these blog posts are written by Dr. alfredo G. Tomasselli, a Retired bio-Chemist and Bio-physicist who spent his life in Academia and The Pharmaceutical Industry researching cures and treatments for diseases such as HIV/Aids, Diabetes, and Rheumatoid arthritis. His daughter sara inspires this blog and helps to write posts. sara was diagnosed with type 1 diabetes on april 4th, 2014 at the age of 30. 

2016 Non-invasive light treatment of the diabetic eyes promises to bring new ammunitions to the fight against diabetes retinopathy

This blog is for informational purposes only and in no way intended as medical and other personal advice

The science leading to the technology

 In order to see objects, light rays reflected from these objects need to hit our eyes and go through a specific pathway before they are interpreted and converted by the brain into the final images we see (Figure 1A and 1B). Specifically, light rays first enter the cornea, the eye’s primary light-focusing structure. The cornea bends the light rays and sends them to the lens through the pupil, a structure which controls the amount of light that enters the eye. The lens fine-tunes the light rays received from the cornea by further bending them and reflecting them into the retina, forming an image reversed (turned backwards) and inversed (turned upside-down), that allow us to see objects much bigger than our eyes. The retina is a fragile thin tissue studded with many tiny blood vessels that supply oxygen and nutrients and remove waste; it lies in the back of the eye where it covers about 65% of the eye ball’s internal surface. It is composed by several cellular layers one of which houses the rods and cones which are specialized cells, called photoreceptors. The rods are both more abundant than the cones (about 120 million vs. about 7 million) and more sensitive to light than cones, in particular to dim light; in fact, cones are found much more concentrated in the central yellow spot of the retina known as macula. The cones distinguish colors, are responsible for the central vision, and are effective during the daylight, while rods are not sensitive to colors, but are responsible for nocturnal peripheral vision, though they require a considerable amount of oxygen to adapt to the dark. Rods and cones interpret the optical signals they receive and convert them into electrical signals that are then delivered to the visual cortex in the brain by the Optic Nerve. The brain understands these signals and converts them into the final image we see.

In order to see clear images from objects, all the parts of our eyes, and the specialized cells they harbor, must work smoothly together. If something fails, like in poorly managed diabetes, problems arise. 

In both T1D and T2D, elevated blood glucose triggers a series of intercommunicating biochemical and biological events including proteins’ glycation, excessive formation of Reactive Oxygen Species (ROS), and reduced delivery of oxygen to retinal tissues, that collectively lead to leakage, damage, and, finally, rupture of the tiny blood vessels of the retina (Diabetes Retinopathy, or DR). 

By keeping a tight blood glucose control a diabetic patient can minimize, delay, or even avoid DR; a periodic eye examination (twice per year) can catch the onset (if it occurs) and/or progression of the disease and suggest the proper treatment(s).

Routine tests performed in both T1D and T2D patients that evaluate glycated hemoglobin (also called hemoglobin A1c test, or HbA1c test) are indispensable to know whether therapy properly controls glucose; if not, therapy needs to be adjusted. The glucose in the blood binds spontaneously and irreversibly to hemoglobin and forms stable glycated hemoglobin molecules that circulate with red blood cells until these cells die (they last about 3 months); the test provides an average of our blood sugar concentration over the previous 3 months. The more glucose is in the blood the more glycated hemoglobin is formed (footnote 1). Furthermore, other proteins, lipids and DNA are also glycated in a process called Advanced Glycosylation End (AGEs) products. Advanced Glycosylation End products are dangerous because they are impaired molecules that may not be able to properly perform the biological tasks of their parent molecules and may lead to triggering biochemical pathways with devastating effects on the health and functions of the cells and the organs where they reside, e.g., the eye. Ironically, AGEs products have also been implicated in the accelerating the process of ageing in people!)

Also Reactive Oxygen Species (ROS) appear to have a role in the pathogenesis of diabetes. They are the products of numerous biochemical reactions and are important to cells functions when they are formed in physiological concentrations. However, there are evidences that hyperglycemia increases the production of ROS and this is bad news as excessive production causes damage to proteins, and DNA, and sets in motion undesirable biochemical pathways leading to impaired cellular functions.

In poorly managed diabetes, AGEs and ROS are increased in the retina, and foster the expression of the Vascular Endothelial Growth Factor (VEGF). Moreover, both AGEs and ROS promote hypoxia (deficiency of oxygen) in the retina. Hypoxia of the retina becomes more serious at night when the rods take over nocturnal vision; remember that the rods are numerous and, at night, they require more oxygen than retinal overall consumption afforded during the day; but rods’ request for oxygen cannot be fulfilled in the diabetic eye. Moreover, hypoxia is a major contributor to VEGF expression. While physiological concentrations of VEGF are indispensable to the wellbeing of the eye, its overproduction promotes the growth of a large number of fragile blood vessels in the retina and increases vessels permeability causing their contents to leak out and dump inflammatory factors into the retina; in other words, a sort of vicious cycle is created in which AGEs, ROS, and hypoxia synergize with each other. As a consequence vision can become blurry and, without intervention, the retina will be destroyed. Inflammation and swelling of the retina is conducive to macular edema (ME), a condition that further aggravates the sight of patients.  The above narrative would suggest that benefits could be obtained from DR therapies that (1) fix the damage caused by faulty blood vessels; and/or (2) inhibit the action of VEGF; and/or (3) reduce the rods activity during the night to use less oxygen thus curbing hypoxia and VEGF production.

