periodontalww.4399.com

Bonesubstitutesinorthopaedicsurgery:frombasicsciencetoclinicalpracticeV.
CampanaG.
MilanoE.
PaganoM.
BarbaC.
CicioneG.
SalonnaW.
LattanziG.
LogroscinoReceived:19December2013/Accepted:9May2014/Publishedonline:28May2014TheAuthor(s)2014.
ThisarticleispublishedwithopenaccessatSpringerlink.
comAbstractBonesubstitutesarebeingincreasinglyusedinsurgeryasovertwomillionsbonegraftingproceduresareperformedworldwideperyear.
Autograftsstillrepresentthegoldstandardforbonesubstitution,thoughthemorbidityandtheinherentlimitedavailabilityarethemainlimitations.
Allografts,i.
e.
bankedbone,areosteoconductiveandweaklyosteoinductive,thoughtherearestillconcernsabouttheresidualinfectiverisks,costsanddonoravailabilityissues.
Asanalternative,xenograftsubstitutesarecheap,buttheiruseprovidedcontrastingresults,sofar.
Ceramic-basedsyntheticbonesubstitutesarealternativelybasedonhydroxyapatite(HA)andtricalciumphosphates,andarewidelyusedintheclinicalpractice.
Indeed,despitebeingcompletelyresorbableandweakerthancorticalbone,theyhaveexhaustivelyprovedtobeeffective.
BiomimeticHAsaretheevolutionoftraditionalHAandcontainsions(car-bonates,Si,Sr,Fl,Mg)thatmimicnaturalHA(biomimeticHA).
Injectablecementsrepresentanotherevolution,enablingmininvasivetechniques.
Bonemorphogeneticproteins(namelyBMP2and7)aretheonlyboneinducinggrowthfactorsapprovedforhumanuseinspinesurgeryandforthetreatmentoftibialnonunion.
Demineralizedbonematrixandplateletrichplasmadidnotprovetobeeffectiveandtheiruseasbonesubstitutesremainscontroversial.
Experimentalcell-basedapproachesareconsideredthebestsuitableemergingstrategiesinseveralregenerativemedi-cineapplication,includingboneregeneration.
Insomecases,cellshavebeenusedasbioactivevehiclesdeliveringosteo-inductivegeneslocallytoachieveboneregeneration.
Inparticular,mesenchymalstemcellshavebeenwidelyexploitedforthispurpose,beingmultipotentcellscapableofefcientosteogenicpotential.
Hereweintendtoreviewandupdatethealternativeavailabletechniquesusedforbonefusion,alongwithsomehintsontheadvancementsachievedthroughtheexperimentalresearchinthiseld.
1IntroductionBonesubstitutesarebeingincreasinglyusedespeciallyinoncologicsurgery,traumatology,revisionprostheticsur-geryandspinesurgery[1].
Bonegraftingfrequencyisindeedthesecondmostfrequenttissuetransplantationworldwide,comingrightafterbloodtransfusion.
Overtwomillionsbonegraftingproceduresareperformedeveryyear,withmorethan500,000implantedintheUSalone[2–5].
Thisisduetotheireaseuseandhandling,improvedsafetyproles,intraoperativecostandtimeadvantages,andadaptabilitytoavarietyofclinicalchallenges.
Theincorporationofabonegraftisdenedasthe''pro-cessofenvelopmentandinterdigitationofthedonorbonetissuewithnewbonedepositedbytherecipient''[6].
Thisprocessfollowsatypicalmultistepcascade:initially,thebonegraftproducesaresponseleadingtotheaccumulationofinammatorycells,followedbythechemotaxisofhostmesenchymalcellstothegraftsite.
Thereafter,theprimitiveW.
LattanziandG.
Logroscinoshareseniorauthorship.
V.
CampanaG.
MilanoE.
PaganoG.
SalonnaG.
Logroscino(&)DepartmentofOrthopaedicsandTraumatology,Universita`CattolicadelSacroCuore,L.
goF.
Vito1,00168Rome,Italye-mail:g.
logroscino@fastwebnet.
itM.
BarbaC.
CicioneW.
LattanziInstituteofAnatomyandCellBiology,Universita`CattolicadelSacroCuore,Rome,ItalyW.
LattanziLatiumMusculoskeletalTissueBank,Rome,Italy123JMaterSci:MaterMed(2014)25:2445–2461DOI10.
1007/s10856-014-5240-2hostcellsdifferentiateintochondroblastsandosteoblasts,aprocessundertheinuenceofvariousosteoinductivefactors.
Theadditionalprocessesofbonegraftrevascularizationandnecroticgraftresorptionoccurconcurrently.
Finally,boneproductionfromtheosteoblastsontothegraft'sthree-dimensionalframeworkoccurs,followedbyboneremodel-inginresponsetomechanicalstress[7,8].
Abonesubstitutecanbedenedas''asynthetic,inorganicorbiologicallyorganiccombinationwhichcanbeinsertedforthetreatmentofabonedefectinsteadofautogenousorallogenousbone''[9].
Awidevarietyofbonesubstituteshavebeenemployedoverthepast50years.
Bonesubstitutescanbebroadlycategorizedintobonegrafts(autograft,allograft,xenograft),ceramics(hydroxyapatite,TCP,cal-ciumsulphate)andgrowthfactors(DBM,PRP,BMP'S)[10].
Theidealbonesubstituteshouldbebiocompatibleandnotevokeanyadverseinammatoryresponse.
Itshouldbeeasilymoldedintothebonedefectwithinashortsettingtime.
Itshouldbeosteoconductive,osteoinductive[11]andre-sorbable.
Itshouldbepossiblytraceableinvivo;tothisaimradiolucencyisidealtoallowoptimalradiographicassess-ment.
Also,theidealbonesubstituteshouldbethermallynonconductive,sterilizable,andreadilyavailableatarea-sonablecost[12].
Althoughautologousbonegraftingisstillconsideredthe''goldstandard''inbonydefectrepair,thepastcenturyhasseensignicantadvancesinthedevelopmentofvalidalternativestonaturalbone.
Thelatterhalfofthetwentiethcenturyhasseentheevolutionofthehydroxyapatiteandcalciumphosphate-basedcementsandceramics.
Currentadvancesarebeingmadewiththedevelopmentoftissue-engineeredproducts,incorporatinggrowthfactorsandstemcells.
Dependingonthetypeofsurgeryandontheboneloss,manyoptionsarepossible.
Corticalstrutgraftsareusedweremechanicstrengthisneeded.
Spongybone,oftenmorcelized,ismoreusefulltollcavitarybonedefectsorinspinefusion.
Ceramicsundergranule,blocks,ormold-ablepasteshapearenormallyusedtoenhanceboneheal,buthavepoormechanicalqualitiesandstablehardwarexationisnecessary.
Growthfactorsareonthemarketasmoldablepaste.
BMPsarecurrentlyindicatedonlyintibialnonunion(BMP-7)andspinesurgery(BMP-2).
Inthisreportwewillreviewsomeofthemostimportantbiomaterialsineachofthesecategories.
2Bonegrafts2.
1AutograftsCurrentlyautograftsarethe''goldstandard''inbonesub-stitution[13,14].
Autologous(orautogenous)bonegraftinginvolvesutilizingboneobtainedfromthesameindividualreceivingthegraft[15].
Bonecanbeharvestedfromnon-essentialbones,suchastheiliaccrestorthebula(Fig.
1),thechin,theribs,themandibleandevenpartsoftheskull.
Autogenousbonepossessesallthepropertiesessentialforboneformation:itisosteoconduc-tiveandosteoinductive,andithousesgrowthfactorsandosteogeniccellswithnoassociatedimmuneorinfective-relatedrisks.
Autologousbonefractsareslowlyreplacedbynewlyformedhostbone.
Thedisadvantagesofauto-graftsresideintheinherentmorbidity:(1)asurgicaldonorsiteisrequired,leadingtopossiblepost-operativepainandcomplications.
[16,17];(2)alikelihoodofbloodlossorhematomas,infection,fracture,neurovascularinjury,aswellascosmeticdeformity,attheexplantationsiteandlongeroperativetime.
Also,autogenousboneavailabilityinapatientrepre-sentsasignicantlimit,especiallyinpediatricpatientsandintheelderly.
Anautograftmayalsobeperformedwithoutasolidbonystructure,forexampleusingbonereamedfromtheanteriorsuperioriliacspine.
Inthiscasethereisanosteoinductiveandosteogenicaction,howeverthereisnomechanicalsupportaction,asthereisnosolidbonystructure[18].
2.
2AllograftsAllograftbiobankedbonerepresentsasuitablealternativetoautogenousbone,beingderivedfromhumansaswell.
Allograftbonecanbecollectedfromeitherlivingdonors(patientstotalhipreplacementsurgery)ornonlivingdonorsandmustbeprocessedwithinabonetissuebank(Fig.
2).
BoneTissueBanksfastlygrewupsincethe'80yearsbutdoubtsandconcernsariseaboutcostsandproblemsrelatedtostoring[19].
Donorboneisosteoconductive,weaklyosteoinductive(growthfactorsmaystillbepresent,dependingonthepro-cessing).
Also,allograftsoftenrequiresterilization(gamma-irradiation),withdetrimentaleffectsonmechanicalproper-tiesofbone,anddeactivationofproteinsnormallyfoundinhealthybone.
Concernsonthepotentialinfectiveriskswereraised,thoughsince1989only2documentedcasesofHIVwerereportedwithariskrateof1:1.
6milions[20].
Anyway,currentprocedurefordonorboneprocurementandpro-cessingaredesignedtosignicantlylimitthepossibletransmissionofknonwpathogens[21].
OthermoreimportantinfectiveriskwerereportedonHBV(1case),HCV(2cases),onefatalinfectionbyClostridiumDifcilis,and26bacterialinfections[22–24].
Thelimitsofsuchtransplantsarecosts,laboriousproce-dure(tissueprocessing,harvesting),mechanicalresistance(infreezedriedandirradiated),limitedosteoinductionandriskofinfection.
2446JMaterSci:MaterMed(2014)25:2445–24611232.
3XenograftsXenograftbonesubstituteshavetheiroriginfromaspeciesotherthanhuman,suchasbovinebone(orporcinebone)whichcanbefreezedriedordemineralizedanddeprotei-nized(Fig.
3).
BovinebonewasrstintroducedbyMaatzandBauermeisterin1957[25].
Xenograftsareusuallyonlydistributedasacalciedmatrix.
MadreporeandormilleporeFig.
1aCorticalstrutautograftfrombulainaproximalhumeralnonuniontreatedbyORIF.
bOneyearX-raycontrolshowbonehealingandthepersistenceoftheautograftFig.
2a,bMorcelizedhomologousbonegraftobtainedfromabankedfemoralhead.
cSevereacetabularbonelossinamobilizedhiprevisioncup.
dX-raycontrolat2yearswithevidenceofbonystableosseointegrationofthenewcupintheremodeledbonegraftJMaterSci:MaterMed(2014)25:2445–24612447123typeofcoralsareharvestedandtreatedtobecome''coralderivedgranules''(CDG)andothertypesofcorallinexe-nografts[26].
