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PRINCIPLES OF REGENERATIVE MEDICINE THIRD EDITION Edited by A A NTHONY TALA R L OBERT ANZA A G. M NTONIOS IKOS R N OBERT EREM AcademicPressisanimprintofElsevier 125LondonWall,LondonEC2Y5AS,UnitedKingdom 525BStreet,Suite1650,SanDiego,CA92101,UnitedStates 50HampshireStreet,5thFloor,Cambridge,MA02139,UnitedStates TheBoulevard,LangfordLane,Kidlington,OxfordOX51GB,UnitedKingdom Copyright©2019ElsevierInc.Allrightsreserved. Nopartofthispublicationmaybereproducedortransmittedinanyformorbyanymeans,electronicormechanical, includingphotocopying,recording,oranyinformationstorageandretrievalsystem,withoutpermissioninwritingfrom thepublisher.Detailsonhowtoseekpermission,furtherinformationaboutthePublisher’spermissionspoliciesandour arrangementswithorganizationssuchastheCopyrightClearanceCenterandtheCopyrightLicensingAgency,canbe foundatourwebsite:www.elsevier.com/permissions. ThisbookandtheindividualcontributionscontainedinitareprotectedundercopyrightbythePublisher(otherthanas maybenotedherein). Notices Knowledgeandbestpracticeinthisfieldareconstantlychanging.Asnewresearchandexperiencebroadenour understanding,changesinresearchmethods,professionalpractices,ormedicaltreatmentmaybecomenecessary. Practitionersandresearchersmustalwaysrelyontheirownexperienceandknowledgeinevaluatingandusingany information,methods,compounds,orexperimentsdescribedherein.Inusingsuchinformationormethodstheyshouldbe mindfuloftheirownsafetyandthesafetyofothers,includingpartiesforwhomtheyhaveaprofessionalresponsibility. Tothefullestextentofthelaw,neitherthePublishernortheauthors,contributors,oreditors,assumeanyliabilityforany injuryand/ordamagetopersonsorpropertyasamatterofproductsliability,negligenceorotherwise,orfromanyuseor operationofanymethods,products,instructions,orideascontainedinthematerialherein. LibraryofCongressCataloging-in-PublicationData AcatalogrecordforthisbookisavailablefromtheLibraryofCongress BritishLibraryCataloguing-in-PublicationData AcataloguerecordforthisbookisavailablefromtheBritishLibrary ISBN:978-0-12-809880-6 ForinformationonallAcademicPresspublicationsvisitourwebsiteat https://www.elsevier.com/books-and-journals Publisher:JohnFedor AcquisitionEditor:MicaHaley EditorialProjectManager:TimothyBennett ProductionProjectManager:PunithavathyGovindaradjane CoverDesigner:MilesHitchen TypesetbyTNQTechnologies This book is dedicated to my family: Katherine, Christopher, and Zachary Anthony Atala To my family: Mary, Georgios, and Lydia Antonios G. Mikos To my wife, Marilyn, and to my four children, Nancy Black, Christy Maser, Steve Nerem, and Carol Wilcox RobertNerem Contents Contributors xix4 .T heM olecuCliarrc uiUtnrdye rlying Preface xxv PluripotienEn mcbyr yonaincdI nduced PluripoStteenmCt e lls I.M olecuOlragra nizaotfCi eolnl s RACHELH .K LEIPNA.U LS .K NOEPFLER JOND .A HLSTROM Introudction 49 GrounSdt ataen dPr i'lendE mbryonSitce mC ells Introduciton HaveU niquSei gnalNientgw orUknsd erlying Moleucels haTtO rganizeC ells PuIr poit ency 49 The pEithle-lMieasechnymalT rnasition InducPeuldr ioptentS temC ells 50 TranscrpitionalP rogram 4 Leukemia nIhibiytF oarctaonrd Bo neM orphogenic MolecuCloanrt rooftl h Eep ithelial-Mesenchymal ProreSiing nalPiadnHvga ysR egulateM ouse Trantsiion 5 EmbryonSitce mC elSle fl�Rene\Val 50 Conclusion 8 TransforGmrionwgt Fh(l; ct13oa rn dF ibrobGlrrolwstth LisotfA cronyamnsd A bbrveiaitons 9 FactoSri gnalinPga twhayRse gultea Human Glsosary 9 EmbryonSitce mC elSle lRfe-newal 52 Refeernces 9 WntS ignalignC on[fibtuotMe asin tenanocfe PuIr pio tenicnyM ousEem bryonSitce mC ellansd z.C ell-ExtracMealtlruiIlxna tre racitni ons tot heN (l;ivHeu manE mbryonSitce mC elSlt ate 52 Repaainrd R egeneration ThreTer anscriFpatcitoonOr csm,m erB inding MELISSPAE TREACMAA.N UELAM ARTINS.GREEN Prote4i.Sn R Y-B2o.xa ndN ango. Formt heC ore PluproietncTy arnsrcpirinoalN etwork 53 Introduciotn 15 MYC LinkCse lSli gnaltioP nlugr irepnocyG ene ComposiatnidDo inv erosfti htEeyx traceMlalturliaxr 1 5 Regultaion 54 ReceptfooErrxs rt acleullaMra trMioxl ceulse 16 A Spceicfi EpigePnreotgircHa em lspM (l;intain SignTarla nsducEtvieonnDt usr inCcgl l- Pluirpol:ency 55 ExtcrealllauMra triIxn ter;l.ctions 18 MicroRNIAnst egrWaitteCh e lSli gnalainndg Cel-lExtralculelraM atriIxn tetriaocnDusr ing TranscriFpatcitoontr oRs e gultaeS temC ell Heailngo fC utaneWoouusn ds 25 ProlifeaTn<dDJi ftfireonetni i(olnt 57 Cell-ExtraMcaetlrlIiunxlt aerr acDtuiroinnsg ChromaSttirnu cDteutreer mRiengeusl aAtcotriyv ity RegenearitevF eulWlo undH ealing 28 ofT ranscriFapctrriB ooinn dgit noP luripotncey ImplicaftoiRroe ngesn eraMteidivcien e 30 Gense 58 Ackonwledegnmts 31 Concluisnos 58 Reefrences 31 LisotfA cronyamnsdA bbreviations 59 3.M echanisomfBs l asteFmoar matiaonnd Acknowledgment 59 References 59 Growrihn R egeneraUtriondge Lliem bs DAVIDL .S TOCUM 5.S carlWeosusn dH ealing: From