分时控释纳米纤维支架的仿生构建及其用于慢性骨髓炎的基础研究

Infectious bone defects especially chronic osteomyelitis have been a thorny issue in clinical practice. The current drug release system was not able to trigger anti-inflammatory effect and simultaneously support bone healing regeneration. Based on the material components selection and multi-level microstructure design, this work aims at a time-response anti-inflammatory and self-degradable biomimetic organic/inorganic composite scaffolds to solve these problems, such as bacterial infection, chronic inflammation and slow healing. Based on the our previous work, the first work is to prepare and tailor the inorganic phase component-trace element doped hollow mesoporous bioglass nanospheres via mussel-mimetic polydopamine treatment, and to evaluate the relationship between the ion release and the drug release rate in the infection environment in vitro and in vivo. The second is to fabricate the multilayer nano-scale biocompatible composite scaffolds the three-dimensional fibrous network structure design, and to explore their basic characteristics, i.e., physicochemical properties, surface interface properties, micro-structure, biologically active ion dissolution products, drug release rate. Specially, the best biological effects of the above characteristics on the controllable degradation, inflammation response and new bone regeneration also are to reveal and clear the intrinsic mechanism. These studies will help to design the self-controllable degradation composite materials for potential application in infectious bone defects, and simultaneously develop the long-term release of drug carrier materials.

慢性骨髓炎型感染性骨损伤一直是骨科临床的棘手问题，目前的药物控释体系往往不能兼顾长效感染防控与高效骨愈合修复。本项目基于材料组分选择、药物分布、多层次微结构设计，构筑一类分时抗炎与自可控降解的仿生有机/无机复合骨修复材料，以期解决感染炎症、愈合缓慢等问题。围绕前期研究微量元素掺杂中空介孔生物玻璃入手，通过表面功能化处理，构建聚多巴胺自组装介孔微粒的可精细剪裁型设计方案，研究离子释放、药物剂量对体内外感染环境的控制规律；通过三维纤维网络结构设计，发展多层次纳米尺寸的生物相容复合支架材料，揭示这类材料理化性能、微结构、活性离子释放、药物释放速率等基本特征对可控降解、感染控制、骨再生效率的最佳生物学效应，阐明这类复合生物材料抗炎、诱导新骨再生的内在机理。本项目旨在探索一种自降解、高效再生修复感染性骨损伤的新材料和新设计模式，同时推动长效释放药物控释体系的发展。

针对骨缺损中的感染炎症和骨修复问题，本项目首先围绕无机/有机组分的生物相容复合支架材料设计入手，利用介孔生物玻璃的多层微纳结构特点，选择微量元素掺杂、表面功能化处理来提高该介孔微粒的药物储存和缓释能力，成功制备了聚多巴胺涂覆掺铜介孔生物玻璃（Cu-MBG@PDA），选用盐酸万古霉素作为药物分子模型，探明了不同pH应答条件下不同粒径的中空介孔生物玻璃微球的药物缓释及控释规律，揭示了该介孔微球对金黄色葡萄球菌的抗菌性能和小鼠成纤维细胞L929生物学效应。其次，利用静电纺丝、冷冻干燥技术分别选择丝素蛋白、海藻酸钠、聚乳酸等高分子基质成功构筑了纤维网络结构的复合纤维支架材料，阐明了这类复合材料的理化性能、生物活性、降解性规律，研究了该复合支架材料于不同pH下药物剂量的药物释放规律，细胞生物学效应结果显示了该复合支架材料对人成骨肉瘤细胞MG-63和鼠骨髓间充质干细胞BMSCs有良好的生物相容性。另外，采用湿法纺丝选择天然高分子基质丝素蛋白构筑了一种三维SF/Cu-MBG@PDA复合纤维支架，研究了这类复合材料的理化性能及抗菌性能，并研究了该载药后该三维纤维支架材料于不同pH条件下药物剂量的药物释放规律，兔胫骨缺损修复实验结果显示了该载药后该三维复合纤维支架有着自抗炎和显著促进胫骨缺损修复作用。这些为后期设计骨修复材料及研究材料与宿主骨之间的作用机理提供实验基础和理论依据。围绕上述研究内容，在《ACS Applied Materials & Interfaces》、《Ceramics International》、《Materials Today Communications》、《Materials Letters》、《浙江理工大学学报<自科版>》等期刊上发表了9篇论文，其中SCI一区Top 1篇，二区Top 1篇；申请了国家发明专利2项，培养了硕士研究生3名。与国家自然科学基金计划书（发表论文4-5篇；申请国家发明专利 1-2 项；培养研究生1-2名）对比，已实现了预期研究目标和任务。