Imaging of the retinal hypoxia: A journey from oxygen microelectrode to the first hypoxia imaging in the living retina

Oxygen is the major element for metabolism in the retina. Reduced oxygen supply causes significant changes in cellular metabolism and gene expression in the retina initiating inflammasome activation, apoptosis of retinal cells, mitochondrial damage, oxidative stress and neurodegeneration. Physiologically, retinal hypoxia plays important role regulating vasculogenesis during our development in early life. Retinal hypoxia also plays key regulatory roles during the onset and progression of many retinopathy conditions including neovascularization at later stages of our life. Though the exact mechanism of neovascularization is still largely unknown, hypoxia may contribute to the over expression of vascular endothelial growth factor (VEGF), and VEGF is a known inducer of neovascularization. Thus, molecular imaging of retinal hypoxia could be an important diagnostic tool assessing the risk of retinopathy, its progression, and response to therapy. Imaging retinal hypoxia is also an important diagnostic tool assessing the risk of inflammasome activation, mitochondrial damage, oxidative stress and apoptosis of retinal cells at molecular levels. This review will provide an overview of technologies to detect retinal hypoxia in the living retinal tissues before the onset of tissue damage. This review will also discuss the design and development of HYPOX-4, a highly sensitive molecular imaging probe capable of detecting retinal hypoxia in the living retina before the onset of neovascularization. The author will further discuss a quantitative method to assess HYPOX-4 fluorescence intensity measurement by computational methods, correlating with levels of retinal hypoxia and create a predictive biomarker for retinal neovascularization. An overview of the technology development will also include Dr. Linsenmeier's early development of microelectrode for our fundamental understanding of retinal tissue oxygenation using an invasive measurement technique. An overview of the other emerging technologies, including retinal oximetry, phosphorescence lifetime imaging and photoacoustic imaging will be discussed.