Anti-Thrombogenic Membrane-Mimetic Assemblies

描述（由申请人提供）：在一系列血液动力学条件下，通过识别并将在血液-物质界面起作用的主动抗血栓形成机制整合到假体中，可以实现临床耐用的小直径血管移植物。我们认为，含有CD39 （E- ntpase -1）作为嘌呤能介导的血小板活化、聚集和募集抑制剂的模拟膜组装为这种方法提供了合理的设计策略。具体来说，我们打算：(1)合成并表征一种含CD39作为“按需”抗血小板反应介质的膜模拟薄膜。CD39将被纳入可聚合磷脂囊泡和稳定的，底物支持的平面膜组件将被生产和原子水平的性质表征。在此过程中，表面的催化活性取决于CD39浓度、脂质膜动力学和局部血流动力学的程度将被定义。(2)明确血流动力学机制在调节表面介导嘌呤能通路抑制血小板血栓生长中的作用。在模拟动脉和静脉流动条件下，将使用平行板流反应器评估基于CD39的策略在由表面结合粘附蛋白或组织因子启动时限制血小板激活和血栓生长的能力。(3)确定CD39整合到膜模拟界面中影响血栓形成和体内吻合口新生内膜增生的能力。小直径血管假体将被一种含有CD39的模拟膜功能化。最初的研究将集中在狒狒体外分流模型中的急性血小板和纤维蛋白原沉积，以及短期生物稳定性分析。接下来将是对移植物愈合和通畅的长期灵长类动物研究。摘要：分子工程表面血栓形成的控制可能是开发小直径动脉假体的重要一步，对心脏、整形和血管外科领域至关重要，对人工器官和代谢支持系统的成功植入也至关重要。

DESCRIPTION (provided by applicant): A clinically durable small diameter vascular graft may be achievable by identifying and incorporating into the prosthesis actively antithrombogenic mechanisms that are operative at the blood-material interface under a range of hemodynamic conditions. We believe that a membrane-mimetic assembly that contains CD39 (E- NTPDase-1) as an inhibitor of purinergic mediated platelet activation, aggregation, and recruitment provides a rational design strategy for such an approach. Specifically, we intend to: (1) Synthesize and characterize a membrane-mimetic thin film that incorporates CD39 as a mediator of an "on-demand" antiplatelet response. CD39 will be incorporated into polymerizable phospholipid vesicles and stable, substrate-supported, planar membrane assemblies will be produced and atomic level properties characterized. In the process, the extent to which the catalytic activity of the surface is dependent upon CD39 concentration, lipid membrane dynamics, and the local hemodynamic flow regime will be defined. (2) Define the role of the hemodynamic flow regime in modulating the effect of surface mediated purinergic pathway inhibition on platelet thrombus growth. The capacity of a CD39 based strategy to limit platelet activation and thrombus growth when initiated either by surface bound adhesive proteins or tissue factor will be evaluated using a parallel plate flow reactor under simulated arterial and venous flow conditions. (3) Determine the capacity of CD39 integrated into a membrane-mimetic interface to influence both thrombus formation and the development of anastomotic neointimal hyperplasia in vivo. Small diameter vascular prostheses will be functionalized with a membrane-mimetic film containing CD39. Initial studies will focus on acute platelet and fibrinogen deposition in a baboon ex vivo shunt model, as well as short-term biostability analysis. This will be followed by long-term primate studies of graft healing and patency. Lay summary: The control of thrombus formation on molecularly engineered surfaces may be an important step in the development of a small diameter arterial prosthesis critical to the fields of cardiac, plastic, and vascular surgery, as well as to the successful implantation of artificial organs and metabolic support systems.