Coralbasedxenograftsaremainlycalciumcarbonate(andanimportantproportionofuorides,usefulinthecontextofgraftingtopromotebonedevelopment)whilenaturalhumanboneismadeofhydroxyapatitealongwithcalciumphosphateandcarbonate.
Thecoralmaterialisthuseithertransformedindustriallyintohydroxyapatitethroughahydrothermalprocess,yieldingtoanon-resorb-ablexenograft,orsimplytheprocessisomittedandthecorallinematerialremainsinitscalciumcarbonatestateforbetterresorptionofthegraftbythenaturalbone.
Thecoralxenograftisthensaturatedwithgrowthenhancinggelsandsolutions[27].
InJanuary2010Italianscientistsannouncedabreakthroughintheuseofwoodasabonesubstitute,thoughthistechniqueisnotexpectedtobeusedforhumansuntilattheearliest2015.
Variousspeciesofwoodarepyrolizedinaninertatmosphere,thecarbonaceousresidueissaturatedwithcalciumsaltsandnallyreheatedtoobtainahighlyporouscrystallizedmaterialofmuchhigherporositythantrabeculartitaniumorporoushardceramicbone-substitutes;theinventorsclaimthewoodbasedmaterialwillpermitbetterpenetrationduringbonegrowthandmoreexionthanmetalorhardceramicgrafts[28].
Xenograftshavegivengoodresultsindentistry,butscarcevalidationinorthopaedics.
Clinicallyavailablecoral-basedproductsareInterporeandPro-osteon(InterporeInternational,Inc.
,Irvine,CA)aswellasbovinederivedproductssuchasBio-Oss(GeistlichBiomaterials,Geistlich,Switzerland),Osteograf-N(Cera-MedCo.
,Denver,CO),andEndobon(MerckCo.
,Darmstadt,Germany).
Doubtswereargumentedregard''zoonose''diseasestransmittedfromanimalstohumans,likeBSE(BovinespongiformEncephalopathy)orPERV(PorcineEndogenousRetroviruses)[29].
Resultsarecontradictorywithsomeauthorsreportingfavourabledata,butintheclinicalpracticexenograftsarescarcelyused[30–34].
Moreoverpoorresultsinhipsurgery,with25%ofpseudoinfectionscomplications,wererecentlyreported[35].
Theadvantagesaretheeasyavailability,theosteocon-ductivity,thegoodmechanicalpropertiesandlowcosts.
3CeramicsGenerallyceramicsbonesubstitutesarecalciumbasedsubstitutes,amixofHA(Hydroxyapatite)andTCP(Tri-calcium.
Phosphate),theamorphousphaseofHA.
HAisarelativelyinertsubstancethatisretained''invivo''forFig.
3a,bBovinebonesubstitute(Xenograft)inchipsandblocksshape.
cThexenograftisclearlyvisibleandnotresorbedinawellbonehealedproximalhumeralfractureat1yearoffollowup.
dAcetabularbonedefectlledwiththesamematerial2448JMaterSci:MaterMed(2014)25:2445–2461123prolongedperiodsoftime,whereasthemoreporousTCPtypicallyundergoesbiodegradationwithin6weeksofitsintroductionintotheareaofboneformation.
HAachieveveryhighmechanicalstrenght,whileTCPhaspoormechanicalqualities.
Generallythebaseisabiphasiccal-ciumphosphate,whichcombine40–60%TCPwith60–40%HA,thatmayyieldamorephysiologicalbalancebetweenmechanicalsupportandboneresorption[36].
AlevelIIandalevelIVstudyfoundlesserpain,operatingtime,bloodlossandcomplicationinsyntheticsubstitutescomparedwithiliaccrestgrafts[37].
Ceramicsarewidelyknownandareprovedtobesafeandeffectiveinbonesubstitution.
HA-TCParenowavailableinformofblocks,granules,andinjectablekits.
Macroporosityofabout100–400landinterconnectedporosityarenecessaryforboneingrowth.
DependingontheconcentrationofHAandTCPthestrengthisvariablebetween10and60MPthatisverylowerthancorticalbonecompressionstrength(150–200MP),andthisisoneofthemajorlimitofcera-micbasedbiomaterials.
4HydroxyapatiteandtricalciumphosphateHydroxyapatite[Ca10(PO4)6(OH)2](HA)isthecristallineformoftricalciumphosaphate(TCP)andistheprimarymineralcomponentofteethandbone.
Forthepast30years,ithasbeenpopularinorthopaedic,craniofacialandorthog-nathicsurgery,llingbonydefectsandsmoothingcontourirregularities.
HAceramicscomeinbothnaturallyandsyntheticforms.
HAandTCPceramicsaremanufacturedinavarietyofformsincludinggranulesandporousblocks(Fig.
4).
TCPismoresolublethanHA.
AlthoughHAaccountsfornearly70%ofthemineralcontentofteethandbone,theoccurringHAinthehumanbodyexistsinasubstitutedform.
Carbonate,silicates,andmagnesiumamongotherions,mayreplacehydroxylorphosphategroupsoftheapatitestructure.
Investigatorshaveattemptedtoproducealginate[38],strontium[39],silicon[40],carbonateandmagnesium[41–46]substitutedsyntheticHAinanefforttoproduceHAthatmorecloselyresemblesthemineralcontentofnativebone,enhancingbioactivityandosteo-conduction(Biomimeticceramicsubstitutes)[47].
AlthoughtherearefewofproductsmadeofbiomimeticHAintheclinicaluseatthistime,theresearchisongoingonthisdirectionandbiomimeticHAsubstitutionwilllikelyremainoneofthemostpromisingareaofresearch.
5CalciumphosphatecementsCalciumphosphatecements(CPC)aresyntheticbonesubstitutesthatwereinventedin1986byChowandBrown,scientistsattheAmericanDentalAssociation[48].
Thecementsareawhitepowder,consistingofcalciumphos-phate,thatwhenmixedwithaliquid,formsaworkablepastewhichcanbeshapedduringsurgerytotthecon-toursofboneloss.
Thecementshardenwithin20min.
Thehardeningreaction,whichformsnanocrystallinehydroxy-apatite(HA)isisothermicandoccursatphysiologicpHsotissuedamagedoesnotoccurduringthesettingreaction.
CPCswereFDAapprovedforthetreatmentofnon-load-bearingbonedefectsin1996.
HAistheprimaryinorganiccomponentofnaturalbonewhichmakesthehardenedcementbiocompatibleandosteoconductive.
Overtime,CPCsaregraduallyresorbedandreplacedwithnewbone.
BecauseCPCsarebrittle,theyareusedfornon-load-bearingapplicationssuchasdental,cranio-facialandorthopaedicapplications.
CPCshavetwosignicantadvantagesoverpre-formed,sinteredceramics.
First,theCPCspastecanbesculptedduringsurgerytotthecavi-ties.
Second,thenanocrystallinehydroxyapatitestructureoftheCPCmakesitosteoconductivecausingittobegraduallyresorbedandreplacedwithnewbone.
CPCsareinjectableandwererecentlyintroducedintheclinicalpracticetoadjuvateminimallyinvasiveprocedures(MIS)andtissueSparingsurgery(TSS)inordertoreducemor-bidityandcosts(Fig.
5).
Therstcementthatwasintro-ducedonthemarketinthelate1990swastheNorian,byCupertino(Synthes-De-Puy),aselfhardeningcarbonateHA,evenknownas''Dhallite''[49].
Fromthenmanyotherphosphatecementswerepro-posedforclinicalpractice,likeBonesource(Stryker),Calcibone(Biomet),CrhonOs(Synthes),Hydroset(Syn-thes)[50],Sintlife(Finceramica)[47],KyphOs(Medronic).
RecentlytheresearchonCPChasfocusedonimprovingmechanicalproperties,makingpremixedcements,makingthecementmacroporousandseedingcellsandgrowthfactorsintothecement.
6CalciumsulphateCalciumsulphate(CS),evenknownas''gypsum''or''PlasterofParis'',wasrstlyimplantedinhumansasavoidlleroftubercolousosteomyelitisbyDreesmanin1892[51].
MorerecentlyitwasreintroducedintheclinicalpracticeasabonesubstitutebyPeltierin1959,inamorepureandcrystallineform[52–54]CSisresorbedvariablywithin6–8weeks.
Proponentsofcalciumsulfateclaimthatthepelletsprovideaneffectivegapller,allowforvascularingrowth,andresorbrapidlyandcompletely,allowingforphysiologicbonehealing[55].
Apparentlyduetorapidgraftresorption,theresultingcalcium-richuidincitesinammation.
FirstreportsshowedverypromisingresultsJMaterSci:MaterMed(2014)25:2445–24612449123invitro[56]and''invivo'':HuffandGrisoniinthemouse[57],Cunninghaminthesheep[58],Hadjiipavlouinthesheep[59],Turnerinthedog[60],andalsoinhumans[61,62].
Recentlymanyadverseornoeffectswerereported,mainlyexplainedbecauseofthetoofastresorptionandtheproductionofasimilarinammatoryreactionwithoutboneformation(13–18%)[63–67](Fig.
6).
SubsequentlyCSwasproposedasascaffoldfordemineralizedbonematrix(DBM).
ThemixturewithCSenhancedtheclinicalout-comemorethancalciumsulfatealone.
7Polymer-basedbonegraftsubstitutesPolymershavephysical,mechanical,andchemicalprop-ertiescompletelydifferentfromtheotherbonesubstitutes.
Thepolymerscanbedividedintonaturalpolymersandsyntheticpolymers.
These,inturn,canbedividedfurtherintodegradableandnondegradabletypes.
Oneofthemostimportantnaturalpolymerinboneiscollagen.
Cortossisaninjectableresin-basedproductwithappli-cationsforload-bearingsites[68].
Itconsistsof33%difunctionalmethacrylatesthatformahighlycross-linked3-dimensionalpolymer,reinforcedwith67%radiopaqueandbioactiveglassceramicparticles.
InitialresultsusingCortossinvertebroplastyforosteoporoticandmetastaticvertebralcompressionfractureswereencouraging[69].
Degradablesyntheticpolymers(i.
e.
,naturalpolymers)areresorbedbythebody.
Thebenetisthattheyenhancehealingwithoutremainingforeignbodies.
Degradablepolymerssuchaspolylacticacidandpoly(lactic-co-gly-colicacid)havebeenusedasstandalonedevicesandasextendersofautograftsandallografts.
Fig.
4HA-TCPbonesubstitutesinproximalhumeralandtibialtraumaticboneloss.
aIntraoperatoryimplantofthematerialintheproximalhumerus.
bX-raycontrolat1yearshowthesubstituteinsidethehumeralhead.
c–fXrayandCTscanat3yearoffollowupintheproximaltibia.
TheHA-TCPmaterialresultedwellosseoin-tegrated,butwithoutanysignofresorptionorbonesubstitution2450JMaterSci:MaterMed(2014)25:2445–2461123Mostresearchhasbeendirectedtopolylacticacid(PLA),polyglycolicacid(PGA)andpolylactic-co-gly-colide(PLGA)copolymers.
TissueRegenerationThera-peutics(Toronto,Canada)hasdevelopedaporouspoly(lactic-co-glycolicacid)foammatrixbyusingaparticu-late-leachingprocesstoinduceporosity.