ExperimeTnatragltoe tC liniRceaall ity Inrtoduction 37 BlastFeomram ation 37 ALESSANDRLA.M OORE.C LEMENDT. M ARSHALL• ALLIOSN NAUTA, HERMA1N'LN.O RENZ. BlastGerlonwat h 42 MICHAETL. L ONGAKER LisotfA cronyamnsdA bbrevi.Jtions 45 Glossayr 45 Introduction 65 Acknowledgments 45 AdulStk in 66 Reefrences 45 FetSakli n 7Z vii viii CONTENTS RegenenlHteiavlei anngdS caRre ductTihoeno ry 73 Conclusions 144 CurreTnhte rapeuItnitvceen rtinos 77 References 144 FutuTrhee raupreiIcn terventions 80 Perspective 85 10.C ordB looSdt emC ells LisotfA bbreiavtinos 86 KRISTINP AMG.E J,E SSIMC.AS UNJ,O ANNEK URTZBERG References 86 Itnrodcuiton 149 6.P rogeniantdoS rt emC elHle terogeneityA: BriHe ifs raty 149 UsinBgi gD attao D iviadned C onquer CordB looBd,m king 150 PublViecr sFuasm i(loyr r ivPact) Banks 150 MELANIE RODRIPGAUUELSA ..M ITTERMILLER. jAGANNATPHA DMANABHAGNE,O FFRECY.G URTNER PublCiocr Bdl ooBda nkiPnrgo cedures 151 CliniUcsaelos fU mbiliCcoarldB lood 156 Inotdruciton 93 CordB loodT herapisef oIrn ehritaenddA cqureid Singleel-IlCs oloant i 95 BraiDni seases 157 AcquirSiinnglge- CellDa w 96 Ivnestigaitnit ohneTs r eatmoefAn ctq uiredB rain An�llySziignnlge -CDealtla 100 InjruieWsi thU mbiilcaClor d Blood 159 DetermiSniubpngo pautloins 103 References 162 CliniIcmapll icaotfiC oenlsl uHleatrreo getnyie ni TissRueep aainrd D iesase 105 I.I InducPeldu ripoStteenmCt e lls Conlcusions 108 ANDRESM .B RATT·LEAAILZ ,H ANGY,A NLINWGA NG, Refreenecs 109 JEANNFE.L ORING 7.E mbryonSitce mC ellDse:r ivation, Itnroudction 169 PropertainedCs h,a llenges McchaniosfmR se proagmrming 169 EpiegnetRiecm odeling 170 IRINKAL iMANSYK AA ReprogramTmeichnngiq use 170 Inrtoduicotn 113 inducTer da ndsiefrfentiation 171 DerivaotfEi mobnr yonSitecm C ells 113 GenomiSct ability 172 SourcoefHs u manEm broynicS teCme lls 114 ApplicaotifIo nndsu cPeldu ripSotteeCmne tl ls 172 HumanE lly"olnbirSct emC elMla intenance 116 DiesaesM odeling I7Z N'liEvmeb royniSct emC ells 119 Chalnlgeeasn dF utuProes siiltbiieisn Disease HumanE mbryonSitce mC elDli fferentainadt ion Modeling 174 M�mufac(UfroiCrnli gn icAfplp1l ication 119 PersonaMleidizcneeid 174 Conclusions Iz o CelTlh erapy 175 References 120 ConservaotfEi nodnnag ereSdp ecies 176 FutrherR eadnig 123 ConclusainodnF su tuDrieer ctions 176 LisotfA cronyamnsd A bbreviations 177 8.A lternaStoiuvreco efHs u manE mbryonic References 177 StemC ells 12.M ultipotAednutlP tr ogeniCreolll's SVETLANGAA VRIOLV.V II\GIEN.PI AAP AI OANNOU. DONALDW.L ANDRY RANGARAjASNA MBATHKUMAMRA,N OjK UMAR. CATHERINME.V ERFAILLIE Intorduciton 125 OrganismaillycD C�Elmdb roys IZ7 SteCme lls 181 Conclusion 130 AdulStt eCme lls 181 Reefrences 130 IsolaotfiR oond eMnuttl ipotnerA dult Progenitor Cell 182 9.S temC ellFsr omt heA mnion IsolaotfiH ounm anM ultpioetntA dulPtr ogenitor Cells 183 PAOLOD EC OPPIA,N THONYA TALA DiffnetrtieiaoPno tentoifRa old enatn dH uman Introduciton 133 MulitpotentA dulPtr ogenCietloIlrnsV itro 183 PlaceFnutnac:l :Oiroing,ian nd,C omposition 133 RegenerCmaipvaiecit seo fM ultpoitnetA dult AmnoitiFcl uiFdu:n ctiOorni,g iann,dC ompositio1n3 4 Progenit oCre l is 183 AmniotEipci theCleilalls 134 ConcluasnidoF nu tuDrier ections 187 AmniotMiecs ecnhymalS temC ells 135 ConfloifcI tne treSstta tement 187 AmnoitiFcl du iSteCme lls 138 References 187 CONTENTS ix 13H.e matopoietiCce lSPltr eomp erties, 17C.a rdiSatce mC ellBsi:o loagnyd Markerasn,dT herapeutics TherapeuAtpipcl ications JOHND .J ACKSON KONSTANTINOES. H ATZISTERGOSSA,I \AHS ELEM. WAYNE BALKAN,jOSHUMA. H ARE Introduction 191 HematopoSiteetCmie cl Plr operties 191 Developomeftn hteH e arFtr oCma rdiSatce m/ HematopoSiteetCmie cl Tlh erapies 195 ProgenCietlolrs 247 Conclusion 199 CardiSatce m/ProgCeenliiltnsto hreA dulHte art 248 LisotfA cronyamnsdA bbreviations 199 Cell�BTahseerda pefuotHrie casrD ti sease 252 References 200 Mech::miosfArn cst ion 254 CliniTcraila ls 255 14.M esenchySmtaelm C ells Metho(dosEr x pansoi(Ao dnu lCta rdiac SteCme lls 265 ZULMAG AZITG.A OlP ELLEDD,M ITRISYH EYN, [lORON C.Y AKUllOVICDHA,N GAZIT CombinSetde Cme lTlh erapeutics 265 Conclusions 267 IntroduOcvteorrvyi ew 205 References 267 DefiniotfMi eosne nchySmraelCm e lls 206 TheS teCme lNla tuorfeM esenchySmtaeClme lls 206 18.Sk eleMtuaslc lSet emC ells WhicThi ssCuoenst aMiens enchySmtaeClme lls? 207 NORA YUCEL, HEML.EB NL AU MesenchySmtaeClle ll)Il s olaTteicohnn iques 208 MesenchySmtaelCm e lElx osomcs 208 Introduction 273 Immul1omoduElfafreoocfrMt yes s enchySmtaelm SatelCleiltAlers e M uscSltee Cme lls 274 Cells 211 TheM olecuClhaarr acteorfiM sutsicScltsee Cme lls InducPeldu ripSotteeCmne tl l-Derived DuriMnygo geniensR iesg eneration 274 MesenchySmtaeClme lls 212 FunctiCohnaarla cteorfiM sutsicScltsee Cne1l ls 276 LisotfA cronyamnsdA bbreviations 213 IsolaotfMi uosnc Sltee Crenl ls 277 Acknowledgments 213 TrackMiunsgc Sltee Cme lBle havTihorro uLgihv e References 214 