Project Summary/Abstract While the steady transition from 2-D mammography to 3-D digital breast tomosynthesis (DBT) in recent years has resulted in improved breast cancer diagnosis, x-ray based breast imaging techniques are inherently limited by their inability to provide physiologically relevant functional information. The persistent high percentages of unnecessary biopsies and poor sensitivity to malignant tumors among dense breasts and early-stage cancers have motivated the research community to seek additional functional assessment. Diffuse optical tomography (DOT) – a non-invasive imaging modality using only non-ionizing near-infrared light – has shown promise in fulfilling such a role by exploiting cancer’s high endogenous contrasts in angiogenesis and metabolism. However, the low spatial sampling density due to use of optical fibers and the ill-posedness of the DOT inverse problem have resulted in low image resolution in DOT, hampering its clinical translation. For nearly two decades, our group has been a key contributor in advancing DOT for breast clinical diagnosis via multi-modal imaging. We have developed translational imaging systems combining DOT with DBT as well as prior-guided algorithms that “fuse” x-ray contrasts with DOT reconstructions, and tested these systems in clinical studies with over 450 subjects. Under the initial funding period, we have developed a new DOT imaging architecture that utilizes fiber-less widefield pattern-illumination and camera detection to achieve ultra-high-density and uniform spatial sampling. We have also developed highly efficient compressive-sensing strategies to take advantage of such unprecedented dense datasets without long acquisition time. With these advances, our optical mammography co-imager (OMCI) system prototype is capable of providing a raw measurement density several orders of magnitude higher than previously reported high-density DOT systems at only a fraction of the cost and instrument size. Built on this strong momentum, in the renewed period, we aim to further enhance optical measurement density by developing the first-in-the-field widefield frequency-domain (FD) DOT system combining single-pixel imaging with our compressive-sensing approaches. Moreover, we will also implement real-time adaptive illumination/detection patterns optimized for individual breasts. Furthermore, through our decade-long research in DOT, we have developed a comprehensive suite of toolboxes that have been rigorously validated using clinical data, offering unique capabilities for widefield DOT forward modeling, pattern compression/optimization, and prior-guided image reconstructions. With a strong track record for developing and maintaining high-quality open-source tools, we are excited to share these packages with the biophotonics research community as open-source software. Both our next-generation widefield FD breast DOT hardware and algorithm innovations will be tested by an experienced clinical team with ...