Controlled Release Vascular Grafts

描述（由申请人提供）：在美国，估计有800万人患有外周动脉疾病（PAD）。PAD的特点是动脉粥样硬化引起下肢肌肉动脉的血流量逐渐减少。对于严重的PAD患者，下肢旁路移植术仍然是肢体保留的主要选择。虽然原生血管仍然是旁路移植术的金标准导管，但由于固有静脉疾病或先前的静脉采集，大约三分之一的患者无法使用它们。在这些病例中，尽管由于血栓形成和内膜增生导致通畅率低，但膨胀性聚四氟乙烯（ePTFE）移植物是最常用的替代方法。为了解决这些问题，许多研究人员一直在研究涉及移植物管腔表面修饰的替代策略。然而，迄今为止的方法取得的成功有限。聚（1,8辛烷二醇柠檬酸酯）（POC）包被ePTFE移植物提供了一个潜在的替代方案，因为在猪动物模型中，它们已被证明具有生物相容性、顺应性和抗血栓形成特性。此外，POC还可以作为药物控释的载体。一种潜在的候选药物，全反式维甲酸（ATRA），在几种动物模型中已被证明可以抑制平滑肌细胞增殖和新生内膜增生，并诱导抗血栓基因和上调血管内皮细胞中的一氧化氮。本提案的目的是开发一种生物相容性，非血栓性的POC-ePTFE血管移植物，可以以可控的方式释放ATRA，并评估这种小分子的可控释放是否可以减少内膜增生和血栓形成。为了实现这一目标，具体的目的是：a)制造具有不同释放率的非血栓性ATRA洗脱POC-ePTFE移植物；b)评估ATRA控制释放对颈动脉ePTFE猪旁路模型中血栓形成和内膜增生的影响。特别是POC-ePTFE接枝将通过溶胀在溶剂中负载ATRA，并通过不同的聚合条件来调节释放，以控制溶胀程度和降解速率。在体外，对平滑肌和内皮细胞有控制释放和影响的移植物将被植入猪颈动脉旁路模型中，以评估炎症、血栓形成和内膜增生。I期申请的成功完成将通过开发一种新颖的原型来证明我们概念的可行性，该原型可以在II期提案中进行患者测试。综上所述，我们认为我们的创新产品最终将对血管疾病患者的护理产生重大影响。公共卫生相关性：用于治疗严重外周动脉疾病的膨胀聚四氟乙烯（ePTFE）移植物由于血液凝固和细胞过度生长导致闭塞和移植物失败，其通畅率低。聚（1,8-辛二醇柠檬酸酯）（POC）聚合物包覆ePTFE移植物具有提高通畅率的潜力，因为与裸ePTFE相比，它们已经证明可以减少凝血，并且可以以受控的方式释放药物以防止细胞过度生长。VesselTek Biomedical旨在制造药物释放可控的POC- ePTFE血管移植物，以提高旁路移植术的通畅性，降低严重外周动脉疾病导致的截肢发生率。

DESCRIPTION (provided by applicant): In the United States, it is estimated that 8 million people suffer from peripheral artery disease (PAD). PAD is characterized by a gradual reduction in blood flow to the muscular arteries of the lower extremities caused by atherosclerosis. For those with severe PAD, lower extremity bypass grafting remains the predominant option for limb salvage. Although native vessels remain the gold standard conduit for bypass grafting, they are not available in approximately one-third of patients due to intrinsic venous disease or prior vein harvesting. In these cases, expanded polytetrafluoroethylene (ePTFE) grafts are the most commonly used alternative despite dismal patency rates due to the formation of thrombosis and neointimal hyperplasia. To address these problems, many researchers have been investigating alternative strategies that involve surface modification of the graft's lumen. However, approaches to date have met with limited success. Poly(1,8 octanediol citrate) (POC)-coated ePTFE grafts offer a potential alternative as they have been shown to be biocompatible, compliant, and have anti-thrombogenic properties in vitro and in vivo in a porcine animal model. Furthermore, POC can serve as a vehicle for the controlled release of drugs. A potential drug candidate, all-trans retinoic acid (ATRA), has been shown to inhibit smooth muscle cell proliferation and neointimal hyperplasia in several animal models as well as induce antithrombotic genes and upregulate nitric oxide in vascular endothelial cells. The objective of this proposal is to develop a biocompatible, non- thrombogenic POC-ePTFE vascular graft that can release, in a controlled manner, ATRA and assess whether the controlled release of this small molecule can reduce neointimal hyperplasia and thrombosis. Toward this goal, the specific aims are to a) fabricate non-thrombogenic ATRA-eluting POC-ePTFE grafts with varying release rates and b) assess the effect of the controlled release of ATRA on thrombosis and neointimal hyperplasia in a carotid artery ePTFE porcine bypass model. In particular, POC-ePTFE grafts will be loaded with ATRA by swelling in solvent, and release will be modulated by varying polymerization conditions to control the degree of swelling and degradation rate. Grafts that show controlled release and an effect on smooth muscle and endothelial cells in vitro, will be implanted in a porcine carotid artery bypass model to assess inflammation, thrombosis, and neointimal hyperplasia. Successful completion of this Phase I application will demonstrate feasibility of our concept by developing a novel prototype that can be tested in patients in a Phase II proposal. In summary, we feel that our innovative product will ultimately have a significant impact on the care of patients with vascular disease. PUBLIC HEALTH RELEVANCE: Expanded polytetrafluoroethylene (ePTFE) grafts used to treat severe peripheral artery disease have dismal patency rates due to blood clotting and overgrowth of cells leading to occlusion and graft failure. Poly(1,8-octanediol citrate) (POC) polymer coated ePTFE grafts have the potential to improve patency rates as they have demonstrated reduced clotting compared to bare ePTFE and can release drugs in a controlled manner to prevent the overgrowth of cells. VesselTek Biomedical aims to create controlled drug release POC- ePTFE vascular grafts to improve the patency of bypass grafts and reduce the incidence of limb amputation caused by severe peripheral artery disease.