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，主要由聚对苯二甲酸乙二醇酯（聚酯）或膨胀聚四氟乙烯（ePTFE）组成。不幸的是，由于急性血栓形成和不完全、不调节的细胞增殖相关的继发性并发症，这些移植物的失败率仍然很高。这些并发症只会随着假体血管移植物直径的减小（6-8mm内径或ID）而更加深刻和严重。到目前为止，在美国还没有小血管移植物（小于5mm）被fda批准用于临床。我们的假设是将APC共价固定在功能化聚酯血管移植物表面上，通过在移植物植入时可再生地失活FVa和fviii来防止表面血栓形成。此外，表面结合的APC通过高度特异性、高亲和力的配体-受体结合反应，促进血液中循环的成熟内皮细胞和祖内皮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，使其在表面上增殖和迁移，从而直接控制邻近组织的细胞增殖。在表面1，相官能团是在现有的小直径编织聚酯接枝基质中创建的，（BioFunc）接枝具有表征的化学和物理性质。此外，将天然抗凝活性蛋白C （APC）共价固定在这些表面官能团上，并优化了APC的结合（BioFunc-APC显著维持了APC固定的表面材料）。移植物抗血栓特性以及促进内皮细胞粘附到这种生物活性移植物表面。最后，在模拟动脉血流条件下，APC在移植物表面保持稳定。该II期str的目标是通过动脉移植模型评估BioFunc-APC移植体的愈合和抗血栓性。这项第二期研究的具体目标是：1)在小直径（4mm ID）紧密编织上创建官能团2)表征移植物技术（BioFunc专有移植物，使用bioofunc移植物的聚酯物理/化学特性，3）将APC固定在BioFunc移植物表面（BioFunc-APC移植物）4)评估BioFunc-APC移植物的表面抗血栓和细胞粘附特性5)使用犬动脉移植模型评估体内急性和慢性植入期。6)观察BioFunc-APC移植物的宏观/微观外植。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/增殖，这将对动脉修复和替代产生重大影响。这些移植物可用于外周搭桥（特别是膝下重建）以及冠状动脉搭桥。因此，用于中小型血管重建的“现成”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。

DESCRIPTION (provided by applicant): Over 60,000 prosthetic grafts, which are primarily comprised of polyethylene terephthalate (polyester) or expanded polytetrafluoroethylene (ePTFE), are implanted in the United States each year. Unfortunately, these grafts continue to have high failure rates due to secondary complications associated with acute thromboses and incomplete, unregulated cellular proliferation. These complications are only more profound and severe as the diameter of the prosthetic vascular graft decreases (6-8mm internal diameter or ID). To date, there are no small vascular grafts (<5mm ID) that are FDA-approved for clinical use in the United States. Our hypothesis is covalent immobilization of APC onto the functionalized polyester vascular graft surface will prevent surface thrombus formation via renewably inactivating FVa and FVIIIa upon graft implantation. Additionally, surface bound APC would promote adherence of mature and progenitor endothelial 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, thus having a direct effect in controlling cellular proliferation in the adjacent tissue. In surface I, Phase functional groups were created within an existing small-diameter woven polyester graft matrix, (BioFunc) graft functionalized the of properties chemical and physical with characterized. Additionally, the natural anticoagulant Activated Protein C (APC) was covalently immobilized to these surface functional groups, with APC binding optimized (BioFunc-APC significant maintained APC immobilized Surface material). Graft antithrombotic properties as well as promoted increased endothelial cell adhesion to this bioactive graft surface. Lastly, APC was stable on the graft surface over an extended period of time under simulated arterial flow conditions. The goal of this Phase II STTR grant healing and antithrombotic for vivo in graft BioFunc-APC the assess to is characteristics using an arterial grafting model. canine The specific objectives of this Phase II study are to: 1) create functional groups on small diameter (4mm ID) tight woven 2) characterize graft), technology (BioFunc proprietary grafts using polyester physical/chemical properties of BioFunc graft, 3) immobilize APC onto BioFunc graft surface (BioFunc-APC graft), 4) evaluate surface antithrombotic and cell adhesion properties of BioFunc-APC graft, 5) assess in vivo acute and chronic implantation periods using a canine arterial grafting model, and 6) examine macroscopically/microscopically explanted BioFunc-APC grafts. Development of a bioactive polyester vascular graft that would provide localized surface antithrombin properties and stimulate endothelial cell-specific attachment/proliferation would have a significant impact on arterial repair and replacement. These grafts could be utilized in peripheral bypass (specifically below-knee reconstruction) as well as for coronary artery bypass. Thus, the potential annual market value for an "off-the-shelf" bioactive synthetic arterial bypass graft that would be available for medium and small vessel reconstruction could exceed $1.5 billion. PUBLIC HEALTH RELEVANCE: Over 60,000 prosthetic grafts, which are primarily comprised of polyethylene terephthalate (polyester) or expanded polytetrafluoroethylene (ePTFE), are implanted in the United States each year. Unfortunately, these prosthetic arterial grafts continue to have high failure rates due to secondary complications associated with acute thromboses and incomplete, unregulated cellular proliferation. These complications are only more profound and severe as the diameter of the prosthetic vascular graft decreases. To date, there are no small vascular grafts (< 5mm I.D.) that are FDA-approved for clinical use in the United States. Development of a novel artificial artery with a surface designed to prevent these types of failures from occurring would have application for complex devices such as artificial arteries, total implantable heart and left ventricular assist devices as well as simple devices such as catheter cuffs. Thus, the potential annual market value for an "off-the-shelf" bioactive synthetic arterial bypass graft that would be available for medium and small vessel reconstruction could exceed $1.5 billion.