ItiscurrentlymarketedunderthetradenameOsteoScaf.
Immix(Osteo-biologics,SmithandNephew,Memphis,Tennessee)anditisusedasagraftextender[70].
Thesuccessofthesehasfurtherledtotheevaluationofaliphaticpolyesterssuchaspolye-caprolactone(PCL).
Itappearsassemicrystallinepolyesterandishighlypro-cessableasitissolubleinawiderangeoforganicsol-vents.
TheuncommonthingsofPCLisitshighthermalstability,withdecompositiontemperature(Td)of350°C,whereasothersaliphaticpolyestersarebetween235and255°C[71].
Inboneengineering,PCLcanbecategorizedasapromisingbiocompatibleandbiodegradablepolymersinceitisbeingusedtoenhanceboneingrowthandregenerationinthetreatmentofbonedefects[72,73],however,PCLispoorlyusedduetotheslowdegradationtime[74].
8Compositematerials8.
1CompositeofcollagenandhydroxyapatiteBoneismainlymadeofcollagen(Col)andcarbonatesubstitutedhydroxyapatite(HA).
ActuallyitispossibletoobtainCol–HAbyaselfassemblingprocessonanano-metricscale[75].
Thus,animplantmanufacturedfromsuchcomponentsislikelytobehavebetterthanotherbonesubstitutesmadeasmonolithicdevices.
Indeed,bothcollagentypeIandhydroxyapatitewerefoundtoenhanceosteoblastdiffer-entiation[76],butcombinedtogether,theywereshowntoaccelerateosteogenesis.
Acompositematrixwhenembeddedwithhuman-likeosteoblastcells,showedbetterosteoconductivepropertiescomparedtomonolithicHAandproducedcalcicationofidenticalbonematrix[77,78].
Inaddition,Col-HAcompositesprovedtobebio-compatiblebothinhumansandinanimals[77,79].
Moreoverthesecompositeshavesomemechanicaladvan-tages.
Theductilepropertiesofcollagenhelptoincreasethepoorfracturetoughnessofhydroxyapatites.
TheFig.
5InjectableTCPcementbonesubstitutes:a–binjectablecementshavetheadvantagetobemouldableandcontourabletothebonelossinmininvasiveoropensurgery;cbonelossinadistaltibialopenfracturedelayedunion(CTscan);d1yearX-raycontrol,showedboneconsolidationandosseointegrationoftheTCPcementJMaterSci:MaterMed(2014)25:2445–24612451123additionofacalcium/phosphatecompoundtocollagensheetsgavehigherstability,increasedtheresistance[80]andenhancedthemechanical'wet'properties[81].
ThedirectcomparisonofothermaterialscomparedwithCol–HAcompositesforbonesubstituteshaveyettobeclearlyinvestigated.
However,increasingthebiomimeticproper-tiesofanimplantmayreducetheproblemsofbacterialinfectionsassociatedwithinsertingaforeignbody[82].
Evidenceofthebiologicaladvantagecomparedtoarticialpolymericscaffoldshavebeenfurtherdemonstratedincartilageregeneration[83].
Theadditionofcollagentoaceramicstructurecanprovideotheradditionaladvantagestosurgicalapplications:shapecontrol,spatialadaptation,increasedparticleanddefectwalladhesion,andthecapa-bilitytofavorclotformationandstabilization[79].
Healos(DePuyOrthopaedics,Inc,Warsaw,Ind)isanaturalpolymer-basedproduct,apolymer-ceramiccompositeconsistingofcollagenberscoatedwithhydroxyapatiteandindicatedforspinalfusions[84].
Insummarytherefore,combiningbothcollagenandhydroxyapatiteshouldprovideanadvantageoverothermaterialsforuseinbonetissuerepair[85].
Furtherclinicalstudiesarerequiredtovalidateitseffectiveness.
9Growthfactors9.
1DemineralizedbonematrixTheasepticalprocessingofbankeddonorbonetoproducehumandemineralizedbonematrix(DBM),wasrstdescribedin1975[86]andintroducedintheorthopedicandperiodontalpracticesincetheearly1980s.
Thedecal-ciedbone(residualcalcium\5%)ismainlyrepresentedFig.
6Calciumsulphate(CS):aPelletslltheresidualgapafterDHSexplantinahealedintertrochantericfracture.
bTwomonthsaftertheCSwastotallyresorbed.
cAntibioticloadedCSpelletsinatibialosteomyelitis.
dThreeyearsCTscancontroldonotshowanyevidenceofboneregeneration.
NosignsofCSwerefoundedwhiletheinfectionwashealed2452JMaterSci:MaterMed(2014)25:2445–2461123bythecollagenmatrixthatissupposedtoreplicatethetridimensionalarchitectureofbone,hencefacilitatingandguidinghostcellinvasion,growthanddifferentiation[87].
MoreoverDBMshouldretainingbone-inducinggrowthfactors,suchasbonemorphogeneticproteins(BMP),insulingrowthfactor(IGF),transforminggrowthfactor(TGF),broblastgrowthfactor(FGF),abletostimulateactivationandmigrationofosteogenicstemcellsandprogenitorcells,andtoinducerevascularization.
None-theless,DBMlacksofanymechanicalstrength,henceareusedexclusivelyforllingpurposesandnormallyareassociatedwithcarrierslikeglycerol(Grafton-Osteotech),calciumsulphate(Allomatrix-Whright),hyaluronicacid(DBX-Synthes),porcinecollagen(Osteol-Medtronics-SofamorDanek),carbossimetilcellulose(Dynagraft-Gen-SciRegenerationSciences)(Fig.
7).
DespiteacopiousamountofliteraturedatareportstheeffectivenessofDBM,mostlyinpreclinicalstudies[20],asasafeandeffectivebonegraftingmaterial[88],thereisstilllimitateevidenceproducedinLevel1-2studies,tosupporttheuseofDBMasastand-alonebonesubstitute[89].
Moreover,concernswereraisedabouttheextremevariabilityinBMP2andBMP7contentindifferentcommerciallyavailableDBMlots,whichmaybeduetotheabsenceofstandardizedprocessesforproductionalongwithdonor-relatedissues[89,90].
9.
2Plateletrichplasma(PRP)Bloodplateletsareeasilycollectedfrombloodandrepre-sentavaluablesourceofgrowthfactors,suchastheplateletderivedgrowthfactor,theinsulin-likegrowthFig.
7DemineralizedBoneMatrix(DBM):a–cComplexproximalhumeralfracturetreatedbyORIF,DBMandcalciumsulphate(Allomatrix-Wright);dOneyearfollowupdemonstrategoodconsolidationofthefractureJMaterSci:MaterMed(2014)25:2445–24612453123factors,andthetransforminggrowthfactors[91–93].
Platelet-richplasma(PRP)iseasilyobtainedbyconcen-trationofautologousbloodplateletthroughgradientden-sitycentrifugation(Fig.
8).
PRPprovedtoexertchemotacticandmitogenicpropertiesforosteoblastandbroblastcellsinvitro,tostimulatebroblasthyaluronatesynthesis,aprerequisitefortheformationoftheextra-cellularmatrix,therebyenhancingboneformation[94–98].
Unfortunately,diverseclinicalstudiessofarreportedunsuccessfulresultsinspinesurgery,withadecreasedincidenceofspinefusions(15–19%),evenwhenusedincombinationwithbonemarrowcells[99].
ThisfailurewasbelievedtobeduetoaparadoxicalinhibitoryeffectonBMP2athighconcentrations[100–102].
Indeed,currentlyPRPisnotvalidatedasastand-alonebonesubstitutebutisratherconsideredaco-growthfactorforbonehealing.
9.
3BonemorphogeneticproteinsOriginallyidentiedandnamedaftertheirabilitytoinduceectopicboneformation[103],bonemorphogeneticproteins(BMPs)representawideandheterogeneousfamilyofhighlyconservedsecretedproteins,withinthetransforminggrowthfactor-bsuperfamily,deeplyinvolvedintheskel-etogenicprocess[104,105].
SelectedBMPsappeartopromoteinvitroboneforma-tionby:inducingthedifferentiationofpluripotentme-senchimalcellstowardsthechondrogenicandosteogeniclineages,stimulatingangiogenesisandalkalinephospha-taseactivity[94].
Theosteogenic/osteoinductivepotentialoftheBMPswasstronglyvalidatedinbothpreclinicalandclinicalstudies,generallyreportingperformancethatwerecomparabletoautogenouscancellousbone,withfusionratesbetween80and99%[106–112].
Todate,onlytheuseofrecombinanthumanBMP2andBMP7hasbeenapprovedbothinEuropeandtheUnitedStatesforselectedclinicalapplications:BMP2withacollagencarrier(INFUSE,MedtronicSofamorDanek,Minneapolis)forlumbarvertebralinterbodyfusionandBMP7(OP-1,Stryker,Kalamazoo,Michigan)fortibialnonunion,inpatientswhounderwentpreviousunsucces-fulltreatments.
Darkandlightspersistalsoduetothevariableneededdosage,whichmaybepatient-andsite-dependent,andtothestillhighcosts,whichmakestheiruseprohibitiveinmostsettings.
Inaddition,BMPsshowedadverseeffectincervicalspineandarehencecontraindi-catedinthisapplication[113].
Fig.
8PlateletRichPlasma(PRP):a–dautologousbloodisobtainedintheoperatingroom.
Aftercentrifugationthedifferentcomponentsaredifferentiate.
e,fAplateletconcentrateisobtainedforinjectionordepositionintothebonegaporwound2454JMaterSci:MaterMed(2014)25:2445–246112310Emergingstrategiesforbonesubstitution10.
1BiomimeticandsmartmaterialsinbonetissueengineeringThechallengetotissueengineersistodesignanddeveloptemporarybonescaffoldswhichdeliverbioactivemole-culesanddrugsorcellstotheinjurysiteandhenceextenditsbiologicalfunctionality(acceleratehealingandtissueregenerationwhilesimultaneouslypreventingpathology).
Althoughmimickingthegeometricarchitectureofboneinasyntheticscaffoldhasbeenshowntopromotefavorablecellularactivity,theoverallcapacityforascaffoldtodirectcellbehaviorcanbesubstantiallyimprovedthroughthecontrolleddeliveryofbiospeciccues[114–119].
Administrationofgrowthfactorsandotherbioactivemoleculestopromoteboneformationandrepairhasachievedpromisingresultsinseveralpreclinicalandclin-icalmodels[120–125].
Avarietyofadministrationmeth-odshavebeeninvestigatedincluding:bolusinjection,surfaceadsorbedproteinrelease,osmoticpumps,andcontrolledreleasefrombiodegradablescaffolds.
Theef-cacyofthedeliveryvehiclereliesonitsabilitytoprovidetheappropriatedoseovertheappropriatetherapeutictime.
Ideally,thepresentationofbioactivemoleculesordrugsmustbenelytunedtodynamicallymatchthephysiolog-icalneedsofthetissueasitregenerates.
Becauseofthehydrolyticallyunstablelinkagesintheirbackboneandtunablebiodegradationrate,polymershavedemonstratedtobeeffective.
