具有三维取向连通孔结构的多孔聚合物支架的构筑与性能研究

Constructing aligned porous scaffolds to imitate extracellular matrix could promote anisotropic tissue regeneration effectively. However, in most cases, the aligned structures only form on the surface of scaffolds, impeding spatial cell growth and thus being detrimental to tissue repair. Although a unidirectional freeze-drying technology was employed to prepare three-dimensional (3D) scaffolds with aligned microtubes, low interconnection between the parallel microtubes limited homogeneous cell seeding and distribution. Besides, large amount of organic solvent used in the fabrication process may jeopardize the biocompatibility of scaffolds. In this proposal, we plan to employ the “melting extrusion-hot stretching” technique to induce the oriented phase deformation of co-continuous blends (one phase is the water-soluble polymer) by exerting intense stretching field. Then, the interconnected aligned structure is generated in the 3D porous scaffolds after hydrosoluble phase removal. Systematic investigation will be performed on effects of polymer composition, molecular weight, proportion, and stretching conditions on the formation mechanism of aligned co-continuous phases. The above results could further guide structure evolution and control during the “melting extrusion-hot stretching”. We intend to reveal the formation mechanism of aligned phases and interconnected oriented pores, obtain the processing window of oriented porous scaffolds, and establish the correlation between microstructure with macroscopic mechanical and biological performance. Finally, the “processing-structure-performance” relationship of the aligned porous scaffolds is set up. The obtained fundamentals will offer theoretical guidelines and technical assistance for manufacturing aligned porous scaffolds with superior performance.

构建具有仿生细胞外基质结构的取向支架能有效促进各向异性组织的修复和重建，但目前多数取向结构只能在支架表面形成，限制了细胞的三维生长，不利于组织修复。虽然单轴冷冻干燥技术能制备三维取向微管支架，但微管间连通率低，不利于细胞接种和均匀分布，而且制备过程中使用大量的有机溶剂会损害支架的生物相容性。本项目拟采用“熔融挤出-热拉伸”技术提供的强可控拉伸流动场，诱导共连续共混物（其中一相为水溶性聚合物）发生相取向变形；之后，萃取水溶性高分子相，获得具有三维取向连通结构的多孔支架。系统研究共混物种类、分子量、比例及拉伸条件诱导取向共连续相形态和结构的影响规律；基于此，指导“熔融挤出-热拉伸”过程中的结构调控，揭示构筑取向相及取向连通孔的机理，获得制备取向连通多孔支架的临界加工条件。将支架的微观结构与宏观力学性能和生物学性能相关联，建立“加工-结构-性能”关系，为制备高性能取向多孔支架提供理论和技术支持。

高分子材料虽具有良好的生物相容性和生物可降解性，但其自身生物惰性和缺乏骨整合性能，限制了在组织工程领域的应用。为提高高分子支架促进骨再生的能力，本项目通过调控支架微纳结构和引入化学线索等加工手段，制备了具有良好生物活性的取向互连多孔支架，主要取得如下重要发现：（1）构筑了独特的取向纳米片拓扑结构，显著提高了高分子支架促进前成骨细胞增殖和分化的能力；（2）构建了相互垂直交叉的微纳凹槽拓扑结构，揭示了细胞在微纳凹槽上发生不同方向极化的细胞力学原因：只有粘附诱导的极化（纳米）增强了细胞内力，通过减少染色质凝聚来促进干细胞的成骨分化。（3）引入化学线索，增强了多孔支架促进骨再生能力。（4）利用蚀刻方式使结晶型高分子支架表面暴露出致密的片晶，形成独特的纳米拓扑结构，并在支架表面修饰聚多巴胺涂层或修饰氨基，制备纳米拓扑结构和化学线索复合的支架，实现成骨细胞粘附、扩散和增殖，显著增强了支架的成骨能力。（5）通过共连续共混物的单轴形变构筑了取向互连多孔支架，相比各向同性支架，其能够诱导骨再生和抑制星型胶质细胞过激活。进一步，将取向互连的微米拓扑结构与片晶自组装形成的纳米拓扑结构相结合，协同提高了支架的成骨性能。本项目的主要研究工作旨在通过结构设计引入物理线索，提高支架的生物活性，为新型高分子骨植入支架的开发提供了新思路。本项目研究成果共发表高水平论文12篇，申请授权国家发明专利4件，发表会议论文12篇。培养硕博士研究生10名（博士3名、硕士7名），其中已毕业5名。