A Bioactive Prosthetic Vascular Graft

描述(申请人提供)：美国每年植入超过60,000个假体移植物，主要由聚对苯二甲酸乙二醇酯(聚酯)或膨体聚四氟乙烯(EPTFE)组成。不幸的是，这些移植物仍然有很高的失败率，原因是与急性血栓相关的继发性并发症和不完全的、不受控制的细胞增殖。这些并发症只会随着人造血管直径的减小(内径6-8 mm或ID)而变得更加严重和严重。到目前为止，在美国还没有FDA批准临床使用的小型血管移植物(直径5 mm)。我们的假设是，将APC共价固定在功能化的聚酯血管移植表面上，将通过在移植后可再生地灭活FVA和FVIIa来防止表面血栓的形成。此外，表面结合的APC可通过高特异性、高亲和力的配体-受体结合反应，促进血液中循环的成熟和祖细胞与聚酯移植物表面的黏附，并通过信号传递移植物贴壁细胞或来自相邻内皮的细胞在表面上增殖和迁移，从而在控制邻近组织中的细胞增殖方面发挥直接作用。在表面I中，在现有的小直径机织聚酯接枝基质(BioFunc)中创建了相官能团，(BioFunc)接枝对化学和物理性能进行了功能化。此外，天然抗凝剂活化蛋白C(APC)被共价固定到这些表面官能团上，并对APC的结合进行了优化(BioFunc-APC显著保持了APC固定化的表面材料)。移植物的抗血栓性能以及促进内皮细胞与生物活性移植物表面的粘附性。最后，在模拟动脉血流条件下，APC在移植物表面长期稳定存在。这一第二阶段STTR的目标是通过动脉移植模型对移植物BioFunc-APC的IS特性进行评估，以实现体内的愈合和抗血栓。犬这项第二阶段研究的具体目标是：1)在小直径(4 mm内径)紧密编织的支架上创建官能团；2)鉴定移植物的特性；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黏附特性；5)使用犬动脉移植模型评估体内急慢性植入期；6)宏观/微观检查可解释的BioFunc-APC移植物。开发一种具有生物活性的聚脂血管移植物，将提供局部的表面抗凝血酶特性，并刺激内皮细胞特异性的附着/增殖，将对动脉修复和替换产生重大影响。这些移植物可用于外周搭桥术(尤其是膝下重建)以及冠状动脉搭桥术。因此，可用于中小型血管重建的“现成”生物活性合成动脉搭桥移植物的潜在年市场价值可能超过15亿美元。 与公共健康相关：美国每年植入60,000多个假体移植物，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，由于与急性血栓和不完全、不受控制的细胞增殖相关的继发并发症，这些人工动脉移植物的失败率仍然很高。随着人造血管移植物直径的减小，这些并发症只会更加严重和严重。到目前为止，还没有小血管移植(&lt；5 mm内径)。这些药物是FDA批准在美国临床使用的。开发一种表面旨在防止此类故障发生的新型人工动脉，将适用于复杂设备，如人工动脉、全植入性心脏和左心室辅助设备，以及简单设备，如导管袖口。因此，可用于中小型血管重建的“现成”生物活性合成动脉搭桥移植物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.