NicolasL’Heureux,Ph.D.DirectorofResearch(DR2–Inserm)DeputyDirector,BioTis(U1026)CoordinatorofTissueEngineeringandBiofabrication,BordeauxConsortiumforTissueEngineering(BxCRM).

Nicolas.lheureux@inserm.frTel:+(33)05.57.57.17.23

ResearchInterests:Cell-assembledextracellularmatrix(CAM)Myinterestshavealwaysbeencenteredontheuseofhumancellstoproducetissue-engineeredconstructsfortherapeuticapplications.1,2MyexperiencehasbeenfocusedonthefieldofcardiovasculartissueengineeringbutIliketoalsodabbleinotherareas.For30years,Ihaveworkedonusingtheextracellularmatrixproducedbynormalhumancellsinculture.ThisCell-AssembledMatrix(CAM)isauniquematerialthatcanhaveremarkablemechanicalstrengthwhenproducedintherightcultureconditions.IhaveusedthisCAMtoproducesmall-diameter,tissue-engineeredbloodvessels(TEBV)thatdisplayburstpressuressimilarthatofnativehumanbloodvessels,butwithouttheneedforanyexogenousscaffoldingsuchasyntheticpolymersoranimal/cadaverictissues.1,3,4Becausetheydonotincludeforeignmaterials,becausetheCAMisnotchemicallyorotherwisedenatured,andbecausetheCAMisofhumanorigin,wewouldnotexpectconstructsbuildfollowingthisapproachtotriggeraresponsefromneithertheadaptivenortheinnateimmunesystem.Ispent15yearsastheco-founderandChiefScientificOfficerofCytograftTissueEngineering(SanFrancisco,California)drivingtheR&DefforttobringtheseTEBVstotheclinic.TheseautologousCAM-basedTEBVswerethefirstcompletelybiologicalTEBVstobeimplantedinhumansandthefirstTEBVstobeimplantedinthehigh-pressurearterialsystem.5,6TheseTEBVshaveshownremarkablepatencyasarteriovenousshuntforhemodialysisofendstagerenaldiseasepatientswith

A sheet of human CAM is a true bio-material that can have remarkablemechanical propertieswhile avoidingimmune and inflammatory reactions.(fromreview7)

durabilityofupto3years.Allogeneicandnon-livingTEBVshavealsobeensuccessfullyusedinpatients.8,9Thread-BasedTissueEngineering:orhowtomakeHumanTextiles.TheCAMisproducedatthebottomofcultureflasksassheetsofvariousshapesandsizes.10Thesheetscanbecut,stacked,foldedor,likeinthecaseoftheabove-mentionedbloodvessel,rolledtocreateavarietyoftissues.InthespecificcaseofTEBVs,thesheet-basedapproachhasasignificantdrawback:theneedforalongcultureperiod(maturation)toallowthecellstofusethedifferentlayersofsheetstogether.Inaddition,fusionislimitedtoacertaindepthbecauseoftransportissues,whichentailsatwo-layerstrategytocreatethickertissues.AtBioTis,IamnowdevelopinganewproductionmethodbasedontheuseofthreadsofCAMinsteadofsheets.11Takingadvantageofvarioustextiletechnologies(weaving,knitting,braiding),wecanliterallyproducehumantextileswithawiderangeofgeometries,porosities,(anisotropic)mechanicalproperties,andallthatwithregionaltunability.Inaddition,becausethreadscanbeconnectedtoeachother,thesizeoftheconstructsisnolongerlimitedtothesizeofcultureflasks.Butthemostinterestingadvantageofthisthread-basedapproachisthefactthatthecohesionoftheconstructsdoesnotrelyonamaturationphaseandisnothinderedbytransportlimitations.Indeed,thetextilesarereadyforuseassoonastheyareassembled,whichtakestheproductiontimeoftheTEBVfromroughly6monthstoabout2months(orevenless).Thedevelopmentofathread-basedTEBVisoneofthemainresearchprojectsinmygroup.However,becausetheCAMcanprovidenear-nativeconjunctivetissueinawiderangeofconfigurations12,wearealsoexploringotherapplicationsinRegenerativeMedicine.Particle-BasedTissueEngineering:moldableandinjectable.HumanCAMcanalsobeproducedintheformofparticlesthatcanbemoldedorinjected.Thisparticle-basedapproachcanbeusedtoproduceporousstructuresfortissueengineeringorcanevenbeinjecteddirectlyinvivotocreatenewtissues.Thishasobviousaestheticapplicationsbutalsotissuereconstructionandcell-deliveryapplications.BelowisschematicrepresentationofthevariousbuildingstrategieswehavedevelopedusingCAM:

