双控释骨支架的制备及其在感染性骨缺损中的应用及机制研究

Treatment of infected bone defect remains a big clinical challenge. Infected bone defect is caused by osteomyelitis. The ideal treatment was that the bone defect could be completely repaired after bacterium and inflammation were inhibited.The time node of bone regeneration and the construction of bone scaffold which could be used in controllable and "sequential" antibiosis, anti-inflammatory and bone healing play a key role in infected bone defect. Through this study, the regulation mechanism of NF-kappa B channel network in inflammatory bone destruction and bone regeneration would be revealed, and the time node of ideal bone promoting regeneration would be obtained.. Our long-term goal is to develop injectable multifunctional bone scaffold as ultrasound-responsive controllable drug eluting device for the treatment of infectious bone defects. This research goal is supported by our previous studies on the preparation of functional bone graft substitutes and programmed drug release both in vitro and in vivo. The aim of this proposal is to construct a double controlled release bone scaffold with the ability of sequential bacterial eradication and promoting bone healing. Calcium phosphate cement (CPC) will be strengthened by hyaluronic acid/pectin dialdehyde-RGD composites which are designed by us and embeded of vancomycin-doped for a sustained vancomycin release. In addition, ultrasound responsive BMP-2 embedded multiblock copolyamides microcapsule which are designed by us will be mixed with bone scaffold that allows a controllable BMP release when the bone infection is controlled by vancomycin treatment. An optimal bone scaffold formula will be identified based on its favorable in vitro biocompatibility, drug release profiles and physiochemical properties. We will then determine the therapeutic efficacies of the bone scaffold in a rabbit infected bone defect model,which will provide a theoretical basis for clinical treatment of infectious bone defects.

感染性骨缺损临床上较为常见，常继发于骨髓炎；其理想治疗方案：获得杀菌抗炎满意效果后，再促骨再生，使缺损完全修复。其两个关键问题亟需解决：①促骨再生的时间节点确定；②具有可控的“顺序性”杀菌抗炎及促骨愈合的骨支架构建。本项目将通过炎症骨破坏及骨再生中NF-κB通道网络调控的机制研究，得出理想促骨再生的时间节点。同时将课题组前期研发的接枝精氨酸-甘氨酸-天门冬氨酸的透明质酸/氧化果胶水凝胶（HAP）包裹万古霉素、具有B超响应功能的多嵌段共聚酰胺（MBCPA）微囊包裹BMP，与聚磷酸钙（CPP），三者混合制备出双控释可注射骨支架并优化构建：除具有满意力学、生物学性能、降解及骨替代能力外；还具有早期长期稳定有效的抗菌功能，及后期特定时间点开始的促骨愈合功能。项目还将通过体外及体内研究证实该支架的疗效，为临床治疗感染性骨缺损提供理论基础。

本课题将课题组前期研发的接枝精氨酸-甘氨酸-天门冬氨酸的透明质酸/氧化果胶水凝胶（HAP）包裹万古霉素、具有B超响应功能的多嵌段共聚酰胺（MBCPA）微囊包裹BMP，与聚磷酸钙（CPP），三者混合制备出双控释可注射骨支架并优化构建：除具有满意力学、生物学性能、降解及骨替代能力外；还具有早期长期稳定有效的抗菌功能，及后期特定时间点开始的促骨愈合功能。本课题还完成了 HAPVA-CPP/MBCPABMP载药系统的优化，确定相关生物因子在药物缓释系统中的配比以及检测相关的缓释效能。并通过体外及体内研究证实该支架的疗效，为临床治疗感染性骨缺损提供理论基础。此外，本课题通过炎症骨破坏及骨再生中NF-κB通道网络调控的机制研究，得出理想促骨再生的时间节点。