Table Of ContentThe Biomedical Engineering Handbook
Third Edition
Tissue Engineering
and Artificial Organs
© 2006 by Taylor & Francis Group, LLC
The Electrical Engineering Handbook Series
Series Editor
Richard C. Dorf
University of California, Davis
Titles Included in the Series
The Handbook of Ad Hoc Wireless Networks, Mohammad Ilyas
The Avionics Handbook, Cary R. Spitzer
The Biomedical Engineering Handbook, Third Edition, Joseph D. Bronzino
The Circuits and Filters Handbook, Second Edition, Wai-Kai Chen
The Communications Handbook, Second Edition, Jerry Gibson
The Computer Engineering Handbook, Vojin G. Oklobdzija
The Control Handbook, William S. Levine
The CRC Handbook of Engineering Tables, Richard C. Dorf
The Digital Signal Processing Handbook, Vijay K. Madisetti and Douglas Williams
The Electrical Engineering Handbook, Third Edition, Richard C. Dorf
The Electric Power Engineering Handbook, Leo L. Grigsby
The Electronics Handbook, Second Edition, Jerry C. Whitaker
The Engineering Handbook, Third Edition, Richard C. Dorf
The Handbook of Formulas and Tables for Signal Processing, Alexander D. Poularikas
The Handbook of Nanoscience, Engineering, and Technology, William A. Goddard, III,
Donald W. Brenner, Sergey E. Lyshevski, and Gerald J. Iafrate
The Handbook of Optical Communication Networks, Mohammad Ilyas and
Hussein T. Mouftah
The Industrial Electronics Handbook, J. David Irwin
The Measurement, Instrumentation, and Sensors Handbook, John G. Webster
The Mechanical Systems Design Handbook, Osita D.I. Nwokah and Yidirim Hurmuzlu
The Mechatronics Handbook, Robert H. Bishop
The Mobile Communications Handbook, Second Edition, Jerry D. Gibson
The Ocean Engineering Handbook, Ferial El-Hawary
The RF and Microwave Handbook, Mike Golio
The Technology Management Handbook, Richard C. Dorf
The Transforms and Applications Handbook, Second Edition, Alexander D. Poularikas
The VLSI Handbook, Wai-Kai Chen
© 2006 by Taylor & Francis Group, LLC
The Biomedical Engineering Handbook
Third Edition
Edited by
Joseph D. Bronzino
Biomedical Engineering Fundamentals
Medical Devices and Systems
Tissue Engineering and Artificial Organs
© 2006 by Taylor & Francis Group, LLC
The Biomedical Engineering Handbook
Third Edition
Tissue Engineering
and Artificial Organs
Edited by
Joseph D. Bronzino
Trinity College
Hartford, Connecticut, U.S.A.
Boca Raton London New York
A CRC title, part of the Taylor & Francis imprint, a member of the
Taylor & Francis Group, the academic division of T&F Informa plc.
© 2006 by Taylor & Francis Group, LLC
Published in 2006 by
CRC Press
Taylor & Francis Group
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Boca Raton, FL 33487-2742
© 2006 by Taylor & Francis Group, LLC
CRC Press is an imprint of Taylor & Francis Group
No claim to original U.S. Government works
Printed in the United States of America on acid-free paper
10 9 8 7 6 5 4 3 2 1
International Standard Book Number-10: 0-8493-2123-9 (Hardcover)
International Standard Book Number-13: 978-0-8493-2123-8 (Hardcover)
Library of Congress Card Number 2005044776
This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with
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Library of Congress Cataloging-in-Publication Data
Tissue engineering and artificial organs / edited by Joseph D. Bronzino.
p. cm. -- (The electrical engineering handbook series)
Includes bibliographical references and index.
ISBN 0-8493-2123-9 (alk. paper)
1. Tissue engineering. 2. Artificial organs. I. Bronzino, Joseph D., 1937- II. Title. III. Series.
R857.T55T547 2006
612.028--dc22 2005044776
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© 2006 by Taylor & Francis Group, LLC
Introduction and Preface
During the past five years since the publication of the Second Edition — a two-volume set — of the
BiomedicalEngineeringHandbook,thefieldofbiomedicalengineeringhascontinuedtoevolveandexpand.
