An inorganic polyphosphate-impregnated synthetic periosteum drives allograft osteointegration

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Bone allografts provide an essential alternative to autografts. However, there is a significant need to improve host osteointegration of allografts, as without it, allografts have no mechanism of repair, eventually rendering them incompetent to support a structural load. The critical barriers of allograft osteointegration are limited techniques to i) support either pre- or post-transplant graft loading with host progenitor cells and ii) drive osteogenesis within the graft. To overcome these barriers, we hypothesize that the application of a ‘synthetic periosteum’ composed of ceramic polyphosphate (polyP), contained within a hydrogel to the outer surface of a structural allograft, is sufficient to recruit host progenitor cells and instigate osteointegration of the graft. This approach is innovative as it takes account i) the novel capacity of ceramic-polyP to drive progenitor recruitment and osteogenesis, ii) the physical design of applying the biologic to the periphery of the graft in order to harness the main pool of host progenitor cells located in the periosteum and muscle, and iii) that ossification is driven by endochondral mechanisms, which is well suited to overcome hypoxia within the grafting microenvironment. In Aim 1 we will use innovative genetic tracing animal models, in vivo imaging, and sensitive endpoint measures, to design the optimal hydrogel-ceramic-polyP construct that promotes their required biological potential (progenitor cell recruitment/expansion and endochondral ossification), while limiting possible toxicity (inflammation/apoptosis). Guided by these results, in Aim 2 we will then examine the optimized hydrogel-polyP-NP coating on allografts implanted in a femoral murine critical size defect model. If our hypothesis is proven true, the application of a hydrogel-ceramic-polyP as a synthetic periosteum offers a practical and cost-effective alternative to directly implanting progenitor cells pre-transplant. Compared to previously proposed organic biological constructs (rBMP2, mesenchymal stem cells, etc.), this hydrogel-polyP-NP construct is designed to be cost- effective, shelf-stable, and result in limited toxicity and host-rejection, making it promising for clinical translation. Therefore, these materials are well positioned for rapid, cost-effective, clinical application globally, not just in first-world medical communities that can afford medical technologies such as recombinant proteins.