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.

同种异体骨移植是自体骨移植的重要替代方法。然而，有很大的需求 以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，最终使他们无法支持结构负荷。关键障碍 同种异体移植骨整合是有限技术，以i）支持移植前或移植后的移植物 装载宿主祖细胞和ii）驱动移植物内的骨生成。克服这些 屏障，我们假设应用由陶瓷组成的“合成骨膜” 聚磷酸盐（polyP），包含在水凝胶内，附着在结构同种异体移植物的外表面上， 足以募集宿主祖细胞并引发移植物的骨整合。这 方法是创新的，因为它考虑到i）陶瓷-聚P的新颖能力， 祖细胞募集和成骨，ii）将生物制剂应用于骨形成的物理设计， 为了利用位于移植物外周的宿主祖细胞的主要池， 骨膜和肌肉，和iii）骨化是由软骨内机制驱动的， 非常适合克服移植微环境内的缺氧。在目标1中，我们将使用 创新的遗传追踪动物模型、体内成像和敏感的终点测量， 设计最佳的水凝胶-陶瓷-polyP结构， 潜力（祖细胞募集/扩增和软骨内骨化），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，我们将研究 植入小鼠股骨临界尺寸的同种异体移植物上的优化水凝胶-聚P-NP涂层 缺陷模型如果我们的假设被证明是正确的，那么将水凝胶-陶瓷-聚P作为 人造骨膜提供了一种实用且经济的替代直接植入的方法 移植前的祖细胞。与先前提出的有机生物结构相比， （rBMP 2、间充质干细胞等），这种水凝胶-聚P-NP结构被设计成成本低， 有效、贮存稳定，并导致有限毒性和宿主排斥，使其有希望用于 临床翻译。因此，这些材料非常适合于快速、经济、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 重组蛋白等技术。