Thomas Gardner would prefer not to perform another laser surgery on a patient going blind from diabetes.
Laser surgery is often the treatment of choice, explains Gardner, vice chair for ophthalmology research at the Penn State College of Medicine. But while the procedure can prevent further damage by sealing leaky retinal blood vessels, it can't restore vision already lost.
Diabetic retinopathy, the leading cause of blindness among 25-74 year-olds in the industrialized world, occurs when high levels of sugar in the blood damage the retina's blood vessels, causing them to leak blood and plasma. Untreated, this leakage can damage and even destroy the photoreceptor neurons that process images.
Gardner has spent years researching the relationship between insulin and the survival of retinal neurons among diabetics, with the goal of developing a more successful approach to treatment. "We found that intensive insulin therapy is very useful for this condition," he says, "but giving it systemically can create a dangerously high risk of hypoglycemia."
Reducing this risk while still delivering the benefits of intensive therapy required "a long-lasting, localized drug-delivery system," notes Gardner. "We knew we needed something that was easy to administer and offered sustained-release therapy, because things like injections and daily eye drops discourage patient compliance."
Gardner and colleagues turned for help to Tao Lu Lowe, assistant professor of surgery, bio-engineering, and materials science and engineering at the College of Medicine. Lowe's focus is the development of innovative drug-delivery systems using synthetic polymers.
As Lowe remembers it, Alan Snyder, associate dean for technology development at Hershey, liked Gardner's new treatment and commented on the need for a better delivery system. "Tom Gardner then contacted me and said 'We should talk,'" recalls Lowe. "We sat down to think about what material would be most applicable for his purposes."
Lowe and her team created a non-toxic polymer hydrogel—"a little gel capsule" as they describe it—that could be implanted under the surface of the eye with a simple in-office procedure, and ideally could offer continuous low-dose insulin directly to the retina for up to six to twelve months.
Lowe explains, "A lot of protein drugs such as insulin have short lifetimes, from a couple of seconds to no more than a couple of hours, so that's why you have to renew insulin in your body every day for the rest of your life once you're diabetic."
Adds Lowe, bioengineering techniques make it possible to have the active agent released from the material in a pre-designed way. "We can adjust the material's chemistry and physics to achieve a therapeutic dose with a long-term release," she notes. "In this case, the size needed was pretty small—two millimeters in diameter and 1.6 in thickness—because we needed to implant the polymer gel directly in the eye's subconjunctival space," the transparent mucous membrane lining the inside of the eyelid and covering the eyeball's surface.
Polymers—long repeating chains of small molecules—have become "a popular candidate for biomedical applications" for many reasons, Lowe says. "Polymer materials can be tailored to many different needs, depending on the kind and size of molecules used. It can be as hard as a table or as soft and thin as the hydrogel capsule we created."
Working with insulin can pose particular challenges. "Insulin is a protein drug, which means that it is water soluble," explains Lowe. "Scientists usually use organic solvents to load protein-based drugs into delivery materials, and that can sometimes cause denaturation and a loss of biomedical activity. Protein drugs are very expensive so you want to avoid losing any of their potency."
Lowe and Gardner found their way around this problem by changing the solvent. "A unique thing we are working on," Lowe says, "is loading the protein drug into the biomaterial in an aqueous environment—water, just water." This approach preserves the insulin's biological activity within the hydrogel. At the present time, says Lowe, "we can achieve two months long-term release with the aqueous loaded drug, and we're hopeful we'll soon see that extended to six months and even longer."
Reflecting on the strength of their collaboration, Lowe makes note of the very specific knowledge each partner brought to bear. "Dr. Gardner knows a lot about the biological and physiological systems of the eye and, in my lab, we know just what type of material is needed for a given application."
When asked about the future outlook for this patent-pending treatment, Lowe is optimistic. "So far, so good. We are eventually looking for sustained release over a full year."
Adds Gardner: "The incidence of diabetes is predicted to double over the next 30 years, and diabetic retinopathy is often not treated until the late stages, when there is a limit to what laser surgery can achieve. Our work is focused on finding minimally to non-invasive methods with high patient compliance, so we can help people sooner and more effectively."
About the promising therapy he and Lowe have pioneered, he adds, "I'd be happy to see human trials in the next five years."
Tao Lu Lowe, Ph.D., is assistant professor of surgery, bioengineering, and materials science and engineering in the College of Medicine; tlowe@psu.edu. Thomas Gardner, M.D., is professor of ophthalmology and cellular and molecular physiology and vice chair for ophthalmology research in the College of Medicine; tgardner@psu.edu.