Asaresult, thisThirdEditionconsistsof athree-volumeset, whichhasbeensignificantlymodifiedto
reflectthestate-of-the-fieldknowledgeandapplicationsinthisimportantdiscipline. Morespecifically,
thisThirdEditioncontainsanumberofcompletelynewsections,including:
• MolecularBiology
• Bionanotechnology
• Bioinformatics
• Neuroengineering
• InfraredImaging
aswellasanewsectiononethics.
Inaddition,allofthesectionsthathaveappearedinthefirstandsecondeditionshavebeensignificantly
revised. Therefore, this Third Edition presents an excellent summary of the status of knowledge and
activitiesofbiomedicalengineersinthebeginningofthe21stcentury.
Assuch,itcanserveasanexcellentreferenceforindividualsinterestednotonlyinareviewoffunda-
mentalphysiology,butalsoinquicklybeingbroughtuptospeedincertainareasofbiomedicalengineering
research.Itcanserveasanexcellenttextbookforstudentsinareaswheretraditionaltextbookshavenot
yetbeendevelopedandasanexcellentreviewofthemajorareasofactivityineachbiomedicalengineer-
ingsubdiscipline,suchasbiomechanics,biomaterials,bioinstrumentation,medicalimaging,etc.Finally,
itcanserveasthe“bible”forpracticingbiomedicalengineeringprofessionalsbycoveringsuchtopicsasa
historicalperspectiveofmedicaltechnology,theroleofprofessionalsocieties,theethicalissuesassociated
withmedicaltechnology,andtheFDAprocess.
Biomedical engineering is now an important vital interdisciplinary field. Biomedical engineers are
involvedinvirtuallyallaspectsofdevelopingnewmedicaltechnology.Theyareinvolvedinthedesign,
development,andutilizationofmaterials,devices(suchaspacemakers,lithotripsy,etc.)andtechniques
(suchassignalprocessing,artificialintelligence,etc.)forclinicalresearchanduse;andserveasmembers
of the health care delivery team (clinical engineering, medical informatics, rehabilitation engineering,
etc.)seekingnewsolutionsfordifficulthealthcareproblemsconfrontingoursociety.Tomeettheneeds
ofthisdiversebodyofbiomedicalengineers,thishandbookprovidesacentralcoreofknowledgeinthose
fieldsencompassedbythediscipline.However,beforepresentingthisdetailedinformation,itisimportant
toprovideasenseof theevolutionof themodernhealthcaresystemandidentifythediverseactivities
biomedicalengineersperformtoassistinthediagnosisandtreatmentofpatients.
Evolution of the Modern Health Care System
Before 1900, medicine had little to offer the average citizen, since its resources consisted mainly of
the physician, his education, and his “little black bag.” In general, physicians seemed to be in short
© 2006 by Taylor & Francis Group, LLC
supply, but the shortage had rather different causes than the current crisis in the availability of health
careprofessionals.Althoughthecostsofobtainingmedicaltrainingwererelativelylow,thedemandfor
doctors’servicesalsowasverysmall,sincemanyoftheservicesprovidedbythephysicianalsocouldbe
obtainedfromexperiencedamateursinthecommunity. Thehomewastypicallythesitefortreatment
andrecuperation,andrelativesandneighborsconstitutedanableandwillingnursingstaff.Babieswere
delivered by midwives, and those illnesses not cured by home remedies were left to run their natural,
albeitfrequentlyfatal,course.Thecontrastwithcontemporaryhealthcarepractices,inwhichspecialized
physicians and nurses located within the hospital provide critical diagnostic and treatment services, is
dramatic.
The changes that have occurred within medical science originated in the rapid developments that
took place in the applied sciences (chemistry, physics, engineering, microbiology, physiology, phar-
macology, etc.) at the turn of the century. This process of development was characterized by intense
interdisciplinarycross-fertilization,whichprovidedanenvironmentinwhichmedicalresearchwasable
totakegiantstridesindevelopingtechniquesforthediagnosisandtreatmentof disease. Forexample,
in 1903, Willem Einthoven, a Dutch physiologist, devised the first electrocardiograph to measure the
electrical activity of the heart. In applying discoveries in the physical sciences to the analysis of the
biologic process, he initiated a new age in both cardiovascular medicine and electrical measurement
techniques.
