Development of Drug-Eluting Vascular Graft for Hemodialysis

Abstract

Vascular access (VA) serves as a lifeline for hemodialysis patients. Timely creation and meticulous maintenance of these lifelines are crucial for the care of hemodialysis patients. VA-related expenditures are the largest component of dialysis-related costs. There are several types of vascular access such as central venous catheter (CVC), arteriovenous fistula (AVF) and arteriovenous graft (AVG). The greatest morbidity and mortality are associated with the use of dialysis catheters, the major risks being infection and thrombosis. Therefore, the use of catheters should be minimal. According to the NKF-K/DOQI guidelines, a period of at least 2 months should be allowed for adequate maturation of an AVF before first cannulation. For early cannulation without serious infection, AVG is the best choice of vascular access. Four decades of hemodialysis therapy have shown that prevention of complications is the best therapy, when it can be achieved. Therefore, it is not surprising that vascular access continues to be an important area for quality improvement. In the following studies, I developed several types of drug-eluting vascular grafts for effective suppression of neointimal hyperplasia and evaluated the tissue reaction around the implanted vascular grafts. In the first chapter, perigraft inflammation, graft wall inflammation, stromal cell proliferation, blood vessel formation, tissue necrosis and edema were analyzed for paclitaxel-coated expanded polytetrafluoroethylene (ePTFE) graft made by dipping method. In the study, non-coated control graft and paclitaxel-coated vascular grafts of low dose and high dose were placed in the backs of 12 rabbits, simultaneously. After 1 or 2 weeks from implantation, the number of inflammatory cells per unit area in relation to the paclitaxel coating amount on each graft were analyzed and stromal cell infiltration into graft interstices were confirmed using immunohistochemistry. As a result, paclitaxel-coated ePTFE grafts were found to effectively suppress inflammation around the implanted grafts, and the paclitaxel-coated graft with low dose showed less inhibitory effect on stromal cell proliferation than graft with high dose. To reduce the influence of paclitaxel on the fibrosis, I developed a novel paclitaxel-coating method to load the drug only on the inner surface of the vascular graft, which was shown in the second chapter. A peristaltic pump and a double-solvent system were used to achieve an inner coating of paclitaxel. At the ratio of 90% acetone, paclitaxel was homogeneously coated only on the luminal surface of the graft without changing the physical properties. In animal study, paclitaxel inner-coated grafts effectively inhibited the neointimal hyperplasia of hemodialysis grafts. However, paclitaxel on the outer surface of ePTFE grafts might prevent myofibroblast proliferation, which might cause hematomas, seromas, infections, or pseudoaneurysms in the space between the graft and surrounding tissue and result in incomplete hemodialysis needle insertion. Therefore, paclitaxel inner-coated vascular grafts can reduce the coated amount of this toxic drug to avoid such unwanted effects, whilst preserving its efficacy inhibiting stenosis. Later chapter of thesis is regarding the sirolimus-eluting vascular grafts in comparison with paclitaxel-coated grafts. Compared with the control group, neointimal hyperplasia in the venous anastomosis sites of sirolimus-coated groups was significantly suppressed without infection. However, the inhibitory effects of sirolimus-eluting ePTFE grafts were weaker than those observed for paclitaxel-coated vascular grafts. These drug-eluting vascular grafts showed a high patency rate than non-coated graft without any unwanted tissue response. Therefore, they can be expected to shorten the maturation time of implanted graft, thereby allowing early cannulation.