Visionary Research

Few processes carried out by the human body are more complex than the bioelectrical dance known as sight. An intricate cascade of light and current sends images to the brain through a series of highly specialized cell types and millions of tightly packed neurons, forming our most indelible perceptions of the world.

This complexity of sight is one reason scientists have found it so challenging to develop artificial eyes, even as the rest of the medical community announces breakthroughs like cochlear implants that restore hearing or self-contained pumps that replace chronically diseased hearts.

Researchers at UofL's Department of Ophthalmology and Visual Sciences hope one day to change that with corneal implants and artificial eyes that could be used to help millions of people struggling with diseases that cause blindness.

These are just two of the leading-edge research projects currently under way in the department, which is internationally recognized for its innovative work.

Located in the Kentucky Lions Eye Center, which also houses the Rounsavall Eye Clinic, the Kentucky Vision Center, the Kentucky Lions Eye Foundation and the Kentucky Lions Eye Bank, the department's comprehensive research program includes work in the areas of ocular immunology and inflammation, retinal cell biology and degeneration, lens membrane structure and function, corneal cell biology, and glaucoma.

The department is lead by Henry J. Kaplan, M.D., the William H. and Blondina Evans Chair of Ophthalmology and Visual Sciences and director of the Kentucky Lions Eye Center. Since his arrival in 2000, Kaplan has recruited nine new vision scientists and dynamically expanded the center's reach within the university.

The faculty currently is comprised of eight clinicians and 14 scientists engaged in clinical and basic-science research, teaching and patient care. Their work focuses on finding solutions to multiple eye diseases, including age-related macular degeneration, or AMD; retinitis pigmentosa, or RP, and other hereditary retinal degenerations; uveitis; glaucoma; cataracts; diabetes; and dry-eye syndrome.

The department collaborates on multiple fronts with clinicians, scientists and engineers throughout the University of Louisville and beyond.

Projects are ongoing with groups such as the James Graham Brown Cancer Center, the Institute for Cellular Therapeutics, the Kentucky Spinal Cord Injury Research Center, the Speed School of Engineering and the medical school departments of anatomy and cell biology, microbiology and immunology, pharmacology, and biochemistry.

The department's expertise in operating in the subretinal area of the eye also has led to collaboration with Harvard University and the Massachusetts Institute of Technology.

Scientists engaged in vision research at the University of Louisville currently hold multiple grants from the National Eye Institute, with more than $4.4 million in annual research funding.

The Artificial Eye

Among the department's more compelling work is its research to develop an artificial eye. Just as the artificial cochlea helped the deaf to hear, researchers hope the artificial eye, or retinal prosthesis, will help people with conditions such as age-related macular degeneration and retinitis pigmentosa to see again.

AMD is the leading cause of legal blindness in people over 50 in the Western World. The condition is caused by a gradual decay of the macula located in the back of the eye, which results in a visual obstruction similar to that of an eclipse.

Retinitis pigmentosa is a group of diseases that causes deterioration of the retina, the thin layer of tissue that lines the inside of the back of the eye. Approximately 400,000 Americans have retinitis pigmentosa and other related retinal disorders.

Work on the prosthesis started 15 years ago at Harvard University and MIT. UofL was asked to join the consortium in 2001 because of its expertise in performing surgical operations underneath the retina, explained Kaplan, who is the primary investigator on the Louisville team. The UofL effort also includes faculty from the Speed School of Engineering.

"Their expertise in bioengineering, microfabrication and radiotelemetry have allowed us to establish a specialized research program for the retinal prosthesis," Kaplan said.

The device actually consists of several parts, including a camera attached to glasses and electrodes that are located in a "microarray" chip that is implanted beneath the retina.

Electrical signals generated by the camera are transmitted to the microarray chip, which then stimulates bipolar cells in the eye. Using the eye's innate physiology, these bipolar cells pass the signal on to ganglion cells, which relay the information along the optic nerve to the brain's visual cortex.

