Bioresorbability, porosity and mechanical strength of bone substitutes: what is optimal for bone regeneration?

Bioresorbability, porosity and mechanical strength of bone

substitutes

Citation for published version (APA):

Hannink, G., & Arts, J. J. C. (2011). Bioresorbability, porosity and mechanical strength of bone substitutes: what

is optimal for bone regeneration? Injury, 42(SUPPL. 2), S22-S25. https://doi.org/10.1016/j.injury.2011.06.008

DOI:

10.1016/j.injury.2011.06.008

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Published: 01/09/2011

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Bioresorbability,

porosity

and

mechanical

strength

of

bone

substitutes:

What

is

optimal

for

bone

regeneration?

Gerjon

Hannink

a

,

J.J.

Chris

Arts

b,

*

a_{OrthopaedicResearchLaboratory,DepartmentofOrthopaedics,RadboudUniversityNijmegenMedicalCentre,Nijmegen,TheNetherlands} b

DepartmentofOrthopaedicSurgery,ResearchSchoolCaphri,MaastrichtUniversityMedicalCentre,Maastricht,TheNetherlands

Introduction

Annually,morethan2.2millionbonegraftingproceduresare performedworldwide.1_{Thecurrentgoldstandardforbonerepair}

istheuseofautologousbonegraftsharvestedfromaremotesitein thepatient.Afewofthemanyproblemsassociatedwithautografts includedonor site morbidity andthe restrictedavailability.2 _In

additiontoautografts,successhasbeenreportedwiththeuseof allografts.Liketheautografts,theseallograftsarealsolimitedin supplyandthereexistsariskofdiseasetransmissionandimmune rejection.Despitethebenefitsofbothautograftsandallografts,the relativeconcerns over their usehasled tothedevelopment of numeroussyntheticbonesubstitutes.

Oneofthemostpromisinggroupsofsyntheticbonesubstitutes arecalciumphosphateceramics(CaPs).Themostcommonlyused CaPsarehydroxyapatite(HA)andtricalciumphosphate(TCP)oran intrinsiccombinationofthetwo.3,4

The rationale for the development of CaPs has been their similarityincompositiontobonemineralandtheirsimilaritiesin

somepropertiesofbone,suchasbiodegradability,bioactivityand osteoconductivity. Another important property of bone, inter-connectingporositycanbeintroducedduringthemanufacturing processofCaPs.Besidesthesedesirableproperties,CaPsareknown tohave relatively low mechanical properties and are therefore mostlynotsuitableforapplicationinload-bearingareas,astheydo notprovidesufficientstructuralsupport.5_{Aproperunderstanding}

oftheseproperties,bothbiologicalandmechanical,arecriticalfor the successful application of CaPs as bone substitutes. In this review we describe and discuss the interaction between these propertiesinsearchofwhatisoptimalforboneregeneration. Bonecell–ceramicinteractions

AlthoughTCPandHA derivedthroughthermaltreatmentdo notexistnaturally,theyhavebeenshowntoinduceabiological responsesimilartothatofbone.3,5_{Cellsattachtoandengulfthe}

CaPs,causingthemtobiodegradeinvitroandinvivo.CaPsallow osteoblastcellstoattach,proliferate,anddifferentiate. Differenti-atingosteoblastcellsproducecollagentypeI,alkaline phospha-tase, proteoglycans, and matrix proteins, such as osteocalcin, osteopontin, and bone sialoprotein known to signify bone formation.5 _{Cellular response is affected bythe composition of} ARTICLE INFO Keywords: Bonesubstitutes Porosity Calciumphosphate Biodegradability Boneregeneration ABSTRACT

Bonerepairisamulti-dimensionalprocessthatrequiresosteogeniccells,anosteoconductivematrix, osteoinductivesignalling,mechanicalstabilityandvascularization.Inclinicalpractice,bonesubstitute materialsarebeingusedforreconstructivepurposes,bonestockaugmentation,andbonerepair.Over thelast decade,theuseofcalciumphosphate(CaP)basedbone substitutematerialshasincreased exponentially.Thesebonesubstitutematerialsvaryincomposition,mechanicalstrengthandbiological mechanismoffunction,eachhavingtheirownadvantagesanddisadvantages.Itisknownthatintrinsic materialpropertiesofCaPbonesubstituteshaveaprofoundeffectontheirmechanicalandbiological behaviour and associated biodegradation. These material properties of bone substitutes, such as porosity, composition and geometry change the trade-off between mechanical and biological performance.Thechoiceoftheoptimalbone substitutesisthereforenotalwaysaneasyone,and largelydependsontheclinicalapplicationanditsassociatedbiologicalandmechanicalneeds.Notall bonegraftsubstituteswillperformthesameway,andtheirperformanceinoneclinicalsitemaynot necessarilypredicttheirperformanceinanothersite.CaPbonesubstitutesunfortunatelyhaveyetto achieveoptimalmechanicalandbiologicalperformanceandtodateeachmaterialhasitsowntrade-off betweenmechanicalandbiologicalperformance.Thisreviewdescribestheeffectofintrinsicmaterial propertiesonbiologicalperformance,mechanicalstrengthandbiodegradabilityofCaPbonesubstitutes.

