A Bioactive Prosthetic Vascular Graft

生物活性人工血管移植物

• 批准号: 8213474
• 负责人: Matthew Douglas Phaneuf
• 金额: $ 36.94万
• 依托单位: BIOSURFACES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8213474
• 关键词: Acute; Adherence; Affinity; Anticoagulants; Antithrombins; Arteries; Binding; Biocompatible; Biological Assay; Blood; Bypass; Caliber; Canis familiaris; Carotid Arteries; Catheters; Cell Adhesion; Cell Proliferation; Cells; Characteristics; Chronic; Clinical; Complex; Coronary Artery Bypass; Development; Devices; Endothelial Cells; Endothelium; FDA approved; Failure; Goals; Grant; Growth; Healed; Heart; Histologic; Immobilization; Implant; Knee; Left; Ligands; Marketing; Modeling; Peripheral; Phase; Polyesters; Polyethylene Terephthalates; Polytetrafluoroethylene; Principal Investigator; Proliferating; Property; Prosthesis; Proteins; Reaction; Research; Role; Secondary to; Signal Transduction; Simulate; Small Business Technology Transfer Research; Structure; Surface; Surface Properties; Technology; Thrombin; Thrombosis; Thrombus; Time; Tissues; Transplanted tissue; United States; Vascular Graft; activated Protein C; chemical property; design; economic impact; functional group; healing; implantation; in vivo; novel; phase 2 study; physical property; prevent; progenitor; public health relevance; receptor binding; reconstruction; repaired; ventricular assist device

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.

描述（由申请人提供）：每年在美国植入超过60，000件主要由聚对苯二甲酸乙二醇酯（聚酯）或膨胀型聚四氟乙烯（ePTFE）组成的假体移植物。不幸的是，这些移植物由于与急性血栓形成和不完全、不受调节的细胞增殖相关的继发性并发症而继续具有高失败率。随着人工血管移植物直径的减小（6- 8 mm内径或ID），这些并发症只会更加严重。到目前为止，在美国还没有FDA批准用于临床的小血管移植物（<5 mm ID）。我们的假设是APC共价固定到官能化聚酯血管移植物表面上将通过移植物植入后可再生地灭活FVa和FVIIIa来防止表面血栓形成。此外，表面结合的APC将通过高度特异性、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，并向移植物粘附细胞或来自相邻内皮的细胞发出信号以在表面上增殖和迁移，从而在控制相邻组织中的细胞增殖方面具有直接作用。在表面I中，在现有的小直径编织聚酯接枝基质内产生相官能团，（BioFunc）接枝官能化表征了化学和物理性质。此外，天然抗凝剂活化蛋白C（APC）共价固定于这些表面官能团，APC结合优化（BioFunc-APC显著保持APC固定的表面材料）。移植物抗血栓形成特性以及促进内皮细胞粘附到该生物活性移植物表面。 最后，在模拟动脉血流条件下，APC在移植物表面上稳定了一段时间。本II期STTR的目标是使用动脉移植模型评估移植物BioFunc-APC的体内愈合和抗血栓形成特征。 本II期研究的具体目的是：1）在小直径（4 mm ID）紧密编织上创建功能组2）表征移植物），技术（BioFunc专有移植物使用BioFunc移植物的聚酯物理/化学性质，3）将APC涂覆到BioFunc移植物表面上（BioFunc-APC移植物），4）评估BioFunc-APC移植物的表面抗血栓形成和细胞粘附性质，5）使用犬动脉移植模型评估体内急性和慢性植入期，和6）用肉眼/显微镜检查固定的BioFunc-APC移植物。开发一种生物活性聚酯血管移植物，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，将对动脉修复和置换产生重大影响。这些移植物可用于外周旁路（特别是膝下重建）以及冠状动脉旁路。因此，可用于中小血管重建的“现成”生物活性合成动脉旁路移植物的潜在年市场价值可能超过15亿美元。 公共卫生相关性：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）或膨胀聚四氟乙烯（ePTFE）组成。不幸的是，这些人工动脉移植物由于与急性血栓形成和不完全、不受调节的细胞增殖相关的继发性并发症而继续具有高失败率。随着人工血管移植物直径的减小，这些并发症只会更加严重。迄今为止，没有小血管移植物（<5 mm I.D.）FDA批准在美国临床使用的药物。具有设计成防止这些类型的故障发生的表面的新型人造动脉的开发将应用于复杂装置，例如人造动脉、完全可植入心脏和左心室辅助装置以及简单装置，例如导管套囊。因此，可用于中小血管重建的“现成”生物活性合成动脉旁路移植物的潜在年市场价值可能超过15亿美元。