.
`Perhapsa greater potential benefit occurring from the use of biomedical engineeringis identifi-
`cation of the problems and needsof 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 continuingbattle to provide high-quality health care at a reasonable cost;
`andif properly directed toward solving problemsrelated to preventive medical approaches, ambu-
`latory care services, andthelike, biomedical engineers can provide the tools and techniques to make
`our health care system moreeffective andefficient.
`
`Joseph D. Bronzino
`Editor-in-Chief
`
`vii
`
`Petitioner Apple Inc. – Ex. 101(cid:28), p. (cid:89)(cid:76)(cid:76)
`Petitioner Apple Inc. — Ex. 1019, p. vii
`
`7
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`

`

`The Discipline of Biomedical Engineering
`
`Biosensors
`.
`.
`.
`Medical Informatics:
`(Clinical Engineering
`
`
`
`; enMedicalandBiologica
`Detection ofbiologic
`Ofpatient-related data,
`ign
`and development
`5
`events andtheir
`Auaiicie
`interpretresults and
`Clineally relavedfoeiities
`éduversian
`to iteottcal
`To detect, classify, and
`assist in clinical
`devices, systems, and
`signals
`analyze bioelectric
`decision making,
`procedures
`erected
`signals
`systems and neural
`networks
`
`
`
`
`
`
`
`
`Bumactanis ilitaiMedicaljologic Modell Imaging ionee
`
`
`
`Electromagnetic
`;
`;
`ineeri
`static
`To provide graphic
`
`displays ofanatomic
`Fields
`andfluid
`
`mechanics
`detail andphysiologic
`Function
`associatedwith
`“eae
`pitysiolagic
`eneae
`
`systems
`fields on
`biologic tissue
`
`
`
`To create or modify
`Amtificial Organs
`Design and development
`1,
`re
`table
`ii
`
`
`for beneficial ends,
`pamentals:
`Design and development
`
`
`incheaingtissue
`ofdevicesforeeay
`
`or augmentationofbodily ineeri
`engineering
`c
`
`
`
`
`Petitioner Apple Inc. – Ex. 101(cid:28), p. (cid:89)(cid:76)(cid:76)(cid:76)m
`
`a‘d“6101“xq—‘ourojddysouonnog
`
`8
`
`

`

`oy
`
`Optical Sensors
`
`“
`
`Yitzhak Mendelson
`Worcester Polytechnic Institute
`
`52.1 Instrumentation ©... ... 0. cece cece e ee tte eee eee 765
`Light Source + Optical Element » Photodetectors + Signal Processing
`52.2 Optical Fibers 0... cece cee cece bene e ene net teee 766
`Probe Configurations - Optical Fiber Sensors + Indicator-Mediated
`Transducers
`
`52.3 General Principles of Optical Sensing ..............2..0065 767
`Evanescent Wave Spectroscopy * Surface Plasmon Resonance
`52.4 Applications ....... 060. c cence cece erence een eee 769
`Oximetry + Blood Gases + Glucose Sensors ° Immunosensors
`,
`
`Optical methods are amongthe oldest and best-established techniques for sensing biochemical
`analytes. Instrumentation for optical measurements generally consists ofa light source, a number
`of optical components to generate a light beam with specific characteristics and to directthis light
`to some modulating agent, and a photodetectorfor processing the optical signal. The central part
`of an optical sensoris the modulating component, and a majorpart of this chapter will focus on
`howto exploit the interaction of an analyte with optical radiation in order to obtain essential
`biochemical information.
`The number of publicationsin thefield of optical sensors for biomedical applications has grown
`significantly during the past two decades. Numerousscientific reviews and historical perspectives
`have been published,and the readerinterested in this rapidly growingfield is advised to consult these
`sourcesfor additional details. This chapterwill emphasize the basic conceptoftypical optical sensors
`intended for continuous in vivo monitoring of biochemical variables, concentrating on those
`sensors which have generally progressed beyondtheinitialfeasibility 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. Theanalyte 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 wavein
`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. Changesin the intrinsic optical properties of
`the medium itself are sensed by an external spectrophotometer.
`3. An indicator or chemical reagentplacedinside, or on, a polymeric support nearthetip 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
`changesin the optical signal.
`
`764
`
`0-8493-8346-3/95/$0.00+8.50
`© 1995 by CRCPress, Inc,
`
`Petitioner Apple Inc. – Ex. 101(cid:28), p. 764
`Petitioner Apple Inc. — Ex. 1019, p. 764
`
`9
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`

