Evidenced Based Use of Biologics

with the Shoulder

ChristopherDoumas,MD

ClinicalAssistantProfessorOrthopaedicSurgery

Rutgers:RWJMedicalSchool

ChiefofHandSurgeryJerseyShoreUniversityMedical

Center

Discolsure –  Ihavenorelevantdisclosurestodiscuss.

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Questions???

•  Whatdobiologicsoffertoshouldersurgery?

•  IsthereanyevidencethatbiologicsmakeshouldersurgerybeIer?

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Why Biologics? •  Rotatorcuffre-tearrates=22-94%!

•  Timing•  LocaSon•  Size•  Age•  Chronicity

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BrianJ.ColeMD,MBA,L.PearceMcCartyMD,RichardW.KangMD,MS,WinslowAlfordMD,PaulB.LewisMD,MSandJenniferK.HaydenMSN,RN.JournalofShoulderandElbowSurgery,2007-09-01,Volume16,Issue5,Pages579-585

Early Failed Repair = Poor Construct

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Late Failed Repair = Poor Biology

Chronic Rotator Cuff tears

•  Typicallyretract•  Maybelarge•  Reliablyprogresswithatrophytothemusclebelly

•  Doesitreallyma-eriftheRTCheals?

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Patients prefer a strong shoulder

StructuralIntegrityAaerRotatorCuffRepairDoesNotCorrelatewithPaSentFuncSonandPain:AMeta-Analysis.Russell,RobertDMD;Knight,JusSnRMD;Mulligan,EdwardDPT;Khazzam,MichaelSMD.JournalofBone&JointSurgery-AmericanVolume.96(4):265-271,February2014.

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14studieswith861paSentsMeta-analysis

78.3%Healedand21.7%Re-tearHealedpa(entshadgreaterstrengthandsa(sfac(on

Can we improve the tendon bone interface?

•  PatchespromotematerialproperSes

•  GrowthfactorspromotestructuralproperSes

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Patches

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SyntheScs

Xenograas

Allograas

Preclinical For Patches Rotatorcuffrepairusinganacellulardermalmatrixgraa:aninvivostudyinacaninemodel.AdamsJE1,ZobitzME,ReachJSJr,AnKN,SteinmannSP.Arthroscopy.2006Jul;22(7):700-9.

RotatorCuffRepairUsinganAcellularDermalMatrixGraa:AnInVivoStudyinaCanineModel.JulieE.Adams,M.D.a,MarkE.Zobitz,M.S.b,JohnS.ReachJr,M.D.a,Kai-NanAn,Ph.D.b,ScoIP.Steinmann,M.D.Arthroscopy.Volume22,Issue7,July2006,Pages700–709

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BiomechanicalanalysisofgapformaSonandfailuremechanicsofaxenograa-reinforcedrotatorcuffrepairinacadavericmodel.KevinP.SheaMD,ElimoObopilweMS,JohnW.SperlingMD,MBAandJosephP.IannonMD,PhD.JournalofShoulderandElbowSurgery,2012-08-01,Volume21,Issue8,Pages1072-1079

ReconstrucSonoflargerotator-cufftearswithacellulardermalmatrixgraasinrats.JunjiIdeMD,KenshiKikukawaMD,JunHiroseMD,Ken-ichiIyamaMD,HidetoshiSakamotoDrEngandHiroshiMizutaMD.JournalofShoulderandElbowSurgery,2009-03-01,Volume18,Issue2,Pages288-295

Patch Augmentation Indications

•  Young•  Failuresoratriskforfailure•  Massivetears•  Chronicchanges•  Salvagecases

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Relative Contraindications

•  Rotatorcuffarthropathy•  Pseudoparalysis•  Irreparabletears•  UnrealisScexpectaSons

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Patch Interposition Outcomes Level of Evidence 4

Long-termsuccessfularthroscopicrepairoflargeandmassiverotatorcufftearswithafunc(onalanddegradablereinforcementdevice.ChristopherS.ProctorMDJournalofShoulderandElbowSurgery,2014-10-01,Volume23,Issue10,Pages1508-1513

•  Thepoly-l-lacScacidbioabsorbablepatchdesignedspecificallytoreinforcethesurgicalrepairoftendonssupportedsuccessfulrepairoflargetomassiverotatorcufftearsin83%ofpa(entsat12monthsaOersurgeryand78%ofpa(entsat42monthsaOersurgery,withsubstanSalfuncSonalimprovement.

