Improving Graft Patency: A Novel L-Ascorbic Acid ePTFE Modification

描述(申请人提供)：治疗严重外周动脉疾病的黄金标准仍然是自体静脉搭桥术。然而，当静脉不可用时，必须使用假体移植物，并且与非常高的失败率相关，仅3年就接近70%。假体移植物长期失败的主要原因是新生内膜增生。众所周知，一氧化氮(NO)是一种有效的抑制新生内膜增生的物质。用于局部抑制新生内膜增生的两类NO供体主要是二氮杂二醇和S-亚硝硫醇。在这两种物质中，RSNO存在于人的血浆中，由于它们可以释放NO并被再生为RSNO，因此它们起到了NO储存库的作用。通过L-抗坏血酸(AA)还原，NO容易从RSNO中释放出来。我们设想创造一种改良的假体移植物，利用这一机制，并利用潜在的无限内源性NO供应。利用以柠檬酸为基础的生物相容性聚合物材料聚柠檬酸二醇(POC)，研制了AA-POC-ePTFE血管移植物。初步数据表明，这些移植物在体外与S-亚硝硫醇接触时会产生较长时间的NO。因此，我们假设，与传统的ePTFE移植物相比，AA-POC-ePTFE移植物会与循环中的RSNO反应，导致体内血液-材料界面长期产生NO，并将抑制新的内膜增生的形成。为了解决这一假设，本建议的具体目的如下：1)利用体外灌流电路对AA-POC-ePTFE移植物的特性进行表征和优化；2)建立并验证豚鼠ePTFE体外循环模型；3)评价AA-POC-ePTFE移植物在体内产生NO和抑制新生内膜增生方面的安全性、生物相容性和有效性。目前，人工血管仍然是一种很差的自体静脉替代品。迫切需要开发新的生物材料来解决这些不足之处。通过多学科的合作，我们开发了一种创新的血管移植物，并证实了在体外延长了NO的生成。这项建议中描述的研究将使我们能够优化这种移植物，并在体内研究这项技术的安全性和有效性，从而加速进一步的临床前研究。

DESCRIPTION (provided by applicant): The gold standard for the treatment of severe peripheral artery disease remains bypass grafting with autologous vein. However, when vein is not available, prosthetic grafts must be utilized and are associated with very high failure rates, approaching 70% at just 3 years. The primary cause of long-term failure of prosthetic grafts is development of neointimal hyperplasia. It is well established that nitric oxide (NO) is a potent inhibitor of neointimal hyperplasia. The two main classes of NO donors that have been used to inhibit neointimal hyperplasia locally are diazeniumdiolates and S-nitrosothiols (RSNO). Of these two, RSNO are present in human plasma and act as a NO reservoir since they can release NO and be regenerated back to RSNO. One mechanism by which NO is readily released from RSNO is through reduction by L-ascorbic-acid (AA). We envisioned creating a modified prosthetic graft that exploits this mechanism and taps into the potentially limitless endogenous supply of NO. Using a citric acid-based biocompatible polymeric material, poly (diol citrate) (POC), we developed an AA-POC-ePTFE vascular graft. Preliminary data have demonstrated prolonged generation of NO from these grafts upon contact with S-nitrosothiols in vitro. Thus, we hypothesize that an AA-POC-ePTFE graft will react with circulating RSNO and result in long-term NO generation at the blood-material interface in vivo and will inhibit the formation of neointimal hyperplasia as compared to traditional ePTFE grafts. To address this hypothesis, the specific aims of this proposal are as follows: 1) characterize and optimize the properties of the AA-POC-ePTFE grafts using an ex vivo perfusion circuit~ 2) develop and validate a guinea pig ePTFE bypass model~ and 3) evaluate the safety, biocompatibility, and efficacy of AA-POC-ePTFE grafts at generating NO and inhibiting neointimal hyperplasia in vivo. Currently, prosthetic grafts continue to be a poor substitute for autologous vein. There is a tremendous need for development of new biomaterials to address these inadequacies. Through a multidisciplinary collaboration, we developed an innovative vascular graft and confirmed prolonged NO generation in vitro. The studies described in this proposal will enable us to optimize this graft and investigate the safety and efficacy of this technology in vivo, hastening further preclinical investigation.