Imagi(nBgi olumineIsmcaegniacnnegdI ntravital Imaging) 278 15M.e senchySmtaelm C ellisn RegulaotfMi uons cle CSetleblmysT heiNri che 279 RegeneraMteidviec ine S;;![eClellSilet lcf ,ReMneecwhaaln isms 281 AR NOLDI .CA P LAN MuscSltee Cme ll-IntDreifnesciitnAcs g inagn d Disease 283 IntroduacntdHi iosnto ry 219 Challeinngt ehseU seo fS atelCleiltilens NewI nsighr 220 RegenerMaetdiivcei ne 284 AllM esenchySmtaeClme lAlrse N otC reatEeqdu al2 22 GeneE ditSitnrga tegies 285 CliniTcraila ls 224 OtheSrt eCme lTly peWsi thiMnu scle 285 TheN ewM esenchySmtaelCm e lls 224 Conclusions 287 References 225 References 287 16.Ce lTlh eraopfyL iveDri sease: 19.S temC ellDse rivFerdo mF at FromH epatoctyotSe tse mC ells JAMESc .B ROWN.A DAM jK.A TZ STEPHENC. STROM,C ARLj ORNS Introduction 295 Introduction 229 CelluFlraarc tions 295 BackgroSutnudd ies 231 CelluClhaarr acterization 296 CliniHceaplr ltTOr cayntsep lantacion 232 CliniDcealli voefAr dyi pose-DCeerlilvse d 297 HepacoTcr yacnes planNtoavceUilso enCs I,l (lllengesE.n gineNecroe,dT issue 300 andF utuDrier ections 237 Ther<1pSe<u1tfoicfcAt dyi pose-DCeerlilvse d 301 SU lTarl my 241 Conclusions 302 References 242 References 302 x CONTENTS 20.P eriphBelroaolS dt emC ells LisotfA cronyamnsd A bbreviations 386 Acknowledgments 386 ABiUTEDEA HL.G RAC;:A ALMEIDA.PC)I(ADA. CHRISTOPHDE.RP ORADAS.H AY SOKER References 387 Introduction 307 24.M echaniDceatle rminoafnT tiss sue Typeasn dS ourcoefS temC ellisnt heP eripheral Development Blood 307 VOLHAL lADUANSKAYAD.I SHSAO OD. EndothePlrioagle nCieclolfs 311 DAVIDI .K.A PLNA Mesenchymal Stem/Marrow Stroma 3C1e5l ls TherapeuAtpipcl icatoifPo enrsi phBelroaolSd t em Introduction 391 Cells 317 MechanornlllsMcieucchrainoinsa mnsdM ajor ConclusainodnF su tuDrier ections 325 Effectors 392 References 326 Nucleausst heC enrrOarlg aneilnlR ee gulating MechflnOtransduction 396 21F.r omA dulPta ncreaItsilceto tSst em CelluMleacrh anotransdMueccthiaonni sms 397 CellRse:g eneraSttirvaet efgoirte hse Conclusions 400 TreatmeonfDt i abeatnedsI tCso mplicationsA cknowledgments 401 MARTA POKRYWCZYNSKAG.I ACOMO LANZONI. References 401 CAMILLOI UCORDI 25M.o rphogenBeosnieMs o,r phogenetic Introduction 335 ProteiannsdR, e generaotfiB oonn ea nd FromA dulPta ncreaItsilceto tSst emC ells 335 ArticuClaarrt ilage Strate(goitreh seG enemtioofn� Cell(so r ReplacemTehnetr apy 336 A.H.R EDDI. KENJIROI WASA J3C ellFsr om PluriSptoetmCe enltl( sE mbryonic Introduction 405 StemC ellasn dI nducPeldu ripotent Stem3 .3C6e lls) BoneM orphogenPertoitce ins 406 ICIe llFsr omA dulStt em/progeCneiltloosftr h e StemC ells 409 BiliTarreyae n dP ancreas 341 SC::IffoofEl xdtsr ttceMlml:urliaaxnr dB iomimcric MesenchySmtaelmC elltos M odul<Ilmtmeu niatnyd Biomaterials 409 PromoTties sRueep aiinrD iabetes 344 ArticuClaarrt ilRaeggee neraatnidCo anr tilage Conclusion 345 MorphogenPertoitce ins 412 References 346 RegeneraMteidviec iannedS urgeorfAy r ticular 22.St emC ellfsor D iseaosfet sh eR etina Cartilage 412 RegeneraotriA ornt icuClaarrt ilSaugref aacned AARON NAGILE.S TEVEND. S CHWARTZ Lubrication 413 LisotfA cronyamnsd A bbreviations 414 lmroducrion 351 Acknowledgments 414 Cell-ReplacTehmeernatp y 355 References 414 Cell-BaNseeudr oprotection 361 Disease�irMHold-eDliisfnhog Rr e tinDails orders 362 26.Ph ysiSctarle asssa FactionrT issue Conclusion 364 Growtahn dR emodeling References 365 JOELD .l JOERCKCEHLI.� ISTOIV'.GH EEMRM ITI. 23.S temC ellfso Tr raumatBirca iInn jury DEVONE .M ASON.Y ASHM .K OLAMBKAR. BLAISDE.P ORTERR.O BERET. G ULDBERG CHRISTOPHME.RS CHNEIDEMRA.R GARTE L.J ACKSON. SUPINDES.RB EDIC.H ARLES SC.O X.J R. Introduction 417 DescrtihbeeM echaniEcnavli ronment 418 Introduction 369 UndersttahneRd o loef M echanical PhasoefsB raiInn jury 370 Stimuli 423 CurreTnrta umatBirca iInn juMrayn agement MechaniRceaglu latoifVo ans cularTiizsesdu e Strategies 376 Regeneration 427 PreclinDiactaSalu pportSitnegmC elTlh erapfioers EvaluaFtuen ctioRneaslt oration 432 TraumatBirca iInn jury 376 Conclusions 432 Clinical Trials 381 References 433 Conclusion 385 CONTENTS xi 27.C ell-SubsItnrtaetrea ctions M�mufactliu trya bi 517 MUHAMMADR IZWAN,JOWH.NT SEA,P ARNA NORI, Summary 517 KAM W.L EONG,E VELYKN. FY.I M References 518 Introduction 437 31.P roteCionnst rolWlietdhP recisaito n Cell-ExtraMcaetlrlIiunxlt aerr actions 437 OrganiPco,l ymeraincdB, i opolymer Cell-SubIsnttreartaec tions 438 InterfacTeiss sfEuonerg ineearnidn g EffecotfD imensionality 451 RegeneraMteidviec ine Conclusion 460 DAVIDG. C ASTNER,B UDDYD .R ATNER Acknowledgments 461 Re(erences 461 Whyt heN eedf oPrr eciCsoinotnr oofPl r oteaitn s InterfianTc iesssE uneg ineearnidRn egg enerative 28.I ntelliSguerfnatfc oerCs e lSlh eet Medicine! 