Table Of ContentEDITOR-IN-CHIEF
PAULDUCHEYNE
UniversityofPennsylvania,Philadelphia,PA,USA
CO-EDITORS
KEVINE.HEALY DAVIDW.GRAINGER
UniversityofCalifornia,Berkeley,Berkeley,CA,USA UniversityofUtah,SaltLakeCity,UT,USA
DIETMARW.HUTMACHER C.JAMESKIRKPATRICK
QueenslandUniversityofTechnology,Brisbane, JohannesGutenbergUniversityMedicalCenter,
QLD,Australia Mainz,Germany
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EDITOR-IN-CHIEF BIOGRAPHY
PaulDucheyne
Paul Ducheyne is currently Professor of Bioengineering and Professor of Orthopaedic Surgery Research at the University of
Pennsylvania,Philadelphia,PA,USA,andDirectorofitsCenterforBioactiveMaterialsandTissueEngineering.HeisalsoSpecialGuest
ProfessoratK.U.Leuven,Belgium.
Ducheyne graduated from K.U. Leuven in Materials Science and Engineering (M.Sc.: 1972; Ph.D.: 1976). With fellowships from
the National Institutes of Health (International Postdoctoral Fellowship) and the Belgian American Educational Foundation
(HonoraryFellowship),heperformedpostdoctoralresearchattheUniversityofFlorida.
Over a diverse research career, he has organized a number of significant symposia and meetings, including the Fourth European
ConferenceonBiomaterials(1983),theEngineeringFoundationConferenceonBioceramics(1986)andthe6thInternationalSymposium
onCeramicsinMedicine(1993).The1986meetingleddirectlytotheNewYorkAcademyofSciencespublicationsBioceramics,material
characteristicsversusinvivobehavior(1988).Hehaslecturedaroundtheworldandcurrentlyserves,orhasservedon,theeditorialboardof
morethantenscientificjournalsinthebiomaterials,bioceramics,bioengineering,tissueengineering,orthopaedicsanddentalfields.Hehas
beenamemberoftheeditorialboard,andthenanAssociateEditor,ofBiomaterials(Elsevier),theleadingbiomaterialsjournal,sinceits
inceptioninthelate1970s.Hehasauthoredmorethan300papersandchaptersinavarietyofinternationaljournalsandbooks,andhehas
editedtenbooks.Hehasalsobeengrantedmorethan40USpatentswithinternationalcounterparts.Hispapershavebeencitedabout
7,000times;histenmostvisiblepapershavebeencitedmorethan2000times.
Ducheyne started his career in Europe. While at K.U. Leuven (1977–1983), he was one of the co-founders of the Post-Graduate
CurriculuminBioengineering.ThisprogramisnowafullM.Sc.programintheSchoolofEngineeringandAppliedSciences.Inthose
initialyears,hewasalsochairman-founderofthechapteronBiomedicalEngineeringoftheBelgianEngineeringSociety(Flemishsection)
and director of Meditek, the Flemish Government body created to promote Academia to Industry Technology Transfer in the area of
BiomedicalEngineering.
HefoundedGentis,Inc.,whichfocusesonbreakthroughconceptsforspinaldisorders.Previously,hefoundedOrthovita(NASDAQ:
VITA) in 1992 and served as Chairman of its Board of Directors until 1999. Orthovita focuses on bioceramic implant materials for
orthopaedics.
DucheynehasbeenSecretaryoftheEuropeanSocietyforBiomaterials,isPastPresidentoftheSocietyforBiomaterials(USA)andPast
PresidentoftheInternationalSocietyforCeramicsinMedicine.HehasbeenrecognizedasafellowoftheAmericanAssociationforthe
Advancement of Science (AAAS), fellow of the American Institute of Medical and Biological Engineering (AIMBE), and fellow of
theInternationalAssociationofBiomaterialsSocieties.HewasthefirstNanyangVisitingProfessorattheNanyangInstituteofTechnology,
SingaporeandhehasreceivedtheC.WilliamHallAwardfromtheSocietyforBiomaterials.
Many of Ducheyne’s PhD students and postdoctoral fellows have become leaders of the next generation. Among his students are
ProfessorsattheUniversityofCaliforniaatBerkeley,theUniversityofMichigan,ColumbiaUniversity,GeorgiaInstituteofTechnology,
KyushuUniversityandK.U.Leuven.AmongthesixU.S.AssociateEditorsoftheJournalforBiomedicalMaterialsResearch(WileyandSociety
forBiomaterials),threewerehisPhDstudents.