ß2011ElsevierLtd.

*Correspondingauthor.Tel.:+31433874502. E-mailaddress:j.arts@mumc.nl(J.J.ChrisArts).

ContentslistsavailableatScienceDirect

Injury

j ou rna l h ome p a ge : w ww . e l se v i e r. co m/ l oc a te / i n j ury

0020–1383ß2011ElsevierLtd.

doi:10.1016/j.injury.2011.06.008

Open access under the Elsevier OA license.

CaPs.Forexample,zincfromzinccontainingtricalciumphosphate orfluoride (F)fromF-apatite or carbonate-F-apatite have been showntoinhibitosteoclasticactivity.5,6_{Ontheotherhand,Fin}

F-apatiteorMgorZnand/orForcombinationofthethreeionsin carbonateapatitematrixwasshowninvitrotopromotecollagen production and phenotypic expression of proteoglycans and matrixproteinsassociatedwithbonemineralization.The forma-tion of distinct resorption pits on HA and TCP surfacesin the presenceofosteoclastswasalsoobserved.7,8 _{Factorsthat affect}

cellularresponsetoCaPsincludesurfacetopography(roughness), geometry,composition,andparticlesize.5

Biodegradability

Ideally,therateofresorptionofCaPsissimilartotherateofnew bone formationbut for obvious reasonsnot anyfaster. In vivo biodegradabilitycanbeachievedbydissolutionoriscellmediated. The population of cells responsible for the resorption of CaPs mainlyconsistsofmultinuclearcellsandosteoclasts.7,8_However,

macrophagesareinvolvedinthephagocytosisofCaPsaswell.9_The

speed of biodegradability and the cell type involved in the resorption processare determinedby both material properties, suchas Ca/P ratio,crystallinity, particle size, surface area, and porosity and the local biological environment, suchas pH, the presenceofcells,andH2Ocontent.3Ingeneral,CaPsconsistingof

TCPhavehigherdegradationratesascomparedtoCaPsconsisting ofHA.10

Recently, new tools have been developed to assess the incorporation, remodelling, and resorption of biomaterials in patients. High-resolution peripheral QCT makes it possible to assesschangesinboneandbiomaterial/CaPstructureanddensity invivo/insituwitharelativelyhigh(82

m

m)resolution.11_Thelow

radiationexposureassociatedwiththistechniquemakes longitu-dinalfollow-upin patients possibleandwill providelong-term clinicaldataoftheincorporation,remodellingandresorptionbone substitutematerials over time. In addition,FEA modelscan be buildfromtheQCTimagestoquantifychangesinboneandbone graft substitutestrength. Another, promising method tofollow bonemetabolismand bloodflowinpatientsis18F-fluoridePET scanning.12,13_{However,dataon thelong-termfollow-upofCaP}

bonesubstitutesimplantedinpatientsisstillratherlimited. Poresize

Poresincalciumphosphatematerialsarenecessaryforbone tissueformationbecausetheyallowmigrationandproliferationof osteoblastsandmesenchymalcells,aswellasvascularization.In addition, a porous surface improves mechanical interlocking (interdigitation) between the implant biomaterial and the surroundingnaturalbone,providinggreatermechanicalstability atthiscriticalinterface.14

Poresizecanbedividedintwodifferentgroups:microporous (<5

m

mpores)andmacroporous(>100

m

mpores).14,15

Micropo-rosityandmacroporosityareimportantforthebioresorbabilityof thematerial.Inaddition,macroporosityplaysanimportantrolein theosteoconductivity.3,5

Theminimumrecommendedporesizeforabonesubstituteis 100

m

m,16_{butsubsequentstudieshaveshownbetterosteogenesis}

for substitutes with pores >300

m

m.14,17,18 _{Smaller pores (75–}

100

m

m)resultediningrowthofunmineralizedosteoidtissueor werepenetratedonlybyfibroustissue(10–44and44–75

m

m).16

However,usinglaserperforationtechniquesandtitaniumplates, fourdifferentporesizes(50,75,100and125

m

m)weretestedin rabbitfemoraldefectsundernon-load-bearingconditions.19_Bone

ingrowthwassimilarinalltheporesizessuggestingthat100

m

m maynotbethecriticalporesizefornon-load-bearingconditions.A

very interesting aspect of the effect of pore size on bone regenerationistheimpactontheprogressiontowards osteogene-sis.Relativelylargerporesfavourdirectosteogenesis,sincethey allowvascularizationandhighoxygenation,whilstsmallerpores result in osteochondral ossification, although the type of bone ingrowthdependsonthematerialitselfandthegeometryofthe pores.18,20