In regard to point (1), laser surgery has been performed for over thirty years to eliminate both the damaged blood vessels and the newly formed fragile vessels; this treatment stops hemorrhage and edema. Moreover, vitrectomy has been employed to remove blood from the back of the eye. 

In regard to point (2), biological drugs have been introduced over the past ten years; they are proteins designed to trap VEGF and make it inactive; when injected in the eyes, they block the damage to the retina. 

Both laser and biological drugs therapies are rather effective, but expensive and have side effects.

In regard to point (3), a new therapy, presently in clinical trials, relates to light treatment of the diabetic eyes and promises to bring new ammunitions to the fight against diabetes retinopathy. The underlying principle of eyes’ light treatment is rather easy to understand as it is based on the principle of tricking the eyes’ rods to believe that they still receive daylight during the night, so that they use much less oxygen and should minimize both hypoxia and the production of VEGF and their serious consequences. The selection of the color of the light is made to have it mainly absorbed by the rods, without involving the cones to avoid keeping people awake. Moreover, the brightness of the light is regulated in such a way that the rods do not adapt to the dark. 

In a recent review titled “Diabetic retinopathy and a novel treatment based on the biophysics of rod photoreceptors and dark adaptation”, Drs. Geoffrey B. Arden and David J. Ramsey (Reference 1) give a comprehensive account of Diabetes Retinopathy with regard the biochemical and biological mechanisms of its onset, the treatments currently available, and current clinical trials regarding light treatment (Drs. Arden and Ramsey are involved in some of these trials). In the clinical trials, the patients wear “light masks” to illuminate the retina through the closed eyelids during sleep. Only one eye is illuminated, while the other is kept in the dark to be used as a control.

A Phase I clinical trial demonstrated three important things: (1) No adverse reactions were encountered by light administration to the eye; (2) the mask was well accepted by the patients during sleep; and (3) therapy resulted in a significant improvement in the 10 eyes in the study relative to their controls (unusual for a Phase I stage clinical trial that typically is intended to verify that therapy is safe).

Benefits and lack of side effects similar to those achieved in the Phase 1 clinical trial, were obtained in a Phase II trial with 42 patients. Many of the treated eyes improved, while the untreated eyes did not. 

The review’s authors concluded that “such studies provide a “Proof of Principle” that retinal hypoxia in darkness must be an important driving force for diabetic retinopathy” and that more work needs to be done to validate these positive results (reference 1). They also mention that “small commercial companies have manufactured masks which can be used in such trials, and apparently one trial carried out at the Department of Ophthalmology, Vinohrady, Prague, Czech Republic, produced encouraging results. These results have not been published in detail yet. Further trials are starting in London (UK), Cardiff (UK), and Boston (USA)”.

A light mask, the Noctura 400 Sleep Mask from Polyphotonix for preventing Diabetes Retinopathy was selected as one of “the Best Medical Technologies of 2015”.  Watch this movie concerning how the mask works and the details about its availability in Europe. 

Footnote

1) In healthy people, the normal range for the hemoglobin A1c test is between 4.0% and 5.6% and people with diabetes are recommended to bring hemoglobin A1c to less than 7%; this can be accomplished with therapy involving properly matching insulin dosage to carbohydrate content of meals, diet, and exercise.

Reference 

1)Arden G.B. and Ramsey D.J. (2015) Diabetic retinopathy and a novel treatment based on the biophysics of rod photoreceptors and dark adaptation. Webvision, the Organization of the Retina and Visual System; pp 1-50. 

Figure 1A. Image formation of an object in the retina. The image of the object formed in the retina is turned backwards and upside-down compared to the real image; this allows the retina to register images far bigger than the eye. The backwards upside-down image is converted into electrical signals that are then delivered to the visual cortex in the brain by the optic nerve; they are interpreted by the brain and converted in the image we see.

Figure1B. Illustration of the anatomy of a normal human eye from the American Macular Degeneration Foundation (AMDF)
Cornea. The transparent "front window" of the eye. It is a thick, nearly circular structure covering the lens. The cornea is an important part of the focusing system of the eye.

Pupil. The round black hole in the center of the iris. The size of the pupil changes automatically to control the amount of light entering the eye.

Iris. The pigmented (colored) membrane of the eye, the iris is located between the cornea and the lens. Its color varies from pale blue to dark brown.

Lens. A transparent biconvex structure located behind the iris. It focuses light rays entering through the pupil in order to form an image on the retina.

Retina. A thin multi-layered membrane which lines the inside back two-thirds of the eye. It is composed of millions of visual cells and it is connected by the optic nerve to the brain. The retina receives light and sends electrical impulses to the brain that result in sight. The light sensitive retina consists of four major layers: the outer neural layer, containing nerve cells and blood vessels; the photoreceptor layer, a single layer that contains the light sensing rods and cones; the retinal pigment epithelium (RPE) and the choroid, consisting of connective tissue and capillaries.

Macula. An area of the eye near the center of the retina where visual perception is most acute. The macula is responsible for the sharp, straight-ahead vision that is used for seeing fine detail, reading, driving, and recognizing faces. It is one hundred times more sensitive to detail than the peripheral retina. The macula is sometimes referred to as "the bull's eye center of the retina."

Optic Nerve. Cable-like structure composed of thousands of nerve fibers that connect the macula and retina with the brain. The optic nerve carries electrical impulses from the macula and retina to the processing center of the brain where they are interpreted into clear, colorful sight.

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