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Patch Interposition Outcomes Level of Evidence 4

Long-termsuccessfularthroscopicrepairoflargeandmassiverotatorcufftearswithafunc(onalanddegradablereinforcementdevice.ChristopherS.ProctorMDJournalofShoulderandElbowSurgery,2014-10-01,Volume23,Issue10,Pages1508-1513

•  Thepoly-l-lacScacidbioabsorbablepatchdesignedspecificallytoreinforcethesurgicalrepairoftendonssupportedsuccessfulrepairoflargetomassiverotatorcufftearsin83%ofpa(entsat12monthsaOersurgeryand78%ofpa(entsat42monthsaOersurgery,withsubstanSalfuncSonalimprovement.

Rotatorcuffrepairaugmenta(onusinganovelpolycarbonatepolyurethanepatch:preliminaryresultsat12months'follow-up.IvanEncalada-DiazMD,BrianJ.ColeMD,MBA,JohnD.MacGillivrayMD,MichellRuiz-SuarezMD,MS,JamesS.KercherMD,NicoleA.FrielMSandFernandoValero-GonzalezMDJournalofShoulderandElbowSurgery,2011-07-01,Volume20,Issue5,Pages788-794

•  ThepolycarbonatepolyurethanepatchwasdesignedtosupportSssueingrowthandenhancehealingasshownbypreclinicalanimalstudies.Clinically,thepatchiswelltoleratedandshowspromisingefficacy,witha10%retearrateatthe12-month(mepoint.

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Patch Extension Outcomes Level of Evidence 4

Aprospec(ve,mul(centerstudytoevaluateclinicalandradiographicoutcomesinprimaryrotatorcuffrepairreinforcedwithaxenograOdermalmatrix.EvanS.LedermanMD,AlisonP.TothMD,GregoryP.NicholsonMD,RobertJ.NowinskiDO,GeorgeK.BalMD,GeraldR.WilliamsMDandJosephP.IannobMD,PhD.JShoulderElbowSurg.2016Apr26Epubaheadofprint

•  RepairoflargerotatorcufftearsstructurallyreinforcedwithxenograOECMresultedinimprovedfunc(onaloutcomesscoresandstrength.Adverseeventswereuncommon,andtherateofrevisionsurgerywaslow.

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Patch Extension Outcomes Level of Evidence 4

Aprospec(ve,mul(centerstudytoevaluateclinicalandradiographicoutcomesinprimaryrotatorcuffrepairreinforcedwithaxenograOdermalmatrix.EvanS.LedermanMD,AlisonP.TothMD,GregoryP.NicholsonMD,RobertJ.NowinskiDO,GeorgeK.BalMD,GeraldR.WilliamsMDandJosephP.IannobMD,PhD.JShoulderElbowSurg.2016Apr26Epubaheadofprint

•  RepairoflargerotatorcufftearsstructurallyreinforcedwithxenograOECMresultedinimprovedfunc(onaloutcomesscoresandstrength.Adverseeventswereuncommon,andtherateofrevisionsurgerywaslow.

Dermal(ssueallograOfortherepairofmassiveirreparablerotatorcufftears.AnilK.Gupta,KevinHug,DavidJ.Berkoff,BlakeR.Boggess,MollyGavigan,PaulC.MalleyandAlisonP.TothAmJSportsMed.2012Jan;40(1):141-7

•  Inourseriesofcarefullyselectedcandidates,allpa(entsdemonstratedasignificantimprovementinpain,rangeofmo(on,andstrength.SubjecSveoutcomemeasures,includingmeanASESandSF-12scores,alsodemonstratedsignificantimprovementatanaverage3-yearfollow-up.

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Patch Extension Outcomes Level of Evidence 3

•  ThebenefitofsyntheScversusbiologicalpatchaugmentaSonintherepairofposterosuperiormassiverotatorcufftears:a3-yearfollow-upstudy.

PietroCiampi,CelesteScon,AlessandroNonis,MaIeoVitali,CleliaDiSerio,GiuseppeM.PerenandGianfrancoFraschini.AmJSportsMed.2014May;42(5):1169-75

•  CONCLUSION:•  Polypropylenepatchaugmenta(onofrotatorcuffrepairwas

demonstratedtosignificantlyimprovethe36-monthoutcomeintermsoffunc(on,strength,andretearrate.

