Retinal Hypoxia as an Early-Detection Imaging Biomarker for Diabetic Retinopathy.

Under diabetic conditions, hyperglycemia significantly disrupts oxygen metabolism, leading to retinal hypoxia, which affects all retinal cell types. The retina is structurally complex, comprising multiple layers of metabolically active cells. The diabetic retina is especially vulnerable to fluctuations in tissue oxygen pressure, making them more susceptible to hypoxia-related damage. Hyperglycemia-induced retinal hypoxia has been reported in the diabetic retina. Early detection of retinal hypoxia could improve outcomes in diabetic retinopathy and help prevent irreversible vision loss; however, conventional imaging tools, such as optical coherence tomography and fluorescein angiography, lack sensitivity in detecting hypoxia-related changes before permanent, irreparable damage has occurred. This review explores emerging technologies aimed at detecting retinal hypoxia and vascular oxygenation as two separate imaging objectives. It highlights pioneering work by Linsenmeier and colleagues, who used invasive microelectrodes to map oxygen distribution across retinal layers, and focuses on the development of HYPOX-4, a novel, highly sensitive molecular imaging probe for detecting hypoxia in the living diabetic retina. Additionally, this review provides an overview of other emerging technologies for imaging oxygenation in the diabetic retina, including retinal oximetry, phosphorescence lifetime imaging, functional magnetic resonance imaging, and photoacoustic imaging, which may collectively enhance the understanding and management of diabetic retinopathy.