AthreadofhumanCAMcanbespooledandusedas a suture or can be assembled in a complextridimensional tissue using classic textiletechnologies (weaving, braiding, knitting) tocreatehumantextiles.

Keywords/expertise:• Humancellculture• Bioreactors• Cardiovascularbiology• Endothelium• Fibroblasts• Smoothmusclecells• Tissue-engineering• Bioengineering• RegenerativeMedicine

• Cell-basedtherapies• Vasculargraft• Extracellularmatrix• Collagen• Histology• Immunofluorescence• Electronmicroscopy• Mechanicalproperties• Mechanicalstimulation

• Pre-clinicalstudies• Clinicaltrials• Translationalmedicine• Entrepreneurship• Startup• Patents• Technologytransfer

Citedpublications:

[1]L'Heureux,N.,Paquet,S.,Labbe,R.,Germain,L.,Auger,F.A.,Acompletelybiologicaltissue-engineeredhumanbloodvessel,FASEBJ.12(1)47-56(1998).

[2]L'Heureux,N.,Germain,L.,Labbe,R.,Auger,F.A.,Invitroconstructionofahumanbloodvesselfromculturedvascularcells:amorphologicstudy,JournalofVascularSurgery17(3)499-509(1993).

[3]Konig,G.,McAllister,T.N.,Dusserre,N.,Garrido,S.A.,Iyican,C.,Marini,A.,Fiorillo,A.,Avila,H.,Wystrychowski,W.,Zagalski,K.,Maruszewski,M.,Jones,A.L.,Cierpka,L.,delaFuente,L.M.,L'Heureux,N.,Mechanicalpropertiesofcompletelyautologoushumantissueengineeredbloodvesselscomparedtohumansaphenousveinandmammaryartery,Biomaterials30(8)1542-50(2009).

[4]L'Heureux,N.,Dusserre,N.,Konig,G.,Victor,B.,Keire,P.,Wight,T.N.,Chronos,N.A.,Kyles,A.E.,Gregory,C.R.,Hoyt,G.,Robbins,R.C.,McAllister,T.N.,Humantissue-engineeredbloodvesselsforadultarterialrevascularization,Nat.Med.12(3)361-5(2006).

[5]McAllister,T.N.,Maruszewski,M.,Garrido,S.A.,Wystrychowski,W.,Dusserre,N.,Marini,A.,Zagalski,K.,Fiorillo,A.,Avila,H.,Manglano,X.,Antonelli,J.,Kocher,A.,Zembala,M.,Cierpka,L.,delaFuente,L.M.,L'Heureux,N.,Effectivenessofhaemodialysisaccesswithanautologoustissue-engineeredvasculargraft:amulticentrecohortstudy,Lancet373(9673)1440-6(2009).

[6]L'Heureux,N.,McAllister,T.N.,delaFuente,L.M.,Tissue-engineeredbloodvesselforadultarterialrevascularization,N.Eng.J.Med.357(14)1451-3(2007).

[7]Peck,M.,Gebhart,D.,Dusserre,N.,McAllister,T.N.,L'Heureux,N.,Theevolutionofvasculartissueengineeringandcurrentstateoftheart,CellsTissuesOrgans195(1-2)144-58(2012).