•  Re-tearRates:Control41% CollagenPatch51% Polypropelyne17%

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Growth Factors

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PRPincludesmanygrowthfactorsidenSfiedascrucialinnormalbone-to-tendonhealing:TGF-β,bFGF,PDGF,vascularendothelialgrowthfactor,connecSveSssuegrowthfactor,andepidermalgrowthfactor.HighPlateletConcentraSon

butalsolowWBCconcentra(onimportant

Growth Factors Tenocytesofchronicrotatorcufftendontearscanbes(mulatedbyplatelet-releasedgrowthfactors.HoppeS,AliniM,BennekerLM,MilzS,BoileauP,ZumsteinMA.JShoulderElbowSurg.2013Mar;22(3):340-9

•  CLINICALRELEVANCE:•  Biologicaugmenta(onof

repairedrotatorcuffswithPRGFmayenhancetheproper(esoftherepair(ssue.However,furtherstudiesareneededtodetermineifapplicaSonofPRGFremainssafeandeffecSveinlong-termclinicalstudies.

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TGF-B2minutesBMP-2<16minutesPDGFA-Chain2.4hoursFGF-2<14hours

GrowthFactorHalfLife

Where does the GF go?

•  Ontopofthetendon–  LiquidPRP

•  GFgonein7-12hours

•  Betweentendonandbone–  Fibrinconstruct

•  GFreleasedoverapprox.7days

•  Nexttothetendon–  CrimsonDuvet

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PRPFM (PRP with fibrin matrix)

Theeffectofplatelet-richfibrinmatrixonrotatorcufftendonhealing:aprospec(ve,randomizedclinicalstudy.RodeoSA,DelosD,WilliamsRJ,AdlerRS,PearleA,WarrenRF.AmJSportsMed.2012Jun;40(6):1234-41

•  LevelofEvidence2

•  Platelet-richfibrinmatrixappliedtothetendon-boneinterfaceattheSmeofrotatorcuffrepairhadnodemonstrableeffectontendonhealing,tendonvascularity,manualmusclestrength,orclinicalra(ngscales.Infact,theregressionanalysissuggeststhatPRFMmayhaveanega(veeffectonhealing.FurtherstudyisrequiredtoevaluatetheroleofPRFMinrotatorcuffrepair.

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PRPFM (PRP with fibrin matrix)

Theeffectofplatelet-richfibrinmatrixonrotatorcufftendonhealing:aprospec(ve,randomizedclinicalstudy.RodeoSA,DelosD,WilliamsRJ,AdlerRS,PearleA,WarrenRF.AmJSportsMed.2012Jun;40(6):1234-41

•  LevelofEvidence2

•  Platelet-richfibrinmatrixappliedtothetendon-boneinterfaceattheSmeofrotatorcuffrepairhadnodemonstrableeffectontendonhealing,tendonvascularity,manualmusclestrength,orclinicalra(ngscales.Infact,theregressionanalysissuggeststhatPRFMmayhaveanega(veeffectonhealing.FurtherstudyisrequiredtoevaluatetheroleofPRFMinrotatorcuffrepair.

Platelet-richplasmaaugmenta(onforarthroscopicrotatorcuffrepair:arandomizedcontrolledtrial.CastriciniR,LongoUG,DeBenedejoM,PanfoliN,PiraniP,ZiniR,MaffulliN,DenaroV.AmJSportsMed.2011Feb;39(2):258-65

•  LevelofEvidence1

•  OurstudydoesnotsupporttheuseofautologousPRFMforaugmenta(onofadouble-rowrepairofasmallormediumrotatorcuffteartoimprovethehealingoftherotatorcuff.Ourresultsareapplicabletosmallandmediumrotatorcufftears;itispossiblethatPRFMmaybebeneficialforlargeandmassiverotatorcufftears.Also,giventheheterogeneityofPRFMpreparaSonproductsavailableonthemarket,itispossiblethatotherprepara(onsmaybemoreeffec(ve.

