An inorganic polyphosphate-impregnated synthetic periosteum drives allograft osteointegration

同种异体骨移植为自体移植提供了一种重要的替代方法。然而，有一个重要的需求 为了改善同种异体移植物的宿主骨整合，因为没有它，同种异体移植物没有机制 修复，最终使它们无法承受结构荷载。的关键障碍 同种异体骨结合技术仅限于：1)支持移植前或移植后移植 负载宿主祖细胞和ii)促进移植物内的成骨。要克服这些障碍 我们假设一种由陶瓷组成的“合成骨膜”的应用 聚磷酸盐(息肉)，包含在水凝胶中至结构异体移植物的外表面， 足以招募宿主祖细胞并促进移植物的骨整合。这 方法是创新的，因为它考虑到了i)陶瓷息肉驱动的新能力 祖细胞招募和成骨，II)将生物应用于骨移植的物理设计 移植物的外围，以利用位于宿主祖细胞的主库 骨膜和肌肉，以及iii)骨化是由软骨内机制驱动的，这是 非常适合克服嫁接微环境中的低氧。在目标1中，我们将使用 创新的基因追踪动物模型、活体成像和敏感的终点测量，以 设计最佳的水凝胶-陶瓷-息肉结构，以促进其所需的生物 潜能(祖细胞招募/扩增和软骨内成骨)，同时限制 可能的毒性(炎症/细胞凋亡)。在这些结果的指导下，在目标2中，我们将检查 优化的水凝胶-息肉-纳米粒涂层植入小鼠股骨临界大小的同种异体移植物 缺陷模型。如果我们的假设被证明是正确的，水凝胶陶瓷息肉作为一种 合成骨膜为直接植入提供了一种实用且经济实惠的选择。 祖细胞移植前。与先前提出的有机生物结构相比 (rBMP2、间充质干细胞等)，这种水凝胶-Polyp-NP构建物被设计成成本- 有效，货架稳定，毒性和寄主排斥有限，使其在 临床翻译。因此，这些材料非常适合快速、经济有效的临床应用。 在全球范围内应用，而不仅仅是在能够负担得起医疗费用的第一世界医疗社区 重组蛋白质等技术。

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.