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 2 years. The primary cause of failure of prosthetic grafts is development of neointimal hyperplasia. It is well established tht 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). Graft modifications with either class of NO donors have shown only limited improvement in graft function due to a short duration of NO release. However, RSNO remain attractive because they are present in human plasma and can release NO upon reaction with light, metal ions, or L-ascorbic acid (AA). Thus, to overcome the limitation of drug delivery duration, we propose to develop and evaluate a catalytically active graft that will release NO at the blood-material interface for an extended duration of time by immobilizing AA to the luminal surface of the graft. This concept takes advantage of the limitless reservoir of circulating RSNO that will react with AA on the graft surface to release NO. We hypothesize that a catalytically active prosthetic graft engineered to incorporate AA on the lumen surface will utilize endogenous circulating RSNO to generate NO at the blood-material interface and inhibit the formation of neointimal hyperplasia. To confirm the feasibility of our approach, we synthesized a first generation poly(1,8 octanediol-citrate-ascorbate) (POCA) copolymer and demonstrated prolonged generation of NO upon contact with RSNO solutions in vitro. Preliminary data show 30% POCA degradation at 2 months. This is important, as NO will be released as long as POCA is present on the graft. By the time POCA is completely degraded, the NO will have simulated endogenous endothelialization of the graft, thereby abrogating the need for external NO release. Supporting our approach, we implanted a POCA graft using a guinea pig aortic interposition model and found less graft hyperplasia at 1 month. Thus, given our promising preliminary data, we propose to investigate our hypothesis with the following Specific Aims: 1) synthesize and characterize biocompatible AA containing polydiolcitrate copolymers that catalyze the conversion of RSNO to NO and use these copolymers to fabricate catalytically active ePTFE grafts; 2) evaluate the safety, biocompatibility, and efficacy of the catalytically active POCA-ePTFE graft at inhibiting neointimal hyperplasia in vivo; and 3) evaluate the biocompatibility and efficacy of an optimized catalytically active POCA-ePTFE graft at inhibiting neointimal hyperplasia in an atherosclerotic animal model in vivo. Currently, prosthetic grafts are a poor substitute for autologous vein and there is a significant need to develop novel strategies to improve prosthetic graft patency rates. Through a multidisciplinary collaboration, we have demonstrated the feasibility of our approach. Successful completion of the studies described in this proposal will provide an innovative approach to locally generate NO, an important therapeutic agent, while overcoming limitations of other graft modification approaches, and directly lead to preclinical investigations. Once validated, this technology has the potential to positively impact veteran health care.
Peripheral artery disease (PAD) affects approximately 8 million Americans and results in significant impairment of function and quality of life. While the gold standard for the treatment o severe PAD remains bypass grafting with autologous vein, vein is often not available, necessitating the use of prosthetic grafts which are associated with very high failure rates. Showing the impact on veterans, in 1998, the VA provided 4,822 hospitalizations for peripheral vascular procedures, and unfortunately 5,329 hospitalizations for limb amputation. Our goal is to develop a novel graft that will significantly improve patient outcomes following bypass grafting, thereby preventing limb amputation. We propose to develop a catalytically active graft that will generate nitric oxide, a small molecule that promotes vascular health, for an extended duration of time, thereby preventing graft failure. Successful completion of the studies described in this proposal will have a significant impact on veteran care.
| Gregory, Elaine K; Vercammen, Janet M; Flynn, Megan E et al. (2016) Establishment of a rat and guinea pig aortic interposition graft model reveals model-specific patterns of intimal hyperplasia. J Vasc Surg 64:1835-1846.e1 |
