Thromboresistant vascular grafts:heparin-peptidomimetics

人造血管移植物的血栓形成是目前移植物的一个主要问题，需要 预防，可能会导致通畅性丧失，需要重复手术，并伴随着肢体丧失的高风险。申请人建议开发抗血栓扩展 聚四氟乙烯(EPTFE)血管移植物使用吸收的肝素涂层来控制急性和亚急性血栓形成，还加入了一种生物活性多肽模拟剂，以促进血管移植物表面的内皮化，以减少慢性通畅性的丧失。 申请者建立在体外和体内研究的平台上，表明吸附的肝素涂层提供长达30天的血栓抗性。吸附的肝素涂层是浸渍涂层，并且可以容易地应用于制造环境中的移植物。对此，申请者将带来其单独开发的一系列独特的多肽仿制药。多肽类药物被设计成与肝素络合，并通过这种相互作用提供了一种简单的制造模式。申请者将使用一系列的体外和体内测试来评估提供最高水平的移植物内皮化的多肽模拟物。研究也将是 以确定包被多肽/肝素的移植物是否能经受ePTFE的首选灭菌途径环氧乙烷的灭菌。预计第一阶段的研究将导致选择一种肽模拟剂(S)用于第二阶段的大型动物研究，目的是在伴随的情况下在较长时间内提供持久的血栓抵抗 移植物表面的内皮化。

Thrombosis of synthetic vascular grafts is a major problem with current grafts that necessitates prophylaxis, can lead to loss of patency with an attendant need for repeat surgery, and comes with a high risk of limb loss. The applicant proposes to develop thromboresistant extended polytetrafluoroethylene (ePTFE) vascular grafts that use an absorbed coating of heparin to control acute and subacute thrombosis, and also incorporates a bioactive peptidomimetic to encourage endothelialization of the vascular graft surface to reduce chronic loss of patency. The applicant builds on a platform of in vitro and in vivo studies indicating that the adsorbed heparin coating provides thromboresistance for up to 30 days. The adsorbed heparin coating is a dipcoating and can be easily applied to grafts in a manufacturing setting. To this, the applicant will bring a unique series of peptidomimetics that it has separately developed. The peptidomimetics have been designed to complex to heparin and through that interaction provide a facile manufacturing mode. The applicant will use a series of in vitro and in vivo tests to evaluate the peptidomimetic that provides the highest level of graft endothelialization. Studies will also be conducted to establish if the peptide/heparin-coated graft can withstand sterilization with ethylene oxide, the preferred sterilization route for ePTFE. It is expected that Phase I studies will lead to the selection of a peptidomimetic(s) to be used in large animal studies of Phase II with the goal of providing durable thromboresistance over a protracted period of time with concomitant endothelialization of the graft surface.