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。本项目的目标是设计具有良好机械强度和生物化学微环境的骨传导和骨诱导人工骨，用于修复自然愈合能力受损的骨缺损。移植物的设计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愈合。具体地说，我们建议将BMP-2、RANKL和VEGF的外源性供应整合到合成的骨移植中，以诱导适当的宿主细胞反应，以诱导移植物与血管内长的协调重塑和骨整合。采用开环聚合、反加成裂解转移聚合和高保真生物共轭化学相结合的方法，在硅基纳米颗粒核心周围依次接枝了聚合物生物降解域、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，在没有或存在钙磷灰石的情况下，将所得到的可注射星形大单体进行交联，以生成本体聚合物或聚合物-矿物复合骨。模块化设计使移植物的每个功能域能够被独立地调制，以优化移植物的整体性能。 对人工骨的结构和力学性能、降解特性、羟基磷灰石成核能力和体外生物活性进行了详细的表征。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被用来评估合成移植物的体内性能和生存能力。移植物的重塑、血管化和骨整合的程度和质量取决于聚合物结构域组成、骨传导矿物含量和移植物局部释放的外源性信号分子，将通过组织学、微型计算机断层扫描、电子显微镜和扭转测试来分析。

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.