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Review of GFs

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•  RESULTS:•  Regularbone-to-tendonhealingformsafibrousjuncSonbetween

tendonandbonethatisdisSnctfromtheoriginalbone-to-tendonjuncSon.TendonaugmentaSonwithcellularcomponentsservesasscaffoldingforfibroblasSccellsandapossiblesourceofgrowthfactorsandfibroblasSccells.ExtracellularmatricesprovideascaffoldforincomingfibroblasSccells,althoughcurrentresearchdoesnotconclusivelyconfirmwhichifanyofthesescaffoldsenhancerepairowinginparttointer-manufacturervaria(onsandthelimitedhumanresearch.Growthfactorsandplatelet-rich-plasmaareestablishedinotherfieldsofresearchandmayenhancerepairbuthavenotbeenrigorouslytested.

•  CONCLUSIONS:•  ThereispotenSalapplicaSonofbiologic

augmentaSontoimprovehealingaaerrotatorcuffrepair.However,researchinthisfieldiss(llinconclusiveandhasnotbeensufficientlydemonstratedtomeritregularclinicaluse.FuturehumantrialscanelucidatetheuseofbiologicaugmentaSoninrotatorcuffrepairs.

Strategiesinbiologicaugmenta(onofrotatorcuffrepair:areview.CheungEV,SilverioL,SperlingJW.ClinOrthopRelatRes.2010Jun;468(6):1476-84

Liquid vs. Solid PRP

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Crimson Duvet

Mul(plechannelingimprovesthestructuralintegrityofrotatorcuffrepair.JoCH,ShinJS,ParkIW,KimH,LeeSY.AmJSportsMed.2013Nov;41(11):2650-7.

•  CONCLUSION:•  Thefindingsofthestudyshowedthat

mul(plechannelingsignificantlydecreasedthere-tearrateaOerarthroscopicrotatorcuffrepair,probablyviatherecruitmentofendogenousMSCsfromtheproximalhumerus.Althoughtheresultsdidnotshowsignificantdifferencesintheclinicaloutcomesbetweenthe2groups,bejerclinicaloutcomesmightbean(cipatedinthemulSplechannelinggroupviaimprovedstructuralintegrityinalong-termfollow-up.

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Crimson Duvet

Mul(plechannelingimprovesthestructuralintegrityofrotatorcuffrepair.JoCH,ShinJS,ParkIW,KimH,LeeSY.AmJSportsMed.2013Nov;41(11):2650-7.

•  CONCLUSION:•  Thefindingsofthestudyshowedthat

mul(plechannelingsignificantlydecreasedthere-tearrateaOerarthroscopicrotatorcuffrepair,probablyviatherecruitmentofendogenousMSCsfromtheproximalhumerus.Althoughtheresultsdidnotshowsignificantdifferencesintheclinicaloutcomesbetweenthe2groups,bejerclinicaloutcomesmightbean(cipatedinthemulSplechannelinggroupviaimprovedstructuralintegrityinalong-termfollow-up.

Bonemarrows(mula(onatthefootprintofarthroscopicsurface-holdingrepairadvancescuffrepairintegrity.TaniguchiN,SuenagaN,OizumiN,MiyoshiN,YamaguchiH,InoueK,ChosaE.JShoulderElbowSurg.2015Jun;24(6):860-6.

•  CONCLUSIONS:•  Thesefindingsdemonstrate

thatapplyingBMStothefootprintduringASHrepairresultsinimprovedcuffrepairintegrity,par(cularlyinlarge-massivetears,andsuggesttheimportanceofbiologictreatmentforrotatorcuffhealingaaerarthroscopicrotatorcuffrepair.

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Outcomes of Combined Bone Marrow Stimulation and Patch Augmentation for Massive Rotator Cuff Tears.

YoonJP,ChungSW,KimJY,LeeBJ,KimHS,KimJE,ChoJH.AmJSportsMed.2016Apr;44(4):963-71.

•  LevelofEvidence3 •  CONCLUSION:•  Concomitantbonemarrow

s(mula(onandpatchaugmenta(onsignificantlyreducedre-tearandmedial-rowfailureratesinthearthroscopicrepairofmassiverotatorcufftears.

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Role of Acromioplasty ReleaseofgrowthfactorsaOerarthroscopicacromioplasty.RandelliP,Margheri(niF,CabitzaP,DogliobG,CorsiMM.KneeSurgSportsTraumatolArthrosc.2009Jan;17(1):98-101.

•  ConcentraSonshigherofTGF-beta1,PDGF-AB,andbFGF.

