ANTITHROMBOGENIC MEMBRANE-MIMETIC ASSEMBLIES

描述（来自申请人摘要的逐字描述）：临床上耐用的小型 直径的血管移植物可以通过识别并结合到 假体主动抗血栓形成机制，其在 在一系列血液动力学条件下的血液-材料界面。的 研究人员认为，含有 血栓调节蛋白（TM）作为内源性蛋白C抗凝剂的激活剂 Pathway为这种方法提供了合理的设计策略。具体地说， 研究者打算： 合成并表征了一种含有 血栓调节蛋白作为"按需"抗凝反应的介质。tm将 被掺入可聚合的磷脂囊泡中并稳定， 将生产衬底支撑的平面膜组件， 水平特性表征。在此过程中，脂质 头部组成，TM浓度和膜动力学在激活 蛋白C将被阐明，并确定对凝血酶生成的影响。 确定血液动力学流动状态在调节蛋白C中的作用 使用膜模拟模型系统的活化和凝血酶生成。的 基于TM的策略产生抗血栓形成环境的程度 在动脉和静脉流动环境下，将使用管状 流动反应器系统壁面剪切速率在调节动力学过程中的作用 将确定活化蛋白C生产的参数。此外，本发明还提供了一种方法， 我们将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途径都是在 改变流动条件。 测定血栓调节蛋白整合到膜模拟物中的能力 界面，以影响血栓形成和 吻合口新生内膜增生。小直径人造血管 将用含有掺入的TM的膜模拟膜官能化。 最初的研究将集中在急性血小板和纤维蛋白原沉积， 狒狒离体分流模型，以及短期生物稳定性分析。这 随后将进行移植物愈合和通畅性的长期灵长类动物研究。

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.