Diabetic retinopathy (DR) is a leading cause of blindness in working age populations. Glycemic control remains the best strategy for preventing or slowing disease progression. However, early detection of vision threatening retinal changes and prompt treatment is necessary for preserving visual function in more advanced stages. Clinical management of DR also requires objective tools for assessing retinal structure and microvascular abnormalities, as well as methods to evaluate treatment response. The goal of this multidisciplinary program is to develop novel optical coherence tomography (OCT) imaging methods and biomarkers that can identify and characterize retinal microvasculature and blood flow alterations in DR, which can be used for early disease detection, predicting progression, monitoring treatment response, and improving clinical trial efficiency. We will develop next generation OCT angiography (OCTA) technology and analysis frameworks (Aim 1). This hardware- software innovation will develop ultrahigh speed swept-source OCT (SS-OCT) to enable increased dynamic range OCTA characterization of retinal blood flow, higher definition volumetric data to visualize vasculature at the capillary level, and enable wide field structural and vascular imaging. These advances will develop a quantitative surrogate marker for capillary level blood flow speeds in retinal microvasculature. The ability to assess blood flow speeds at the capillary level represents a paradigm shift in OCTA imaging, enabling detection of subtle vascular flow alterations that occur at earlier disease stages, which are related to pathogenesis of diabetic macular edema (DME), capillary non-perfusion and neovascularization. New software motion correction technology can correct volumetric OCT/OCTA data for eye motion in three dimensions and artificial intelligence / deep learning techniques can generate reliable layer segmentations for OCTA, to facilitate tracking longitudinal changes across multiple patient visits. Using ultrahigh speed SS-OCT and OCTA blood flow biomarkers, we will perform a cross-sectional study in a cohort of diabetic patients and age-matched healthy controls (Aim 2). The study will evaluate repeatability of OCTA-driven VISTA flow markers, investigate if OCTA blood flow biomarkers are correlated with DR severity, and if they are associated with DME, capillary non-perfusion or neovascularization. Finally, we will monitor DR eyes longitudinally to investigate the role of subtle blood flow alterations in disease progression and predicting treatment response (Aim 3). The hypothesis is that OCTA blood flow biomarkers can identify regions with abnormal blood flow, which are at increased risk of thrombosis and leakage, and hence DME, as well as regions that are ischemic, and at increased risk of neovascularization. Similarly, we will also investigate if OCTA blood flow biomarkers can be used to predict response to anti-VEGF (vascular endothelial growth factor) therapy, i...