523 Engineering SurfAancae lyasnidIs t Rso lient hPer ecision HIRONOBTUA KAHASHTIA.T SUYAS HIMIZU, DelivoefBr iyo logSiicganla ls 524 TERUOOKANO A ShoRret vioefw KSeuyr fAancael yMseitsh o�dls1 1d SupporTtoionlgs 525 Introduction 469 TechniqaunedTs e chnolofogPrir eesc ision TheI ntelliogfTe hnecrem orespPoonlsyimvfeeor rs ImmobiliaztaS tuirofna ces 527 CelSlh eet Engineering 469 Conclusions 531 CliniAcpapll icaftoiCroe nlSslh eeEtn gineerin4g7 2 References 532 CelSlh eeEtn gineePrriondgu Scceasf fForlede·, Three-DimeTnisisosCnuoaenl s tructs 474 32.N aturOarli gMiant erifaolBrs o nTei ssue CombinaotfiC oenlS lh eeEtn gineearnidn g EngineerPirnogp:e rtPireosc,e ssainndg , ScaffBoalsdeE·dn gineering 477 Perofrmance MicrofabrIinctaetlelSdiu grefnaftco Eern gineering ComplTeixs sCuoen structs 478 F.R AQUELM AlAV,I TORM .C ORRELO, JOAQUIMM. O LIVEIRRAU,IL .R EIS Conclusions 481 References 482 Introduction 535 Naturasle�dPB oalymers 538 29.A pplicatoifNo annso technofloorg y Chitosan 538 RegeneraMteidviec iHneea;l iTnigs suaets Collagen 540 theN anoscale GelhGmu m 543 YAFENYG ANGA,D ITYCAH AW LA.J INZ HANG, Polyhydroxyalkanoates 545 ADAME SAH,A ELI JANGA.L IK HADEMHOSSEINI SilFki broin 547 Starch 548 introduction 485 Natural�BBiaosceedr amics 550 ProperotfNi aenso rnaterials 486 CalciPuhmo sphates 551 Nanobiomaterials 491 SilicCaetrea mics 553 N:111otechnology-iBnaR seegde nSetrfa<'tlitveeg ies Conclusions 554 Medicine 493 LisotfA cronymsA babnrde viations 555 NanotechnoloSgtye·CmBe alsTleh de rapy 497 Acknowledgments 555 Conclusion 499 References 555 References 499 33.S ynthePtoilcy mers 30.D esigPnr inciipnlB eiso materainadl s MICHAEcL. H ACKERJ,A NK RIEHGO FF, Scaffolds ANTONIOGS. M IKOS YANGZ HU,W ILLIARM.W AGNER Introduction 559 FunctioAnp palnidc ation�DOersiioegfnn t ed PolymSeyrn thesis 560 BiomateSrciaaflfo lds 505 NondegraSdyanbtlheeP toilcy mers 561 SafeatnydB iocompatRiebqiuliirteymf eonrt s BiodegraSdyanbtlheeP toilcy mfeorRrse generative BiomateSrciaaflf olds 513 Medicine 567 xii CONTENTS ApplicatoifSo ynnst hePtoilcy mers 580 BiologMiocdailf icaotfSi uornf aces 656 Conlcu soin/Smu mar y 580 SurfaCchee micPaalt terning 6j9 References 581 ConclusainodFn u tuPrreo spects 659 References 659 34.Ca lciuPmh osphaBtieo ceramics and Cements 38.Hi srogenienTs hirse e-Dimensional NATHAN W.K UCKO.R ALF·PETHEERR BER, Scaffolds SANDERC G. LEEUWENIJURGJHO,H NA .J ANSEN MELISSKA .M CHALE, NICOML.EB ERGMANN. jENNIFELI.W� E ST Introduction j91 ClsaseosfC alciPlhiolsnp hCaetmee nts 594 TheN eedf orR eplacemTeinsts ues 661 PhysiochePmriocpaelr ties 595 TissCuoem ponents 661 Stragtieetos ImprotvheeM echaniPcraolp erties 60I RegeneraotfDi iosne ased Tissues 662 CliniAcpapll icmions 606 DesigPna rameterHsi stfoogre nesis 663 Conclusion 607 SyntheMtaitce rifaolHrsi stogenoefs ciwsO rgans 669 LisotfA cronyamnsd A bbreviations 608 Future DirienTc htrieoens, DimenSsciaofnfaoll ds: Glsosary 608 Three,DimenMsiicornoafla brication 670 References 608 Concsliuons 670 Reefrences 671 35B.i oloSgciacff olCdosm poseodf ExtracelMlautlraifroxr R egenerative 39.Bi ocompariabnidl iBriyo restpoo nsc Medicine Biomarerials MICHELLSEC ARRITTM,A RK MURDOCK, JAMESM .A NDERSON STEPHENF .l lADYLAK Introduction 675 Introdounc ti 613 Inflamma(tIinonnaI tmem uniatnyd)W oundH c,;llin6g7 6 ExtralcleulMaatrr iFxu:n ctiaonndC omponents 613 FibroasnidFs i broEunsc apsulation 683 IntaacntdS olubziedlE ixtcreallruM laatraisx(l Immunotoxi(cAictqyu iIrmemdu nity) 684 ScaoflfdM aterial 619 Conculsion 691 CliniacnadCl o mmercAipapll ications 622 References 691 Conclusions 622 FurthReera ding 694 LisotfA cronyamnsd A bbreviations 622 Glsosary 623 40.H ybriCdo mposiBrieo materials References 623 NIRMALYAT RII'ATHEYL,U MALAIP ERUMAL, RAFIQA HMAD.J EONGE UN SONG,G ILSONK HANG 36.H ydrogienlR se generaMteidviec ine Introduction 695 DAVIDF .W ltLIAMS FundamenotfBa olnse D evelopmaenndDt e fetcs 696 Introduction 627 FunctioofSn csa oflfdianngdE xtcreallruM laatrix 696 BiomateTreimapllsa tes 628 ScaoflfdiAnpgp roacihneB so neTi ssEuneg ineerin69g7 Strurcet-uPropReertlyao tnisihpisn H ydrogels 631 ScaoflfdiMnOI:ge rials 699 IncreaSsoipnhgi sticoafSt yinotnh eHtyidcr ogfeolrs Conclounssai ndF utuPrreo spects 710 TissEuneg ineering 632 Acknwoledgments 710 NaturBailo polyamseE rxst ralcleuMlaatrr ix-Analog Reefrensc e 710 Hydrolgse 639 4\ .M aterialsC-aBnacseerd SyntheHtyidcr ogfeolTrs i ssEuneg ineering Templast e 646 Immunotherapies Conclusions 648 JAREDM . NEWTON. ANDREGW. S IKORA, References 649 SIMONY OUNG 37S.u rfaMcoed ificaotfBi ioonm aterials IntroducatnidOo vne rvioefwC ancer I1l"unuenroatphy 715 RACHITA GARWAL,A NDREsj .G ARCiA Advatnageasn dD isadvanotfaC gaensc er Introduction 651 Immuntoherapy 717 PhysicocheSmuircfaaMlco ed ifications 653 NanopartBiicolmea tcrfoiCr; ":ldnsc cr OvercoatTiencgh noglioes 655 Immnuothepry a 718

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Principles of Regenerative Medicine PDF

1416 Pages·2019·31.455 MB·English
by  Anthony Atala, Robert Lanza, Antonios G. Mikos, Robert Nerem (eds.)