Porosity

Manystudieshavedemonstratedagreaterdegreeand faster rate of bone ingrowth or apposition withpercentage porosity; however, there still seems to be some dispute regarding the optimum ‘‘type’’ of porosity. The rate and quality of bone integration have been related to a dependence on pore size, porosityvolumefraction,andinterconnectivity,bothasafunction ofstructuralpermeabilityandmechanics.21_{Boneregenerationina}

scaffoldinvivoinvolvesrecruitmentandpenetrationofcellsfrom the surroundingbone tissue, as wellas vascularization.Higher porosity is expected to enhance osteogenesis and numerous studieshaveverifiedthishypothesis.Theseresultswerelikelydue tothelargersurfaceareathatresultedinhigherionexchangeand bone-inducingfactoradsorption.10,21_{Therearealimitednumber}

ofreportsintheliteraturethatshownoeffectofporosityonthe amountofappositedbone.22,23_{Theabsenceofanyreportsonthe}

beneficialeffectsoflowerporosityscaffoldsinvivosolidifiesthe requirementofhighlyporousimplantsforboneregeneration.

Microporosityresultsinlargersurfaceareathatisbelievedto contributetohigherboneinducingproteinadsorptionaswellasto ionexchangeandbone-likeapatiteformationbydissolutionand reprecipitation.21Surfaceroughnessenhancesattachment, prolif-erationanddifferentiationofanchoragedependentboneforming cells.5

High porosity and large pores enhance bone ingrowth and osseointegrationoftheimplantaftersurgery.14_{Althoughthereare}

afewreportsinliteratureshowingnodifferenceintheosteogenic outcomeforscaffoldswithdifferentporosities,therearenoreports indicatingabeneficialeffectforimplantswithlowporosity.Other factors, such as the rate of degradation and the mechanical performanceofthescaffoldshouldbetakenintoaccountwhen porosityisassessed.

Interconnectivity

Anotherimportantfactorthatdeterminestheeffectivenessof porosityisthestructureoftheporeswithrespecttoeachother. Theporesmayeitherbeinterconnectingortheycontain ‘‘dead-ends’’.15_{Interconnectingmacroporosityis introducedby adding}

porogens,suchasnaphthalene,H2O2,polymericporogensorusing

the foaming method.4 _{Microporosity depends on sintering}

temperatureorsinteringprogram.CaPsinteredat12008Cshows significantlylessmicroporositythanthatsinteredat10008Canda dramaticchangeincrystalsize.5

Ingeneral,calciumphosphateswithinterconnectiveporesare advantageousoverbiomaterialscontainingdead-endpores,because aspatialcontinuousconnectionoftheporesystemhasadecisive meaningfortheingrowthofnewbone,especiallyinlong-termtissue interfacemaintenance.15_{However,whenusedincombinationwith}

osteogeniccells,materialscontaininginterconnectiveporesareless abletocontainosteogeniccells,resultinginalongerperioduntilthe porespacehasbeenfilledwithnewlyformedbone.24

Biomechanicalproperties

The property that is most often used to characterize the mechanical behaviour of bone substitutes is their compressive G.Hannink,J.J.C.Arts/Injury,Int.J.CareInjured42(2011)S22–S25 S23

strength.Sincethesematerialsareintendedtobeusedasbone substitutes,itisimportanttokeepinmindthatthecompressive strengthofhumancorticalbonerangesbetween90and230MPa (withtensilestrengthsrangingfrom90to190MPa),whereasthe compressivestrength ofcancellousbone rangesbetween2 and 45MPa.25,26

Calcium phosphates generallyprovidelimited biomechanical support,becausetheyarebrittleandhavelittletensilestrength. TCPs are less brittle compared with HA. However, the faster degradation of TCP results in subsequent quicker loss of mechanicalstrengthovertime.

Although increased porosity and pore size facilitate bone ingrowth,theresultisareductioninmechanicalproperties,since thiscompromisesthestructuralintegrityofthescaffold.Moreover, scaffoldsfabricatedfromceramicswitha highdegradationrate shouldnothavehighporosities(>90%),sincerapiddepletionofthe materialwillcompromisethemechanicalandstructuralintegrity beforesubstitutionbynewlyformedbone.14

However,thereisanupperlimitinporosityandporesizesetby constraintsassociatedwithmechanicalproperties.Anincreasein thevoidvolumeresultsinareductioninmechanicalstrengthof thescaffold,whichcanbecriticalforregenerationinload-bearing bones.Forexample,anincreaseofthetotalporousvolumefrom10 to20%resultsinafactorfourdecreaseinmechanicalstrength.15,27

The extent to which pore size can be increased whilst maintaining mechanical requirements is dependent on many factors,includingthenatureofthematerialandtheprocessing conditionsusedinitsfabrication.