`

`Optical Sensors
`
`765
`
`52.1
`
`Instrumentation
`
`Theactual implementation ofinstrumentation designed to interface with optical sensors will vary
`greatly dependingonthe type of optical sensor used andits intended application. A block diagram
`of a generic instrumentis 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 wideselection oflight sources are available for optical sensor applications. These include: highly
`coherent gas and semiconductor diodelasers, broad spectral band incandescent lamps, and narrow-
`band,solid-state, light-emitting diodes (LEDs). The important requirementof a light source is
`obviously good stability. In certain applications, for example in portable instrumentation, LEDs
`havesignificant advantages over other light sources because they are small and inexpensive, con-
`sume low power, produceselective wavelengths, and are easy to work with. In contrast, tungsten
`lamps producea broader range of wavelengths, higher intensity, and better stability but require a _
`sizable power supply and can cause heating problemsinside the apparatus.
`
`Optical Elements
`Various optical elements are used routinely to manipulatelight in optical instrumentation. These
`includelenses, mirrors,light choppers, beam splitters, and couplers for directing the light from the
`light source into the small apertureofa fiber optic sensoror a specific area on a waveguide surface
`andcollecting the light from the sensorbeforeit is processed by the photodetector. For wavelength
`selection,optical filters, prisms, and diffraction gratings are the most common components used to
`provide a narrow bandwidth ofexcitation when a broadwidth light source is utilized.
`
`Photodetectors
`
`In choosing photodetectors for optical sensors, a numberof factors must be considered. These
`
`includesensitivity, detectivity, noise, spectral response, and response time. Photornultipliers and
`
`FIGURE52.1 General diagram representing the basic building blocks ofan optical instrument
`for optical sensor applications.
`
`Petitioner Apple Inc. – Ex. 101(cid:28), p. 765
`Petitioner Apple Inc. — Ex. 1019, p. 765
`
`10
`
`10
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`766
`
`Biomedical Sensors
`
`semiconductor quantum photodetectors, such as photoconductors and photodiodes,are both suit-
`able. The choice, however, is somewhat dependent on the wavelength region ofinterest. Generally,
`both give adequate performance. Photodiodesare usually moreattractive because of the compact-
`ness and simplicity of the circuitry involved.
`Typically, two photodetectors are used in optical instrumentation becauseit is often necessary to
`include a separate reference detector to track fluctuations in source intensity and temperature. By
`taking a ratio between the two detector readings, wherebya partofthelightthatis not affected by
`the measurementvariable is used for correcting any optical variations in the measurementsystem,
`a more accurate and stable measurement can be obtained.
`
`Signal Processing
`Typically, thé signal obtained from a photodetector provides a voltageor a current proportionalto
`the measuredlight intensity. Therefore, either simple analog computingcircuitry (e.g., a current-
`to-voltage converter) or direct connection to a programmable gain voltage stage is appropriate.
`Usually, the output from a photodetector is connected directly to a preamplifier beforeit is applied
`to sampling and analog-to-digital conversion circuitry residing inside a computer.
`Quite often two different wavelengthsoflightare utilized to perform a specific measurement. One
`wavelength is usually sensitive to changesin 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 overtime. 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
`enhancedsignal-to-noise ratio.
`
`52.2 Optical Fibers
`
`
`Several types of biomedical measurements can be made by usingeither plain opticalfibers as a
`remote device for detecting changes in the spectral properties oftissue and blood oroptical fibers
`tightly coupled to various indicator-mediated transducers. The measurementrelies either on direct
`illumination of a sample through the endface ofthefiber or by excitation of a coating on theside
`wall surface through evanescent wave coupling. In both cases, sensing takes place in a region out-
`side the opticalfiberitself. Light emanating from thefiber endis scattered or fluoresced back into
`thefiber, allowing measurementof the returninglight as an indication of the optical absorption or
`fluorescence of the sample at the fiber optictip.
`,
`Optical fibers are based on theprinciple of total internal reflection. Incidentlight is transmitted
`through thefiberif it strikes the cladding at an angle greater than the so-called critical angle, so that
`it is totally internallyreflected atthe core/claddinginterface. A typical instrumentfor performingfiber
`optic sensing consists of a light source, an optical coupling arrangement, the fiber optic light guide
`with or without the necessary sensing medium incorporatedatthedistal tip, andalight detector.
`A variety of high-quality optical fibers are available commercially for biomedical sensor applica-
`tions, depending on the analytic wavelength desired. These includeplastic, 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. Onthe other hand,glass and quartzfibers
`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 manydifferent ways to implementfiber optic sensors. Mostfiber optic chemical sensors
`employeither a single-fiber configuration, wherelight travels to and from the sensing tip in one
`
`|
`
`Petitioner Apple Inc. – Ex. 101(cid:28), p. 766
`Petitioner Apple Inc. — Ex. 1019, p. 766
`
`11
`
`11
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`

`Optical Sensors
`
`,
`
`767
`
`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 andpotentially least expensive
`implementation. However, additional challenges in instrumentation are involved in separating the
`illuminating signal from the composite signal returning for processing.
`The design ofintravascular catheters require special considerationsrelatedto thesterility and bio-
`compatibility of the sensor. For example, intravascularfiberoptic sensors must besterilizable and
`their material nonthrombogenic andresistantto platelet and protein deposition. Therefore, these
`catheters are typically made of materials covalently bound with heparin orantiplatelet agents. The
`catheter is normally introducedinto the jugular vein via a peripheral cut-down and a slow heparin
`flush is maintaineduntil it is removed from the blood.
`
`Optical Fiber Sensors
`
`Advantagescited for fiber optic sensors includetheir small size and low cost. In contrastto electri-
`cal measurements, where the difference of two absolute potentials must be measured,fiber optics
`are self-contained and do notrequire an externalreference signal. Becausethe signal is optical, there
`is no electrical risk to the patient, and thereis no direct interference from surroundingelectric or
`magnetic fields. Chemical analysis can be performedin real-time with almost an instantaneous
`response. Furthermore, versatile sensors can be developed that respond to multipie analytes by
`utilizing multiwavelength measurements.
`Despite these advantages,opticalfiber 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, ambientlight can interfere with the optical measurementunless optical shielding
`or special time-synchronousgatingis 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 usingspecific reagents that are properly immobilized on the surface of an optical sensor.
`The most difficult aspect of developing an optical biosensoris the couplingoflight to the specific
`recognition elementso that the sensor can respondselectively and reversibly to a change in the con-
`ce