Modeling Human Veins, Venous Thrombosis & Therapeutics with Organ-On-Chips

Abstract

Venous valves are anatomical structures in the veins, small and large, that help in the unidirectional flow of blood towards the heart. Unwanted clot (thrombus) formation at these valves and its subsequent complications is the third leading cause of cardiovascular deaths in the world. Our knowledge of this thrombus formation is limited due to our over reliance on murine models, which do not have venous valves. As human in vivo study of these valves is difficult due to its location there is a need for physiologically relevant in vitro models that can efficiently dissect the contribution of Virchow’s triad – endothelial inflammation, blood flow dynamics and coagulable nature of blood, at the venous valves for thrombus formation. This dissertation focusses on the development of physiologically relevant in silico and in vitro models of veins containing venous valves.

An in silico model was used to analyze the unique flow patterns within physiological and pathological non-actuating micro venous valves (vein diameter less than 200 µm). I observed that an incompetent non-actuating micro venous valve may have a different mechanism of thrombus formation compared to valves at larger veins.

Deep vein thrombosis (DVT) that occurs at the valves of the deep (larger) veins and its consequences lead to around 100,000 deaths annually in the US alone. I used the organ-on-chip technology to create a Vein-Chip platform that integrated fully vascularized venous valves and its hemodynamic, as seen in vivo. The vascular endothelium of valves adapted to the locally disturbed microenvironment by expressing a different phenotype from the other regions of the vein that had uniform flow. The platform is used to modulate the three factors of Virchow’s triad to investigate the determinants of fibrin and platelet dynamics of DVT.

Healthy venous valves actuate to help unidirectional blood flow in the body. I extended the current model by including a 3D printed hydrogel valve that could actuate. The current model helps us understand how an actuating venous valve may keep the valves healthy and thrombus free.

Overall, the Vein-Chip offers a new preclinical approach to study venous pathophysiology and show effects of antithrombotic drug treatment.