Therepairoflargecartilagelesions,whicharecontraindicatedforcurrentlyavailablefirst-linetissue regenerationtechniques,remainsasignificantclinicalproblemwithfewgoodtreatmentoptions.Previouswork atCytexhasfocusedonthedevelopmentofa3Dmicrowoventextilescaffoldforcartilagerepair,designedto functionimmediatelyafterimplantationwhileencouragingcellingrowth,proliferation,andsubsequenttissue development.Whencombinedwithmesenchymalstemcells(MSCs),wehavedemonstratedtheabilitytoform biomechanicallyfunctionalimplantsforthetreatmentoflargecartilagelesions,includingresurfacingthe femoralcondyles.However,forastemcell-basedcartilageimplanttobesuccessfulintheosteoarthritic(OA) joint,itmustwithstandthethehighdegreeofinflammationandtheassociatedcatabolicanddegenerative environmentfoundindiseasedjoints.Theobjectiveofthisproposalistoaddananti-inflammatorycapabilityto ourconstructinordertoprotecttheengineeredtissuesfromthehostilejointenvironment.Wewilltransduce theMSCsinourimplantwithaninflammation-responsivepromoterthatwilldrivetheexpressionofInterleukin 1(IL-1)receptorantagonist(IL-1Ra)orsolubletumornecrosisfactor(TNF)receptor(sTNFR),natural modulatorsthatinhibittheinflammatorysignalingofIL-1andTNF?,respectively.Theresultingcartilage constructwillprovideinflammationresistanceonlywheninflammatorysignalingispresent,thuseliminatingthe needforexogenousinjectionsandthepotentialsideeffectsassociatedwithlong-termadministrationofanti- cytokinetherapy.
In Aim1, wewillexamineourlentiviraltransductionconditionsinanefforttominimizetherisk ofgeneticsideeffectsintheMSCs.Theresultingcartilageconstructswillalsobeanalyzedtoensurethatthey containnoactivelentiviralparticles,whichcouldbereleaseduponimplantation,therebyvalidatingtheclinical safetyofthegeneticapproach.
In Aim2, wewilluseourbiomimeticcartilageimplantstoresurfacethemedial femoralcondyleinagoatmodelofunicompartmentalosteoarthritis.Ourcurrenttissueengineeredimplantwill becomparedtoimplantsinwhichtheMSCpopulationhasbeentransducedtoexpressanti-cytokine therapeuticsineitheraconstant,oraninflammation-responsivemanner.Allanimalswillbeevaluatedat3,6,9, and12-monthtimepointsfollowingrepairthroughclinicallyrelevantmeasuresoffunction,pain,andimaging usingX-RaysandMRI.Atsacrifice,jointtissueswillbeassessedhistologicallyandbiomechanicallytoquantify degradativechangesandOAprogression.Serum,synovialfluid,andsynoviumwillbeanalyzedforbiomarkers ofosteoarthritis,aswellasforadverseinflammatoryreactionsandtotestforweardebrisinthejoint. Additionally,allmajororgansystemswillbeexaminedtoassessthesafetyofimplantingtransducedcellsand utilizinglocalizedanti-cytokinetherapy.Ultimately,thisproposalwilldevelopacartilageresurfacingproduct thatisnotonlybeabletofunctionmechanicallywithinthejointbutwillalsoprotectitselfandsurrounding tissuesfrominflammatorysignaling,andhopefullypreventfurtherOAprogression.
Osteoarthritis is a significant source of pain and disability that affects over 30 million adults in the United States. Diseased and damaged joints exhibit elevated levels of inflammation that can compromise the effectiveness of biologically-based cartilage repair strategies. The objective of this study is to develop functionalengineeredarticularcartilagethatcansensethedegreeofinflammationinthejointenvironmentand respondinananti-inflammatorymannertoprotectitselffromdegradation.
