A Nanofibrous Biocomposite Small-Diameter Graft

描述（由申请人提供）： 目前尚无小直径（内径<5 mm）人造血管获批用于小血管重建的临床应用。目前的假体不能模拟正常动脉壁的生物和物理特性，导致高故障率。在第一阶段，合成了一种由涤纶和IV型胶原蛋白（ESDC）组成的纳米纤维生物复合材料小直径血管移植物，在移植物结构内产生了抗扭结性。这种新型的薄壁接枝物具有最小的水渗透性和优异的物理性能。然后将有效的抗凝血酶剂重组水蛭素（rHir）和内皮细胞特异性促分裂原血管内皮生长因子（VEGF）共价结合到ESDC表面（ESDC-rHir-VEGF）。这些表面结合剂是生物活性的，如通过特定的体外测定确定的，并且在模拟动脉血流条件下显示稳定性。最后，在移植物的初步体内评价中，当植入犬股动脉时，ESDC移植物显示出优异的操作特性。该II期提案的目标是使用犬动脉移植模型评估ESDC-rHir-VEGF移植物的血液渗透和移植物通畅性/愈合。我们的假设是，下一代人工动脉移植物必须具有多种结构和生物学特性，模拟天然动脉固有的一些过程，以防止血栓形成等并发症的发生。II期的具体目标是：1）合成用于植入研究的ESDC血管移植物，2）开发自动化移植物合成过程，3）评价ESDC移植物的物理和化学性质，4）将rHir和VEGF共价结合到ESDC表面，5）评估体内急性和慢性植入期，以及6）检查肉眼/显微镜下植入的移植物。本项目的第III阶段将继续在第II阶段采用的犬股动脉移植模型中对这种新型ESDC-rHir-VEGF移植物进行长期评估。开发具有生物活性的小直径血管移植物将对小血管修复和置换产生重大影响。这些移植物可用于外周旁路以及冠状动脉旁路，在美国每年植入约500，000个移植物。潜在的，“现成的”合成动脉旁路移植物的年市场价值可能超过15亿美元。

DESCRIPTION (provided by applicant): There is no small-diameter (< 5mm internal diameter) vascular prosthesis approved for clinical use in small vessel reconstruction. Current prostheses are not capable of emulating the biological and physical properties of the normal arterial wall, resulting in high failure rates. In phase I, a nanofibrous biocomposite small-diameter vascular graft comprised of Dacron and Type IV collagen (ESDC) was synthesized, with kinkresistance created within the graft structure. This novel thin-walled graft had minimal water permeation and excellent physical properties. The potent antithrombin agent recombinant hirudin (rHir) and endothelial cellspecific mitogen Vascular Endothelial Growth Factor (VEGF) were then covalently bound to the ESDC surface (ESDC-rHir-VEGF). These surface bound agents were biologically active as determined via specific in vitro assays and showed stability under simulated arterial flow conditions. Lastly, the ESDC graft showed excellent handling characteristics when implanted into a canine femoral artery in a preliminary in vivo evaluation of the graft. The goal of this Phase II proposal is to assess blood permeation and graft patency/healing of the ESDC-rHir-VEGF graft using a canine arterial grafting model. Our hypothesis is that the next generation of prosthetic arterial grafts will have to possess multiple structural and biological properties that mimic some of those processes inherent to native arteries in order to prevent complications such as thrombosis from occurring. The specific objectives of Phase II are to: 1) synthesize ESDC vascular grafts for implantation studies, 2) develop an automated graft synthesis process, 3) evaluate physical and chemical properties of the ESDC graft, 4) covalently immobilize rHir and VEGF to ESDC surface, 5) assess in vivo acute and chronic implantation periods, and 6) examine macroscopically/microscopically explanted grafts. Phase III of this project will continue long-term assessment of this novel ESDC-rHir-VEGF graft in the canine femoral arterial grafting model employed in Phase II. Development of a bioactive small-diameter vascular graft would have a significant impact on small vessel repair and replacement. These grafts could be utilized in peripheral bypass as well as for coronary artery bypass, which have some 500,000 grafts implanted annually in the United States. Potentially, the annual market value for an "off-the-shelf" synthetic arterial bypass graft could exceed $1.5 billion.