Ceramicmaterialshavealsodemonstratedtheabilitytobiodegradeandreleasebioactivemoleculesatacontrolledrate[126–130].
Naturalpolymerssuchascollagen,brin,alginate,gelatin,andGAGshavealsobeenextensivelyinvestigatedasdrugdeliveryvehiclesinbonetissueengineering.
Thesenaturalpolymershavedistinctadvantagesduetotheirinherentbiocompatibilityandbioactivitybutlackthemechanicalpropertiesrequiredforloadbearingapplications,mayhaveinappropriate(xed)degradationrates,aredifculttoharvestandsterilize,andmayinduceanimmunogenicresponse.
Bioactivemole-culescanbecovalentlyboundtopolymersorphysicallyentrappedinsideapolymermatrix[131,132].
Ineithercase,themoleculeisreleasedasthepolymerdegradesinthephysiologicalenvironment.
Aliphaticpolyesterssuchaspoly(lactic-acid)(PLA),poly(glycolic-acid)(PGA),andpoly(caprolactone)(PCL),andtheircopolymersarethemostcommonlyutilizedpolymersinbonetissueengineering[133–135].
BothPGAandPLAscaffoldshasbeeninvestigatedasaslow-deliverycarrierforgrowthfactorsinseveral''invitro''and''invivo''studies,anddemonstratedtheabilitytopromotehealingandosseointegrationcomparedwithcontrolscaf-folds[136–138].
Researcherscombinemultiplepolymersinachemicalprocesscalledcopolymerizationtogainmorecontroloverthedegradationrate,hydrophobicity,crystal-linity.
Copolymerizationisanalogoustothedesignofcompositematerialswheremultipleconstituentsarecom-binedresultinginanewmaterialwithdesirablepropertiesfromeachconstituent.
Undoubtedly,themostcommonlyutilizedcopolymerforbioactivemoleculeencapsulationandreleaseforbonetissueengineeringisthecopolymerpoly(lacticacid-co-glycolicacid)(PLGA).
Severalresearchershaveutilizedthiswell-characterizedcopolymerforencapsulationandreleaseofawidevarietyofbioactivemoleculesanddrugsincludingTGF-b,BMPs,IGFs,VEGF,NGF,DNA,vancomycin,gentamycin,cisplatin,andothers[139–146].
However,althoughPLGAhasshowntobepromisingeinbonescaffoldapplications,itsclinicalutilityislimitedduetoitsrelativelypoormechanicalproperties(specicallyYoung'sModulus)comparedwithcancellousbone,andthereforemustbecombinedwithothermaterialstoenhanceitsmechanicalproperties[147].
Manysyntheticbonescaffoldsrelyonthedeliveryofsinglefactors,whichmaypartiallyexplainthelimitedclinicalutilityofmanycurrentapproaches[140].
There-fore,researchershavebeeninvestigatingtechniquestoencapsulateandreleasemultiplebioactivemoleculesinahighlycontrolledspatialandtemporalmanner.
Researchhasshownthatthismethodsignicantlyenhancestissueregenerationcomparedwiththecontrolledreleaseofsinglebiologicalcues[148–150].
Thetechnologyofincorporat-ingmultiplechemicaleffectorsandcontrollingtheirspatialandtemporalreleaseisaverypromisingstrategy,butisstillexperimentalandhasnotyetdemonstratedwidespreadpreclinicalorclinicalutilitytodate.
Thefailuretoidentifyeitherasinglematerialorgrowthfactorasthepanaceaforboneregeneration,orabiologicalscaffoldthatwillpromoteintegrationandvascularization,hasledtoanincreasedinterestinoptimizingbiomaterialstopromotespeciccell-biomaterialinteractions.
Forexample,Arg–Gly–Asp(RGD)sequencepeptides(involvedinintegrin-mediatedcelladhesion)canbeincorporatedontothescaffoldsurfacetoenhancecelladhesionandspreading[151].
Yangetal.
[152]havedemonstratedthepotentialtopromotehumanosteopro-genitordifferentiationonRGD-coupledbiodegradeablescaffolds.
Morerecentlydrugdeliverytechniquessuchasentrap-mentwithinahydrogelmatrixallowinggrowthfactorstobereleasedinacontrolledfashionfromthescaffoldtoaidtheregeneratingtissuehavebeenapplied[153–156].
Suchapproachesareappealingastheyavoidtheuseofsolvents,andhightemperatures(andthereforeproteindegradation)andsubsequentreleaseofthegrowthfactoriscontrolled,inresponsetoenvironmentalstimuli.
ThisstrategyhasbeenJMaterSci:MaterMed(2014)25:2445–24612455123employedinbonetissueengineering,whererhBMP-2[157]basicbroblastgrowthfactor[155]andvascularendothelialgrowthfactor[156]haveallbeensuccessfullyincorporatedintoahydrogelpriortoinvivoimplantation.
Supercriticaluidtechnologyhasevolvedasapromisingapproachinthedevelopmentofporousbiodegradablescaffoldsfortissueengineering[158].
TheabsenceofsolventsandthermalprocessingmakesthisanattractiveapproachtogrowthfactorincorporationandHowdleandcolleagueshavedemonstratedhighprotein(ribonuclease)loadingintofoamedPLAscaffoldswhichretainedfullactivityonsubsequentreleasefromthePLAover3months[153,159].
Thistechnologycouldprovideasimpleone-stepprocesstothedifcultiesofincorporatinggrowthfactorsand/orguestparticles(suchashydroxyapatite)intoacontrolledreleasedeliverysystem.
Newstrategiesworkstoencapsulateandreleasedrugswhichpreventpathologiesthatcanoccurpostimplantationofasyntheticscaffold.
Awidevarietyofdrugshavebeenencapsulatedandreleasedfrombiodegradablepolymerscaffoldsincludingantibiotics,DNA,RNA,cathepsininhibitors,chitin,chemotherapeutics,bisphosphonates,statins,sodiumuoride,dihydropyridine,andmanyothers[160–164].
Researchersareaggressivelypursuingstrate-giestodeliverantibioticslocallytothesiteofinjury/sur-gery.
Themostcommonbiodegradablepolymer/antibioticcombinationisPLGAscaffoldsloadedwithantibioticssuchasciprooxin,gentamycin,andvancomycin[165,166].
PLGAscaffoldshavedemonstratedsuccessfulsus-tainedlocaldeliveryoftheseantibioticsforupto20ormoredaysinvitroandinpreclinicalanimalmodels[141,142,167–169].
Althoughlocaldeliveryofantibioticshasaverypromisingoutlook,thereremainsanumberofchal-lenges(suchasantibioticstabilitywithinthescaffoldandantibioticdeactivationduringfabrication),whichneedtobeaddressedbeforeclinicaltrialscanbegin[170].
10.
2Cell-basedandgenetherapyThechallengesofferedbycurrentbonegraftingtechniqueshavebeendrivingtheintensiveresearcheffortsspentduringthelastdecadestodevelopnewapproachesandtechnologies.
Tothisaim,cell-basedgenetherapyhasattractedgreatinterestfromthescienticcommunity,representingatentativeapproachtoachievebonesubsti-tution[171].
Ingenetherapyapproaches,cellsareusedasbioactivevehiclesdeliveringosteoinductivegeneslocallytoachieveboneregeneration.
Differentmoleculeshavebeentestedtothisaim,mainlyrepresentedbygenesbelongingtotheBMPfamilyandrelatedcascade[172].
Indeed,geneticallyengineeredcellsarebelievedtomain-tainphysiologicdosesofageneproductforasustainedperiodonceinoculatedintotheselectedanatomicalsite,facilitatinganefcientbonehealing[173].
Inaddition,theoverwhelmingamountofdatathathavebeenclarifyingthewholemolecularscenarioorchestratingosteogenesisandbonehealing,providednewosteoinductivemoleculestobetestedaspotentialtherapeutics[174].
Cell-basedgenetherapyapproachesbasedonengineered-osteoinductivecellsallowedachievingthemostconvincingresultsintermsofbonehealinginanimalmodels[172,174,175].
Though,anumberofsafetyissuescurrentlylimittheuseofgeneticengineeringprocedures,basedonviralandnonviralvectors,intheclinicalsetting.
Thus,strictly-namedgenetherapyapproachesforboneregenerationceasedtorepre-sentsuitablefortranslationalpurposes.
Cell-basedapproachesaremainlybasedonmesenchy-malstemcells(MSCs),thathavebeenwidelyemployed,inconjunctionwithappropriateosteoinductivescaffolds,andconsideredthemosteffectivebioactivebonesubstitutes''invivo''[172,176,177].
MSCsaremultipotentstemcellsthatarecapableofextensiveself-renewal,plasticityandmultilineagepotential[178,179].
Thesecellsresidesinthestromaofbonemarrowandotherorgansandtissues(fat,muscle,skin,synovialmembrane,tendonslung,etc.
);hencetheyarealsonamed''stromalstemcells''[180].
ThegreatadvantagesofMSCsresideintheeaseofisolationand''exvivo''expansion,preservingtheirplasticityandself-renewalpotential[181].
Uponappropriateinvitroinduction,MSCscanbedifferentiatedalongtheosteogeniclineage.
MSCderivedfrombonemarrowshowedahighpotentialforosteogenicdifferentiation,whichhasbeenexploitedforcell-basedtherapyofcongenitalbonedisorders[182–184].
TheproposeduseofMSCsinorthopedicsurgerycomesalsofromtheirimmunomodulatoryproperties,thatmakethempotentiallysuitableforallogenictransplantation[185].
Itisnoteworthythatna¨veundifferentiatedMSCsarepronetoenvironment-inducedlineagecommitment[186]meaningthattheycanundergospontaneousosteogenicdifferentiationupon''invivo''inoculationintoadamagedbone[187,176].
Thisfeaturemaysuggesttheirsafeuseasitdoesnotimplyanykindof''exvivo''osteogenicinductionpriorto''invivo''inoculation.
Nonetheless,theproductionofclinical-gradeMSCs,requiresdedicatedcellfactoriesfortheir''exvivo''largescalecultureamplica-tion;theseareGMP-prooffacilitiesthatneedtocomplytothesameregulationsrequiredforthedrugmanufacturingindustries,asculture-ampliedcells,accordingtoEuro-peantissuebankingrules,areconsideredasmedicinalproducts[21,188].
FewactiveclinicaltrialsarecurrentlyongoingthatexploitMSC-basedtreatmentasboneregenerativestrate-gies(www.
clinicaltrials.
gov)[189].
2456JMaterSci:MaterMed(2014)25:2445–246112311ConclusionsBonelosspersiststobeanimportantchallengeinsurgery,andmanyalternativesareavailable.
Despitetheimprove-mentofresearch,humanbonegraftspersisttobethemosteffectivebonesubstitutestoreplaceboneloss.
Alternativestobonegraftslacksofoneormoreoftheconceptsofthe''Diamondtheory''ofGiannoudis:osteogeniccellsandvascularization,mechanicalstability,growthfactors,os-teoconductivescaffolds(incombinationwithgrowthsfactors),thatareaprerequisiteforbonehealing[190].
MoreovermostalternativesareexpensiveandnotvalidatedbyEBM,thusbeingscarcelyrecommendableforclinicaluse.