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CO-EDITOR BIOGRAPHIES
KevinE.Healy
KevinE.Healy,Ph.D.,istheJanFandriantoDistinguishedProfessorinEngineeringattheUniversityofCaliforniaatBerkeleyinthe
DepartmentsofBioengineeringandMaterialsScienceandEngineering.HereceivedaBSc.inChemicalEngineeringfromtheUniversityof
Rochesterin1983.HeobtainedgraduatedegreesinBioengineeringfromtheUniversityofPennsylvania(M.Sc.:1985;Ph.D.:1990).
Hisresearchinterestsincludethedesignandsynthesisofbiomimeticmaterialsthatactivelydirectthefateofembryonicandadult
stemcells,andfacilitateregenerationofdamagedtissuesandorgans.Majordiscoveriesfromhislaboratoryhavecenteredonthecontrol
ofcellfateandtissueformationincontractwithmaterialsthataretunableinboththeirbiologicalcontentandmechanicalproperties.
Thesematerialsfindapplicationsinmedicine,dentistry,andbiotechnology.
Healyhasauthoredorcoauthoredmorethan200publishedarticles,abstracts,orbookchapters.Heisanamedinventoronnumerous
issued United States and international patents relating to biomaterials, and has founded several companies to develop materials for
applicationsinbiotechnologyandregenerativemedicine.
HeiscurrentlyanAssociateEditoroftheJournalofBiomedicalMaterialsResearch.Hehasservedonnumerouspanelsandgrantreview
studysectionsforN.I.H.Hehasgivenmorethan200invitedlecturesinthefieldsofBiomedicalEngineeringandBiomaterials.Hehas
chairedtheGordonResearchConferenceonBiomaterialsandTissueEngineering.
HewaselectedaFellowoftheAmericanInstituteofMedicalandBiologicalEngineering(AIMBE)andwasrecentlyhonoredwiththe
Clemsonawardforoutstandingcontributionstobasicbiomaterialsscience.
DietmarW.Hutmacher
DietmarW.HutmacheriscurrentlyProfessorandChairinRegenerativeMedicineattheInstituteofHealthandBiomedicalInnovation,
QueenslandUniversityofTechnology,Brisbane,Australia.HeholdsAdjunctProfessorshipsattheGeorgiaInstituteofTechnologyandthe
HumboldtUniversity,Berlin,Germany.Beforethis,hewasattheNationalUniversityofSingapore,wherehealsoobtainedhisPh.D.
(2001).HisundergraduatedegreeisinBiomedicalEngineering(1988)andhewasawardedanMBAfromtheHenleyManagementCollege,
UnitedKingdom.
With a strong research focus in the field of biomaterials, tissue engineering, and regenerative medicine, Hutmacher developed an
accomplishedinternationalprofilethatexemplifiesthemainchallengeinthefieldofbiomedicalsciences,namelycrossingtraditional
boundariestonurtureandinitiateresearchandeducationalprogramsacrossdifferentdisciplines,andespeciallytheboundariesbetween
engineering,biology,andmedicine.
Outcomes from Hutmacher’s research have resulted in high-profile scientific and academic contributions as well as patents and
commercialization. He was ranked 45 in the list of the world’s top 100 materials scientists compiled by Thomson Reuters in 2010.
Dr.Hutmacherhaspublishedmorethan180journalarticlesand30bookchaptersandeditedthreebooks.Hiscitationrecordincludes
morethan5700citations,withanh-indexof40.HutmacherservesontheeditorialboardofBiomaterials,TissueEngineering,Journalof
BiomaterialsSci.–PolymerEdition,ArtificialOrgans(AssociateEditor)andPolymersInternational(AssociateEditor).Overthelasttenyears,
Hutmacher has presented more than 30 invited international lectures and has served on more than 20 organizing committees of
internationalconferences.Mostrecently,hewasChairofTissueEngineeringandRegenerativeMedicineInternationalSociety–AsiaPacific
(TERMIS-AP)2010,andChairoftheAustralasianSocietyofBiomaterialsandTissueEngineering(ASBTE)2010meeting.
