The broader impact/commercial potential of this Partnerships for Innovation - Technology Translation (PFI-TT) project concerns the benefits of non-invasively detecting cancer in small samples of accessible bodily fluids (blood, urine, saliva). All biofluids are abundantly populated with small sacs that express specific indicators (biomarkers) when cancer is present. The ability to sample biofluids and detect these indicators is the basis of the "liquid biopsy" concept. A liquid biopsy for blood could be incorporated into routine laboratory tests and catch cancer in its earliest stages where intervention is most impactful. A liquid biopsy in urine could be used to replace highly invasive procedures currently used to routinely surveil for recurrence of bladder cancer. This PFI-TT project seeks to hasten the arrival of routine cancer screening through liquid biopsy by fundamentally advancing the way biosensors are used in these assays to make them faster and more sensitive. Educationally, the project will train two talented post-graduate scientists in the key elements of technical entrepreneurship. The project will also maintain several opportunities for undergraduates to conduct academic research including programs supporting under-represented groups and individuals unlikely to otherwise be exposed to research in college. The proposed project will advance the concept of the liquid biopsy by developing flow-through sensors that detect cancer biomarkers on extracellular vesicles (EVs) in urine. Current biomarker detection schemes require the analyte to diffuse from the sample to the sensing surface, resulting in slow and often incomplete, responses. The project will emphasis a different paradigm where the sensor is built on a highly permeable membrane and EVs carrying the biomarkers pass through the membrane where they are captured and revealed through enzyme-based detection. The team will develop and optimize the chemistries for capture of biomarkers and development of signal on the ultrathin silicon nitride membranes with precision slit-pores. The team will also develop mathematical models of flow through slit-pore membranes and the EV capture process. Finally, the team will compare our experiments and models to results with diffusion-limited sensors. This will directly test the hypothesis that the flow-through configuration enables more sensitive and faster responding devices that can improve detection of cancer in liquid biopsies. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.