原位血栓应激性血液相容性材料的构建

Surface-induced thrombosis has caused the failure of various blood-contacting material applications. Incorporation of antithrombotic molecules into materials is the main strategy to solve this problem. However, the materials modified in this way can seldom mimic biological systems, following the rule of bio-response and feedback regulation under a certain microenvironmental change, thus achieving self-regulation of biofunctions. Ideal antithrombotic materials should be able to in situ promote antithrombotic function in response to local thrombosis, and to shut off the function when the information of thrombus clearance was fed back. Based on this conception, this project is planned to construct thrombin-responsive materials and surface coatings, since thrombin generation is the characteristic event during thrombus formation. The materials or coatings are designed to initiate both antithrombogenic and thrombolytic functions in response to thrombin generation by releasing anticoagulants and thrombolytic molecules at the same time. Once thrombosis is inhibited along with the disappearance of thrombin, both functions are shut off. The main characteristic of this project is to make materials sensing the microenvironmental change caused by thrombosis, then defensing thrombosis by molecularly activating specific functional blood systems. The abnormal level of coagulation factors will be regulated by these functional systems so that thrombotic reaction is inhibited. This strategy will open up a new and more effective way for antithrombotic modification of blood-contacting materials.

材料表面血栓的形成是导致血液接触材料应用失败的主要原因之一。多数研究仅通过在材料中引入抗血栓活性分子赋予材料抗血栓功能，但这些材料却很少能效仿生物系统对特定微环境变化做出应激反应和反馈调节，进而实现功能的自我调控。理想的抗血栓材料应能够启动具有原位血栓应激性的抗血栓功能，且血栓被抑制后能够将该信息反馈给材料使其关闭抗血栓功能。基于该构想，本项目针对血栓形成时伴随凝血酶产生的特征性微环境变化，拟构建凝血酶响应性抗血栓材料，使其在血栓形成并产生凝血酶时释放抗凝血分子和纤溶活性分子，同时启动抑制血栓生成和溶解血栓的双重功能，而当血栓被抑制且凝血酶水平恢复正常时及时关闭该功能。本项目最大的特色在于使材料能够感应血栓生成时的分子微环境变化，同时从分子水平上启动特定的血液功能系统，进而调节微环境中的非正常凝血因子水平直至彻底抑制血栓生成反应。该策略将为抗血栓材料的研究开辟一条全新而更有效的途径。

应用于血液环境的材料，往往通过对其表面修饰具有抗凝活性的物质来避免血栓在材料表面的形成。然而，在正常的血液环境中持续暴露具有抗凝活性的物质，不但可能会导致凝血功能紊乱，还会减少抗凝物质的活性寿命。一种理想的血液接触材料，应效仿血管内皮，不但能够抑制血栓在其表面的生成，而且当凝血反应不可避免的发生时，又可以及时清除初步形成的血栓。基于这一设想，本项目利用凝血反应过程中大量生成凝血酶这一特征事件，基于凝血酶底物多肽，设计并制备了一系列具有凝血酶响应性释放组织型纤溶酶原激活剂（t-PA）功能的涂层，或称为血栓应激性纤溶功能涂层。主要研究内容包括：首先在水凝胶模型体系中实现了血栓应激性（凝血酶响应性）纤溶功能概念，其次，将水凝胶模型中构建的系统转化成凝血酶响应性t-PA纳米胶囊，并以其作为主要构筑单元，制备了一系列具有血栓应激性的纤溶功能涂层以及结合了抗凝活性的多功能涂层。最终实现的涂层不但具有抑制凝血反应的活性或保持生物惰性，而且当凝血酶存在的时候，能够立即响应释放t-PA，进而溶解初生血栓。该涂层制备过程简单，适用于多种基材，在血液接触类医疗器械（如体外血液循环管路及心血管植入器械）方面具有很好的应用前景。该项目成果发表8篇SCI论文，其中2篇影响因子大于10。申请发明专利2件，其中1件已授权。