DavidGrainger
DavidW.GraingeristheGeorgeS.andDoloresDore´EcclesPresidentialEndowedChairinPharmaceuticsandPharmaceuticalChemistry,Chair
oftheDepartmentofPharmaceuticsandPharmaceuticalChemistry,andProfessorofBioengineeringattheUniversityofUtah.
Graingerreceived his Ph.D. in Pharmaceutical Chemistryfrom the University of Utahin 1987. With an Alexandervon Humboldt
Fellowship,heundertookpostdoctoralresearchunderProf.HelmutRingsdorf,UniversityofMainz,Germany.
Grainger’sresearchfocusesonimprovingimplantedmedicaldeviceperformance,drugdeliveryofnewtherapeuticproteins,nucleic
acidsandlivevaccines,nanomaterialsinteractionswithhumantissues,low-infectionbiomaterials,andinnovatingdiagnosticdevicesbased
onDNAandproteinbiomarkercapture.Healsohasexpertiseinperfluorinatedbiomaterialsandapplicationsofsurfaceanalyticalmethods
tobiomedicalinterfaces,includingsurfacecontamination,micropatterns,andnanomaterials.
Graingerhaspublishedover130researchpapersattheinterfaceofmaterialsinnovationinmedicineandbiotechnology,andnovel
surfacechemistry.HehasorganizedmanyinternationalscientificsymposiaandchairedtheGordonResearchConferenceinBiomaterials
andTissueEngineering.Hefrequentlylecturesworldwide,includingdeliveringmanynamed,keynote,andplenarypresentations.
Graingerservesontheeditorialboardsoffourmajorjournalsinthebiomedicalmaterialsfield.HeiscurrentlyChairoftheEmerging
BioanalyticalandImagingTechnologiesscientificreviewgroup(SRG)attheNIH,andhasservedonmanyothernationalandinternational
reviewpanels,includingtheNIH’sSurgeryandBioengineeringSRG.Heremainsactiveonacademicscientificadvisoryboardsformany
academicprogramsintheUnitedStates,Asia,andEurope,includingmajorresearchcentersattheUniversitiesofWisconsin-Madisonandof
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Co-EditorBiographies ix
Washington,theAOFoundationandEMPA,Switzerland,severalothercompetencecentersinEurope,andWasedaUniversity’sASMeW
ResearchCenter,Japan.Graingeralsositsonthescientificadvisoryboardsforfourbiomedicalcompaniesandactivelyconsultsinterna-
tionallywithindustriesinapplicationsofmaterialsinbiotechnologiesandmedicine.
Hisscientificandtechnicalaccomplishmentsarewidelyrecognized,bothathisinstitutionandworldwide.Amongseveralcitations,
GraingerisfellowoftheAmericanAssociationfortheAdvancementofScience(AAAS),theAmericanInstituteofMedicalandBiologicalEngineering
(AIMBE), and the International Union of the Societies of Biomaterials Science and Engineering. He has also been honored with the 2007
ClemsonAwardforBasicResearch,SocietyforBiomaterials,andthe2005AmericanPharmaceuticalResearchandManufacturer’sAssocia-
tion’sawardfor‘ExcellenceinPharmaceutics’.
CharlesJamesKirkpatrick
C.JamesKirkpatrickisProfessorofPathologyandChairmanoftheInstituteofPathologyattheJohannesGutenbergUniversityof
Mainz,Germany,havingtakenupthispositionin1993.HeisalsohonoraryprofessoratthePekingUnionMedicalCollege,Beijingandthe
SichuanUniversity,Chengdu,bothinChina.
KirkpatrickisagraduateoftheQueen’sUniversityofBelfastandholdsatripledoctorateinscienceandmedicine(PhD:1977;MD:1982;
DSc: 1992). Previous appointments were in pathology at the University of Ulm, where he did postdoctoral research in experimental
pathology,ManchesterUniversity(LecturerinHistopathology)andtheRWTHAachen(ProfessorofPathology&ElectronMicroscopy).
OnmovingtoAachenin1987,heestablishedacellculturelaboratorywhichbeganusingmodernmethodsofcellandmolecular
biologytostudyhowhumancellsreacttobiomaterials.Sincethen,hisprincipalresearchinterestscontinuetobeinthefieldofbiomaterials
intissueengineeringandregenerativemedicine,withspecialfocusonthedevelopmentofhumancellculturetechniques,includingnovel
3Dcoculturemethodologyforbiomaterialsandtheapplicationofmodernmolecularpathologytechniquestothestudyofbiofunctionality
ofbiomaterials.
