PROJECT SUMMARY Approximately 16,000 patients received artificial pulmonary support via extra-corporeal membrane oxygenation (ECMO) in 2019. During ECMO, hollow fiber membrane (HFM) gas exchangers require a surface area of ~2 m2 to achieve therapeutic gas transfer; however, this large contact area with the blood activates the coagulation cascade that requires systemic anticoagulation for suppression, usually with heparin. Although heparin reduces the frequency of clotting, it does not effectively inhibit the surface deposition of platelets and proteins. The consumption of these critical clotting components, as well as continuous administration of systemic anticoagulant, results in an increased risk of bleeding during ECMO and increases the risk of complications and mortality. We propose that reducing the surface area of the HFM gas exchanger will lead to less clotting and require less anticoagulant use, reducing the incidence of both thrombosis and hemorrhage. To achieve this, Boundless Science is developing a novel blood oxygenation system that uses ultrasound to dramatically enhance gas transfer efficiency, and thereby reduce the required gas exchanger area. A smaller gas exchanger will induce less clotting and require less anticoagulation and associated bleeding risks. An additional benefit is that a smaller surface area will allow us to develop a dramatically smaller ECMO system, offering the potential for ambulatory ECMO. Our initial results with ultrasound-enhanced ECMO (US-ECMO) show that ultrasound (US) enhances the rate of oxygen transport across a planar nano-porous polypropylene membrane by 4–6.4-fold. We hypothesize that US enhances transport through two mechanisms. First, the absorption of US travelling through the blood induces a bulk force, which in turn generates flow known as bulk streaming. Second, US oscillates gas/blood menisci at the membrane surface, rapidly mixing the blood near the membrane in a process known as microstreaming. Blood mixing from these mechanisms disrupts the boundary layer at the blood-membrane interface, steepening the oxygen gradient and driving faster diffusion. This proposal seeks to identify the US and membrane configurations that maximize gas exchange within clinically relevant HFM. We will constrain US parameters to avoid blood damage. We will progress toward this objective through the following specific aims. Aim 1) Determine the specific ultrasound parameters (amplitude, frequency, duty cycle, pulse duration, and transducer geometry) that separately optimize bulk streaming and microstreaming, while avoiding hemolysis, inertial cavitation, excessive heating, and bubble generation. Aim 2) Determine the maximal fiber bundle thickness over which acoustic streaming and microstreaming are effective. Aim 3) Fabricate and evaluate a custom ultrasound delivery system that safely enhances oxygen transport by at least seven-fold. Successful results will not only show the potential of US-ECMO but will provide...