ABSTRACT Vascular access is both the Lifeline and the Achilles heel for the 500,000+ patients on hemodialysis in the United States (3million+ worldwide). Thus, while arteriovenous fistulae (AVF) have good long-term patency, they also have a high maturation failure rate due to a venous segment stenosis which results in multiple interventional procedures, and a prolonged period of catheter (CVC) use, with all its attendant complications. Arteriovenous grafts (AVGs) in contrast, have good early function but develop a later stenosis at the graft-vein anastomosis. Despite the very significant morbidity, mortality and economic cost (over 5 billion USD annually) associated with vascular access dysfunction, there are currently no effective therapies for this huge and unmet clinical need. We believe that the current situation mandates a disruptive innovation approach. Thus, we have recently developed biodegradable vessel scaffolds with a unique polymer composition (poly [glycerol sebacate] – polycaprolactone with palmitate [PPGS-PCL]) that (a) promotes active cellular and matrix integration (b) generates an asymmetric thickness and diameter from the arterial to venous end to avoid compliance mismatch and (c) displays self-sealing properties for early cannulation and rapid CVC removal. The central hypothesis of this proposal, therefore, is that the modulation of biomaterial characteristics (composition and fiber orientation) and scaffold configuration (changes in diameter, thickness and compliance between the arterial and venous ends) of a bioengineered INtegrated Vascular Access Conduit (IN-VAC), will influence hemodynamic stressors (shear and pulsatility) and cell-matrix integration, resulting in a “living-breathing” vascular conduit with optimized process of care (cannulation), functional (flow), anatomic (stenosis) and histological (morphometry) end points, in clinically relevant (with and without uremia) pig models of arteriovenous access. We plan to address this central hypothesis through the following specific aims: In Specific Aim 1, we will design, produce, and test a variety of IN-VAC devices in-vitro. In Specific Aim 2, we aim to assess safety and biocompatibility, and also optimize the impact of upstream engineering and biophysical profiles on downstream clinical endpoints. Finally in Specific Aim 3, we will assess the optimized IN-VAC device for clinical efficacy against the AcusealTM graft, in the setting of both uremic and non-uremic pig models of arteriovenous stenosis. In summary, this proposal combines our hemodynamic, vascular biology and bioengineering strengths, to both advance our mechanistic understanding of vascular access biology, and to create a unique and innovative vascular conduit. We believe that such a device could significantly reduce the morbidity, mortality and economic cost associated with both hemodialysis vascular access dysfunction and (in the future) coronary, carotid, and peripheral vascular disease, all of which are...