Kirkpatrickisauthor/coauthorofmorethan380publicationsinpeer-reviewedjournalsandhasmademorethan1000presentationsto
scientificmeetingsworldwide.HeisaformerpresidentofboththeGermanSocietyforBiomaterials(2001–2005)andtheEuropeanSociety
forBiomaterials(2002–2007)andhasservedonitscouncilsince1995.HeisalsoamemberoftheCounciloftheEuropeanChapterofthe
TissueEngineering&RegenerativeMedicineInternationalSociety(TERMIS-EU).
Kirkpatrick is a long-standing member of the editorial board of the premier journal Biomaterials and is currently associate editor
(since2002).HehasalsoservedasassociateeditoroftheleadingJournalofPathology(2001–2006).Intotal,heservesorhasservedasan
editorialboardmemberof18internationaljournalsinpathology,biomaterials,andtissueengineering.
KirkpatrickwastheScientificProgrammeCommitteeChairforthe8thWorldBiomaterialsCongressinAmsterdamin2008.
KirkpatrickisamemberoftheScientificAdvisoryBoardofanumberofresearchinstitutes,centresofexcellenceandcompaniesin
biomaterialsandregenerativemedicineinEurope,aswellastheMedicalTechnologyCommittee,FederalMinistryofEducation&Research
inGermany(BMBF)(since2005)andtheGermanFederalInstituteforDrugs&MedicalDevices(BfArM)(since2007).
Kirkpatrickhasbeenrecognizedforhiscontributions.HeisaFellowoftheRoyalCollegeofPathologists,LondonandaFellowof
Biomaterials Science & Engineering (FBSE) of the IUS-BSE (International Union of Societies for Biomaterials Science & Engineering).
He receivedthe ResearchPrize oftheState ofRhineland-Palatinatefor Researchon Replacement andAlternative Methodsfor Animal
Research.HewastherecipientoftheGeorgeWinterAwardfromtheEuropeanSocietyforBiomaterials(2008),andin2010,hereceived,as
firstmedicalgraduate,theChapmanMedalfromtheInstituteofMaterials,Minerals&MininginLondonfor“distinguishedresearchinthe
fieldofbiomedicalmaterials”.
PREFACE
Biomaterials is a dynamic, changing field that influences modern medicine and therapeutics in diverse ways.
InviewofthemajorexpansionofthefieldofBiomaterialsoverthelastdecade,itwasconsideredmosttimelyto
publishthepresentwork,ComprehensiveBiomaterials,withtheintenttobringingtogetherthemyriadfacetsof
biomaterialsinone,majorseries of sixeditedvolumes thatwould coverthe fieldof biomaterials inamajor,
extensivefashion.
Expertsfromaroundtheworldinhundredsofrelatedbiomaterialsareashavecontributed tothis publica-
tionthataddressesthecurrentstatusofmostbiomaterialsinthefield.Thecontributionsdiscusstheirstrengths
and weaknesses, their appropriate analytical methods and testing, and their device applications and perfor-
mance.Thechapterstreatthesubjectsnotonlyfromaretrospectivelensbutonethatistrulyprospective,with
manyarticlesexaminingforthcomingmaterialsasdisruptivefuturetechnologies.
Fromtheoutset,itwasourgoaltoreviewmaterialsinthecontextofmedicaldevicesandtissueproperties,
biocompatibilityandsurfaceanalysis,tissueengineeringandcontrolledrelease.Itwasalsotheintentboth,to
focusonmaterialpropertiesfromtheperspectivesoftherapeuticanddiagnosticuse,andtoaddressquestions
relevanttostate-of-the-artresearch endeavors.Thus,in this publication, conventional, clinicallyused bioma-
terialsaswellascurrentemergingprototypes,studiesandnewideas,alongwithvisionarypredictionsoffuture
biomaterialscompositionsandcapabilitieshavebeenextensivelycoveredbymanycolleaguesinthefield.The
editorial team is cognizant of the major efforts our contributors have made in this regard, and appreciates
themany,veryinsightfulchaptersreceived.