Newdiscoveriesinmedicalsciencesfollowedoneanotherlikeintermediatesinachainreaction.How-
ever, the most significant innovation for clinical medicine was the development of x-rays. These“new
kinds of rays,” as their discoverer W.K. Roentgen described them in 1895, opened the“inner man”to
medicalinspection.Initially,x-rayswereusedtodiagnosebonefracturesanddislocations,andinthepro-
cess,x-raymachinesbecamecommonplaceinmosturbanhospitals.Separatedepartmentsofradiology
wereestablished,andtheirinfluencespreadtootherdepartmentsthroughoutthehospital.Bythe1930s,
x-rayvisualizationofpracticallyallorgansystemsofthebodyhadbeenmadepossiblethroughtheuseof
bariumsaltsandawidevarietyofradiopaquematerials.
X-raytechnologygavephysiciansapowerfultoolthat,forthefirsttime,permittedaccuratediagnosis
of a wide variety of diseases and injuries. Moreover, since x-ray machines were too cumbersome and
expensive for local doctors and clinics, they had to be placed in health care centers or hospitals. Once
there,x-raytechnologyessentiallytriggeredthetransformationofthehospitalfromapassivereceptacle
forthesicktoanactivecurativeinstitutionforallmembersofsociety.
Foreconomicreasons,thecentralizationofhealthcareservicesbecameessentialbecauseofmanyother
importanttechnologicalinnovationsappearingonthemedicalscene.However,hospitalsremainedinsti-
tutionstodread,anditwasnotuntiltheintroductionofsulfanilamideinthemid-1930sandpenicillinin
theearly1940sthatthemaindangerofhospitalization,thatis,cross-infectionamongpatients,wassigni-
ficantlyreduced.Withthesenewdrugsintheirarsenals,surgeonswereabletoperformtheiroperations
withoutprohibitivemorbidityandmortalityduetoinfection. Furthermore, eventhoughthedifferent
bloodgroupsandtheirincompatibilitywerediscoveredin1900andsodiumcitratewasusedin1913to
prevent clotting, full development of blood banks was not practical until the 1930s, when technology
providedadequaterefrigeration.Untilthattime,“fresh”donorswerebledandthebloodtransfusedwhile
itwasstillwarm.
Oncethesesurgicalsuiteswereestablished,theemploymentofspecificallydesignedpiecesofmedical
technologyassistedinfurtheradvancingthedevelopmentofcomplexsurgicalprocedures.Forexample,
theDrinkerrespiratorwasintroducedin1927andthefirstheart–lungbypasswasdonein1939.Bythe
1940s,medicalproceduresheavilydependentonmedicaltechnology,suchascardiaccatheterizationand
angiography(theuseof acannulathreadedthroughanarmveinandintotheheartwiththeinjection
of radiopaque dye) for the x-ray visualization of congenital and acquired heart disease (mainly valve
disordersduetorheumaticfever)becamepossible, andaneweraof cardiacandvascularsurgerywas
established.
Following World War II, technological advances were spurred on by efforts to develop superior
weaponsystemsandestablishhabitatsinspaceandontheoceanfloor.Asaby-productoftheseefforts,
© 2006 by Taylor & Francis Group, LLC
thedevelopmentof medicaldevicesacceleratedandthemedicalprofessionbenefitedgreatlyfromthis
rapidsurgeoftechnologicalfinds.Considerthefollowingexamples:
1. Advancesinsolid-stateelectronicsmadeitpossibletomapthesubtlebehaviorofthefundamental
unitofthecentralnervoussystem—theneuron—aswellastomonitorthevariousphysiological
parameters,suchastheelectrocardiogram,ofpatientsinintensivecareunits.
2. Newprostheticdevicesbecameagoalofengineersinvolvedinprovidingthedisabledwithtools
toimprovetheirqualityoflife.
3. Nuclear medicine — an outgrowth of the atomic age — emerged as a powerful and effective
approachindetectingandtreatingspecificphysiologicabnormalities.