Actually,ceramicssubstitutesarethebestforsafeness,effectivenessandcosts.
BMP2andBMP7areEBMvalidated,forspecicuse,butcostsareelevated.
Othertechniquesoralternativesareexpensive,andnotvalidated,thusneedingstandardrandomizedclinicaltrialspriortobeapprovedforroutinelyclinicaluse.
AcknowledgmentsTheresearchleadingtotheseresultshasreceivedfundingfromtheEuropeanUnion'sSeventhFrameworkProgramme([FP7/2007-2013])underGrantAgreementNo.
246373,OPHIS.
OpenAccessThisarticleisdistributedunderthetermsoftheCreativeCommonsAttributionLicensewhichpermitsanyuse,dis-tribution,andreproductioninanymedium,providedtheoriginalauthor(s)andthesourcearecredited.
References1.
BhattRA,RozentalTD.
Bonegraftsubstitutes.
HandClin.
2012;28(4):457–68.
2.
GreenwaldAS,BodenSD,GoldbergVM,KhanY,LaurencinCT,RosierRN.
Bone-graftsubstitutes:facts,ctionsandapplications.
JBoneJointSurgAm.
2001;83:98–103.
3.
FinkemeierCG.
Bone-graftingandbone-graftsubstitutes.
JBoneJointSurgAm.
2002;84(3):454–64.
4.
VanHeestA,SwiontkowsiM.
Bone-graftsubstitutes.
Lancet.
1999;353(Suppl1):S28–9.
5.
FaourO,DimitriouR,CousinsCA,GiannoudisPV.
Theuseofbonegraftsubstitutesinlargecancellousvoids:anyspecicneedsInjury.
2011;42(Suppl2):S87–90.
6.
MoroneMA,BodenSD,HairG,MartinGJJ,RacineM,TitusL,ButtonWC.
Geneexpressionduringautograftlumbarspinefusionandtheeffectofbonemorphogeneticprotein2.
ClinOrthopRelatRes.
1998;351:252–65.
7.
GoldbergVM,StevensonS.
Thebiologyofbonegrafts.
SeminArthroplast.
1993;4(2):58–63.
8.
ZipfelGJ,GuiotBH,FesslerRG.
Bonegrafting.
NeurosurgFocus.
2003;14(2):e8.
9.
SchlickewieW,SchlickewieC.
Theuseofbonesubstitutesinthetreatmentofbonedefects—theclinicalviewandhistory.
MacromolSymp.
2007;253(1):10–23.
10.
ArnerJW,SantrockRD.
Ahistoricalreviewofcommonbonegraftmaterialsinfootandanklesurgery.
FootAnkleSpec.
2014;7(2):143–51.
11.
MironRJ,ZhangYF.
Osteoinduction:areviewofoldconceptswithnewstandards.
JDentRes.
2012;91(8):736–44.
12.
PryorLS,GageE,LangevinCJ,HerreraF,etal.
Reviewofbonesubstitutes.
CraniomaxillofacTraumaReconstr.
2009;2(3):151–60.
13.
RawlinsonJN.
Morbidityafteranteriorcervicaldecompressionandfusion.
Theinuenceofthedonorsiteonrecovery,andtheresultsofatrialofsurgibonecomparedtoautologousbone.
ActaNeurochir.
1994;131(1–2):106–18.
14.
BlokhuisTJ,CaloriGM,SchmidmaierG.
AutograftversusBMPsforthetreatmentofnon-unions:whatistheevidenceInjury.
2013;44(Suppl1):S40–2.
doi:10.
1016/S0020-1383(13)70009-3.
15.
PapeHC,EvansA,KobbeP.
Autologousbonegraft:propertiesandtechniques.
JOrthopTrauma.
2010;24(Suppl1):S36–40.
16.
WangJC,WalshMC.
(2009)www.
spineuniverse.
com.
http://www.
spineuniverse.
com/exams-tests/bone-grafts-new-developments.
17.
BaumhauerJ,PinzurMS,DonahueR,BeasleyW,DigiovanniC.
Siteselectionandpainoutcomeafterautologousbonegraftharvest.
FootAnkleInt.
2014;35(2):104–7.
18.
BodenSD.
Overviewofthebiologyoflumbarspinefusionandprinciplesforselectingabonegraftsubstitute.
Spine.
2002;27(16Suppl1):S26–31.
19.
CalvoR,FigueroaD,Daz-LedezmaC,VaismanA,FigueroaF.
Boneallograftsandthefunctionsofbonebanks.
RevMedChil.
2011;139(5):660–6.
20.
KhanSN,CammisaFPJ,SandhuHS,DiwanAD,GirardiFP,LaneJM.
Thebiologyofbonegrafting.
JAmAcadOrthopSurg.
2005;13(1):77–86.
21.
ManyalichM,NavarroA,KollerJ,LotyB,deGuerraA,CornuO,VabelsG,FornasariP,CostaA,SiskaI,etal.
Europeanqualitysystemfortissuebanking.
TransplantProc.
2009;41(6):2035–43.
22.
TomfordWW.
Transmissionofdiseasethroughtransplantationofmusculoskeletalallografts.
JBoneJointSurgAm.
1995;77(11):1742–54.
23.
MrozTE,JoyceMJ,SteinmetzMP,LiebermanIH,WangJC.
MusculoskeletalallograftrisksandrecallsintheUnitedStates.
JAmAcadOrthopSurg.
2008;16(10):559–65.
24.
LomasR,ChandrasekarA,BoardTN.
BoneallograftintheUK:perceptionsandrealities.
HipInt.
2013;23(5):427–33.
25.
BauermeisterA,MaatzR.
Amethodofbonemacerationresultsofanimalexperiments.
JBoneJointSurgAm.
1957;39(1):153–66.
26.
JensenSS,TerheydenH.
Boneaugmentationproceduresinlocalizeddefectsinthealveolarridge:clinicalresultswithdif-ferentbonegraftsandbone-substitutematerials.
IntJOralMaxillofacImplants.
2009;24(Suppl):218–36.
27.
DumitrescuAL.
Bonegraftsandbonegraftsubstitutesinperi-odontaltherapy.
In:Chemicalsinsurgicalperiodontaltherapy.
Berlin:Springer;2011.
p.
92.
28.
TampieriA,SprioS,RufniA,CelottiG,LesciIG,RoveriN.
Fromwoodtobone:multi-stepprocesstoconvertwoodhier-archicalstructuresintobiomimetichydroxyapatitescaffoldsforbonetissueengineering.
JMaterChem.
2009;19:4973–80.
29.
LaurencinCT,El-AminSF.
Xenotransplantationinorthopaedicsurgery.
JAmAcadOrthopSurg.
2008;16(1):4–8.
30.
LofgrenH,JohannssonV,OlssonT,RydL,LevanderB.
Rigidfusionafterclowardoperationforcervicaldiscdiseaseusingautograft,allograft,orxenograft:arandomizedstudywithra-diostereometricandclinicalfollow-upassessment.
Spine.
2000;25(15):1908–16.
31.
MalcaSA,RochePH,RossetE,PelletW.
Cervicalinterbodyxenograftwithplatexation:evaluationoffusionafter7yearsofuseinpost-traumaticdiscoligamentousinstability.
Spine.
1996;21(6):685–90.
32.
RamaniPS,KalbagRM,SenguptaRP.
CervicalspinalinterbodyfusionwithKielbone.
BrJSurg.
1975;62(2):147–50.
JMaterSci:MaterMed(2014)25:2445–2461245712333.
SavolainenS,UseniusJP,HernesniemiJ.
Iliaccrestversusarticialbonegraftsin250cervicalfusions.
ActaNeurochir.
1994;129(1–2):54–7.
34.
SiqueiraEB,KranzlerLI.
CervicalInterbodyfusionusingcalfbone.
SurgNeurol.
1982;18(1):37–9.
35.
CharalambidesC,BeerM,CobbAG.
Poorresultsafteraug-mentingautograftwithxenograft(Surgibone)inhiprevisionsurgery:areportof27cases.
ActaOrthop.
2005;76(4):544–9.
36.
BoyanBD,McMillanJ,LohmannCH,RanlyDM,SchwartzZ.
Basicinformationforsuccessfulclinicalusewithspecialfocusonsyntheticgraftsubstitutes.
In:LaurencinCT,editor.
Bonegraftsubstitutes.
Philadelphia:ASTMInt;2002.
p.
231–59.
37.
LernerT,BullmannV,SchulteTL,SchneiderM,LiljenqvistU.
Alevel-1pilotstudytoevaluateofultraporousbeta-tricalciumphosphateasagraftextenderintheposteriorcorrectionofadolescentidiopathicscoliosis.
EurSpineJ.
2009;18(2):170–9.
38.
ChaeT,YangH,LeungV,KoF,TroczynskiT.
Novelbiomi-metichydroxyapatite/alginatenanocompositebrousscaffoldsforbonetissueregeneration.
JMaterSciMaterMed.
2013;24(8):1885–94.
39.
LandiE,TampieriA,CelottiG,BelmonteMM,LogroscinoG.
Syntheticbiomimeticnanostructuredhydroxyapatite.
KeyEngMater.
2005;284:949–52.
40.
LandiE,TampieriA,CelottiG,SprioS,SandriM,LogroscinoG.
Sr-substitutedhydroxyapatitesforosteoporoticbonereplacement.
ActaBiomater.
2007;3(6):961–9.
41.
SprioS,TampieriA,LandiE,SandriM,MartoranaS,CelottiG,LogroscinoG.
Physico-chemicalpropertiesandsolubilitybehaviourofmulti-substitutedhydroxyapatitepowderscon-tainingsilicon.
MaterSciEng.
2008;28(1):179–87.
42.
BigiA,ForestiE,GregorianiR,RipamontiA,RoveriN,ShahJS.
Theroleofmagnesiumonthestructureofbiologicalapatite.
CalcifTissueInt.
1992;50(5):439–44.
43.
BigiA,FaliniG,ForestiE,GazzanoM,RipamontiA,RoveriN.
Magnesiuminuenceonhydroxyapatitecrystallization.
JInorgBiochem.
1993;49(1):69–78.
44.
TenHuisenKS,BrownPW.
Effectsofmagnesiumonthefor-mationofcalciumdecienthydroxyapatitefromCaHPO42H2OandCa4(PO4)2O.
JBiomedMaterRes.
1997;36(3):306–14.
45.
ReyC,RenugopalakrishnanV,CollinsB,GlimcherM.
Fouriertransforminfraredspectroscopicstudyofthecarbonateionsinbonemineralduringaging.
CalcifTissueInt.
1991;49(4):251–8.
46.
LandiE,TampieriA,Mattioli-BelmonteM,CelottiG.
Biomi-meticMg-andMg,CO3-substitutedhydroxyapatites:synthesischaracterizationandinvitrobehaviour.
JEurCeramSoc.
2006;26(13):2593–601.
47.
LandiE,LogroscinoG,ProiettiL,TampieriA,SandriM,SprioS.
BiomimeticMg-substitutedhydroxyapatite:fromsynthesistoinvivobehaviour.
JMaterSciMaterMed.
2008;19(1):239–47.
48.
FriedmanCD,CostantinoPD,TakagiS,ChowLC.