•  Therearehighconcentra(onsofseveralgrowthfactorsinthesubacromialspaceaOeracromioplasty.

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Stem Cells Effectoftheadipose-derivedstemcellfortheimprovementoffajydegenera(onandrotatorcuffhealinginrabbitmodel.OhJH,ChungSW,KimSH,ChungJY,KimJY.JShoulderElbowSurg.2014Apr;23(4):445-55

•  RESULTS:

•  ThedegreeoffatstainingincreasedfromtheADSC+repairgroup(unclearorweak)tothesaline-onlygroup(stronglypresent).

•  CONCLUSION:

•  Localadministra(onofADSCsmighthavethepossibilitytoimprovemusclefunc(onandtendonhealinganddecreasefajyinfiltra(onaOercuffrepair.

Adiposederivedstemcells

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Take Home Messages

•  Preclinicaltrialsdonotalwaystranslatetogoodresults.

•  PatcheshavebeengainingtracSonbuttechniques,costandreimbursementareproblems.Synthe'candpermanent…thefuture?

•  LiquidPRPmaybeeffecSvebutsolidPRPappearstogivebeIerhealing.

•  MarrowSSmulaSontechniquesarelowcostandcanbeeffecSve

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Take Home Messages

•  BonemarrowaspiratesshowveryliIleevidenceatthispoint.

•  StemCells???•  Minimalevidencepresentasfarasdosage,Smingandfrequency.

•  Mostclinicaltrialsforgrowthfactorscost30-50milliondollars,sotheseareverydifficultproductstodevelopforthehopethatitworks!

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Thank You!

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References •  1.BrianJ.ColeMD,MBA,L.PearceMcCartyMD,RichardW.KangMD,MS,WinslowAlfordMD,PaulB.LewisMD,MSandJenniferK.HaydenMSN,RN.JournalofShoulderandElbowSurgery,

2007-09-01,Volume16,Issue5,Pages579-585•  2.GalatzL.M.,BallC.M.,TeefeyS.A.,MiddletonW.D.,andYamaguchiK.Theoutcomeandrepairintegrityofcompletelyarthroscopicallyrepairedlargeandmassiverotatorcufftears.JBoneJoint

SurgAm2004;86:pp.219-224•  3.StructuralIntegrityAaerRotatorCuffRepairDoesNotCorrelatewithPaSentFuncSonandPain:AMeta-Analysis.Russell,RobertDMD;Knight,JusSnRMD;Mulligan,EdwardDPT;Khazzam,

MichaelSMD.JournalofBone&JointSurgery-AmericanVolume.96(4):265-271,February2014.•  4.BiomechanicalanalysisofgapformaSonandfailuremechanicsofaxenograa-reinforcedrotatorcuffrepairinacadavericmodel.KevinP.SheaMD,ElimoObopilweMS,JohnW.SperlingMD,MBA

andJosephP.IannonMD,PhD.JournalofShoulderandElbowSurgery,2012-08-01,Volume21,Issue8,Pages1072-1079•  5.ReconstrucSonoflargerotator-cufftearswithacellulardermalmatrixgraasinrats.JunjiIdeMD,KenshiKikukawaMD,JunHiroseMD,Ken-ichiIyamaMD,HidetoshiSakamotoDrEngandHiroshi

MizutaMD.JournalofShoulderandElbowSurgery,2009-03-01,Volume18,Issue2,Pages288-295•  6.Rotatorcuffrepairusinganacellulardermalmatrixgraa:aninvivostudyinacaninemodel.AdamsJE1,ZobitzME,ReachJSJr,AnKN,SteinmannSP.Arthroscopy.2006Jul;22(7):700-9.•  7.RotatorCuffRepairUsinganAcellularDermalMatrixGraa:AnInVivoStudyinaCanineModel.JulieE.Adams,M.D.a,MarkE.Zobitz,M.S.b,JohnS.ReachJr,M.D.a,Kai-NanAn,Ph.D.b,ScoIP.

