感染性骨缺损修复一直是临床医生面临的难题，采用骨组织工程方法修复倍受关注。课题组前期研究发现：NBD多肽可防治炎症对成骨细胞分化的抑制且与其阻断NF-KB信号通路有关；含锶硫酸钙治疗骨缺损兼具骨传导及骨诱导优势。针对感染性骨缺损病程较长，成骨活性不足，NBD多肽局部用药效率低下、难以持续抗炎问题，本研究拟合成PLGA/NBD多肽载药缓释微球，采用三维打印技术将Sr-CaS与PLGA/NBD多肽载药缓释微球混合，低温制备符合骨缺损形状个性化支架材料。采用FTIR、XRD、Micro-CT、生物力学和分子生物学等手段观察材料表征、药物缓释特性、异位抗炎成骨及生物力学特点。该研究将微球缓释技术与三维打印技术相结合，实现药物高量装载和缓慢释放，保持药物活性同时利用Sr-CaS优良生物活性提高复合支架促新骨再生能力，为感染性骨缺损个性化治疗，维持病灶局部长效抗炎同时实现骨质缺损修复提供新的思路。

Repairment for infective bone defect (IBD) is always the challenge clinically, and bone tissue engineering have been payed more attention in such area recently. In the previous study, we have proved that inflammation inhibits osteoblast differentiation, NBD peptide as an agonist was able to effectively antagonize the inhibition of osteoblast differentiation through down-regulating NF-κB pathway. Moreover, Sr-CaS has osteoconduction and osteoinduction in repairment for infective bone defect. Based on that IBD has a long course and insufficient osteogenic activity, and local application of NBD peptide is inefficiency in continuous anti-inflammatory, we will design PLGA/NBD peptide sustained-release microspheres, structure personalized scaffold material of Sr-CaS/PLGA/NBD peptide according with bone defect shape relied on Three- Dimensional Printing (3DP) at low temperatures in this project. We will investigate materials characterization, drug sustained-release characteristic, biomechanics, anti-inflammatory and osteogenic capacity of scaffold, according to FTIR, XRD, Micro-CT, histology, biomechanics and molecular biology. The study will integrate sustained-release microspheres and 3DP technology, achieve high volume load, slow release and activity maintenance of NBD peptide, take advantage of osteogenic capacity of Sr-CaS. It will provide scientific evidence for individual-based treatment of IBD with both lasting anti-inflammatory and bone defect repairment.

本课题的主要研究内容包括PLGA多肽载药缓释微球的制备；对PLGA多肽载药缓释微球进行表面特征分析；对PLGA多肽载药缓释微球的进行检测分析；对PLGA多肽载药缓释微球的优化；PLGA多肽载药缓释微球的体外释放研究。 本课题通过通过改良剪切沉淀法成功现实微球的制备，这一方法具备设备简单，高效，所制备微球包封率高等特点。通过对所制备微球进行扫描电镜测试，发现微球为圆球形，表面存在孔洞，平均粒径在11.16 to 27.51μm之间；通过研究不同制备参数对所制备微球的特征的影响，发现随着聚合物浓度的增加，微球的包封率增加，载药量降低，微球的粒径增大；随着初始载药量的增加，微球的包封率降低，载药量增加，初始载药量的变化对微球粒径无显著影响；随着十聚甘油二油酸酯的增加，微球的包封率、载药量及粒径降低；随着水溶性药物溶液容积的增加，微球的包封率和载药量降低，粒径增加；随着乳化液的注射速度增加，微球包封率、载药量及粒径增加；随着剪切液中乙醇/甘油比率的降低，微球的包封率和载药量增加；通过对所制备微球进行为期1个月的体外释放实验发现，所制备的微球表现出双相释放模式，突释为14.8%释放实验进行30天仅45.9%包裹的药物被释放出来，因而本制备方法所制微球有发展成为缓释药物传递系统的巨大潜力。