程序释放VEGF/BMP载药系统强化磷酸钙治疗股骨头缺血性坏死的研究

Avascular Necrosis of the Femoral Head (ANFH), often seen in the age of 30 to 50 years, still presents a challenge to clinicians. It is important to treat patients early to prevent any further disintegration and collapse of the femoral head. Data generated from our previous clinical studies demonstrated that a large number of patients in the early stage of ANFH can be healed by removing the necrotic bone and using bone graft substitutes with sufficient mechanical strength. We have proved that the biocompatibility and mechanical strength can be improved by incorporation of RGD peptides into calcium phosphate cements (CPCs). We also developed coaxial PCL/PVA electrospun nanofibers (NFs) that can be used as a desirable device for the controllable and sustained release of embedded drugs and growth factors. The purpose of this proposal is to develop novel CPCs reinforced with coaxial PCL/PVA NFs doped with both VEGF and BMP. We propose that the defects of ANFH can be filled and healed by enhanced CPCs with controllable release of VEGF and BMP encapsulated in the coaxial NFs. The key concepts are to determine the appropriate formulations of the CPC/VEGF/BMP/Coaxial PCL/PVA composites with desired physiochemical and biological properties and determine whether a desired controllable sustained bio-factors release can improve the osteogenesis and angiogenesis in vitro and have a good effect on ANFH in vivo.

股骨头缺血性坏死（ANFH）较为常见，多发于中青年且致残率极高；在该病早中期对其进行“保头”治疗是目前研究热点。课题组前期研究表明，清除股骨头内坏死病灶，并给予良好的力学支撑和满意的骨移植物即可有效治疗早中期ANFH。课题组在发现接枝RGD的高分子纤维能有效提高磷酸钙（CPC）的生物学及生物力学性能，和发现同轴纳米管可在特定时间点控制药物缓慢释放等研究基础上；拟通过纳米纤维+同轴纳米管制备的载药系统来程序化控制VEGF和BMP释放，再用该载药系统与CPC混合制备成强化CPC填充于ANFH病灶中。随着CPC微孔打开，即获得VEGF/BMP在支架内的时空释放，改善局部血供及促进骨修复。本项目将通过体外载药系统设计、药物缓释研究、生长因子时空表达、成骨和成血管能力促进等研究及ANFH治疗的体内研究，对该强化型CPC的促骨修复能力和机制进行全面和深入地探讨，为该治疗新手段的临床应用提供理论依据。

本课题在前期同轴PCL/PVA静电纺丝纳米管研究的基础上，成功制备“程序释放VEGF/BMP的载药系统”。此外，课题组完成了生物相关因子对成骨作用的研究、脱细胞内膜作为新型材料的适用性验证等一系列工作，辅助优化实验方案。课题组按计划完成了VEGF/BMP和CPC载药系统的优化，然而在研究中发现，虽能达到稳定缓释，但是生长因子在体外炎症及氧化应激条件下失活过快，预期疗效不够理想。为此课题组创新性地筛选出多种药物单体，在动物模型中成功验证其促成骨功能。同时我们进行了涂层及接枝相关缓释系统的构建方法学的研究，用于延长接枝药物或生长因子生物活性及提高缓释效率，促进后期稳定的成骨愈合。项目结果显示该骨支架有利于股骨头缺血性坏死的修复，并揭示了炎症微环境对骨组织工程修复的重要意义。本项目的研究成果为骨复合移植物治疗股骨头缺血性坏死提供了科学依据。