Osteogenic synthetic bone grafts for the repair of musculoskeletal defects

用于修复肌肉骨骼缺陷的成骨合成骨移植物

• 批准号: 7858465
• 负责人: Jie Song
• 金额: $ 28.66万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-10 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7858465
• 关键词: Accounting; Adhesives; Apatites; Binding; Biochemical; Biodegradation; Biological; Biological Assay; Blood Vessels; Bone Transplantation; Calcium; Cell Adhesion; Cell Proliferation; Cells; Characteristics; Chemistry; Defect; Electron Microscopy; Endothelial Cells; Exhibits; Extracellular Matrix; Femur; Fracture; Goals; Growth; Growth Factor; Healed; Histology; Hybrids; Hydroxyapatites; Impairment; In Vitro; Injectable; Lead; Length; Libraries; Ligands; Mechanics; Minerals; Modeling; Musculoskeletal; Nature; Nuclear; Osteoclasts; Peptides; Performance; Phage Display; Polymers; Population; Property; RGD (sequence); Rattus; Regimen; Screening procedure; Shapes; Signaling Molecule; Silicon; Site; Stimulus; Techniques; Testing; Time; Tissues; Torsion; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; Vascularization; Weight-Bearing state; aqueous; base; bone; bone morphogenetic protein 2; copolymer; crosslink; cytokine; design; economic implication; effective therapy; graft healing; healing; improved; in vitro testing; in vivo; mineralization; nanoparticle; osteogenic; polymerization; receptor; reconstruction; repaired; response; skeletal; social; tomography; tricalcium phosphate

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.

描述（由申请人提供）：据估计，美国人口中有一个遭受某些形式的肌肉骨骼损害。有效治疗这些条件的社会和经济影响是巨大的。该项目的目的是设计具有理想的机械强度和生化微环境，以重建具有损害的自然愈合能力的骨骼缺陷，以设计具有理想的机械强度和生化微环境的骨诱导性和骨诱导合成骨移植物。移植物旨在为骨缺陷部位提供即时的机械保护和结构稳定，并局部释放外源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的外源供应与合成骨移植物融合在一起，以诱导适当的宿主细胞反应，以引起与血管内核的配位重塑和移植物的骨整合。使用环环聚合和反向添加碎片转移聚合聚合结合与高保真生物偶联化学，聚合物生物降解结构域，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和细胞粘附结构域是基于SI基的Nananopiles cores围绕的。然后在不存在或存在钙磷灰石的情况下交联的可带注射的星形宏观分子以产生散装聚合物或聚合物矿物质复合骨移植物。模块化设计可以独立调制移植物的每个功能域，以优化移植物的整体性能。 提出了一种详细的策略来表征结构和机械性能，降解特性，核酸核能力和合成骨移植物在体外的生物活性。此外，考虑了肌肉骨骼组织的重量性质的大鼠股骨分段缺陷模型，用于评估合成移植物的体内性能和生存能力。移植物的重塑，血管化和取整组的程度和质量与聚合物结构域组成，整骨矿物质含量以及从移植物局部释放的外源信号分子的函数将通过组织学，组织学，微型计算机显微镜，电子显微镜和肿瘤进行分析。