[8]Wystrychowski,W.,McAllister,T.N.,Zagalski,K.,Dusserre,N.,Cierpka,L.,L'Heureux,N.,Firsthumanuseofanallogeneictissue-engineeredvasculargraftforhemodialysisaccess,J.Vasc.Surg.60(5)1353-7(2014).

[9]Wystrychowski,W.,Cierpka,L.,Zagalski,K.,Garrido,S.,Dusserre,N.,Radochonski,S.,McAllister,T.N.,L'Heureux,N.,Casestudy:firstimplantationofafrozen,devitalizedtissue-engineeredvasculargraftforurgenthemodialysisaccess,JVascAccess12(1)67-70(2011).

[10]Magnan,L.,Labrunie,G.,Marais,S.,Rey,S.,Dusserre,N.,Bonneu,M.,Lacomme,S.,Gontier,E.,L'Heureux,N.,CharacterizationofaCell-AssembledextracellularMatrixandtheeffectofthedevitalizationprocess,ActaBiomater.8256-67(2018).

[11]Magnan,L.,Labrunie,G.,Fenelon,M.,Dusserre,N.,Foulc,M.P.,Lafourcade,M.,Svahn,I.,Gontier,E.,Velez,V.J.,McAllister,T.N.,L'Heureux,N.,Humantextiles:Acell-synthesizedyarnasatruly"bio"materialfortissueengineeringapplications,ActaBiomater.105111-120(2020).

[12]Peck,M.,Dusserre,N.,McAllister,T.N.,L'Heureux,N.,Tissueengineeringbyself-assembly,MaterialsToday14(5)218-224(2011).

Patents:1- McAllister,T.,andL'Heureux,N.Tissueengineeredcellularsheets,andmethodsofmakingsame.

USPTOPatentNo.8,076,137(December13,2011).2- McAllister,T.,andL'Heureux,N.Bioreactorforthemanufactureoftissueengineeredblood

vessels.USPTOPatentNo.7,744,526(June29,2010).3- McAllister,T.,andL'Heureux,N.Tissueengineeredcellularsheets,methodsofmakinganduse

thereof.USPTOPatentNo.7,504,258(March17,2009).4- McAllister,T.,andL'Heureux,N.Methodofculturingcellstoproduceatissuesheet.USPTO

PatentNo.7,166,464(January23,2007).5- McAllister,T.,andL'Heureux,N.Tissueengineeredbloodvesselsandapparatusfortheir

manufacture.USPTOPatentNo.7,112,218(September26,2006).6- McAllister,T.,andL'Heureux,N.Tissueengineeredbloodvesselsandmethodsandapparatusfor

theirmanufacture.USPTOPatentNo.6,503,273(January7,2003).7- L'Heureux,N.,Auger,F.A.,andGermain,L.Productionofacontractilesmoothmuscle.USPTO

PatentNo.5,618,718(April8,1997).

Education:1991-96 Ph.D.inMolecular&CellBiology UniversitéLaval,Québec,Canada Laboratoired'AngiogénèseExpérimentale/LOEX1994 Internship(3months) UniversitéLouisPasteurdeStrasbourg,France. UMRCNRS7034(Pr.J-CStoclet)1989-91 M.Sc.inImmunol.&CellBiology UniversitéLaval,Québec,Canada Laboratoired'AngiogénèseExpérimentale/LOEX1990 Internship(3months) UniversitéClaudeBernard,Lyon,France INSERMU209(Pr.J.Thivolet)1986-89 B.Sc.inBiochemistry UniversitéLaval,Québec,Canada Links:Linkedin:https://www.linkedin.com/in/nicolas-l-heureux-199554b?trk=nav_responsive_tab_profileReaserchGate:https://www.researchgate.net/profile/Nicolas_LHeureuxBxCR:BordeauxConsortiumforTissueEngineering:https://bcrm.u-bordeaux.frBIOMAT:TheFrenchassociationforthedevelopmentofbiomaterials,TissueEngineeringandRegenerativeMedicine:http://www.biomat.frISACB(BoardMember):InternationalSocietyforAppliedCardiovascularBiology:http://isacb.org