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Preview Principles of Regenerative Medicine

PRINCIPLES OF REGENERATIVE MEDICINE THIRD EDITION Edited by A A NTHONY TALA R L OBERT ANZA A G. M NTONIOS IKOS R N OBERT EREM AcademicPressisanimprintofElsevier 125LondonWall,LondonEC2Y5AS,UnitedKingdom 525BStreet,Suite1650,SanDiego,CA92101,UnitedStates 50HampshireStreet,5thFloor,Cambridge,MA02139,UnitedStates TheBoulevard,LangfordLane,Kidlington,OxfordOX51GB,UnitedKingdom Copyright©2019ElsevierInc.Allrightsreserved. Nopartofthispublicationmaybereproducedortransmittedinanyformorbyanymeans,electronicormechanical, includingphotocopying,recording,oranyinformationstorageandretrievalsystem,withoutpermissioninwritingfrom thepublisher.Detailsonhowtoseekpermission,furtherinformationaboutthePublisher’spermissionspoliciesandour arrangementswithorganizationssuchastheCopyrightClearanceCenterandtheCopyrightLicensingAgency,canbe foundatourwebsite:www.elsevier.com/permissions. ThisbookandtheindividualcontributionscontainedinitareprotectedundercopyrightbythePublisher(otherthanas maybenotedherein). Notices Knowledgeandbestpracticeinthisfieldareconstantlychanging.Asnewresearchandexperiencebroadenour understanding,changesinresearchmethods,professionalpractices,ormedicaltreatmentmaybecomenecessary. Practitionersandresearchersmustalwaysrelyontheirownexperienceandknowledgeinevaluatingandusingany information,methods,compounds,orexperimentsdescribedherein.Inusingsuchinformationormethodstheyshouldbe mindfuloftheirownsafetyandthesafetyofothers,includingpartiesforwhomtheyhaveaprofessionalresponsibility. Tothefullestextentofthelaw,neitherthePublishernortheauthors,contributors,oreditors,assumeanyliabilityforany injuryand/ordamagetopersonsorpropertyasamatterofproductsliability,negligenceorotherwise,orfromanyuseor operationofanymethods,products,instructions,orideascontainedinthematerialherein. LibraryofCongressCataloging-in-PublicationData AcatalogrecordforthisbookisavailablefromtheLibraryofCongress BritishLibraryCataloguing-in-PublicationData AcataloguerecordforthisbookisavailablefromtheBritishLibrary ISBN:978-0-12-809880-6 ForinformationonallAcademicPresspublicationsvisitourwebsiteat https://www.elsevier.com/books-and-journals Publisher:JohnFedor AcquisitionEditor:MicaHaley EditorialProjectManager:TimothyBennett ProductionProjectManager:PunithavathyGovindaradjane CoverDesigner:MilesHitchen TypesetbyTNQTechnologies This book is dedicated to my family: Katherine, Christopher, and Zachary Anthony Atala To my family: Mary, Georgios, and Lydia Antonios G. Mikos To my wife, Marilyn, and to my four children, Nancy Black, Christy Maser, Steve Nerem, and Carol Wilcox RobertNerem Contents Contributors xix4 .T heM olecuCliarrc uiUtnrdye rlying Preface xxv PluripotienEn mcbyr yonaincdI nduced PluripoStteenmCt e lls I.M olecuOlragra nizaotfCi eolnl s RACHELH .K LEIPNA.U LS .K NOEPFLER JOND .A HLSTROM Introudction 49 GrounSdt ataen dPr i'lendE mbryonSitce mC ells Introduciton HaveU niquSei gnalNientgw orUknsd erlying Moleucels haTtO rganizeC ells PuIr poit ency 49 The pEithle-lMieasechnymalT rnasition InducPeuldr ioptentS temC ells 50 TranscrpitionalP rogram 4 Leukemia nIhibiytF oarctaonrd Bo neM orphogenic MolecuCloanrt rooftl h Eep ithelial-Mesenchymal ProreSiing nalPiadnHvga ysR egulateM ouse Trantsiion 5 EmbryonSitce mC elSle fl�Rene\Val 50 Conclusion 8 TransforGmrionwgt Fh(l; ct13oa rn dF ibrobGlrrolwstth LisotfA cronyamnsd A bbrveiaitons 9 FactoSri gnalinPga twhayRse gultea Human Glsosary 9 EmbryonSitce mC elSle lRfe-newal 52 Refeernces 9 WntS ignalignC on[fibtuotMe asin tenanocfe PuIr pio tenicnyM ousEem bryonSitce mC ellansd z.C ell-ExtracMealtlruiIlxna tre racitni ons tot heN (l;ivHeu manE mbryonSitce mC elSlt ate 52 Repaainrd R egeneration ThreTer anscriFpatcitoonOr csm,m erB inding MELISSPAE TREACMAA.N UELAM ARTINS.GREEN Prote4i.Sn R Y-B2o.xa ndN ango. Formt heC ore PluproietncTy arnsrcpirinoalN etwork 53 Introduciotn 15 MYC LinkCse lSli gnaltioP nlugr irepnocyG ene ComposiatnidDo inv erosfti htEeyx traceMlalturliaxr 1 5 Regultaion 54 ReceptfooErrxs rt acleullaMra trMioxl ceulse 16 A Spceicfi EpigePnreotgircHa em lspM (l;intain SignTarla nsducEtvieonnDt usr inCcgl l- Pluirpol:ency 55 ExtcrealllauMra triIxn ter;l.ctions 18 MicroRNIAnst egrWaitteCh e lSli gnalainndg Cel-lExtralculelraM atriIxn tetriaocnDusr ing TranscriFpatcitoontr oRs e gultaeS temC ell Heailngo fC utaneWoouusn ds 25 ProlifeaTn<dDJi ftfireonetni i(olnt 57 Cell-ExtraMcaetlrlIiunxlt aerr acDtuiroinnsg ChromaSttirnu cDteutreer mRiengeusl aAtcotriyv ity RegenearitevF eulWlo undH ealing 28 ofT ranscriFapctrriB ooinn dgit noP luripotncey ImplicaftoiRroe ngesn eraMteidivcien e 30 Gense 58 Ackonwledegnmts 31 Concluisnos 58 Reefrences 31 LisotfA cronyamnsdA bbreviations 59 3.M echanisomfBs l asteFmoar matiaonnd Acknowledgment 59 References 59 Growrihn R