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Understanding calcification in bone regeneration through a synthetic biomineralization-based approach


Bone is one of the most transplanted tissues, with over 500,000 bone grafting procedures carried out annually in the United States. While autografts, allografts and recombinant protein-based devices are widely used in these procedures, they suffer from numerous shortcomings such as cost, donor site morbidity, batch-to-batch variation and potential risks & side effects. This thesis demonstrates the development of biomineralized synthetic grafts and investigates their efficacy by probing their ability to induce osteoinduction in vitro and in vivo. Briefly, Chapter 1 describes the current state of the field in the use of calcium phosphate-based biomaterials for bone regeneration, as well as current progress in the development of mineral-polymer composites. Chapter 2 describes the development of a novel mineralization process to synthesize biomimetic mineral-synthetic hydrogel composites and utilizes this process to probe the effect of matrix hydrophobicity on the templated mineralization of these substrates. This conclusively demonstrates a non-monotonic dependence of matrix hydrophobicity and pendant side chain length on the templated mineralization of synthetic materials, and further demonstrates that hydrogels containing N-acryloyl 6-aminocaproic acid-based moieties as optimally suited for templated mineralization. Chapter 3 then investigates the osteoinductivity of the biomineralized A6ACA hydrogels in vitro. Indeed, these matrices were found to promote the osteogenic differentiation of human mesenchymal stem cells even in the absence of soluble osteogenic supplements, suggesting their ability to promote osteoinduction. Chapter 4 then proceeds to investigate two potential pore structures for use in porous synthetic grafts through their ability to support osteogenic differentiation of hMSCs in vitro. A pore structure consisting of isotropic, cellular pores was found to support osteogenic differentiation to a greater extent than a pore structure consisting of lamellar, oriented pores. Furthermore upon mineralization, these matrices were found to promote extensive vascularization and ectopic bone formation upon subcutaneous implantation in nude rats both with and without pre-seeded hMSCs prior to implantation, thereby providing evidence of their osteoinductive potential. Chapter 5 then proceeds to evaluate these grafts in a rodent posterolateral fusion model; the biomineralized grafts were found to promote spinal fusion to a similar extent, both with and without addition of bone marrow flush and to a significantly greater extent than sham surgery. Finally, Chapter 6 demonstrates the tuning of interfacial properties for eliciting matrix-matrix interactions for the creation of hydrogels capable of undergoing rapid, and reversible self-healing via cross- interfacial hydrogen bonding

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