Biodegradable and Elastic Vascular Grafts for Hemodialysis

Anova Biomedical, Inc., Ithaca NY

Investigators

Abstract

Vascular access is a “lifeline” for the >500,000 end stage renal diseases (ESRD) patients requiring hemodialysis in the United States. The two forms of permanent dialysis vascular access – arteriovenous fistula (AVF), arteriovenous graft (AVG) – are plagued with various complications. The shortcomings of AVF and AVG frequently necessitate dialysis through a central venous catheter (CVC), a temporary method of vascular access that exposes ESRD patients to extremely high rates of infection, thrombosis, and central vein stenosis. As a result, this “lifeline” is also the “Achilles’ Heel” for ESRD patients. Although AVFs function well once fully matured, their overall unassisted maturation rate is as low as 30% and many patients are not eligible for fistula creation. Taken together, these facts clearly demonstrate the necessity for an alternative option for permanent vascular access – the AVG. Current AVGs are made of expanded polytetrafluoroethylene (ePTFE, Teflon), an industrial polymer repurposed from use as a vascular graft material. ePTFE AVGs fail at exceedingly high rates (25% unassisted patency within one year of access creation) due to their supraphysiological stiffness and irregular hemodynamics at the venous outflow segment of the graft that inevitably leads to aggressive neointimal hyperplasia and eventual graft occlusion. When vascular access cannot achieve sufficient blood flow rates to enable hemodialysis patients are required to undergo repeat endovascular procedures to ensure access function, usually while undergoing emergency hemodialysis through CVC. We feel that a problem of this magnitude requires a disruptive approach. As such, we have developed a new class of AVG that is designed from first principles to serve the purpose of legacy ePTFE AVGs, while avoiding their shortcomings and limitations. Our AVG, the DeNovo1 graft, is made from a novel, fully degradable elastomer called PAS. PAS is designed to closely resemble the mechanical properties of native vasculature. After implantation, these grafts slowly remodel into compliant vascular conduits. We have successfully demonstrated this in sheep common carotid artery interposition. The focus of this proposal is to progress towards our first target indication as a hemodialysis access graft by refining graft fabrication techniques, and testing the grafts in the appropriate, clinically relevant animal model. Correspondingly, Sub Aim 1 focuses on tuning graft manufacturing practices to produce DeNovo1 grafts with distinct arterial and venous zones. Sub Aim 2 consists of implanting these AVG in sheep as a shunt between the common carotid artery and the contralateral external jugular vein. Implants will be routinely cannulated and monitored for 180 days post-implant to mimic routine practice in dialysis clinics, and assess the grafts performance compared to the clinical gold standard ePTFE AVG. Upon completion of these aims, we will be well positioned for a Phase II proposal that expands the number of test subjects and allows for longer term implantation to properly assess host remodeling of the AVG as well as long term access function in a clinically relevant elderly sheep vascular access model.