Principal Investigator: Welsh, John D Project Summary Deep venous thrombosis (DVT) and secondary pulmonary embolism (PE) affect 0.1-0.2% of the population and cause approximately 100,000 deaths annually in the US. Immobility and lack of muscular activity is the primary risk factor for DVT, an effect attributed to reduced venous flow. Autopsy studies have identified the venous valve sinus in the leg as the site of origin for DVT, but a molecular and cellular mechanism for this observation has not been identified. Present therapies for DVT include systemic anticoagulation pneumatic compression devices designed to augment venous flow. Our recent studies reveal that oscillatory shear forces generated in the venous valve sinus by muscular activity are required to stimulate a powerful anti-thrombotic endothelial phenotype that prevents venous thrombosis. Consistent with this mechanism, analysis of venous valves harvested at autopsy from individuals who died of DVT and fatal PE reveals reversal of the anti-thrombotic phenotype in the peri-valvular endothelium. These studies are the first to identify a hemodynamic, cellular and molecular mechanism for DVT that explains its tight association with immobility and its site of origin at the venous valve sinus. They suggests that a mechanical device that restored peri-valvular oscillatory flow in high-risk patients would effectively prevent DVT by maintaining the natural anti-thrombotic mechanism. Analysis of existing pneumatic devices reveals that they fail to drive oscillatory flow at the venous valve required to prevent DVT. Thus, we designed the OsciFlex device that uses a unique actuation technique to create robust oscillatory flow in the peri-valvular pocket. The goal of this proposal is to extend our initial studies to develop a finalized device design that is ready for prolonged human use, regulatory approval, and clinical testing. We will work with clinicians, engineers, and human factors experts to improve the device design and function and be ready to conduct a decisive clinical trial at the end of the project.