egeneraUtriondge Lliem bs DAVIDL .S TOCUM 5.S carlWeosusn dH ealing: From ExperimeTnatragltoe tC liniRceaall ity Inrtoduction 37 BlastFeomram ation 37 ALESSANDRLA.M OORE.C LEMENDT. M ARSHALL• ALLIOSN NAUTA, HERMA1N'LN.O RENZ. BlastGerlonwat h 42 MICHAETL. L ONGAKER LisotfA cronyamnsdA bbrevi.Jtions 45 Glossayr 45 Introduction 65 Acknowledgments 45 AdulStk in 66 Reefrences 45 FetSakli n 7Z vii viii CONTENTS RegenenlHteiavlei anngdS caRre ductTihoeno ry 73 Conclusions 144 CurreTnhte rapeuItnitvceen rtinos 77 References 144 FutuTrhee raupreiIcn terventions 80 Perspective 85 10.C ordB looSdt emC ells LisotfA bbreiavtinos 86 KRISTINP AMG.E J,E SSIMC.AS UNJ,O ANNEK URTZBERG References 86 Itnrodcuiton 149 6.P rogeniantdoS rt emC elHle terogeneityA: BriHe ifs raty 149 UsinBgi gD attao D iviadned C onquer CordB looBd,m king 150 PublViecr sFuasm i(loyr r ivPact) Banks 150 MELANIE RODRIPGAUUELSA ..M ITTERMILLER. jAGANNATPHA DMANABHAGNE,O FFRECY.G URTNER PublCiocr Bdl ooBda nkiPnrgo cedures 151 CliniUcsaelos fU mbiliCcoarldB lood 156 Inotdruciton 93 CordB loodT herapisef oIrn ehritaenddA cqureid Singleel-IlCs oloant i 95 BraiDni seases 157 AcquirSiinnglge- CellDa w 96 Ivnestigaitnit ohneTs r eatmoefAn ctq uiredB rain An�llySziignnlge -CDealtla 100 InjruieWsi thU mbiilcaClor d Blood 159 DetermiSniubpngo pautloins 103 References 162 CliniIcmapll icaotfiC oenlsl uHleatrreo getnyie ni TissRueep aainrd D iesase 105 I.I InducPeldu ripoStteenmCt e lls Conlcusions 108 ANDRESM .B RATT·LEAAILZ ,H ANGY,A NLINWGA NG, Refreenecs 109 JEANNFE.L ORING 7.E mbryonSitce mC ellDse:r ivation, Itnroudction 169 PropertainedCs h,a llenges McchaniosfmR se proagmrming 169 EpiegnetRiecm odeling 170 IRINKAL iMANSYK AA ReprogramTmeichnngiq use 170 Inrtoduicotn 113 inducTer da ndsiefrfentiation 171 DerivaotfEi mobnr yonSitecm C ells 113 GenomiSct ability 172 SourcoefHs u manEm broynicS teCme lls 114 ApplicaotifIo nndsu cPeldu ripSotteeCmne tl ls 172 HumanE lly"olnbirSct emC elMla intenance 116 DiesaesM odeling I7Z N'liEvmeb royniSct emC ells 119 Chalnlgeeasn dF utuProes siiltbiieisn Disease HumanE mbryonSitce mC elDli fferentainadt ion Modeling 174 M�mufac(UfroiCrnli gn icAfplp1l ication 119 PersonaMleidizcneeid 174 Conclusions Iz o CelTlh erapy 175 References 120 ConservaotfEi nodnnag ereSdp ecies 176 FutrherR eadnig 123 ConclusainodnF su tuDrieer ctions 176 LisotfA cronyamnsd A bbreviations 177 8.A lternaStoiuvreco efHs u manE mbryonic References 177 StemC ells 12.M ultipotAednutlP tr ogeniCreolll's SVETLANGAA VRIOLV.V II\GIEN.PI AAP AI OANNOU. DONALDW.L ANDRY RANGARAjASNA MBATHKUMAMRA,N OjK UMAR. CATHERINME.V ERFAILLIE Intorduciton 125 OrganismaillycD C�Elmdb roys IZ7 SteCme lls 181 Conclusion 130 AdulStt eCme lls 181 Reefrences 130 IsolaotfiR oond eMnuttl ipotnerA dult Progenitor Cell 182 9.S temC ellFsr omt heA mnion IsolaotfiH ounm anM ultpioetntA dulPtr ogenitor Cells 183 PAOLOD EC OPPIA,N THONYA TALA DiffnetrtieiaoPno tentoifRa old enatn dH uman Introduciton 133 MulitpotentA dulPtr ogenCietloIlrnsV itro 183 PlaceFnutnac:l :Oiroing,ian nd,C omposition 133 RegenerCmaipvaiecit seo fM ultpoitnetA dult AmnoitiFcl uiFdu:n ctiOorni,g iann,dC ompositio1n3 4 Progenit oCre l is 183 AmniotEipci theCleilalls 134 ConcluasnidoF nu tuDrier ections 187 AmniotMiecs ecnhymalS temC ells 135 ConfloifcI tne treSstta tement 187 AmnoitiFcl du iSteCme lls 138 References 187 CONTENTS ix 13H.e matopoietiCce lSPltr eomp erties, 17C.a rdiSatce mC ellBsi:o loagnyd Markerasn,dT herapeutics TherapeuAtpipcl ications JOHND .J ACKSON KONSTANTINOES. H ATZISTERGOSSA,I \AHS ELEM. WAYNE BALKAN,jOSHUMA. H ARE Introduction 191 HematopoSiteetCmie cl Plr operties 191 Developomeftn hteH e arFtr oCma rdiSatce m/ HematopoSiteetCmie cl Tlh erapies 195 ProgenCietlolrs 247 Conclusion 199 CardiSatce m/ProgCeenliiltnsto hreA dulHte art 248 LisotfA cronyamnsdA bbreviations 199 Cell�BTahseerda pefuotHrie casrD ti sease 252 References 200 Mech::miosfArn cst ion 254 CliniTcraila ls 255 14.M esenchySmtaelm C ells Metho(dosEr x pansoi(Ao dnu lCta rdiac SteCme lls 265 ZULMAG AZITG.A OlP ELLEDD,M ITRISYH EYN, [lORON C.Y AKUllOVICDHA,N GAZIT CombinSetde Cme lTlh erapeutics 265 Conclusions 267 IntroduOcvteorrvyi ew 205 References 267 DefiniotfMi eosne nchySmraelCm e lls 206 TheS teCme lNla tuorfeM esenchySmtaeClme lls 206 18.Sk eleMtuaslc lSet emC ells WhicThi ssCuoenst aMiens enchySmtaeClme lls? 207 NORA YUCEL, HEML.EB NL AU MesenchySmtaeClle ll)Il s olaTteicohnn iques 208 MesenchySmtaelCm e lElx osomcs 208 Introduction 273 Immul1omoduElfafreoocfrMt yes s enchySmtaelm SatelCleiltAlers e M uscSltee Cme lls 274 Cells 211 TheM olecuClhaarr acteorfiM sutsicScltsee Cme lls InducPeldu ripSotteeCmne tl l-Derived DuriMnygo geniensR iesg eneration 274 MesenchySmtaeClme lls 212 FunctiCohnaarla cteorfiM sutsicScltsee Cne1l ls 276 LisotfA cronyamnsdA bbreviations 213 IsolaotfMi uosnc Sltee