It was the objective of the editorial team to compose the publication with chapters that would provide
strategicinsightsforthoseworkingindiversebiomaterialsapplications,researchanddevelopment,regulatory
management,andindustry.Furthermore,wesolicitedpaperswrittenforabroad,cross-disciplinaryaudience,
suchthattheworkwouldincludeup-to-dateinformationinascholarly,readableandcriticalstyle.Wearetruly
gratefulto all authors, each of them leading experts in their own right, who dedicated their time to pursuing
thisgoal.
In the first chapter “Biomaterials”, the genesis of the structure of this publication is described. Materials
are reviewed from the basic building blocks across the formulations and chemistry of Metals, Ceramics and
Polymers to Biologically Inspired and Biomolecular Materials, and Materials of Biological Origin. Properties are
analyzed on the basis of advanced Methods of Analysis. Unique aspects of Biocompatibility, Surface Engineering,
andDeliveryofDrugs,GenesandOtherMoleculesarecovered.Materialsusesintissueengineeredconstructsand
devicesandimplantsaretreatedinTissueandOrganEngineeringandBiomaterialsandClinicalUse.Thischapter
does not contain any references, as all the 200 chapters in these volumes are unique references in their
ownright.
From concept to print, this publication was developed and implemented over a five year time span. Even
thoughattimes,theeditorsmayhaveentertainedthethoughttoaddsomemorechapters,itwouldnothave
beenfairtoallourcolleagueswhosubmittedtheircontributionsinatimelymannertoextendthedevelopment
timeanyfurther.
Thepublishingfieldisundergoingmajorchangesatthistime.Bywayofexample,scientificsocietymember-
shipsoftentimesprovideelectronicsubscriptiontotheirjournals,andmembersmoreoftenthannotsubscribe
tothiselectronicformatofjournalsexclusively.Inaddition,librarieshaveshiftedtoorderingbooks,compen-
dia,monographsandmajorreferenceworksinelectronicformat,andfrequentlynotinprintedform.Itcannot
bedenied,though,thatthelearningprocessisalsoonethattakesplacebyleafingthroughprintedpublications.
Thus,withthegoalofachievingthehighestpossibleimpactonknowledgedisseminationthatcouldresultfrom
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xxii Preface
this Major Reference Work in the field of biomaterials, a printed format was also deemed necessary. The
editorialteamandElsevierhaveworkedcloselytogethertomakethispublicationavailableintwoformats:
(cid:129) onlineviatheScienceDirectplatformguaranteeingworldwidedistributionviaanestablishedmedium;
(cid:129) aprintedversionwithprinting-on-demandrunsdeterminedbyordersreceived.
Thisdualpublicationactuallyalsolendsitselfverywelltopublishingupdatesandadditionssuchasvideo
clips. Elsevier and the editorial team have already discussed some of the concepts in this regard and will be
movingonthisinthenearfuture.
Comprehensive Biomaterials started with a very innocuous email from a publishing consultant requesting
input for a project under discussion at Elsevier. After some soul-searching and corporate restructurings at
Elsevier (what’s really new in the corporate world?), the project got on track, and it has been my and the
editorial team’s delight to work with outstanding publishing professionals. David Sleeman was our first
publisher.Interestingly,healsomoonlightedasafootballreporterwhichremindedmethattherewasalways
lifeafterscience(yesAmerica,thewholeworldcallsthisfootball).HewassucceededbyGrahamNisbetwho
gave up the trappings of a Politics major for science publishing. Louisa Hutchins and Anne Collett managed
mostoftheeditorialflow,ablyassistedbyJoanneWilliamsandMariseWillis.Withthetimedifferencebetween
theUKandtheUS,mattershadmostlybeenhandledbeforethedaybrokeonthissideofthepond.Oncewe
movedtoproduction,JustinTaylortookcharge.Therewasnotasingleemailthatwentunanswered.Closerto
home,actuallyinmyprofessionalhome,theDepartmentofBioengineeringattheUniversityofPennsylvania,
TabithaHymansfirst,andthenJenniferLeungmanagedmypaperflow.
As editors, we want to express a special word of thanks to our colleague, Professor Teruo Okano, Tokyo,
Japan,whosuggestedquiteafewinterestingtopicsandexcellentcontributorswhenwelaunchedtheproject.