Bone-SourceTMhydroxyapatitecement:anovelbiomaterialforcra-niofacialskeletaltissueengineeringandreconstruction.
JBiomedMaterRes.
1998;43(4):428–32.
49.
ConstantzBR,IsonIC,FulmerMT,PoserRD,SmithST,VanWagonerM,RossJ,GoldsteinSA,JupiterJB,RosenthalDI.
Skeletalrepairbyinsituformationofthemineralphaseofbone.
Science.
1995;267(5205):1796–9.
50.
VanderStokJ,VanLieshoutEM,El-MassoudiY,VanKra-lingenGH,PatkaP.
BonesubstitutesintheNetherlands—asystematicliteraturereview.
ActaBiomater.
2011;7(2):739–50.
51.
PeltierLF,BickelEY.
TheuseofplasterofParistolldefectsinbone.
AnnSurg.
1957;146(1):61–9.
52.
ShueL,YufengZ,MonyU.
Biomaterialsforperiodontalregeneration:areviewofceramicsandpolymers.
Biomatter.
2012;2(4):271–7.
53.
PeltierLF.
TheuseofplasterofParistolldefectsinbone.
ClinOrthop.
1961;21:1–31.
54.
PeltierLF,JonesRH.
Treatmentofunicameralbonecystsbycurettageandpackingwithplaster-of-Parispellets.
JBoneJointSurgAm.
1978;60(6):820–2.
55.
KumarCY,KNB,MenonJ,PatroDK,BBH.
Calciumsulfateasbonegraftsubstituteinthetreatmentofosseousbonedefects,aprospectivestudy.
JClinDiagnRes.
2013;7(12):2926–8.
56.
SidquiM,CollinP,VitteC,ForestN.
Osteoblastadherenceandresorptionactivityofisolatedosteoclastsoncalciumsulphatehemihydrate.
Biomaterials.
1995;16(17):1327–32.
57.
HuffW,GrisoniB.
Mechanicalintegrityofratboneafterautograftandcalciumsulfategraft.
In:Fifthworldbiomaterialscongress,Toronto.
1996.
p.
52–3.
58.
BlomAW,CunninghamJL,HughesG,LawesTJ,SmithN,BlunnG,LearmonthID,GoodshipAE.
Thecompatibilityofceramicbonegraftsubstitutesasallograftextendersforuseinimpactiongraftingofthefemur.
JBoneJointSurgBr.
2005;87(3):421–5.
59.
HadjipavlouAG,SimmonsJW,YangJ,NicodemusCL,EschO,SimmonsDJ.
PlasterofParisasanosteoconductivematerialforinterbodyvertebralfusioninmaturesheep.
Spine.
2000;25(1):10–5.
60.
TurnerTM,UrbanRM,GitelisS,HaggardWO,RichelsophK.
Resorptionevaluationofalargebolusofcalciumsulfateinacaninemedullarydefect.
Orthopedics.
2003;26(5Suppl):s577–9.
61.
CoetzeeAS.
Regenerationofboneinthepresenceofcalciumsulfate.
ArchOtolaryngol.
1980;106(7):405–9.
62.
GitelisS,PiaseckiP,TurnerT,HaggardW,ChartersJ,UrbanR.
Useofacalciumsulfate-basedbonegraftsubstituteforbenignbonelesions.
Orthopedics.
2001;24(2):162–6.
63.
KellyCM,WilkinsRM,GitelisS,HartjenC,WatsonJT,KimPT.
Theuseofasurgicalgradecalciumsulfateasabonegraftsubstitute:resultsofamulticentertrial.
ClinOrthopRelatRes.
2001;382:42–50.
64.
RobinsonD,AlkD,SandbankJ,FarberR,HalperinN.
Inammatoryreactionsassociatedwithacalciumsulfatebonesubstitute.
AnnTransplant.
1999;4(3–4):91–7.
65.
LeeGH,KhouryJG,BellJE,BuckwalterJA.
AdversereactionstoOsteoSetbonegraftsubstitute,theincidenceinaconsecutiveseries.
IowaOrthopJ.
2002;22:35–8.
66.
PetruskeviciusJ,NielsenS,KaalundS,KnudsenPR,OvergaardS.
NoeffectofOsteoset,abonegraftsubstitute,onbonehealinginhumans:aprospectiverandomizeddouble-blindstudy.
ActaOrthopScand.
2002;73(5):575–8.
67.
LaddA,PliamN.
Theroleofbonegraftandalternativesinunstabledistalradiusfracturetreatment.
OrthopClinNorthAm.
2001;32(2):337–51.
68.
LaurencinC,KhanY,El-AminSF.
Bonegraftsubstitutes.
ExpertRevMedDevices.
2006;3(1):49–57.
69.
Palussie`reJ,BergeJ,GangiA,etal.
Clinicalresultsofanopenprospectivestudyofabis-GMAcompositeinpercutaneousvertebralaugmentation.
EurSpineJ.
2005;14:982–91.
70.
NandiSK,RoyS,MukherjeeP,KunduB.
Orthopaedicappli-cationsofbonegraft&graftsubstitutes:areview.
IndianJMedRes.
2010;132:15–30.
71.
EngelbergI,KohnJ.
Physico-mechanicalpropertiesofdegrad-ablepolymersusedinmedicalapplications:acomparativestudy.
Biomaterials.
1991;12(3):292–304.
72.
PittCG,GratzlMM,KimmelGL,SurlesJ,SchindlerA.
Ali-phaticpolyestersII.
Thedegradationofpoly(DL-lactide),poly(epsilon-caprolactone),andtheircopolymersinvivo.
Biomate-rials.
1981;2(4):215–20.
73.
PorterJR,HensonA,PopatKC.
Biodegradablepoly(epsilon-caprolactone)nanowiresforbonetissueengineeringapplica-tions.
Biomaterials.
2009;30(5):780–8.
2458JMaterSci:MaterMed(2014)25:2445–246112374.
MondrinosMJ,DembzynskiR,LuL,ByrapoguVK,WoottonDM,LelkesPI,ZhouJ.
Porogen-basedsolidfreeformfabrica-tionofpolycaprolactone-calciumphosphatescaffoldsfortissueengineering.
Biomaterials.
2006;27(25):4399–408.
75.
TampieriA,CelottiG,LandiE,SandriM,RoveriN,FaliniG.
Biologicallyinspiredsynthesisofbone-likecomposite:self-assembledcollagenbers/hydroxyapatitenanocrystals.
JBio-medMaterResA.
2003;67(2):618–25.
76.
XieJ,BaumannMJ,McCabeLR.
Osteoblastsrespondtohydroxyapatitesurfaceswithimmediatechangesingeneexpression.
JBiomedMaterResA.
2004;71(1):108–17.
77.
SerreCM,PapillardM,ChavassieuxP,BoivinG.
Invitroinductionofacalcifyingmatrixbybiomaterialsconstitutedofcollagenand/orhydroxyapatite:anultrastructuralcomparisonofthreetypesofbiomaterials.
Biomaterials.
1993;14(2):97–106.
78.
WangRZ,CuiFZ,LuHB,WenHB,MaCL,LiHD.
Synthesisofnanophasehydroxyapatite/collagencomposite.
JMaterSciLett.
1995;14(7):490–2.
79.
ScabbiaA,TrombelliL.
AcomparativestudyontheuseofaHA/collagen/chondroitinsulphatebiomaterial(Biostite)andabovine-derivedHAxenograft(Bio-Oss)inthetreatmentofdeepintra-osseousdefects.
JClinPeriodontol.
2004;31(5):348–55.
80.
YamauchiK,GodaT,TakeuchiN,EinagaH,TanabeT.
Prep-arationofcollagen/calciumphosphatemultilayersheetusingenzymaticmineralization.
Biomaterials.
2004;25(24):5481–9.
81.
LawsonAC,CzernuszkaJT.
Collagen–calciumphosphatecomposites.
ProcInstMechEngH.
1998;212(6):413–25.
82.
SchierholzJM,BeuthJ.
Implantinfections:ahavenforoppor-tunisticbacteria.
JHospInfect.
2001;49(2):87–93.
83.
WangX,GroganSP,RieserF,WinkelmannV,MaquetV,BergeML,Mainil-VarletP.
Tissueengineeringofbiphasiccartilageconstructsusingvariousbiodegradablescaffolds:aninvitrostudy.
Biomaterials.
2004;25(17):3681–8.
84.
BoughtonP,FerrisD,RuysAJ.
Aceramic-polymerfunctionallygradedmaterial:anoveldiskprosthesis.
In:SinghM,JessenT.
25thAnnualconferenceoncomposites,advancedceramics,materials,andstructures:B:ceramicengineeringandscienceproceedings.
Vol22.
Westerville:AmericanCeramicSociety;2008.
p.
593–600.
85.
WahlDA,CzernuszkaJT.
Collagen-hydroxyapatitecompositesforhardtissuerepair.
EurCellMater.
2006;11:43–56.
86.
UristM,MikulskiA,BoydS.
Achemosterilizedantigen-extractedautodigestedalloimplantforbonebanks.
ArchSurg.
1975;110(4):416–28.
87.
LaneJM.
Bonemorphogenicproteinscienceandstudies.
JOrt-hopTrauma.
2005;19(10Suppl):S17–22.
88.
Mahantesha,ShobhaKS,ManiR,DeshpandeA,SeshanH,KrantiK.
Clinicalandradiographicevaluationofdemineralizedbonematrix(grafton)asabonegraftmaterialinthetreatmentofhumanperiodontalintraosseousdefects.
JIndianSocPeriod-ontol.
2013;17(4):495–502.
89.
KinneyRC,ZiranBH,HirshornK,SchlattererD,GaneyT.
Demineralizedbonematrixforfracturehealing:factorctionJOrthopTrauma.
2010;24(Suppl1):S52–5.
90.
GrabowskiG,CornettCA.
Bonegraftandbonegraftsubstitutesinspinesurgery:currentconceptsandcontroversies.
JAmAcadOrthopSurg.
2013;21(1):51–60.
91.
WitteLD,KaplanKL,NosselHL,LagesBA,WeissHJ,GoodmanDS.
Studiesofthereleasefromhumanplateletsofthegrowthfactorforculturedhumanarterialsmoothmusclecells.
CircRes.
1978;42(3):402–9.
92.
KaplanKL,BroekmanMJ,ChernoffA,LesznikGR,DrillingsM.
Plateletalpha-granuleproteins:studiesonreleaseandsub-cellularlocalization.
Blood.
1979;53(4):604–18.
93.
RossR,VogelA.
Theplatelet-derivedgrowthfactor.
Cell.
1978;14(2):203–10.
94.
DabraS,ChhinaK,SoniN,BhatnagarR.
Tissueengineeringinperiodontalregeneration:abriefreview.
DentResJ.
2012;9(6):671–80.
95.
RossR,RainesEW.
Platelet-derivedgrowthfactor:itsroleinhealthanddisease.
In:KudlowJE,MacLennanDH,BernsteinA,GotliebAI,editors.
Biologyofgrowthfactors,vol.
234.
Berlin:Springer;1988.
p.
9–21.
96.
KondoH,MatsudaR,YonezawaY.