Crenl ls 277 Acknowledgments 213 TrackMiunsgc Sltee Cme lBle havTihorro uLgihv e References 214 Imagi(nBgi olumineIsmcaegniacnnegdI ntravital Imaging) 278 15M.e senchySmtaelm C ellisn RegulaotfMi uons cle CSetleblmysT heiNri che 279 RegeneraMteidviec ine S;;![eClellSilet lcf ,ReMneecwhaaln isms 281 AR NOLDI .CA P LAN MuscSltee Cme ll-IntDreifnesciitnAcs g inagn d Disease 283 IntroduacntdHi iosnto ry 219 Challeinngt ehseU seo fS atelCleiltilens NewI nsighr 220 RegenerMaetdiivcei ne 284 AllM esenchySmtaeClme lAlrse N otC reatEeqdu al2 22 GeneE ditSitnrga tegies 285 CliniTcraila ls 224 OtheSrt eCme lTly peWsi thiMnu scle 285 TheN ewM esenchySmtaelCm e lls 224 Conclusions 287 References 225 References 287 16.Ce lTlh eraopfyL iveDri sease: 19.S temC ellDse rivFerdo mF at FromH epatoctyotSe tse mC ells JAMESc .B ROWN.A DAM jK.A TZ STEPHENC. STROM,C ARLj ORNS Introduction 295 Introduction 229 CelluFlraarc tions 295 BackgroSutnudd ies 231 CelluClhaarr acterization 296 CliniHceaplr ltTOr cayntsep lantacion 232 CliniDcealli voefAr dyi pose-DCeerlilvse d 297 HepacoTcr yacnes planNtoavceUilso enCs I,l (lllengesE.n gineNecroe,dT issue 300 andF utuDrier ections 237 Ther<1pSe<u1tfoicfcAt dyi pose-DCeerlilvse d 301 SU lTarl my 241 Conclusions 302 References 242 References 302 x CONTENTS 20.P eriphBelroaolS dt emC ells LisotfA cronyamnsd A bbreviations 386 Acknowledgments 386 ABiUTEDEA HL.G RAC;:A ALMEIDA.PC)I(ADA. CHRISTOPHDE.RP ORADAS.H AY SOKER References 387 Introduction 307 24.M echaniDceatle rminoafnT tiss sue Typeasn dS ourcoefS temC ellisnt heP eripheral Development Blood 307 VOLHAL lADUANSKAYAD.I SHSAO OD. EndothePlrioagle nCieclolfs 311 DAVIDI .K.A PLNA Mesenchymal Stem/Marrow Stroma 3C1e5l ls TherapeuAtpipcl icatoifPo enrsi phBelroaolSd t em Introduction 391 Cells 317 MechanornlllsMcieucchrainoinsa mnsdM ajor ConclusainodnF su tuDrier ections 325 Effectors 392 References 326 Nucleausst heC enrrOarlg aneilnlR ee gulating MechflnOtransduction 396 21F.r omA dulPta ncreaItsilceto tSst em CelluMleacrh anotransdMueccthiaonni sms 397 CellRse:g eneraSttirvaet efgoirte hse Conclusions 400 TreatmeonfDt i abeatnedsI tCso mplicationsA cknowledgments 401 MARTA POKRYWCZYNSKAG.I ACOMO LANZONI. References 401 CAMILLOI UCORDI 25M.o rphogenBeosnieMs o,r phogenetic Introduction 335 ProteiannsdR, e generaotfiB oonn ea nd FromA dulPta ncreaItsilceto tSst emC ells 335 ArticuClaarrt ilage Strate(goitreh seG enemtioofn� Cell(so r ReplacemTehnetr apy 336 A.H.R EDDI. KENJIROI WASA J3C ellFsr om PluriSptoetmCe enltl( sE mbryonic Introduction 405 StemC ellasn dI nducPeldu ripotent Stem3 .3C6e lls) BoneM orphogenPertoitce ins 406 ICIe llFsr omA dulStt em/progeCneiltloosftr h e StemC ells 409 BiliTarreyae n dP ancreas 341 SC::IffoofEl xdtsr ttceMlml:urliaaxnr dB iomimcric MesenchySmtaelmC elltos M odul<Ilmtmeu niatnyd Biomaterials 409 PromoTties sRueep aiinrD iabetes 344 ArticuClaarrt ilRaeggee neraatnidCo anr tilage Conclusion 345 MorphogenPertoitce ins 412 References 346 RegeneraMteidviec iannedS urgeorfAy r ticular 22.St emC ellfsor D iseaosfet sh eR etina Cartilage 412 RegeneraotriA ornt icuClaarrt ilSaugref aacned AARON NAGILE.S TEVEND. S CHWARTZ Lubrication 413 LisotfA cronyamnsd A bbreviations 414 lmroducrion 351 Acknowledgments 414 Cell-ReplacTehmeernatp y 355 References 414 Cell-BaNseeudr oprotection 361 Disease�irMHold-eDliisfnhog Rr e tinDails orders 362 26.Ph ysiSctarle asssa FactionrT issue Conclusion 364 Growtahn dR emodeling References 365 JOELD .l JOERCKCEHLI.� ISTOIV'.GH EEMRM ITI. 23.S temC ellfso Tr raumatBirca iInn jury DEVONE .M ASON.Y ASHM .K OLAMBKAR. BLAISDE.P ORTERR.O BERET. G ULDBERG CHRISTOPHME.RS CHNEIDEMRA.R GARTE L.J ACKSON. SUPINDES.RB EDIC.H ARLES SC.O X.J R. Introduction 417 DescrtihbeeM echaniEcnavli ronment 418 Introduction 369 UndersttahneRd o loef M echanical PhasoefsB raiInn jury 370 Stimuli 423 CurreTnrta umatBirca iInn juMrayn agement MechaniRceaglu latoifVo ans cularTiizsesdu e Strategies 376 Regeneration 427 PreclinDiactaSalu pportSitnegmC elTlh erapfioers EvaluaFtuen ctioRneaslt oration 432 TraumatBirca iInn jury 376 Conclusions 432 Clinical Trials 381 References 433 Conclusion 385 CONTENTS xi 27.C ell-SubsItnrtaetrea ctions M�mufactliu trya bi 517 MUHAMMADR IZWAN,JOWH.NT SEA,P ARNA NORI, Summary 517 KAM W.L EONG,E VELYKN. FY.I M References 518 Introduction 437 31.P roteCionnst rolWlietdhP recisaito n Cell-ExtraMcaetlrlIiunxlt aerr actions 437 OrganiPco,l ymeraincdB, i opolymer Cell-SubIsnttreartaec tions 438 InterfacTeiss sfEuonerg ineearnidn g EffecotfD imensionality 451 RegeneraMteidviec ine Conclusion 460 DAVIDG. C ASTNER,B UDDYD .R ATNER Acknowledgments 461 Re(erences 461 Whyt heN eedf oPrr eciCsoinotnr oofPl r oteaitn s InterfianTc iesssE uneg ineearnidRn egg enerative 28.I ntelliSguerfnatfc oerCs e lSlh eet Medicine! 