A Bioactive Prosthetic Vascular Graft

描述（由申请人提供）：每年在美国植入超过60,000个假体移植物，由聚对苯二甲酸乙二醇酯（聚酯）或膨胀聚四氟乙烯（ePTFE）组成。中等（6-8mm）和小（<5mm）内径（I.D.）的人工动脉移植在临床使用时仍然具有不可接受的高失败率。与这些移植物相关的两个主要并发症是急性血栓形成和不完全、不调节的细胞愈合。STTR I期资助的目标是在体外开发一种具有生物活性表面的新型聚酯血管移植物。我们的假设是，将活化蛋白C (APC)（一种天然抗凝剂）共价固定在功能化聚酯血管移植物表面上，通过可再生地失活FVa和fviia以及防止血小板活化来防止表面血栓形成。此外，表面结合的APC会通过高度特异性、高亲和力的配体-受体结合反应，促进血液中循环的EPCR阳性细胞粘附到聚酯移植物表面，并向移植物贴壁细胞或邻近内皮细胞发出信号，使其在表面增殖和迁移。本研究的具体目的是：1)优化改性聚酯（EDA）接枝表面和固定化APC的表面官能团；2)评价表面结合APC的生物稳定性；3)表面固定化APC的生物学测试。生物活性聚酯血管移植物的发展将提供局部表面抗凝血酶特性并刺激内皮细胞特异性附着，这将对血管修复和置换产生重大影响。这些移植物可以用于外周搭桥（特别是膝盖以下）和冠状动脉搭桥，在美国每年有超过50万的冠状动脉搭桥植入术。因此，一种现成的生物活性合成动脉旁路移植术的潜在年市场价值可能超过15亿美元。在本研究的二期研究中，将在犬双侧颈动脉移植模型中对带有共价结合APC的EDA-APC移植物（内径6mm）进行急性和慢性评估，以评估其长期通畅和整体愈合特性。

DESCRIPTION (provided by applicant): Over 60,000 prosthetic grafts, which are comprised of either polyethylene terephthalate (polyester) or expanded polytetrafluoroethylene (ePTFE), are implanted in the United States each year. Medium (6-8mm) and small (<5mm) internal diameter (I.D.) prosthetic arterial grafts continue to have unacceptably high failure rates when used in the clinical setting. The two major complications associated with these grafts are acute thromboses and incomplete, unregulated cellular healing. The goal of this Phase I STTR grant is to develop in vitro a novel polyester vascular graft with a bioactive surface. Our hypothesis is covalent immobilization of Activated Protein C (APC), a natural anticoagulant, onto a functionalized polyester vascular graft surface will prevent surface thrombus formation via renewably inactivating FVa and FVIIIa and by preventing platelet activation. Additionally, surface bound APC would promote adherence of EPCR positive cells circulating in the blood to the polyester graft surface through a highly specific, high affinity ligand-receptor binding reaction and signal graft-adherent cells or cells from adjacent endothelium to proliferate and migrate on the surface. The specific objectives of this study are to: 1) optimize surface functional groups on the modified polyester (EDA) graft surface and immobilize APC, 2) evaluate the biostability of surface bound APC and 3) biological testing of surface immobilized APC. Development of a bioactive polyester vascular graft that would provide localized surface antithrombin properties and stimulate endothelial cell specific attachment would have a significant impact on vessel repair and replacement. These grafts could be utilized in peripheral bypass (specifically below-knee) as well as for coronary artery bypass, in which there are over 500,000 bypass grafts implanted annually in the United States. Thus, the potential annual market value for an off-the-shelf bioactive synthetic arterial bypass graft could exceed $1.5 billion. In Phase II of this proposal, EDA-APC grafts (6mm internal diameter) with covalently bound APC will undergo acute and chronic evaluation in a canine bilateral carotid grafting model in order to assess long-term patency and overall healing characteristics.