Platelet-derivedgrowthfactorincombinationwithcollagenpromotesthemigrationofhumanskinbroblastsintoadenudedareaofacellmonolayer.
ExpCellRes.
1992;202(1):45–51.
97.
OatesTW,RouseCA,CochranDL.
Mitogeniceffectsofgrowthfactorsonhumanperiodontalligamentcellsinvitro.
JPeriod-ontol.
1993;64(2):142–8.
98.
YangD,ChenJ,JingZ,JinD.
Platelet-derivedgrowthfactor(PDGF)-AA:aself-imposedcytokineintheproliferationofhumanfetalosteoblasts.
Cytokine.
2000;12(8):1271–4.
99.
KitohH,KawasumiM,KanekoH,IshiguroN.
Differentialeffectsofculture-expandedbonemarrowcellsontheregener-ationofbonebetweenthefemoralandthetibiallengthenings.
JPediatrOrthop.
2009;29(6):643–9.
100.
TsaiCH,HsuHC,ChenYJ,LinMJ,ChenHT.
Usingthegrowthfactors-enrichedplateletglueinspinalfusionanditsefciency.
JSpinalDisordTech.
2009;22(4):246–50.
101.
CastroFPJ.
Roleofactivatedgrowthfactorsinlumbarspinalfusions.
JSpinalDisordTech.
2004;17(5):380–4.
102.
WeinerBK,WalkerM.
Efcacyofautologousgrowthfactorsinlumbarintertransversefusions.
Spine.
2003;28(17):1968–70.
103.
UristMR.
Bone:formationbyautoinduction.
Science.
1965;150(698):893–9.
104.
MiyazonoK,MaedaS,ImamuraT.
BMPreceptorsignaling:transcriptionaltargets,regulationofsignals,andsignalingcross-talk.
CytokineGrowthFactorRev.
2005;16(3):251–63.
105.
WuX,ShiW,CaoX.
MultiplicityofBMPsignalinginskeletaldevelopment.
AnnNYAcadSci.
2007;1116:29–49.
106.
BodenSD.
ClinicalapplicationoftheBMPs.
JBoneJointSurgAm.
2001;83(Suppl1):S161.
107.
BodenSD,SchimandleJH.
Biologicenhancementofspinalfusion.
Spine.
1995;20(24Suppl):113S–23S.
108.
CookSD,BarrackRL,ShimminA,MorganD,CarvajalJP.
Theuseofosteogenicprotein-1inreconstructivesurgeryofthehip.
JArthroplasty.
2001;16(8Suppl1):88–94.
109.
GarrisonKR,DonellS,RyderJ,ShemiltI,MugfordM,HarveyI,etal.
Clinicaleffectivenessandcost-effectivenessofbonemorphogeneticproteinsinthenon-healingoffracturesandspinalfusion:asystematicreview.
HealthTechnolAssess.
2007;11(30):1–150.
110.
MussanoF,CicconeG,CeccarelliM,BaldiI,BassiF.
Bonemorphogeneticproteinsandbonedefects:asystematicreview.
Spine.
2007;32(7):824–30.
111.
SalkeldSL,PatronLP,BarrackRL,CookSD.
Theeffectofosteogenicprotein-1onthehealingofsegmentalbonedefectstreatedwithautograftorallograftbone.
JBoneJointSurgAm.
2001;83-A(6):803–16.
112.
PolaE,NastoL,TampieriA,LattanziW,DiGiacomoG,Col-angeloD,CirielloV,PaganoE,SpinelliS,RobbinsP,etal.
Bioplastyforvertebralfractures:preliminaryresultsofapre-clinicalstudyongoatsusingautologousmodiedskinbroblasts.
IntJImmunopatholPharmacol.
2011;24(1Suppl2):139–42.
113.
ShieldsLB,RaqueGH,GlassmanSD,CampbellM,VitazT,HarpringJ,ShieldsCB.
Adverseeffectsassociatedwithhigh-doserecombinanthumanbonemorphogeneticprotein-2useinanteriorcervicalspinefusion.
Spine.
2006;31(5):542–7.
114.
HollandTA,MikosAG.
Biodegradablepolymericscaffolds.
Improvementsinbonetissueengineeringthroughcontrolleddrugdelivery.
AdvBiochemEngBiotechnol.
2006;102:161–85.
JMaterSci:MaterMed(2014)25:2445–24612459123115.
HutmacherDW.
Scaffoldsintissueengineeringboneandcar-tilage.
Biomaterials.
2000;21:2529–43.
116.
LucasPA,LaurencinC,SyftestadGT,DombA,GoldbergVM,CaplanAI,LangerR.
Ectopicinductionofcartilageandbonebywater-solubleproteinsfrombovineboneusingapolyanhydridedeliveryvehicle.
JBiomedMaterRes.
1990;24:901–11.
117.
MoriM,IsobeM,YamazakiY,IshiharaK,NakabayashiN.
Restorationofsegmentalbonedefectsinrabbitradiusbybio-degradablecapsulescontainingrecombinanthumanbonemor-phogeneticprotein-2.
JBiomedMaterRes.
2000;50:191–8.
118.
BabenseeJE,McIntireLV,MikosAG.
Growthfactordeliveryfortissueengineering.
PharmRes.
2000;17:497–504.
119.
DollB,SfeirC,WinnS,HuardJ,HollingerJ.
Criticalaspectsoftissue-engineeredtherapyforboneregeneration.
CritRevEu-karyotGeneExpr.
2001;11:173–98.
120.
RaicheAT,PuleoDA.
Invitroeffectsofcombinedandsequentialdeliveryoftwobonegrowthfactors.
Biomaterials.
2004;25:677–85.
121.
GovenderS,CsimmaC,GenantHK,Valentin-OpranA,AmitY,ArbelR,AroH,AtarD,etal.
Recombinanthumanbonemorphogeneticprotein-2fortreatmentofopentibialfractures:aprospective,controlled,randomizedstudyoffourhundredandftypatients.
JBoneJointSurgAm.
2002;84A:2123–34.
122.
FriedlaenderGE,PerryCR,ColeJD,CookSD,CiernyG,MuschlerGF,ZychGA,CalhounJH,LaForteAJ,YinS.
Osteogenicprotein-1(bonemorphogeneticprotein-7)inthetreatmentoftibialnonunions.
JBoneJointSurgAm.
2001;83A(Suppl1,Part2):S151–8.
123.
JensenTB,OvergaardS,LindM,RahbekO,BungerC,SoballeK.
Osteogenicprotein-1increasesthexationofimplantsgraftedwithmorcellisedboneallograftandProOsteonbonesubstitute:anexperimentalstudyindogs.
JBoneJointSurgBr.
2007;89:121–6.
124.
JensenTB,OvergaardS,LindM,RahbekO,BungerC,SoballeK.
Osteogenicprotein1deviceincreasesboneformationandbonegraftresorptionaroundcementlessimplants.
ActaOrthopScand.
2002;73:31–9.
125.
LindMC,LaursenM,JensenTB,OvergaardS,SoballeK,BungerCE.
Stimulationofbonehealingwithgrowthfactorsinorthopedicsurgery.
UgeskrLaeger.
2000;162:6399–403.
126.
KleinC,DriessenAA,DegrootK,VandenhooffA.
Biodegra-dationbehaviorofvariouscalcium-phosphatematerialsinbonetissue.
JBiomedMaterRes.
1983;17:769–84.
127.
KwonSH,JunYH,HongSH,LeeIS,KimHE,WonYY.
Calciumphosphatebioceramicswithvariousporositiesanddissolutionrates.
JAmCeramSoc.
2002;85:3129–31.
128.
KwonSH,JunYK,HongSH,KimHE.
Synthesisanddissolu-tionbehaviorofbeta-TCPandHA/beta-TCPcompositepow-ders.
JEurCeramSoc.
2003;23:1039–45.
129.
JiJ,RanJ,GouL,WangF,SunL.
MicrowaveplasmasinteringandinvitrostudyofporousHA/b-TCPbiphasicbioceramics.
KeyEngMater.
2005;280–283:1519–24.
130.
LuJ,BlaryM,VavasseurV,DescampsM,AnselmeK,Hard-ouinP.
Relationshipbetweenbioceramicssinteringandmicro-particles-inducedcellulardamages.
JMaterSciMaterMed.
2004;15:361–5.
131.
BurdickJA,AnsethKS.
PhotoencapsulationofosteoblastsininjectableRGD-modiedPEGhydrogelsforbonetissueengi-neering.
Biomaterials.
2002;23:4315–23.
132.
BurdickJA,MasonMN,HinmanAD,ThorneK,AnsethKS.
DeliveryofosteoinductivegrowthfactorsfromdegradablePEGhydrogelsinuencesosteoblastdifferentiationandmineraliza-tion.
JControlRelease.
2002;83:53–63.
133.
KretlowJD,MikosAG.
Review:mineralizationofsyntheticpolymerscaffoldsforbonetissueengineering.
TissueEng.
2007;13:927–38.
134.
RezwanK,ChenQZ,BlakerJJ,BoccacciniAR.
Biodegradableandbioactiveporouspolymer/inorganiccompositescaffoldsforbonetissueengineering.
Biomaterials.
2006;27:3413–31.
135.
LiuX,MaPX.
Polymericscaffoldsforbonetissueengineering.
AnnBiomedEng.
2004;32:477–86.
136.
SchliephakeH,WeichHA,SchulzJ,GruberR.
Invitrochar-acterizationofaslowreleasesystemofpolylacticacidandrhBMP2.
JBiomedMaterResA.
2007;83:455–62.
137.
MontjoventMO,MathieuL,SchmoekelH,MarkS,BourbanPE,ZambelliPY,Laurent-ApplegateLA,PiolettiDP.
Repairofcriticalsizedefectsintheratcraniumusingceramic-reinforcedPLAscaffoldsobtainedbysupercriticalgasfoaming.
JBiomedMaterResA.
2007;83:41–51.
138.
SchliephakeH,WeichHA,DullinC,GruberR,FrahseS.
MandibularbonerepairbyimplantationofrhBMP-2inaslowreleasecarrierofpolylacticacid—anexperimentalstudyinrats.
Biomaterials.
2008;29:103–10.
139.
YoonSJ,ParkKS,KimMS,RheeJM,KhangG,LeeHB.
Repairofdiaphysealbonedefectswithcalcitriol-loadedPLGAscaffoldsandmarrowstromalcells.
TissueEng.
2007;13:1125–33.
140.
RichardsonTP,PetersMC,EnnettAB,MooneyDJ.
Polymericsystemfordualgrowthfactordelivery.
NatBiotechnol.
2001;19:1029–34.
141.
VirtoMR,ElorzaB,TorradoS,ElorzaMDL,FrutosG.
Improvementofgentamicinpoly(D,L-lactic-co-glycolicacid)microspheresfortreatmentofosteomyelitisinducedbyortho-pedicprocedures.
Biomaterials.
2007;28:877–85.
142.
LiuSJ,ChiPS,LinSS,UengSW,ChanEC,ChenJK.
Novelsolvent-freefabricationofbiodegradablepoly-lactic-glycolicacid(PLGA)capsulesforantibioticsandrhBMP-2delivery.
IntJPharm.
2007;330:45–53.
143.
NieH,WangCH.
