Genetically-programmed, mesenchymal stromal cell-laden & mechanically strong 3D bioprinted scaffolds for bone repair

JOURNAL OF CONTROLLED RELEASE

卷:325

Article

Abu Awwad, Hosam Al-Deen M.¹  Thiagarajan, Lalitha¹  Kanczler, Janos M.²  Amer, Mahetab H.^1,4  Bruce, Gordon¹  Lanham, Stuart²  Rumney, Robin M. H.³  Oreffo, Richard O. C.²  Dixon, James E.¹ 

[1] Univ Nottingham, Univ Nottingham Biodiscovery Inst BDI, Sch Pharm, Regenerat Med & Cellular Therapies Div, Nottingham NG7 2RD, England

[2] Univ Southampton, Inst Dev Sci, Bone & Joint Res Grp,Fac Med, Ctr Human Dev Stem Cells & Regenerat,Human Dev &, Southampton SO16 6YD, Hants, England

[3] Univ Portsmouth, Sch Pharm & Biomed Sci, St Michaels Bldg,White Swan Rd, Portsmouth PO1 2DT, Hants, England

[4] Univ Leeds, Sch Mol & Cellular Biol, Fac Biol Sci, Leeds LS2 9JT, W Yorkshire, England

关键词: Intracellular transduction;    Controlled release;    GAG-binding enhanced transduction (GET);    PLGA;    3D bioprinting;   

DOI  :  10.1016/j.jconrel.2020.06.035

来源: Elsevier

【 摘 要 】

Additive manufacturing processes used to create regenerative bone tissue engineered implants are not biocompatible, thereby restricting direct use with stem cells and usually require cell seeding post-fabrication. Combined delivery of stem cells with the controlled release of osteogenic factors, within a mechanically-strong biomaterial combined during manufacturing would replace injectable defect fillers (cements) and allow personalized implants to be rapidly prototyped by 3D bioprinting. Through the use of direct genetic programming via the sustained release of an exogenously delivered transcription factor RUNX2 (delivered as recombinant GET-RUNX2 protein) encapsulated in PLGA microparticles (MPs), we demonstrate that human mesenchymal stromal (stem) cells (hMSCs) can be directly fabricated into a thermo-sintered 3D bioprintable material and achieve effective osteogenic differentiation. Importantly we observed osteogenic programming of gene expression by released GET-RUNX2 (8.2-, 3.3- and 3.9-fold increases in OSX, RUNX2 and OPN expression, respectively) and calcification (von Kossa staining) in our scaffolds. The developed biodegradable PLGA/PEG paste formulation augments high-density bone development in a defect model (similar to 2.4-fold increase in high density bone volume) and can be used to rapidly prototype clinically-sized hMSC-laden implants within minutes using mild, cytocompatible extrusion bioprinting. The ability to create mechanically strong 'cancellous bone-like' printable implants for tissue repair that contain stem cells and controlled-release of programming factors is innovative, and will facilitate the development of novel localized delivery approaches to direct cellular behaviour for many regenerative medicine applications including those for personalized bone repair.

【 授权许可】

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