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: 10636630
• 负责人: JASON R. McCARTHY
• 金额: $ 19.19万
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10636630
• 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; Femur; Genetic; Growth; 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; 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选择。然而，有很大的需求