Preventing neointimal hyperplasia perivascular drug delivery in synthetic hemodialysis grafts

Hyperplasia leading to stenosis of synthetic vascular accesses for chronic hemodialysis is a widespread problem with no established treatment for prevention. Inflammation around the anastomotic region in hemodialysis arteriovenous (AV) grafts is a constant reoccurring factor that likely contributes to hyperplasia development. Perivascular delivery of an anti-inflammatory drug around the anastomotic region could be an effective option in preventing AV graft failure due to stenosis. The objectives of this research were to investigate the involvement of inflammation in arteriovenous hemodialysis graft stenosis, ii) assess whether a novel drug, soluble epoxide hydrolase inhibitor (sEHI), would inhibit cytokine release from inflammatory cells; if so, sEHI may be useful to inhibit AV graft stenosis, and iii) to develop a perivascular drug delivery system that could deliver a wide range of potential therapeutics in a directional and controlled manner to prevent AV graft stenosis. The first part of the dissertation investigates the involvement of inflammation in arteriovenous hemodialysis graft stenosis and if an experimental anti-inflammatory drug, sEHI, could be useful in inhibiting cytokine and chemokine release from primary macrophages. In our porcine AV graft model, macrophage and T-cell accumulation increased over the 7 week time course corresponding with an increase in the hyperplasia formation at the venous anastomosis. Elevated expression of prominent cytokine/chemokines TNF- and MCP-1, was seen in vein-graft anastomotic tissue. The sEHI significantly inhibited LPS induced MCP-1 release and TNF- from primary macrophages. The recruitment and activation of inflammatory cells around the graft anastomoses likely plays an influential role in causing hyperplasia in arteriovenous grafts and sEHI could be an effective therapeutic by preventing MCP-1 and TNF- release. The second part of the dissertation is development of a perivascular delivery system for controlled and directed release of sunitinib, which could be utilized for other iv therapeutics. A bilayer wrap design using either polycaprolactone or poly(lactic-co-glycolide) (PLGA) was produced containing a monolithic backing to provide unidirectional release and to prevent loss of drug to the extravascular space, and either a drug loaded non-porous layer, or a porous layer that could be filled with drug loaded hydrogel. A biodegradable PLGA-based perivascular drug delivery system was created that provided early directed drug delivery and sustained release of sunitinib in vivo around the site of placement for at least four weeks. These results demonstrated that the bilayer PLGA wrap presented is a promising perivascular drug delivery system for the local treatment of arteriovenous graft hyperplasia. sEHI could be useful to incorporate into this delivery system to target the recruitment of inflammatory cells to the anastomotic region by inhibiting MCP-1 release.