仿多级结构的人工心脏瓣膜构建及其抗钙化机制研究

Heart valve disease is prevalent worldwide, with current treatment requiring surgery for valve replacement. With substantial increase of transcatheter valve prosthesis, development of novel heart valve substitute materials that have mechanical property close to that of native valves and show advantage of anti-calcification is of great interest. In this proposal, artificial heart valves mimicking the hierarchical structures of native valves using composites of poly(ethylene glycol) (PEG) hydrogels and electrospun silk fibrion (SF) fibers (PEG-SF composites), will be fabricated. We attempt to achieve the following specific aims: (1) Recapitulating the hierarchical structures of native valves including macroscopic laminated structures, microscopic fibrous structures as well as interpenetrating structures between layers, and leading to optimal mechanical property. (2) Revealing the relationships between the hierarchical structures and hemodynamic property, and effects of the interpenetrating structures between layers on the durability under fatigue tests for the PEG-SF composites. (3) Investigating the mechanisms of early calcification for the artificial heart valves at the microscopic level using both static and dynamic calcification models, and eliminating calcification and enzyme degradation of PEG-SF composites by interpenetrating polymer networks of PEG hydrogels. (4) Evaluating the biocompatibility of the PEG-SF composites using both in vitro and in vivo experiments. The results from this study will shed light on optimal structure design for novel polymeric heart valves.

心脏瓣膜病是危及人类健康的一种严重疾病，现今主要治疗手段是瓣膜置换手术。研究适合用作介入瓣的新型材料，克服现有高分子瓣膜材料力学性能-功能与人体瓣膜不匹配以及体内钙化等问题，具有重要研究意义和临床应用价值。本项目拟利用聚乙二醇与丝素蛋白纤维复合材料构筑仿人体瓣膜多级结构的人工心脏瓣膜，具体研究内容涵盖四个方面：（1）模仿人体瓣膜的多级结构，包括宏观层状结构、微观蛋白质纤维结构以及层层间交联结构，实现与人体瓣膜相近的力学性能；（2）研究人工瓣膜的多级结构对于血流动力学特性的影响规律，探讨层层间交联结构对改善其疲劳服役性能的作用；（3）建立静态-动态钙化模型研究瓣膜纤维材料的微观钙化机制，通过互穿式高分子网络提高复合材料的抗钙化（以及抗酶解）能力；（4）通过体外-体内实验评价人工瓣膜材料的生物相容性。本项目研究工作将为新型瓣膜材料的结构优化设计提供重要科学依据。

心脏瓣膜病是危及人类健康的一种严重疾病，现今主要治疗手段是瓣膜置换手术。研究适合用作介入瓣的新型材料，克服现有高分子瓣膜材料力学性能-功能与人体瓣膜不匹配以及体内钙化等问题，具有重要研究意义和临床应用价值。本项目利用聚乙二醇二丙烯酸酯(Poly(ethylene glycol) Diacrylate, PEGDA)与丝素蛋白(SF)纤维复合材料构筑仿人体瓣膜多级结构的人工心脏瓣膜。我们采用静电纺丝法分别制备了具有各向异性(Anisotropic Silk Fibroin, ASF)和各向同性(Isotropic Silk Fibroin, ISF)的丝素蛋白纤维膜，并进一步与PEGDA水凝胶结合，作为人工高分子瓣膜材料(PEGDA-ASF和PEGDA-ISF)。拉伸实验结果显示各向异性PEGDA-ASF人工瓣膜沿纤维方向弹性模量为10.95±1.09 MPa，垂直纤维方向弹性模量为3.55±0.32 MPa；而各向同性PEGDA-ISF人工瓣膜的弹性模量为4.54±0.43 MPa。有限元分析结果表明PEGDA-ASF瓣膜在心脏舒张期最大主应力值（2.20MPa）低于PEGDA-ISF瓣膜（2.37MPa）。与人体瓣膜相似，收缩期时PEGDA-ASF瓣膜在瓣叶根部附近会产生一个弯折曲区域，而PEGDA-ISF瓣膜的弯折区却接近瓣叶的自由边缘。此外，PEGDA-ASF瓣膜在打开过程中，能够通过动态调整弯折区域获得较为平滑的表面形貌。因此，人工高分子瓣膜的各向异性特征对于实现其与人体瓣膜相似的力学和流体动力学行为起着至关重要的作用。此外，钙化实验证明PEGDA-SBMA水凝胶复合的人工瓣膜上未见钙化斑块，而PEGDA水凝胶复合人工瓣膜上则观察到钙化斑。研究结果说明PEGDA-SBMA复合高分子网络能有效阻止钙离子和酶分子的传输，从而显著提到复合人工瓣膜的抗钙化（抗酶解）性能。本项目研究结果将为新型瓣膜材料的结构优化设计提供重要科学依据。