De Silva Thompson, David Roshan; (2018) Scalable production of tissue engineered microunits for bone regeneration using bioactive glass microspheres and dynamic culture conditions. Doctoral thesis (Eng.D), UCL (University College London).

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Abstract

Bone is one of the most common tissues to be transplanted, with over 2.2 million grafting procedures performed worldwide every year (Van der Stok et al., 2011). Autologous bone grafts, while considered the current gold standard, have inherent risks including limited donor tissue availability, donor site morbidity, surgical complications, and pain of procedure. Alternative approaches to treating bone tissue defects are required based on clinically effective bone graft substitutes that can be manufactured at a commercially relevant scale. Tissue engineering is an alternative strategy that uses biocompatible scaffolds in combination with cells as a bioactive implant to induce bone repair. In this thesis, microspherical bioactive glasses have been studied as a platform for scalable bone tissue engineering that has flexibility to address diverse geometric requirements with the aim of becoming a commercially available tool. Specifically, titanium-doped phosphate glass microspheres have been studied for their ability to support bone progenitor cells. Here, the microspheres (5 and 7 mol% TiO2) were assessed in their ability to support proliferation of osteoblast-like cell (MG63) and proliferation and osteogenic differentiation of human bone-marrow derived mesenchymal stem cells (hBM-MSCs) under static and dynamic agitation culture. Scalability was assessed using scalable dimensionless Froude number to scale microwell plate cultures to 125ml Erlenmeyer flask cultures using Froude as a tool to map mixing systems at both scales. MG63 and hBM-MSC proliferation was observed on the microspheres under all conditions studied as well as extracellular matrix protein secretion, confirming the biocompatibility of the materials tested. Similar growth kinetics was observed at both scales, where moderate agitation stimulated cell proliferation, but higher agitation was damaging to cells. Upregulation of key bone expression markers (COL1A1 and SPP1) was observed also at moderate orbital agitations, while on at high agitation rates this was largely absent, except for upregulation of SPP1 on the control microsphere, Synthemax. Furthermore, biomaterial resorption was observed upon differentiating mouse-derived monocytes into osteoclasts on the titanium-phosphate glass discs. In conclusion, large-scale culture using titanium-doped phosphate glass microspheres was achieved with hBM-MSCs, with the substrate effectively supporting cell proliferation and osteogenic differentiation. This research provides a stepping stone in understanding how biomaterials processed into microcarrier format can be utilised in a commercial environment to create clinically relevant quantities of tissue engineering bone.

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