Osteogenic synthetic bone grafts for the repair of musculoskeletal defects

描述（由申请人提供）：据估计，七分之一的美国人口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。该项目的目标是设计具有理想机械强度和生化微环境的骨传导和骨诱导合成骨移植物，用于重建自然愈合能力受损的骨骼缺陷。该移植物为骨缺损部位提供即时的机械保护和结构稳定，并在局部释放外源性生长因子和细胞因子，促进骨移植物愈合。具体来说，我们建议在合成骨移植物中加入外源的BMP-2、RANKL和VEGF，以诱导适当的宿主细胞反应，引发移植物血管长入的协调重塑和骨整合。利用开环聚合和反向加成碎片转移聚合，结合高保真生物偶联化学，在硅基纳米颗粒核周围依次接枝聚合物生物降解域、生长因子保留域、骨矿物（羟基磷灰石）成核域和细胞粘附域。然后在磷灰石钙缺失或存在的情况下，将得到的可注射的星形大分子交联，生成大块聚合物或聚合物-矿物复合骨移植物。模块化设计使接枝的每个功能域可以独立调制，以优化接枝的整体性能。

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.