In vivo analysis of hybrid hydrogels containing dual growth factor combinations,and skeletal stem cells under mechanical stimulation for bone repair  

作　　者：David Gothard Michael Rotherham Emma L.Smith Janos M.Kanczler James Henstock Julia A.Wells Carol A.Roberts Omar Qutachi Heather Peto Hassan Rashidi Luis Rojo Lisa J.White Molly M.Stevens Alicia J.El Haj Felicity R.J.ose Richard O.C.Oreffo 

机构地区：[1]Bone and Joint Research Group,Centre for Human Development,Stem Cells and Regeneration,Institute of Developmental Sciences,University of Southampton,Southampton,SO166YD,UK [2]Institute for Science and Technology in Medicine,Keele University,Guy Hilton Research Centre,Stoke-on-Trent,ST47BQ,UK [3]Healthcare Technologies Institute,School of Chemical Engineering,Institute of Translational Medicine,University of Birmingham,Birmingham,B152TH,UK [4]Department of Applied Sciences,Pandon Building,Northumbria University,Newcastle-upon-Tyne,NE21XE,UK [5]Wolfson Centre for Stem Cells,Tissue Engineering and Modelling,University of Nottingham,Centre for Biomolecular Sciences,University Park,Nottingham,NG72RD,UK [6]Leicester Institute for Pharmaceutical Innovation(LIPI),Leicester School of Pharmacy,Faculty of Health and Life Sciences,De Montfort University,The Gateway,Leicester,LE19BH,United Kingdom [7]Stem Cells and Regenerative Medicine Section,UCL Great Ormond Street Institute of Child Health,University College London,London,WC1N 1EH,UK [8]Department of Materials,Imperial College London,Royal School of Mines,London,SW72AZ,UK [9]Department of Bioengineering,Imperial College London,South Kensington Campus,London,SW72AZ,UK [10]Instituto de Ciencia y Tecnología de Polímeros(ICTP),CSIC,Calle Juan de la Cierva,3,28006 Madrid,Spain [11]Consorcio Centro de Investigacion Biomedica en Red,CIBER-BBN,Instituto de Salud Carlos III,Calle Monforte de Lemos 3-5,1128029 Pabellon,Madrid,Spain [12]Nottingham Biodiscovery Institute,School of Pharmacy,University of Nottingham,Nottingham,NG72RD,UK [13]Institute for Biomedical Engineering Imperial College London,South Kensington Campus,London,SW72AZ,UK [14]Department of Physiology,Anatomy,&Genetics,Department of Engineering Science,and Kavli Institute for Nanoscience Discovery,University of Oxford,Oxford,OX13QU,UK

出　　处：《Mechanobiology in Medicine》2024年第4期97-109,共13页力学生物学与医学（英文）

基　　金：supported by the BBSRC(sLOLA grant BB/G010579/1);an EU ERC Advanced Grant DYNACEUTICS(grant no.789119).

摘　　要：Bone tissue engineering requires a combination of materials,cells,growth factors and mechanical cues to recapitulate bone formation.In this study we evaluated hybrid hydrogels for minimally invasive bone formation by combining biomaterials with skeletal stem cells and staged release of growth factors together with mechanotransduction.Hybrid hydrogels consisting of alginate and decellularized,demineralised bone extracellular matrix(ALG/ECM)were seeded with Stro-1t human bone marrow stromal cells(HBMSCs).Dual combinations of growth factors within staged-release polylactic-co-glycolic acid(PLGA)microparticles were added to hydrogels to mimic,in part,the signalling events in bone regeneration:VEGF,TGF-β_(3),PTHrP(fast release),or BMP-2,vitamin D_(3)(slow release).Mechanotransduction was initiated using magnetic fields to remotely actuate superparamagnetic nanoparticles(MNP)targeted to TREK1 ion channels.Hybrid hydrogels were implanted subcutaneously within mice for 28 days,and evaluated for bone formation using micro-CT and histology.Control hydrogels lacking HBMSCs,growth factors,or MNP became mineralised,and neither growth factors,HBMSCs,nor mechanotransduction increased bone formation.However,structural differences in the newly-formed bone were influenced by growth factors.Slow release of BMP-2 induced thick bone trabeculae and PTHrP or VitD_(3)increased bone formation.However,fast-release of TGF-β_(3)and VEGF resulted in thin trabeculae.Mechanotransduction reversed the trabecular thinning and increased collagen deposition with PTHrP and VitD_(3).Our findings demonstrate the potential of hybrid ALG/ECM hydrogel–cell–growth factor constructs to repair bone in combination with mechanotransduction for fine-tuning bone structure.This approach may form a minimally invasive reparative strategy for bone tissue engineering applications.

关 键 词：Growth factors Controlled release Bone ECM Bone formation MECHANOTRANSDUCTION Skeletal stem cell 

分 类 号：R318[医药卫生—生物医学工程]