Wealsoreliedonanumberofreferees,amongwhomwewanttosingleoutRaviRadhakrishnan,JeremyGilbert
andChristineKnabe.
Lastly,andveryimportantly,asEditor-in-Chief,itismypleasurementioningthatitwasmyprivilegetowork
withateamofcolleaguesasco-editors.Theirenthusiasmwasinfectiousandtheirinsightmasterful!
PaulDucheyne
UniversityofPennsylvania
Philadelphia,PA,USA
FOREWORD
Almost from the beginning of recorded time, humans have attempted – and often failed – to deploy a wide
variety of substances and materials to treat their diseases and traumas. But only within the past few decades,
as technologies have matured and materials selection and use diversified, have scientists and therapists
discoveredtheabilitytocreateartificialcompoundssuitableforinvivousage.Theconceptofbiomaterialswas
introducednomorethanfiftyyearsago,aroundthemid-1960s.Duringaconferencein1986inChester(UK),
colleaguesandIstruggledmightilytoelaborateaconsensualdefinitionofbiomaterialsunderD.F.Williams’
leadership. This now accepted definition states: “a biomaterial is a non-viable substance used in a medical device,
intendedtointeractwithbiologicalsystems.”
With this definition in mind, one might wonder whether there is a science dedicated to biomaterials? Two
notions present in this definition are important: utility, and interaction with living systems. Per se, they are
enough to claim that biomaterial science does not exist. Of course, that is not to say the field itself does not
exist.Demonstrably,biomaterialsresearchnowstraddlessuchfundamentaldisciplinesaschemistry,physical
chemistry,physics,materialsscience–withitsnumeroussub-divisions,biology–withitsyet-more-numerous
sub-divisions.Biomaterialstudiesincludeapplicationsinsurgery,dentistry,and,morerecently,pharmacology
with the development of medicated devices. The field extends to scaffolds to support tissue cultures, and
degradable and bioresorbable systems to avoid storage after completion of the function. Diversifying the
field yet further from these fundamental aspects of “biomaterials” is the necessary, and now extensively
developed,setofbioengineeringpreceptsthatpushesthefieldforward.
Today“biomaterials”isamaturingresearcharea.Asscientists,ourenterprisestretcheswellbeyondthevery
purest of research characterizing the early “gold rush” days. Furthermore, we are well beyond the initial
generations of prosthetic and therapeutic devices made of industrially derived materials. With materials
developed for other purposes, rather remarkable therapeutic successes were achieved. This period is now
over. Today the challenges are in designing novel therapeutic systems, or finding the means to minimize the
fewpercentoffailuresobservedinsystemswhichhavereachedtheclinic.Havingacommonvisionofsuchan
enormousdomainthatgroupsvarioussciences,methodologiesandtechnologiesisanecessity,butitisdifficult
to achieve by people active in the domain. Individually, there is no chance, for sure. The future depends on
interdisciplinary approaches involving top specialists from the diverse specialties that are capable of sharing
tasks and thus are capable of understanding each others disciplines and approaches. One can hardly find a
textbook, however, to train them and at the same time, to provide initiation to novices. All that has been
availabletodatehavebeenbookscomposedofacollectionofsomearticlesandreviewsthatcaptureasegment
ofthisexpansive,andsometimesconfusing,literature.
Comprehensive Biomaterials seeks to provide just such a common vision for the presently vast, and mush-
roomingdomainofbiomaterials,embracingnumerousperspectivesinanexpansive,inherentlyinterdisciplin-
ary major reference work to support effective current research in a sometimes bewilderingly complex
environment.Significantly,itiswrittenbyapanoramaoftheworld’sexpertsinhundredsofrelatedbiomater-
ialsareas.Theresultisacontinuumofrichinformationappropriateformanyaudiences.Theworkaddresses
thecurrentstatusofnearlyallbiomaterialsinthefield,theirstrengthsandweaknesses,theirfutureprospects,
appropriateanalyticalmethodsandtesting,deviceapplicationsandperformance,emergingcandidatemateri-
als as competitors and disruptive technologies, and strategic insights for those entering and operational in
diversebiomaterialsapplications,researchanddevelopment,regulatorymanagement,andcommercialaspects.
The question may be asked: in such an information-rich environment, what is the interest of this huge
collectionof200contributions?Itofferstheauthority–andthevision–ofwell-knownspecialistsinthefield.
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