三维打印介孔生物活性玻璃/PLGA同心圆柱复合支架用于抗骨结核药物的节律性缓释

Here in this proposal, a novel composite scaffold for treating osteoarticular tuberculosis(TB) after surgical intervention is designed, which could load more than one sufficient anti-TB drugs simultaneously and release them in a controlled wave manner.The scaffold would repair the residul cavity resulted from surgery and realize in-situ advanced chemotherapy. A mesoporous bioactive glasses(MBG)/PLGA composite drug delivery scaffold via 3D-plotting is prepared. High doses of two drugs isoniazed (INH) and rifampicin (RFP) could be loaded in this composite, and then release extremely in a slow and rhythmic pattern. Firstly, MBG materials with proper pore diameters and surface properties are sythesized using different surfactant and post-grafting reactions. The loading amount of INH and RFP and their release rates are adjusted through selecting MBG with right mesoporous properties. Secondly, biodegradable polymer PLGA with proper degradation rate and the drug-loaded mesoporous powders together as alternative layers are 3D-plotted, leading to a concentric cylindrical architecture. INH and RFP are released from the 3D porous cylindrical scaffold in a wave mode, so that the drug concentration in the osseous foci are maintained above MIC (minimum inhibitory concentration). In vitro and in vivo drug release experiments are being carried out to confirm the optimal producing parameters of materials and also improve the 3D-plotting technology. The mechanic properties and bioactivities of the composite scaffold are characterized. Pridictably, this proposal might provide a brand-new approach and theory for the application of mesoporous materials and 3D-plotting technics against osteoarticular TB. The composite drug delivery scaffold has a broad scope in future clinic application.

骨结核病手术后仍需至少半年的系统药物化疗。针对全身系统用药效率低下、耐药性易发及病人负担过重的问题，本项目创新性地设计了一种可节律性缓释多种抗结核药物的复合支架，同时用于骨结核术后残留骨质缺损的修复及原位长效化疗，具有重要的临床实用意义。 采用三维打印技术制备介孔生物玻璃（MBG）基复合载药支架。利用MBG的优良生物活性提高复合支架促进新骨再生的能力。通过介孔孔径控制和表面修饰，调节MBG对一线抗结核药物异烟肼(INH)/利福平(RFP)的装载量和释放速度，实现两种药物的联合高量装载和缓慢释放。选择具有合适降解速度的可降解生物高分子PLGA，与MBG复合通过三维打印构建二者层层交替的同心圆柱体结构，进一步延缓释放的同时保持药物以弦波形式规律释放，维持病灶处较长时间的有效杀菌浓度。该复合支架有望满足联合、高量及规律的临床抗结核化疗要求，是抗骨结核药物缓释支架研究领域的新发展，具有创新性。

骨结核病术后的治疗与恢复一直依赖于全身高剂量、长时间用药，且存在手术造成的骨组织缺损，为避免系统用药的极低效率和副作用，本项目采用了三维打印技术设计制备具有可控结构的MBG/MSNs/PHBHHx复合骨修复支架，该支架可以一方面联合装载高含量的多种抗结核药物，完成药物在支架植入区域的尽可能长时间持续释放，抑制结核杆菌的复发；另一方面，作为支架材料诱导骨组织的再生和骨缺损的修复。项目通过研究合成不同介孔结构和表面特性的介孔氧化硅基陶瓷材料，区别性地高效高量装载一线抗结核药物异烟肼和利福平；通过三维打印技术设计支架结构，探索药物从支架上的持续性缓慢释放；通过对支架材料的多种组合和选择，实现支架良好的生物相容性及成骨性能。结果表明，首先，MBG/PHBHHx复合骨修复支架诱导显著的骨再生，其次，支架中介孔限域、表面化学基团及PHBHHx的逐步降解共同作用，实现了长达12周的两种抗结核药物协同释放，并维持病灶处两种药物的有效抑菌浓度，支架材料和药物释放过程未产生明显的肝肾副作用。在此基础上，项目进一步探索了MBG/PHBHHx复合支架用于DMOG分子的局部缓释，有效促进骨缺损部位不同直径尺寸的新血管生成，血管化进程加快和新血运的构建使得整个支架填充的缺损区域均有良好的成骨表现。项目研究为MBG基骨修复支架的临床研究应用奠定基础，研究成果发表学术论文13篇，培养硕士生2名。