Osteogenic synthetic bone grafts for the repair of musculoskeletal defects

描述（由申请人提供）：据估计，美国人口的七分之一患有某种形式的肌肉骨骼损伤。有效治疗这些疾病的社会和经济影响是巨大的。本项目的目标是设计具有理想机械强度和生物化学微环境的骨传导和骨诱导合成骨移植物，用于重建具有受损自然愈合能力的骨骼缺损。移植物旨在为骨缺损部位提供即时的机械保护和结构稳定，并局部释放外源性生长因子和细胞因子以促进骨移植物愈合。具体而言，我们建议将BMP-2、RANKL和VEGF的外源性供应纳入合成骨移植物中，以诱导适当的宿主细胞反应，从而引发移植物与血管向内生长的协调重塑和骨整合。使用开环聚合和反向加成断裂转移聚合结合高保真生物缀合化学，聚合物生物降解域，生长因子保留域，骨矿物质（羟基磷灰石）成核域和细胞粘附域依次接枝在硅基纳米颗粒核周围。然后在不存在或存在钙磷灰石的情况下交联所得的可注射星形大分子单体以产生本体聚合物或聚合物-矿物复合物骨移植物。模块化设计使得移植物的每个功能域能够被独立地调节以优化移植物的整体性能。 提出了一个详细的策略，以表征的结构和机械性能，降解特性，HA成核能力和体外合成骨移植物的生物活性。此外，考虑到肌肉骨骼组织的承重性质的大鼠股骨节段性缺损模型用于评价合成移植物的体内性能和活力。将通过组织学、显微计算机断层扫描、电子显微镜和扭转试验分析移植物的重塑、血管形成和骨整合的程度和质量，这些是聚合物结构域组成、骨传导矿物质含量和移植物局部释放的外源性信号分子的函数。

DESCRIPTION (provided by applicant): It is estimated that one seventh of the US population suffer from some forms of musculoskeletal impairment. The social and economic implications of the effective treatment of these conditions are enormous. The goal of this project is to design osteoconductive and osteoinductive synthetic bone grafts possessing desirable mechanical strength and biochemical microenvironment for the reconstruction of skeletal defects with compromised natural healing capacities. The grafts are designed to provide instant mechanical protection and structural stabilization to the site of bony defects, and locally release exogenous growth factors and cytokines to promote bone graft healing. Specifically, we propose to incorporate an exogenous supply of BMP-2, RANKL and VEGF to the synthetic bone graft to induce proper host cell responses to elicit the coordinated remodeling and osteointegration of the graft with vascular ingrowth. Using ring opening polymerization and reverse addition fragmentation transfer polymerization in combination with high-fidelity bioconjugation chemistries, polymeric biodegradation domains, growth factor retention domains, bone mineral (hydroxyapatite) nucleation domains and cell adhesion domains are sequentially grafted around Si-based nanoparticle cores. The resulting injectable star-shaped macromers are then crosslinked in the absence or the presence of calcium apatite to generate bulk polymer or polymer-mineral composite bone grafts. The modular design enables that each functional domain of the graft be independently modulated to optimize the overall performance of the graft. A detailed strategy is proposed to characterize the structural and mechanical properties, the degradation characteristics, the HA-nucleation capacity and the bioactivities of the synthetic bone graft in vitro. In addition, a rat femoral segmental defect model that takes into account the weight-bearing nature of the musculoskeletal tissue is utilized to evaluate the in vivo performance and viability of the synthetic graft. The extent and quality of the remodeling, vascularization and osteointegration of the graft as a function of polymer domain compositions, osteoconductive mineral contents and the exogenous signaling molecules locally released from the grafts will be analyzed by histology, microcomputed tomography, electron microscopy and torsion tests.