The treatment is based on the assumption that retinal damage is caused by too little oxygen. The oxygen deficit results from vascular damage stemming principally from too much sugar in the blood. This interventional strategy sacrifices retinal tissue at the extreme field of vision to preserve direct vision for as long as possible. But the deliberate destruction eventually combines with the progressive nature of the disorder to rob diabetics of their vision.

“If you ask most clinicians, they will tell you that hypoxia [oxygen starvation] is proven to be the cause of retinal deterioration in diabetes,” says Ross D. Shonat, Ph.D., a Whitaker investigator and assistant professor of biomedical engineering at the Worcester Polytechnic Institute. “It’s so ingrained. The scientific evidence is highly suggestive, but it hasn’t been shown definitively. What are the oxygen levels? We don’t know.”

High blood sugar alters the biochemistry of living cells, particularly those that line the inside of vessels. Sugars bind to proteins and change how they function, initiating a little-understood domino effect. One result could be alterations in gene behavior. Genes could be called into action when they should be dormant, or they could be shut down when their activity is needed. Some experimental evidence also suggests that the oxygen shortage in retinopathy may be a consequence of retinal deterioration, rather than the cause. But these studies have examined only parts of the retina and not the entire tissue because of limitations in the few instruments available. A second hurdle has been the lack of good animal models of the disease.

Most of what is already known about oxygen in the retina comes from microelectrode studies in animals and from a very few surgical procedures in humans. Each of these has involved single-point measurements using oxygen-sensitive microelectrodes. This approach limits studies of disease progression, since the microelectrodes are too invasive to be used repeatedly. Retinal oxygen can be measured indirectly by magnetic resonance and spectral imaging, but this approach cannot be used to amass quantitative data as the disease progresses.

Shonat, however, recently developed a unique instrument to measure oxygen tension from both of the retina’s blood supplies (retinal and choroidal) and to record these levels over time. The new microscope-based imaging system was detailed in the October 2003 issue of the Annals of Biomedical Engineering. It is specifically designed for studying the mouse retina, since mouse strains are being developed to model human diabetic retinopathy. This opens the way for detailed studies that could reveal new treatment strategies.

“If oxygen isn’t the underlying culprit in retinal degeneration, then we might be able to alter the biochemical pathways and stem the disease with a drug,” Shonat says.

His imaging system uses a phosphorescent palladium-porphyrin compound that is injected into the retinal vasculature. Its glow depends on the amount of oxygen in the blood. The emitted light is captured by a digital camera and analyzed to produce two-dimensional maps of oxygen tension in the vasculatures that supply the retina.

Shonat’s technique could also be applied to direct human studies once the Food and Drug Administration (FDA) approves the use of these palladium-porphrin probes for injection into the bloodstream. Various groups are trying to win this FDA approval, but the process is expensive. Meanwhile, the creation of new mouse models of diabetes will clear the way for animal studies of Shonat’s device. The role of oxygen in many other eye diseases—glaucoma, age-related macular degeneration, retinopathy of prematurity, retinitis pigmentosa, and retinal detachment, etc.—is also in need of further study.

Shonat received a Whitaker Foundation Biomedical Engineering Research grant in 2001 for his work on the oxygen sensor and its use in studying diabetic retinopathy.