载VEGF超声微泡缓释的可控性研究及其在微创骨修复中作用

Injectable bone biomaterials research is one of the hotspots in the field of minimal invasive bone defect repair. In our preliminary study, a new type of injectable nHAC/CS scaffold based on CS, nHA and Col was fabricated with a biomimetic strategy. Ultrasonography was also found to be a good tool to evaluate the in vivo formation of the injectable nHAC/CS scaffolds and monitor the tissue development, solidification and degradation process. The vascularization of the scaffold directly affects the osteogenesis process. Vascular endothelial growth factor(VEGF) ,which is one of the key factors in bone tissue vascularization, has a limited direct effecting cycle within the body and need a carrier to control its release. Our research ideas are as follows: (1) Developing ultrosonic microbubbles carrying VEGF with different monomer ratio of PLGA, exploring the effect of PLGA monomer ratio on VEGF release; (2) utilizing the ultrasonic cavitation effect on microbubbles, Controlling the VEGF quantitative bursting release by giving different doses of ultrasound radiation. By combining the bursting release of VEGF by the ultrasonic cavitation effect and the slow release by the PLGA microbubbles degradation, the vascularization role of VEGF may be promoted more effectively; (3) Establishing animal model of bone defect, Injecting injectable nHAC/CS scaffold together with the ultrasound microbubbles carrying VEGF into the bone defect，Evaluating the effects of the controlled released of VEGF(the bursting release by the ultrasonic cavitation effect and the slow release by the PLGA microbubbles degradation) on vascularization, ectopic osteogenesis and bone defect repair function by real-time three dimension and elastic ultrasonic imaging. Providing new ideas to the research of minimally invasive bone repair.

可注射骨材料是目前微创骨修复领域的研究热点。课题组前期研制了可注射nHAC/CS材料，发现超声能够介导、监测其体内填充及硬化过程。材料在体内的血管化程度直接影响其成骨效果，血管化的关键因子VEGF因活性周期短需载体缓释。本研究拟：①制备不同单体比例的PLGA微泡负载VEGF，按一定比例共混后构成本研究的缓释体系，研究其缓释性能。②利用超声对微泡的空化作用实现对VEGF的控释。在不同时间，给予不同剂量的超声辐射，空化不同单体比例的PLGA微泡，令其负载的VEGF突释，达到控制VEGF定量释放的目的。③构建骨缺损动物模型，将微泡与可注射nHAC/CS材料复合后修复骨缺损，联合超声实时三维及弹性成像技术评估超声调控VEGF释放（微泡降解缓释与空化作用突释结合）对材料的血管化及骨缺损修复性能的影响。旨在通过超声微泡将骨修复工程的介导评估系统、载药系统、控释系统相结合，为微创骨修复的研究提供新思路。

课题组制备了不同单体比例的PLGA微泡负载VEGF，按一定比例共混后构成本研究的缓释体系，研究了其缓释性能，体外实验证实材料缓释性能良好，可利用超声对微泡的空化作用实现对VEGF的控释。微泡表面光滑、粒径均匀、物理化学特性稳定；细胞实验证实载VEGF超声微泡具有较好的生物学活性，联合超声应用可提高其成骨诱导性能；建立颅骨缺损动物模型，将材料植入动物模型体内进行微泡联合超声骨缺损修复研究，证实材料具备良好的体内生物相容性、骨诱导和成骨性能，联合超声照射可促进成骨。通过超声微泡将骨修复工程的介导评估系统、载药系统、控释系统相结合，为微创骨修复的研究提供了新思路。