ANTITHROMBOGENIC MEMBRANE-MIMETIC ASSEMBLIES

描述(逐字摘自申请者摘要)：一种临床耐用的小 直径的血管移植物可以通过识别和结合到 该假体具有积极的抗血栓形成机制，这些机制在 在一系列血流动力学条件下的血液-物质界面。这个 研究人员认为，一种模拟膜的组件含有 血栓调节蛋白(TM)作为内源性蛋白C抗凝剂的激活剂 路径为这种方法提供了一种合理的设计策略。具体来说， 调查员打算： 一种掺入类膜的薄膜的合成与表征 血栓调节蛋白作为“按需”抗凝反应的介体。TM将会 被结合到可聚合的磷脂微囊中并且稳定， 由衬底支撑的平面膜组件将被生产出来并原子化 刻画了级别属性。在这个过程中，脂类之间的关系 头部组成、TM浓度和膜动力学在激活中的作用 蛋白C将被阐明，并确定其对凝血酶生成的影响。 明确血流动力学状态在调节蛋白C中的作用 使用膜模拟模型系统的激活和凝血酶生成。这个 基于TM的策略在多大程度上产生抗血栓形成环境 在动脉和静脉血流环境下将使用管状血管进行评估 流动反应器系统。壁面剪切率在调节运动中的作用 将确定生产活性蛋白C的参数。此外, 我们将在下列情况下定义这些系统限制凝血酶生成的能力 内源性或外源性凝血通路在以下条件下启动 不同的流动条件。 测定血栓调节蛋白结合到膜模拟物中的能力 界面对血栓形成和血管病变发展的影响 体内吻合口新生内膜增生。小口径血管假体 将用含有掺入的TM的膜仿膜进行功能化。 初步研究将集中在急性血小板和纤维蛋白原沉积在一个 体外分流实验模型，以及短期生物稳定性分析。这 随后将对移植物的愈合和通畅性进行长期的灵长类研究。

DESCRIPTION (Verbatim from Applicant's Abstract): 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. The investigator believes that a membrane-mimetic assembly that contains thrombomodulin (TM) as an activator of the endogenous protein C anticoagulant pathway provides a rational design strategy for such an approach. Specifically, the investigator intends to: Synthesize and characterize a membrane-mimetic thin film incorporating thrombomodulin as a mediator of an "on demand" anticoagulant response. TM will be incorporated into polymerizable phospholipid vescles and stable, substrate-supported, planar membrane assemblies will be produced and atomic level properties characterized. In the process, the relationship between lipid head composition, TM concentration, and membrane dynamics in the activation of protein C will be elucidated and the effect on thrombin generation defined. Define the role of the hemodynamic flow regime in modulating protein C activation and thrombin generation using membrane-mimetic model systems. The extent to which a TM based strategy generates an antithrombogenic environment under arterial and venous flow environments will be evaluated using a tubular flow reactor system. The role of wall shear rate in modulating the kinetic parameters for activated protein C production will be determined. In addition, we will define the capacity of these systems to limit thrombin generation when either the intrinsic or extrinsic coagulation pathways are initiated under varying flow conditions. Determine the capacity of thrombomodulin 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 incorporated TM. 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.