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的特征在于由动脉粥样硬化引起的下肢肌肉动脉的血流逐渐减少。对于严重PAD患者，下肢旁路移植术仍然是保肢的主要选择。尽管自体血管仍然是旁路移植术的金标准管道，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自体血管。在这些病例中，尽管由于血栓形成和新生内膜增生导致通畅率低，但膨体聚四氟乙烯（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改性的替代策略。然而，迄今为止，这些方法取得的成功有限。聚（1，8-柠檬酸辛酯）（POC）涂层ePTFE移植物提供了一种潜在的替代方案，因为它们已被证明具有生物相容性、顺应性，并在猪动物模型的体外和体内具有抗血栓形成特性。此外，POC可以用作药物控释的载体。一种潜在的候选药物，全反式维甲酸（ATRA），已被证明可以抑制平滑肌细胞增殖和新生内膜增生在几种动物模型，以及诱导抗血栓形成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、非血栓形成性POC-ePTFE血管移植物，该血管移植物可以以受控方式释放ATRA，并评估该小分子的受控释放是否可以减少新生内膜增生和血栓形成。为了实现这一目标，具体目标是a）制造具有不同释放速率的非血栓形成ATRA洗脱POC-ePTFE移植物，和B）评估ATRA受控释放对颈动脉ePTFE猪旁路模型中血栓形成和新生内膜增生的影响。特别地，POC-ePTFE移植物将通过在溶剂中溶胀而负载ATRA，并且释放将通过改变聚合条件来调节以控制溶胀程度和降解速率。将在体外显示控释和对平滑肌和内皮细胞有影响的移植物植入猪颈动脉旁路模型中，以评估炎症、血栓形成和新生内膜增生。第一阶段申请的成功完成将通过开发一种新的原型来证明我们概念的可行性，该原型可以在第二阶段提案中在患者中进行测试。总之，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型聚四氟乙烯（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而具有令人沮丧的通畅率。聚（1，8-柠檬酸辛酯）（POC）聚合物涂层ePTFE移植物具有提高通畅率的潜力，因为与裸ePTFE相比，它们已证明凝血减少，并且可以以受控方式释放药物以防止细胞过度生长。VesselTek Biomedical旨在创建受控药物释放POC- ePTFE血管移植物，以提高旁路移植物的通畅性，减少严重外周动脉疾病导致的肢体截肢的发生率。

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.