4. Diagnostic ultrasound based on sonar technology became so widely accepted that ultrasonic
studiesarenowpartoftheroutinediagnosticworkupinmanymedicalspecialties.
5. “Spareparts”surgeryalsobecamecommonplace.Technologistswereencouragedtoprovidecar-
diacassistdevices,suchasartificialheartvalvesandartificialbloodvessels,andtheartificialheart
programwaslaunchedtodevelopareplacementforadefectiveordiseasedhumanheart.
6. Advancesinmaterialshavemadethedevelopmentofdisposablemedicaldevices,suchasneedles
andthermometers,aswellasimplantabledrugdeliverysystems,areality.
7. ComputerssimilartothosedevelopedtocontroltheflightplansoftheApollocapsulewereusedto
store,process,andcross-checkmedicalrecords,tomonitorpatientstatusinintensivecareunits,
andtoprovidesophisticatedstatisticaldiagnosesofpotentialdiseasescorrelatedwithspecificsets
ofpatientsymptoms.
8. Developmentofthefirstcomputer-basedmedicalinstrument,thecomputerizedaxialtomography
scanner,revolutionizedclinicalapproachestononinvasivediagnosticimagingprocedures,which
nowincludemagneticresonanceimagingandpositronemissiontomographyaswell.
9. A wide variety of new cardiovascular technologies including implantable defibrillators and
chemicallytreatedstentsweredeveloped.
10. Neuronalpacingsystemswereusedtodetectandpreventepilepticseizures.
11. Artificialorgansandtissuehavebeencreated.
12. Thecompletionofthegenomeprojecthasstimulatedthesearchfornewbiologicalmarkersand
personalizedmedicine.
Theimpactofthesediscoveriesandmanyothershasbeenprofound.Thehealthcaresystemoftoday
consistsof technologicallysophisticatedclinicalstaff operatingprimarilyinmodernhospitalsdesigned
to accommodate the new medical technology. This evolutionary process continues, with advances in
the physical sciences such as materials and nanotechnology, and in the life sciences such as molecular
biology,thegenomeprojectandartificialorgans.Theseadvanceshavealteredandwillcontinuetoalter
theverynatureofthehealthcaredeliverysystemitself.
Biomedical Engineering: A Definition
Bioengineeringisusuallydefinedasabasicresearch-orientedactivitycloselyrelatedtobiotechnologyand
geneticengineering,thatis,themodificationofanimalorplantcells,orpartsofcells,toimproveplants
oranimalsortodevelopnewmicroorganismsforbeneficialends.Inthefoodindustry,forexample,this
has meant the improvement of strains of yeast for fermentation. In agriculture, bioengineers may be
concernedwiththeimprovementof cropyieldsbytreatmentof plantswithorganismstoreducefrost
damage. It is clear that bioengineers of the future will have a tremendous impact on the qualities of
human life. The potential of this specialty is difficult to imagine. Consider the following activities of
bioengineers:
• Developmentofimprovedspeciesofplantsandanimalsforfoodproduction
• Inventionofnewmedicaldiagnostictestsfordiseases
• Productionofsyntheticvaccinesfromclonecells
© 2006 by Taylor & Francis Group, LLC
The world of biomedical engineering
Biomechanics
Medical & Prosthetic devices
biological analysis & artificial organs
Biosensors Medical imaging
Clinical Biomaterials
engineering
Biotechnology
Medical &
bioinformatics Tissue engineering
Rehabilitation Neural
engineering engineering
Physiological Biomedical
modeling instrumentation
Bionanotechnology
FIGURE1 Theworldofbiomedicalengineering.
• Bioenvironmental engineering to protect human, animal, and plant life from toxicants and
pollutants
• Studyofprotein–surfaceinteractions
• Modelingofthegrowthkineticsofyeastandhybridomacells
• Researchinimmobilizedenzymetechnology
• Developmentoftherapeuticproteinsandmonoclonalantibodies
Biomedical engineers, on the other hand, apply electrical, mechanical, chemical, optical, and other
engineeringprinciplestounderstand,modify,orcontrolbiologic(i.e.,humanandanimal)systems,as
wellasdesignandmanufactureproductsthatcanmonitorphysiologicfunctionsandassistinthediagnosis
andtreatmentof patients. Whenbiomedicalengineersworkwithinahospitalorclinic, theyaremore
properlycalledclinicalengineers.