Bioactivity,osteoconductivityandosteoinductivity

Bioactivityisdefinedasthepropertyofmaterialstodevelopa direct,adherent,andstrongbondingwiththebonetissue.3_Froma

cellular perspective, bioactivity reflects the attachment and differentiationofosteogeniccellsonceramicsurfaces.24

Osteoconductivity is the ability of a material to serve as a scaffold toguide formation of newly formingbone along their surfaces.Osteoinductivityistheinherentabilityofamaterialto induceboneformationwithoutthepresenceofosteogenicfactors andisusuallydemonstratedbyboneformationafterimplantation ofthesematerialsinanectopicsite.28,29

CaPmaterialsaregenerallyknowntobeosteoconductivebut notosteoinductive.However,severalCaPmaterials,suchasporous synthetic and coralline HA,

b

-TCP, and calcium phosphate cements, have been shown to have to abilityto form bone in ectopic sites in different animals without the addition of osteogenicfactors.Theosteoinductivepropertiesofthese materi-alsappear tobe based on their architectural features, suchas surfacegeometry,topography,poresize,andporositywhichallow entrapmentandconcentrationofcirculatingBMPsinthebiologic fluid.3,5,30,31 _{The main challenge remains to determine the}

appropriatearchitectureforthesematerialstooptimizetheability toentrapandconcentrategrowthfactorsand/orosteoprogenitor cells.

Independent of architectural features, CaPs or CaP-based compositematerialscombinedwithBMPs,osteoprogenitorcells, andbioactiveproteinsorpeptideshavebeenshowntoenhance bone formation.32–34 _{The main challenges for this so-called}

engineeredosteoinductivityaretodeterminetheoptimalscaffold, the appropriate dose of osteogenic factors, and the controlled releaseofthesefactorsfordifferentapplications.

Discussion

Theideaofanoptimalbonegraftsubstituteusableinallclinical indications, although alluring, is an idle one. Most bone graft

substitutesneedtobeinsertedintoastablehostsitethatcontains adequate vascularity and an adequate source of osteoblast precursorcells. In anappropriate site,thesegraft materialsare eventuallyresorbedand replacedbyhostbone. However,ifthe operativesiteismechanicallyunstableorifthereareinadequate cells orotherhostfactorslimiting bonehealing, problemsmay occur.Co-morbiditiesofthepatient,suchasosteoporosisand/or diabetes,willalsonegativelyinfluencetheinvivoperformanceand capacityofthebiomaterialtoincorporate.

Therefore,thebonesubstituteofchoicedependslargelyonthe clinicalapplicationanditsassociated biologicalandmechanical needs.35_{Itissensibletoassumethatnotallbonegraftsubstitutes}

willperformthesamewayandthatthevalidationofabonegraft substitute in one clinical site may not necessarily predict its performance in another location.1,36 Non-invasive and non-destructivequantitativeimagingmodalitieshavebecomeauseful tools in monitoring the performance of CaPs in different locations.11–13

Thelargevarietyofbonesubstitutesavailableonthemarket represents not only the different clinical needs and scenarios encountered, but also the diversity of the expected clinical outcomes. The surgeon has to assess the requirements of the bonedefecttobegrafted,thinkofthepropertiesneededforrepair, and ultimately choose the appropriate bone substitute and its associatedsurgicaltechnique.Thechoiceoftheappropriatebone substitutescaffoldshouldbebasedonseveralparametershaving inmindthatthegoldstandardremainstheautograft.

Overtherecentyears,hybridbonesubstitutematerialshave appearedonthemarket.Usuallythebasisisanosteoconductive TCPorHAcalciumphosphatescaffoldwhichhasbeencombined withothercompoundstoenhancethemechanicalorthebiological performance.37,38_{Clinicalstudiesinvolvingtheadditionofgrowth}

factors, suchas BMP-2 and BMP-7 toCaPs have demonstrated remarkable osteoinductive capacities.39,40 _{The incorporation}

of such factors to create osteoinductive scaffolds remains a promising option. In the near future, complex combination productsthat includecells,growthfactors,and/orgenetherapy incombinationwithscaffoldswithoptimalgeometriesarelikelyto givesurgeonsmoreeffectivetoolsfordefect/applicationspecific bonerepair.

Conflictofintereststatement

The authors state that theyreceived nothing of value with regardtothismanuscript.Thereisnoconflictofinterest. References

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