3D打印构建载药SF/HA/PVA复合抗骨结核组织工程骨支架及应用基础研究

Implantable drug-loaded sustained release system obtaining local higher bactericidal concentration can replace present high-dose anti-tb drug therapy, in which drug scaffold preparation, drug sustained-release and tissue compatibility are the keys of promote application. This project mainly researches microstructure optimization design of anti-tb bone tissue engineering scaffolds compositing drug-delivery silk fibroin (SF),hydroxyapatite (HA), polyvinyl alcohol(PVA) and 3D printing preparation. It includes the contents as followed: combine multi materials with bionic optimization design of gradient structure, establish a slow-release characteristics and microstructure controllable composite scaffold model, research dose-effect relationship of anti-tb drugs, SF HA and PLA, reveal the influencing mechanism of process parameters such as material ratio on forming quality and the drug release, master the influence law of scaffolds microstructure on bone tissue regeneration, achieve coordination among drug sustained release, scaffold degradation and bone cell regeneration, optimize of bone scaffold preparation platform, explore the controlling mechanism of shape and performance of the scaffolds during the 3D building process. The project aims to explore new methods of anti-tb bone tissue engineering scaffold preparation, realize the scaffold degradation and sustained release rate matching with the bone regeneration rate, achieve dual purpose of bone defect repair and bone tuberculosis treatment.

植入式载药缓释系统以其可获得局部较高杀菌浓度的优势进而可代替目前全身大剂量抗结核药物治疗，其中载药支架制备、药物缓释及组织相容性是促进应用的核心环节。本项目以载药丝素蛋白SF、羟基磷灰石HA、聚乙烯醇PVA复合抗结核组织工程骨支架的微观结构优化设计与3D打印制备为研究对象，开展关键问题研究，内容包括：结合多材料、梯度结构支架仿生优化设计，建立具有缓释特性、微结构可控的复合骨支架模型；研究支架中抗结核药物、SF、HA、PLA等材料间的量效关系，揭示材料配比等工艺参数对成形质量、药物控释的影响机制；掌握支架微结构对骨组织再生的影响规律，实现药物缓释、支架降解与骨细胞再生速率间的协调性；优化骨支架制备平台，揭示3D打印微结构单元过程中控形、控性耦合机理。项目旨在探索抗结核组织工程骨支架制备新方法，并实现支架材料降解与药物缓释速度同骨组织再生速度相匹配，达到骨缺损修复与骨结核治疗并进的双重目的。

本项目对同轴载药可降解组织工程骨支架的设计、制备与验证开展系统研究。针对结核病灶清除后骨缺损部位的治疗与填充修复，研发载药缓释组织工程支架，构建植入式载药缓释系统，多梯度缓释抗结核载药支架对病灶局部进行药物缓慢释放和定向给药，对病灶缺损处再生修复具有重要意义。.本项目完成了对丝素蛋白（SF）、聚乙烯醇（PVA）、羟基磷灰石（HA）等多种材料间的复合机理的探究工作，并通过冷冻-融化方式完成了内芯SF/PVA/HA复合材料的优化，以及对外芯材料PVA/HA间材料组分和配比选取进行优化工作，提高了各复合材料的力学性能、水溶液稳定性能、降解性能及释药稳定性能；通过采用神经网络、响应曲面、单因素实验及正交实验等优化设计方法完成了对各亲、疏水性药物载药微球的制备及择优筛选工艺参数的工作，确定了各抗结核药物的载药微球的最佳制备工艺参数，提高载药率、包封率、释药率等性能；应用ANSYS建模分析了流场对支架结构的影响以及3D打印挤压物料时浆料流动状态以及出丝时形状变化，并通过响应曲面法优化了打印过程中的工艺参数，实现了同轴载药支架的精确打印；分别建立浸渍药物式、单轴混合药物式、同轴内芯混合药物式三种多孔载药骨支架模型，在此基础上又优化并验证了同轴三联载原药骨支架及同轴三联载微球骨支架的降解速率，药物负载率及药物缓释速率。因此，已对构建的同轴三联载药组织工程骨支架的力学性能、生物性能、降解性能、释药性能进行了有效的优化及评估工作。