FabricationandcharacterizationofPLGA/HApcompositescaffoldsfordeliveryofBMP-2plasmidDNA.
JControlRelease.
2007;120:111–21.
144.
LeachJK,KaiglerD,WangZ,KrebsbachPH,MooneyDJ.
CoatingofVEGF-releasingscaffoldswithbioactiveglassforangiogenesisandboneregeneration.
Biomaterials.
2006;27:3249–55.
145.
MurphyWL,PetersMC,KohnDH,MooneyDJ.
Sustainedreleaseofvascularendothelialgrowthfactorfrommineralizedpoly(lactide-co-glycolide)scaffoldsfortissueengineering.
Biomaterials.
2000;21:2521–7.
146.
RichardsonTP,MurphyWL,MooneyDJ.
PolymericdeliveryofproteinsandplasmidDNAfortissueengineeringandgenetherapy.
CritRevEukaryotGeneExpr.
2001;11:47–58.
147.
PeterSJ,MillerMJ,YaskoAW,YaszemskiMJ,MikosAG.
Polymerconceptsintissueengineering.
JBiomedMaterRes.
1998;43:422–7.
148.
ChenRR,SilvaEA,YuenWW,MooneyDJ.
Spatio-temporalVEGFandPDGFdeliverypatternsbloodvesselformationandmaturation.
PharmRes.
2007;24:258–64.
149.
LeachJK.
Multifunctionalcell-instructivematerialsfortissueregeneration.
RegenMed.
2006;1:447–55.
150.
SalvayDM,SheaLD.
InductivetissueengineeringwithproteinandDNA-releasingscaffolds.
MolBioSyst.
2006;2:36–48.
151.
QuirkR,ChanW,DaviesM,TendlerS,ShakesheffK.
Poly(L-lysine)-GRGDSasabiomimeticsurfacemodierforpoly(lacticacid).
Biomaterials.
2001;22:865–72.
152.
YangX,RoachH,ClarkeN,HowdleS,QuirkR,ShakesheffK,OreffoR.
Humanosteoprogenitorgrowthanddifferentiationonsyntheticbiodegradablestruturesaftersurfacemodication.
Bone.
2001;29:523–31.
153.
WhitakerM,QuirkR,HowdleS,ShakesheffK.
Growthfactorreleasefromtissueengineeringscaffolds.
JPharmPharmacol.
2001;53:1427–37.
2460JMaterSci:MaterMed(2014)25:2445–2461123154.
SealB,OteroB,PanitchA.
Polymericbiomaterialsfortissueandorganregeneration.
MaterSciEng.
2001;R34:147–230.
155.
TabataY.
Theimportanceofdrugdeliverysystemsintissueengineering.
PharmSciTechToday.
2000;3:80–9.
156.
LeeK,PetersM,AndersonK,MooneyD.
Controlledgrowthfactorreleasefromsyntheticextracellularmatrices.
Nature.
2000;408:998–1000.
157.
ItohS,KikuchiM,TakakudaK,KoyamaY,MatsumotoH,IchinoseS,TanakaJ,KawauchiT,ShinomiyaK.
Thebiocom-patibilityandosteoconductiveactivityofanovelhydroxyapa-tite/collagencompositebiomaterial,anditsfunctionasacarrierofrhBMP-2.
JBiomedMaterRes.
2001;54:445–53.
158.
CooperA.
Polymersynthesisandprocessingusingsupercriticalcarbondioxide.
JMaterChem.
2001;10:207–34.
159.
HowdleS,WatsonM,WhitakerM,PopovM,DaviesM,MandelF,WangJ,ShakesheffK.
Supercriticaluidmixing:preparationofthermallysensitivepolymercompositescontain-ingbioactivematerials.
ChemCommun.
2001;109–110.
160.
CartmellS.
Controlledreleasescaffoldsforbonetissueengi-neering.
JPharmSci.
2009;98:430–41.
161.
SillTJ,vonRecumHA.
Electrospinning:applicationsindrugdeliveryandtissueengineering.
Biomaterials.
2008;29:1989–2006.
162.
PiskinE,IsogluIA,BolgenN,VargelI,GrifthsS,CavusogluT,KorkusuzP,GuzelE,CartmellS.
Invivoperformanceofsimvastatin-loadedelectrospunspiral-woundpolycaprolactonescaffoldsinreconstructionofcranialbonedefectsintheratmodel.
JBiomedMaterResA.
2009;90(4):1137–51.
163.
KatoY,OnishiH,MachidaY.
Applicationofchitinandchitosanderivativesinthepharmaceuticaleld.
CurrPharmBiotechnol.
2003;4:303–9.
164.
MurphyWL,MooneyDJ.
Controlleddeliveryofinductiveproteins,plasmidDNAandcellsfromtissueengineeringmatrices.
JPeriodontalRes.
1999;34:413–9.
165.
AlbuhairanB,HindD,HutchinsonA.
Antibioticprophylaxisforwoundinfectionsintotaljointarthroplasty:asystematicreview.
JBoneJointSurgBr.
2008;90:915–9.
166.
PriceJS,TencerAF,ArmDM,BohachAG.
Controlledreleaseofantibioticsfromcoatedorthopedicimplants.
JBiomedMaterRes.
1996;30:281–6.
167.
NaraharisettiPK,GuanLeeHC,FuYC,LeeDJ,WangCH.
Invitroandinvivoreleaseofgentamicinfrombiodegradablediscs.
JBiomedMaterResBApplBiomater.
2006;77:329–37.
168.
LiH,ChangJ.
Preparation,characterizationandinvitroreleaseofgentamicinfromPHBV/wollastonitecompositemicro-spheres.
JControlRelease.
2005;107:463–73.
169.
RamchandaniM,RobinsonD.
InvitroandinvivoreleaseofciprooxacinfromPLGA50:50implants.
JControlRelease.
1998;54:167–75.
170.
PorterJR,RuckhTT,PopatKC.
Bonetissueengineering:areviewinbonebiomimeticsanddrugdeliverystrategies.
Bio-technolProg.
2009;25(6):1539–60.
171.
Raposo-AmaralCE,BuenoDF,AlmeidaAB,JorgettiV,CostaCC,GouveiaCH,VulcanoLC,FanganielloRD,Passos-BuenoMR,AlonsoN.
IsbonetransplantationthegoldstandardforrepairofalveolarbonedefectsJTissueEng.
2014;5:2041731413519352.
172.
LattanziW,PolaE,PecoriniG,LogroscinoCA,RobbinsPD.
Genetherapyforinvivoboneformation:recentadvances.
EurRevMedPharmacolSci.
2005;9(3):167–74.
173.
LattanziW,ParrillaC,FetoniA,LogroscinoG,StrafaceG,PecoriniG,etal.
Exvivo-transducedautologousskinbroblastsexpressinghumanLimmineralizationprotein-3efcientlyformnewboneinanimalmodels.
GeneTher.
2008;15(19):1330–43.
174.
LudwigSC,KowalskiJM,BodenSD.
Osteoinductivebonegraftsubstitutes.
EurSpineJ.
2000;9(Suppl1):S119–25.
175.
LogroscinoG,LattanziW.
Bonesubstitutioninspinefusion:thepast,thepresentandthefuture.
In:MenchettiPPM,editor.
Minimallyinvasivesurgeryofthelumbarspine.
Berlin:SpringerVerlag;2014.
p.
311–31.
176.
ParrillaC,SaulnierN,BernardiniC,PattiR,TartaglioneT,FetoniAR,PolaE,PaludettiG,MichettiF,LattanziW.
Undifferentiatedhumanadiposetissue-derivedstromalcellsinducemandibularbonehealinginrats.
ArchOtolaryngolHeadNeckSurg.
2011;137(5):463–70.
177.
Gomez-BarrenaE,RossetP,MullerI,GiordanoR,BunuC,LayrolleP,etal.
Boneregeneration:stemcelltherapiesandclinicalstudiesinorthopaedicsandtraumatology.
JCellMolMed.
2011;15(6):1266–86.
178.
PittengerMF,MackayAM,BeckSC,JaiswalRK,DouglasR,MoscaJD,etal.
Multilineagepotentialofadulthumanmesen-chymalstemcells.
Science.
1999;284(5411):143–7.
179.
SaulnierN,LattanziW,PuglisiMA,PaniG,BarbaM,PiscagliaAC,etal.
Mesenchymalstromalcellsmultipotencyandplas-ticity:inductiontowardthehepaticlineage.
EurRevMedPharmacolSci.
2009;13(Suppl1):71–8.
180.
HorwitzEM,LeBlancK,DominiciM,MuellerI,Slaper-Cor-tenbachI,MariniFC,etal.
ClaricationofthenomenclatureforMSC:theInternationalSocietyforCellularTherapypositionstatement.
Cytotherapy.
2005;7(5):393–5.
181.
ProckopDJ,OhJY.
Medicaltherapieswithadultstem/progen-itorcells(MSCs):abackwardjourneyfromdramaticresultsinvivotothecellularandmolecularexplanations.
JCellBio-chem.
2012;113(5):1460–9.
182.
MuragliaA,CanceddaR,QuartoR.
Clonalmesenchymalpro-genitorsfromhumanbonemarrowdifferentiateinvitroaccordingtoahierarchicalmodel.
JCellSci.
2000;113(Pt7):1161–6.
183.
HorwitzEM,ProckopDJ,FitzpatrickLA,KooWW,GordonPL,NeelM,etal.
Transplantabilityandtherapeuticeffectsofbonemarrow-derivedmesenchymalcellsinchildrenwithosteogenesisimperfecta.
NatMed.
1999;5(3):309–13.
184.
ChamberlainJR,SchwarzeU,WangPR,HirataRK,HankensonKD,PaceJM,etal.
Genetargetinginstemcellsfromindivid-ualswithosteogenesisimperfecta.
Science.
2004;303(5661):1198–201.
185.
UccelliA,MorettaL,PistoiaV.
Mesenchymalstemcellsinhealthanddisease.
NatRevImmunol.
2008;8(9):726–36.
186.
BiancoP,CaoX,FrenettePS,MaoJJ,RobeyPG,SimmonsPJ,WangCY.
Themeaning,thesenseandthesignicance:trans-latingthescienceofmesenchymalstemcellsintomedicine.
NatMed.
2013;19(1):35–42.
187.
BarbaM,CicioneC,BernardiniC,MichettiF,LattanziW.
Adipose-derivedmesenchymalcellsforboneregereneration:stateoftheart.
BiomedResInt.
2013;2013(416391):11.
188.
BarbaM,CicioneC,BernardiniC,CampanaV,PaganoE,MichettiF,LogroscinoG,LattanziW.
Spinalfusioninthenextgeneration:geneandcelltherapyapproaches.
SciWorldJ.
2014;2014(406159):9.
189.
LattanziW,BernardiniC.
Genesandmolecularpathwaysoftheosteogenicprocess.
In:LinY,editor.
Osteogenesis.
Rijeka:In-tech;2011.
p.
21–56.
190.
GiannoudisPV,EinhornTA,MarshD.
Fracturehealing:thediamondconcept.
Injury.
2007;38(Suppl4):S3–6.
JMaterSci:MaterMed(2014)25:2445–24612461123