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金标准仍然是自体静脉旁路移植术。然而，当静脉不可用时，必须使用假体移植物，并且失败率非常高，仅3年就接近70%。人工骨移植长期失败的主要原因是新生内膜增生。一氧化氮（NO）是一种有效的内膜增生抑制剂。用于局部抑制新生内膜增生的两种主要NO供体是重氮双酸酯和s -亚硝基硫醇（RSNO）。其中，RSNO存在于人血浆中，并作为一氧化氮的储存库，因为它们可以释放一氧化氮并再生回RSNO。一氧化氮容易从RSNO中释放的一个机制是通过l -抗坏血酸（AA）的还原。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。我们利用柠檬酸基生物相容性高分子材料聚柠檬酸二醇（POC），研制了一种AA-POC-ePTFE血管移植物。初步数据表明，这些移植物在体外与s -亚硝基硫醇接触后，一氧化氮的产生时间延长。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发生反应，导致体内血液-物质界面长期NO生成，并抑制新生内膜增生的形成。为了验证这一假设，本研究的具体目的如下：1)利用体外灌注回路表征和优化AA-POC-ePTFE移植物的性能；2)建立和验证豚鼠ePTFE旁路模型；3)评估AA-POC-ePTFE移植物在体内产生NO和抑制新生内膜增生的安全性、生物相容性和有效性。目前，假体移植物仍然是自体静脉的较差替代品。我们迫切需要开发新的生物材料来解决这些不足之处。通过多学科合作，我们开发了一种创新的血管移植物，并证实了体外一氧化氮生成的延长。本提案中描述的研究将使我们能够优化这种移植物，并研究该技术在体内的安全性和有效性，从而加快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.