Steinmann,M.D.Arthroscopy.Volume22,Issue7,July2006,Pages700–709•  8.Long-termsuccessfularthroscopicrepairoflargeandmassiverotatorcufftearswithafuncSonalanddegradablereinforcementdevice.ChristopherS.ProctorMD.JournalofShoulderandElbow

Surgery,2014-10-01,Volume23,Issue10,Pages1508-15139.•  9.RotatorcuffrepairaugmentaSonusinganovelpolycarbonatepolyurethanepatch:preliminaryresultsat12months'follow-up.IvanEncalada-DiazMD,BrianJ.ColeMD,MBA,JohnD.MacGillivray

MD,MichellRuiz-SuarezMD,MS,JamesS.KercherMD,NicoleA.FrielMSandFernandoValero-GonzalezMD.JournalofShoulderandElbowSurgery,2011-07-01,Volume20,Issue5,Pages788-794•  10.AprospecSve,mulScenterstudytoevaluateclinicalandradiographicoutcomesinprimaryrotatorcuffrepairreinforcedwithaxenograadermalmatrix.EvanS.LedermanMD,AlisonP.TothMD,

GregoryP.NicholsonMD,RobertJ.NowinskiDO,GeorgeK.BalMD,GeraldR.WilliamsMDandJosephP.IannonMD,PhD.JShoulderElbowSurg.2016Apr26Epubaheadofprint•  11.DermalSssueallograafortherepairofmassiveirreparablerotatorcufftears.AnilK.Gupta,KevinHug,DavidJ.Berkoff,BlakeR.Boggess,MollyGavigan,PaulC.MalleyandAlisonP.TothAmJ

SportsMed.2012Jan;40(1):141-7•  12.ThebenefitofsyntheScversusbiologicalpatchaugmentaSonintherepairofposterosuperiormassiverotatorcufftears:a3-yearfollow-upstudy.PietroCiampi,CelesteScon,AlessandroNonis,

MaIeoVitali,CleliaDiSerio,GiuseppeM.PerenandGianfrancoFraschini.AmJSportsMed.2014May;42(5):1169-75•  13.TenocytesofchronicrotatorcufftendontearscanbesSmulatedbyplatelet-releasedgrowthfactors.HoppeS,AliniM,BennekerLM,MilzS,BoileauP,ZumsteinMA.JShoulderElbowSurg.2013

Mar;22(3):340-9•  14.StrategiesinbiologicaugmentaSonofrotatorcuffrepair:areview.CheungEV,SilverioL,SperlingJW.ClinOrthopRelatRes.2010Jun;468(6):1476-84•  15.Theeffectofplatelet-richfibrinmatrixonrotatorcufftendonhealing:aprospecSve,randomizedclinicalstudy.RodeoSA,DelosD,WilliamsRJ,AdlerRS,PearleA,WarrenRF.AmJSportsMed.

2012Jun;40(6):1234-41•  16.Platelet-richplasmaaugmentaSonforarthroscopicrotatorcuffrepair:arandomizedcontrolledtrial.CastriciniR,LongoUG,DeBenedeIoM,PanfoliN,PiraniP,ZiniR,MaffulliN,DenaroV.AmJ

SportsMed.2011Feb;39(2):258-65•  17.MulSplechannelingimprovesthestructuralintegrityofrotatorcuffrepair.JoCH,ShinJS,ParkIW,KimH,LeeSY.AmJSportsMed.2013Nov;41(11):2650-7.•  18.BonemarrowsSmulaSonatthefootprintofarthroscopicsurface-holdingrepairadvancescuffrepairintegrity.TaniguchiN,SuenagaN,OizumiN,MiyoshiN,YamaguchiH,InoueK,ChosaE.J

ShoulderElbowSurg.2015Jun;24(6):860-6.•  19.OutcomesofCombinedBoneMarrowSSmulaSonandPatchAugmentaSonforMassiveRotatorCuffTears.YoonJP,ChungSW,KimJY,LeeBJ,KimHS,KimJE,ChoJH.AmJSportsMed.2016Apr;

44(4):963-71.•  20.Releaseofgrowthfactorsaaerarthroscopicacromioplasty.RandelliP,MargheriSniF,CabitzaP,DoglionG,CorsiMM.KneeSurgSportsTraumatolArthrosc.2009Jan;17(1):98-101.•  21.Effectoftheadipose-derivedstemcellfortheimprovementoffaIydegeneraSonandrotatorcuffhealinginrabbitmodel.OhJH,ChungSW,KimSH,ChungJY,KimJY.JShoulderElbowSurg.

2014Apr;23(4):445-55

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