Biologically-engineered Transcatheter Vein Valve: Design Optimization and Preclinical Testing

Project Summary This research plan is aimed at creating an off-the-shelf transcatheter vein valve capable of regeneration. If successful, it could treat many thousands of patients who suffer from chronic venous insufficiency in deep veins, untreatable with compression stockings, and the sequelae of debilitating leg ulcers, as there is currently no FDA-approved prosthetic vein valve. This novel vein valve is created from a tissue grown from donor dermal fibroblasts directly on a nitinol stent followed by decellularization. We have shown in a recent publication that the resulting bileaflet valve meets hydrodynamic performance criteria in vitro and regenerates with host cells, including endothelialization, without gross calcification, stenosis, or thickening of the leaflets post-delivery in the ovine iliac vein model based on initial testing. We propose here to make a key improvement upon the initial design and results by using a stent that transitions from a circular section to an oval section, emulating vein valve sinuses to improve hemodynamics and mitigate leaflet fusion to the valve wall that currently occurs in vivo over time. In this milestone-driven plan, valve geometries will first be screened using computational modeling of valve function and then characterized hydrodynamically. Valves of 12 mm diameter enhanced with these sinuses will be delivered via catheter to the ovine iliac vein for up to 24-week duration with (R61 phase) and without (R33 phase) sustained anti-coagulation based on the rate of endothelialization. Delivery will be conducted in the normal anatomy and in a venous reflux model in sheep achieved by compromising the tricuspid valve sufficiently to ensure the valves are cycled in these quadrupeds. Longitudinal assessment of valve function will be made via ultrasound and venogram. Harvested valve leaflets will be assessed for dimensions, tensile mechanical properties, cellularity and phenotype via immunohistochemistry, and matrix composition via biochemical assay and histology. An INTERACT meeting will also be conducted during the R33 phase to ascertain GMP manufacturing and GLP testing expectations of the FDA for a transcatheter vein valve, extending prior FDA interaction regarding the decellularized tissue that we create in vitro to include stent and valve testing in light of ISO standards that exist for transcatheter heart valves. Our Office of Technology Commercialization will also be engaged regarding patent protection beyond the PCT filed and commercialization opportunities.