This proposal is submitted in response to notice NOT-HL-15-282 - NHLBI Announces Small Business Topics of Special Interest (TOSI): HLS16-14: ?New animal models for the study of chronic venous insufficiency (CVI) and post-thrombotic syndrome, and innovative approaches for their prevention and treatment?. Chronic venous insufficiency (CVI) affects 10-35% of American adults and is the seventh most common debilitating disease with treatment costs of $1-3 billion annually. One of the major contributors to venous insufficiency is valve incompetence that causes blood flow reflux, venous hypertension (HTN) and potentially thrombosis. Previous attempts to develop a prosthetic venous valve to treat reflux have failed primarily due to a lack of basic understanding of the interactions between the prosthetic device and the host biological environment that ultimately led to the complete thrombosis of the implants. Recently, we have had success with a novel biomaterial that is remarkably thrombo-resistant when applied to the low flow environment of the venous valve. The objectives of this Phase I SBIR proposal are: 1) To refine the female Greyhound model so that it is predictive of the biological outcomes of venous valve replacement; and 2) To evaluate a novel prosthetic venous valve device in the CVI animal model. The central hypothesis is that persistent venous reflux is detrimental to endothelial venous function and that a mechanically-informed, well-designed bioprosthetic venous valve can restore the mechanical environment and hence biological homeostasis. The primary task of this Phase I is to assess the safety and efficacy of a prosthetic venous valve for treatment of CVI in a translational large animal model that recapitulates venous reflux/HTN and thrombosis observed in patients with CVI. Our rationale is based on the following pillars: A) Valve insufficiency and significant reflux/HTN must be treated to avoid endothelial dysfunction in CVI and subsequent sequela (deep vein thrombosis, limb edema, skin ulcerations, etc.), and B) No prosthetic valve can function long-term in the absence of certain threshold of blood flow and pressure gradient. Hence, safety and efficacy testing of any bioprosthetic valve must be made in an appropriate animal model that allows the ?charging? of the valve (i.e., presence of reflux/HTN, propensity for thrombosis, etc.). To treat venous reflux/HTN, a rigorously tested prosthetic valve is needed that functions under wide range of pathophysiological hemodynamic conditions. The proposed animal model of venous reflux/HTN can then be used to validate the functionality of the venous valve under a range of hemodynamics conditions in a chronic canine model. Our strong preliminary data on the large animal venous reflux/HTN/thrombosis model and the associated insidious effects on venous function along with the patency and competency of the prosthetic venous valve based on the thrombosis-resistant properties of novel lung plural ligament (PL) tissue positions us well for undertaking the proposed program. The success of this proposal may ultimately provide therapy for millions of CVI patients to substantially impact healthcare costs.
Chronic venous insufficiency (CVI) is a debilitating disease that affects millions of Americans with healthcare costs in the billions. The major goal of this proposal is to validate the safety and efficacy of a prosthetic venous valve to treat CVI.