An inorganic polyphosphate-impregnated synthetic periosteum drives allograft osteointegration

无机多磷酸盐浸渍的合成骨膜驱动同种异体移植骨整合

• 批准号: 10431589
• 负责人: JASON R. McCARTHY
• 金额: $ 24.6万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-04 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10431589
• 关键词: Allografting; Anatomy; Animal Model; Animals; Apoptosis; Autologous Transplantation; Automobile Driving; Biological; Biological Products; Biology; Biotechnology; Calcium; Cations; Ceramics; Chondrocytes; Clinical; Collagen; Communities; Data; Defect; Environment; Failure; Genetic; Histologic; Histology; Hydrogels; Hypoxia; Implant; In Situ Nick-End Labeling; Inflammation; Inflammatory; Intramuscular; Knowledge; Libraries; Location; Measures; Medical; Medical Technology; Membrane Biology; Mesenchymal Stem Cells; Methods; Microfils; Modeling; Mus; Muscle; NF-kappa B; Orthopedics; Osteogenesis; Periosteum; Physiologic Ossification; Polyphosphates; Polyps; Positioning Attribute; Recombinant Proteins; Site; Source; Stains; Surface; Techniques; Testing; Tissues; Toxic effect; Transplantation; aggrecan; allogenic bone transplantation; angiogenesis; bone; bone fracture repair; clinical application; clinical practice; clinical translation; cost; cost effective; design; implantation; improved; in vivo; in vivo Model; in vivo imaging; innovation; nanoparticle; novel; osteogenic; post-transplant; progenitor; radiological imaging; recruit; repaired; stem cells; success

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.

同种异体移植物为自体移植提供了必不可少的替代方法。但是，有很大的需求 为了改善同种异体移植物的宿主成骨整合，同种异体移植物没有任何机制 维修，最终使它们无能支持结构负荷。关键障碍 同种异体移植成骨是有限的技术，i）支持移植前或后移植物 用宿主祖细胞加载，ii）在移植物中驱动成骨。克服这些 障碍，我们假设使用由陶瓷组成的“合成perostem”的应用 多磷酸盐（息肉），包含在结构截短的外表面的水凝胶中， 足以募集宿主祖细胞并激发移植物的骨整合。这 方法是创新的，因为它考虑了i）陶瓷式驾驶的新颖能力 祖细胞募集和成骨，ii）将生物学应用于 移植物的外围是为了利用位于 骨膜和肌肉，以及iii）骨化是由内侧软骨机制驱动的， 非常适合克服移植微环境内的缺氧。在AIM 1中，我们将使用 创新的遗传追踪动物模型，体内成像和敏感终点测量 设计最佳的水凝胶 - 陶瓷构建构建体，该结构促进其必需的生物学 势（祖细胞募集/膨胀和内软骨骨化），同时限制 可能的毒性（炎症/凋亡）。在这些结果的指导下，在AIM 2中，我们将检查 植入股鼠临界尺寸的同种异体移植物上优化的水凝胶 - 螺旋 - NP涂层 缺陷模型。如果我们的假设被证明是正确的，则将水凝胶 - 陶瓷型的应用作为一个 合成性peroste骨提供了直接实施的实用且具有成本效益的替代方案 祖细胞前移植。与先前提出的有机生物学结构相比 （rbmp2，间充质干细胞等），这种水凝胶 - 旋转-NP构建体的设计为成本 - 有效，货架稳定，并导致有限的毒性和宿主拒绝，​​使其承诺 临床翻译。因此，这些材料适合快速，成本效益，临床 全球申请，不仅在可以负担医疗的第一世界医疗社区中 诸如重组蛋白之类的技术。