自固化抗结核靶向释药复合体对骨缺损的修复作用和机制

Osteoarticular tuberculosis is highly invasive and destructive to the involved bone tissues. One-stage bone grafting of the infected bone defect area is prohibited due to the penitential pathogen which cannot be completely removed by surgery. Supported by the youth project from National Natural Science Foundation (NSF) of 2010, we investigated the releasing mechanism of anti-tuberculosis drugs and developed an anti-tuberculosis composite for the targeted delivery of antibiotics. According to the treatment principle of tuberculosis, multi-antibiotics could be released by this composite in three phases. They are extensive bactericidal phase, continuous bactericidal phase and inhibitory phase, which can successfully improve the antimicrobial effect and reduce systemic side effects. However, the bone repairing effect of this composite is not ideal. Firstly, the osteogenic activity of combined exogenous growth factor can be damaged by the loaded anti-tuberculosis drugs, which decreases the osteoinductivity of the composite. Secondly, the shape of the preformed composite cannot match the irregular shape of different infected lesions, which decreases the osteoconductivity and bactericidal effect of the composite. In order to overcome these shortcomings, we plan to apply for the support of NSF general program and carry out the further researches which includes switching the endogenous osteogenesis via investigating the osteogenic mechanism of nanoparticles, making the releasing of nanoparticles match the delivery of anti-tuberculosis drugs by controlling the degradation of nanomaterials, making the composite match diversity defects by studying the temperature-depend self-forming mechanism and finally studying the bone defects repairing effects of this composite via animal defect models. To carry out the above studies will contribute to the treatment of osteoarticular tuberculosis by creating a safe and effective method.

骨关节结核感染对骨质破坏重。外科手术无法彻底清除病灶内残留细菌，一期植骨修复成为禁忌。本课题组2010年在国家自然科学基金青年项目资助下通过研究抗结核药物的缓释机制构建出"抗结核靶向释药复合体"。该复合体可根据治疗原则在病灶内分"强效杀菌、维持杀菌和巩固抑菌"三个阶段联合、梯度释放抗结核药物，有效提高抗菌效果、降低全身毒副作用。然而，现阶段复合体的骨修复作用尚不理想，其主要原因是：①所承载的抗结核药物破坏外源性生长因子活性，影响复合体骨诱导作用；②体外一次成型的复合体对骨缺损适应性差，影响骨传导和杀菌作用。为此，课题组拟进一步：①通过研究纳米颗粒成骨机制启动内源性成骨作用；②通过调控纳米颗粒缓释使之与化疗药物释放周期匹配；③通过研究复合体温敏成型机制使其根据缺损形状自固成型，提高骨传导和杀菌作用；④最后通过骨缺损模型验证复合体的骨修复作用。上述研究将为治疗骨结核提供安全、有效的新方法。

骨关节结核感染对骨质破坏重。外科手术无法彻底清除病灶内残留细菌，一期植骨修复成为禁忌。本课题组2014年以来在国家自然科学基金面上项目资助下先后完成了：nHA促进细胞粘附、增殖和诱导成骨分化的相关机制研究；纳米颗粒降解特征和对其进行控释的相关机制研究；温敏型水凝胶定型和自固成型工艺制备；通过建立体外/体内模型，全面评价复合体抗菌和缺损修复作用。通过上述研究，课题组成功构建出具有促进成骨和抗感染活性的抗结核靶向释放药物复合体。研究期间课题组获得发明专利授权2项，实用新型专利授权1项；发表标注课题号的SCI论文8篇，培养博士和硕士研究生各2名。课题相关成果获得教育部自然科学一等奖1项、中华医学科技奖二等奖1项，同时获得中华医学会骨科分会骨科基础青年研究三等奖和中华医学会第十七届骨科学术会议COA骨科基础研究优秀论文二等奖。课题组长获批国家重点研发计划“生物材料表界面及表面改性研究”课题1项以及国家自认科学基金面上项目1项。上述研究为骨结核的治疗提供安全、有效的新方法。