523 Engineering SurfAancae lyasnidIs t Rso lient hPer ecision HIRONOBTUA KAHASHTIA.T SUYAS HIMIZU, DelivoefBr iyo logSiicganla ls 524 TERUOOKANO A ShoRret vioefw KSeuyr fAancael yMseitsh o�dls1 1d SupporTtoionlgs 525 Introduction 469 TechniqaunedTs e chnolofogPrir eesc ision TheI ntelliogfTe hnecrem orespPoonlsyimvfeeor rs ImmobiliaztaS tuirofna ces 527 CelSlh eet Engineering 469 Conclusions 531 CliniAcpapll icaftoiCroe nlSslh eeEtn gineerin4g7 2 References 532 CelSlh eeEtn gineePrriondgu Scceasf fForlede·, Three-DimeTnisisosCnuoaenl s tructs 474 32.N aturOarli gMiant erifaolBrs o nTei ssue CombinaotfiC oenlS lh eeEtn gineearnidn g EngineerPirnogp:e rtPireosc,e ssainndg , ScaffBoalsdeE·dn gineering 477 Perofrmance MicrofabrIinctaetlelSdiu grefnaftco Eern gineering ComplTeixs sCuoen structs 478 F.R AQUELM AlAV,I TORM .C ORRELO, JOAQUIMM. O LIVEIRRAU,IL .R EIS Conclusions 481 References 482 Introduction 535 Naturasle�dPB oalymers 538 29.A pplicatoifNo annso technofloorg y Chitosan 538 RegeneraMteidviec iHneea;l iTnigs suaets Collagen 540 theN anoscale GelhGmu m 543 YAFENYG ANGA,D ITYCAH AW LA.J INZ HANG, Polyhydroxyalkanoates 545 ADAME SAH,A ELI JANGA.L IK HADEMHOSSEINI SilFki broin 547 Starch 548 introduction 485 Natural�BBiaosceedr amics 550 ProperotfNi aenso rnaterials 486 CalciPuhmo sphates 551 Nanobiomaterials 491 SilicCaetrea mics 553 N:111otechnology-iBnaR seegde nSetrfa<'tlitveeg ies Conclusions 554 Medicine 493 LisotfA cronymsA babnrde viations 555 NanotechnoloSgtye·CmBe alsTleh de rapy 497 Acknowledgments 555 Conclusion 499 References 555 References 499 33.S ynthePtoilcy mers 30.D esigPnr inciipnlB eiso materainadl s MICHAEcL. H ACKERJ,A NK RIEHGO FF, Scaffolds ANTONIOGS. M IKOS YANGZ HU,W ILLIARM.W AGNER Introduction 559 FunctioAnp palnidc ation�DOersiioegfnn t ed PolymSeyrn thesis 560 BiomateSrciaaflfo lds 505 NondegraSdyanbtlheeP toilcy mers 561 SafeatnydB iocompatRiebqiuliirteymf eonrt s BiodegraSdyanbtlheeP toilcy mfeorRrse generative BiomateSrciaaflf olds 513 Medicine 567 xii CONTENTS ApplicatoifSo ynnst hePtoilcy mers 580 BiologMiocdailf icaotfSi uornf aces 656 Conlcu soin/Smu mar y 580 SurfaCchee micPaalt terning 6j9 References 581 ConclusainodFn u tuPrreo spects 659 References 659 34.Ca lciuPmh osphaBtieo ceramics and Cements 38.Hi srogenienTs hirse e-Dimensional NATHAN W.K UCKO.R ALF·PETHEERR BER, Scaffolds SANDERC G. LEEUWENIJURGJHO,H NA .J ANSEN MELISSKA .M CHALE, NICOML.EB ERGMANN. jENNIFELI.W� E ST Introduction j91 ClsaseosfC alciPlhiolsnp hCaetmee nts 594 TheN eedf orR eplacemTeinsts ues 661 PhysiochePmriocpaelr ties 595 TissCuoem ponents 661 Stragtieetos ImprotvheeM echaniPcraolp erties 60I RegeneraotfDi iosne ased Tissues 662 CliniAcpapll icmions 606 DesigPna rameterHsi stfoogre nesis 663 Conclusion 607 SyntheMtaitce rifaolHrsi stogenoefs ciwsO rgans 669 LisotfA cronyamnsd A bbreviations 608 Future DirienTc htrieoens, DimenSsciaofnfaoll ds: Glsosary 608 Three,DimenMsiicornoafla brication 670 References 608 Concsliuons 670 Reefrences 671 35B.i oloSgciacff olCdosm poseodf ExtracelMlautlraifroxr R egenerative 39.Bi ocompariabnidl iBriyo restpoo nsc Medicine Biomarerials MICHELLSEC ARRITTM,A RK MURDOCK, JAMESM .A NDERSON STEPHENF .l lADYLAK Introduction 675 Introdounc ti 613 Inflamma(tIinonnaI tmem uniatnyd)W oundH c,;llin6g7 6 ExtralcleulMaatrr iFxu:n ctiaonndC omponents 613 FibroasnidFs i broEunsc apsulation 683 IntaacntdS olubziedlE ixtcreallruM laatraisx(l Immunotoxi(cAictqyu iIrmemdu nity) 684 ScaoflfdM aterial 619 Conculsion 691 CliniacnadCl o mmercAipapll ications 622 References 691 Conclusions 622 FurthReera ding 694 LisotfA cronyamnsd A bbreviations 622 Glsosary 623 40.H ybriCdo mposiBrieo materials References 623 NIRMALYAT RII'ATHEYL,U MALAIP ERUMAL, RAFIQA HMAD.J EONGE UN SONG,G ILSONK HANG 36.H ydrogienlR se generaMteidviec ine Introduction 695 DAVIDF .W ltLIAMS FundamenotfBa olnse D evelopmaenndDt e fetcs 696 Introduction 627 FunctioofSn csa oflfdianngdE xtcreallruM laatrix 696 BiomateTreimapllsa tes 628 ScaoflfdiAnpgp roacihneB so neTi ssEuneg ineerin69g7 Strurcet-uPropReertlyao tnisihpisn H ydrogels 631 ScaoflfdiMnOI:ge rials 699 IncreaSsoipnhgi sticoafSt yinotnh eHtyidcr ogfeolrs Conclounssai ndF utuPrreo spects 710 TissEuneg ineering 632 Acknwoledgments 710 NaturBailo polyamseE rxst ralcleuMlaatrr ix-Analog Reefrensc e 710 Hydrolgse 639 4\ .M aterialsC-aBnacseerd SyntheHtyidcr ogfeolTrs i ssEuneg ineering Templast e 646 Immunotherapies Conclusions 648 JAREDM . NEWTON. ANDREGW. S IKORA, References 649 SIMONY OUNG 37S.u rfaMcoed ificaotfBi ioonm aterials IntroducatnidOo vne rvioefwC ancer I1l"unuenroatphy 715 RACHITA GARWAL,A NDREsj .G ARCiA Advatnageasn dD isadvanotfaC gaensc er Introduction 651 Immuntoherapy 717 PhysicocheSmuircfaaMlco ed ifications 653 NanopartBiicolmea tcrfoiCr; ":ldnsc cr OvercoatTiencgh noglioes 655 Immnuothepry a 718

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