Activities of Biomedical Engineers
The breadth of activity of biomedical engineers is now significant. The field has moved from being
concernedprimarilywiththedevelopmentof medicalinstrumentsinthe1950sand1960stoincludea
morewide-rangingsetofactivities.Asillustratedabove,thefieldofbiomedicalengineeringnowincludes
manynewcareerareas(seeFigure1),eachofwhichispresentedinthishandbook.Theseareasinclude:
• Application of engineering system analysis (physiologic modeling, simulation, and control) to
biologicproblems
• Detection,measurement,andmonitoringof physiologicsignals(i.e.,biosensorsandbiomedical
instrumentation)
• Diagnosticinterpretationviasignal-processingtechniquesofbioelectricdata
• Therapeuticandrehabilitationproceduresanddevices(rehabilitationengineering)
• Devicesforreplacementoraugmentationofbodilyfunctions(artificialorgans)
• Computeranalysisofpatient-relateddataandclinicaldecisionmaking(i.e.,medicalinformatics
andartificialintelligence)
© 2006 by Taylor & Francis Group, LLC
• Medicalimaging,thatis,thegraphicdisplayofanatomicdetailorphysiologicfunction
• Thecreationofnewbiologicproducts(i.e.,biotechnologyandtissueengineering)
• Thedevelopmentofnewmaterialstobeusedwithinthebody(biomaterials)
Typicalpursuitsofbiomedicalengineers,therefore,include:
• Researchinnewmaterialsforimplantedartificialorgans
• Developmentofnewdiagnosticinstrumentsforbloodanalysis
• Computermodelingofthefunctionofthehumanheart
• Writingsoftwareforanalysisofmedicalresearchdata
• Analysisofmedicaldevicehazardsforsafetyandefficacy
• Developmentofnewdiagnosticimagingsystems
• Designoftelemetrysystemsforpatientmonitoring
• Designofbiomedicalsensorsformeasurementofhumanphysiologicsystemsvariables
• Developmentofexpertsystemsfordiagnosisofdisease
• Designofclosed-loopcontrolsystemsfordrugadministration
• Modelingofthephysiologicalsystemsofthehumanbody
• Designofinstrumentationforsportsmedicine
• Developmentofnewdentalmaterials
• Designofcommunicationaidsforthehandicapped
• Studyofpulmonaryfluiddynamics
• Studyofthebiomechanicsofthehumanbody
• Developmentofmaterialtobeusedasreplacementforhumanskin
Biomedicalengineering,then,isaninterdisciplinarybranchofengineeringthatrangesfromtheoretical,
nonexperimentalundertakingstostate-of-the-artapplications.Itcanencompassresearch,development,
implementation, and operation. Accordingly, like medical practice itself, it is unlikely that any single
personcanacquireexpertisethatencompassestheentirefield.Yet,becauseoftheinterdisciplinarynature
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
interestedinprostheticdevicestodevelopameanstodetectandusethesamebioelectricsignaltopower
aprostheticdevice.Thoseengagedinautomatingtheclinicalchemistrylaboratorymaycollaboratewith
thosedevelopingexpertsystemstoassistcliniciansinmakingdecisionsbasedonspecificlaboratorydata.
Thepossibilitiesareendless.
Perhapsagreaterpotentialbenefitoccurringfromtheuseofbiomedicalengineeringisidentification
oftheproblemsandneedsofourpresenthealthcaresystemthatcanbesolvedusingexistingengineering
technologyandsystemsmethodology.Consequently,thefieldofbiomedicalengineeringoffershopein
thecontinuingbattletoprovidehigh-qualitycareatareasonablecost.Ifproperlydirectedtowardsolving
problems related to preventive medical approaches, ambulatory care services, and the like, biomedical
engineerscanprovidethetoolsandtechniquestomakeourhealthcaresystemmoreeffectiveandefficient;
andintheprocess,improvethequalityoflifeforall.
JosephD.Bronzino
Editor-in-Chief
© 2006 by Taylor & Francis Group, LLC