UofL's primary responsibility in the project has been two-fold -- determine the best location for the implantation of the microarray and study the body's reaction to the implant, also known as "biocompatibility."

For patients who received early versions of the prosthesis, the chip was implanted on the surface of the retina rather than underneath it.

UofL's work using animal models showed that the threshold for stimulation is lower when the chip is placed beneath the retina, reducing the chance that the electrical charge will damage surrounding tissue, Kaplan said.

Although the work is promising, researchers cautioned that the device is still in the experimental stage.

Volker Enzmann, Ph.D., who, along with Yasuyuki Yamauchi, M.D., serves as a co-investigator on the project, said UofL's microarrays have just 15 electrodes -- maybe enough to see light and shadows but nowhere near the visual acuity necessary to read.

That kind of increased granularity would require the use of nanotechnology in order to pack the thousands of requisite electrodes into such a small space.

"At the moment, the retinal prosthesis have the potential to be a significant advance in the future," Kaplan said.

Implantable Sensors

Glaucoma is a group of diseases typically associated with elevated pressure inside the eye, which can damage the optic nerve and cause vision loss. According to the American Academy of Ophthalmology, 80,000 Americans currently are blind as a result of the disease.

Glaucoma patients need to continually monitor their eye pressure so they can treat the disease with a simple application of eye drops, but patients currently must visit their doctors in order to get an accurate pressure reading -- a situation the UofL scientists hope to change.

Researchers in the Department of Ophthalmology and Visual Sciences and the Speed School of Engineering are working on a real-time pressure-monitoring system for glaucoma patients that will allow the continuous recording of intraocular pressure over a 24-hour period of time.

"In patients who have lost vision from glaucoma," Kaplan explained, "the implantation of such a device would allow a much more accurate and continuous recording of their pressure variation. It should result in better pharmacologic control of their intraocular pressure and prevent the further loss of vision from glaucoma."

A small pressure sensor, about the size of a few grains of salt, would be placed inside the eye. John Naber, an associate professor of electrical and computer engineering in the Speed School, said researchers envision a set of glasses for daytime use (goggles would be worn at night).

A coil embedded in the frame would transfer power to the sensor in the eye, while a pagerlike device with a battery would display the pressure readings transmitted by the sensor.

In 2002, a team of researchers from the Department of Ophthalmology and Visual Sciences and the Speed School of Engineering formed a biotechnology company to develop and market the device.

Other significant research projects include:

-- A collaboration with Suzanne Ildstad, M.D., at the Institute of Cellular Therapeutics; Scott Whittemore, M.D., at the Kentucky Spinal Cord Injury Research Center; and Mariusz Ratajczak, Ph.D., at the James Graham Brown Cancer Center, to use stem cell populations as a means of restoring diseased eye tissue.

-- Studies using pharmacological means to inhibit the onset of age-related macular degeneration. UofL researchers, in collaboration with Alan Garen, Ph.D., of Yale University, have developed a special antibody, called Icon, that inhibits the development of abnormal blood vessels beneath the retinas of patients suffering AMD.

-- The development of an enzyme called Dispase for clinical use in treating diseases of the eye. When injected intraocularly, Dispase creates a separation of the vitreous on the back of the eye, which is thought to prevent the development of certain forms of AMD and the onset of diabetic retinopathy, one of the long-term major complications of diabetes mellitus.

"The department of ophthalmology and visual sciences is at the forefront of many areas of both clinical and basic science research in blinding diseases," Kaplan said.

"The future holds great promise and should lead to the development of new treatments that are not currently available."

The concept of the prosthesis is deceptively straight-forward: It provides electrical signals to the retinas of patients who are blind. In a healthy eye, light strikes photoreceptor cells in the retina, producing minute electrical signals that are relayed to the brain's visual cortex for decoding into sight.

When disease interferes with these photoreceptor cells, visual acuity begins to plummet. The retinal prosthesis is designed to take over for the failing cells by acting as an artificial light sensor.