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OPHTHALMOLOGY Sights Set on Partial Corneal TransplantsWhen endothelial cells that form the fifth, innermost layer of the cornea deteriorate and start to resemble donuts that are barely touching rather than hexagonal tiles that snugly abut each other, only one option is available to save a patient's sight—a complete corneal transplant.
Clinical trials may be five to 10 years off, yet early research results suggest Nancy Joyce (left) and Dimitri Azar may be on the right track to develop a method for sparing patients from complete corneal transplantation when the diseased innermost layer of their cornea threatens their sight. Photos by Graham Ramsay Damage to the endothelium through surgery, trauma, or underlying disease can lead to corneal edema and loss of visual acuity, making corneal endothelial disease the most common single cause of corneal transplantation. "The corneal endothelium, a single cell layer, has one main function—it maintains corneal transparency. To do this, it forms a physical barrier so the fluid of aqueous humor doesn't flow freely to the cornea, yet it allows enough fluid to get by to nourish the cornea. It also removes excess fluid from the cornea via ionic 'pumps'," said Nancy Joyce, HMS assistant professor of ophthalmology at Schepens Eye Research Institute. "Many times there are cell losses, but you won't detect the problem until the patient has various clinical manifestations," Joyce said. "We don't have any way of curing these problems. The only way right now is full corneal transplantation, healthy tissue and all. In our work, we're trying to facilitate replacement of the diseased tissue only." The New Eye PatchJoyce and HMS associate professor Dimitri Azar, a corneal and refractive surgeon at Massachusetts Eye and Ear Infirmary, are leading a two-pronged research project to grow endothelial cells that eventually can be transplanted back at high concentrations onto Descemet's membrane, which attaches to the cornea's fifth layer. If their method results in the formation of an intact endothelial monolayer with a final density of at least 2,000 cells/mm2, normal morphology, and normal barrier and pump function, the need for complete corneal transplants could be reduced."No matter how many corneas are donated, of those, only a certain percentage can be used for transplants," Joyce said. "In the U.S. we have a larger percentage of corneas available, but in a lot of countries, donating organs is not part of the culture." Over the past year, Joyce and her colleagues have overcome their first major hurdle—getting corneal endothelial cells to grow at the proper density. "Corneal endothelium in vivo does not normally proliferate to replace dead or injured cells and is generally considered to be a nonreplicating tissue," said Joyce. "Since the rate of proliferation does not keep up with the rate of cell loss, the density of human corneal endothelial cells decreases with age, disease, and intraocular surgery or laser procedures." To function properly, the endothelium must be intact. Transparency can be lost when endothelial cell density is reduced below a critical level, 500 cells/mm2. Endothelial cell density in a normal human adult cornea is between 1,500 and 2,000 cells/mm2.
(Left figure) Altered cell shape and the resulting decrease in cell-to-cell connections compromise the barrier function of corneal endothelium and can result in corneal edema and loss of visual acuity. (Right figure) Schematics of corneal endothelial cell density are shown (l to r) in young individuals, older individuals, and those with loss of monolayer integrity leading to gaps between cells (see arrow). Illustrations by Peter Mallen Growth CultureEarly in the research, Joyce worked with Ko-hua Chen, a Taiwanese physician whose work in cell culture media helped pave the way for the generation of new corneal endothelial cells from old ones."We have developed a culture medium that consistently supports proliferation but also permits the cells to stop division in a density-dependent manner," Joyce said. "This program has been going on for two and a half years. The first part was developing the culture medium and learning how to grow cells properly and how to seed cells onto corneas. "Now we want to go more deeply into the morphological aspects," she said. "We need to complete the physiological function test. That's what I'm working on with Dimitri. One thing that is very clear to me is without the collaboration, I truly would not know where to go from here. I know where to go in terms of ivory tower thinking, but you need a clinician who knows the patient population. "Dr. Azar knows the urgency patients have in terms of their willingness to try some of these techniques," she said. "They're facing potentially blinding diseases." Originally funded by the National Eye Institute, Joyce and Azar are currently funded by a grant from the Joint Clinical Research Center. The JCRC was developed two years ago by MEEI and Schepens to promote increased scientific collaboration among basic researchers and clinicians. "The fundamental objective of the center is to revolutionize patient care for those individuals afflicted with, or at risk for, eye diseases," said JCRC director and HMS instructor Kathryn Colby, a corneal specialist. The goal is to develop treatments for diseases that are currently incurable, identify new therapeutic approaches to reduce the cost of care, improve diagnostic capabilities, and, where possible, devise strategies to prevent or delay the onset of diseases that lead to vision loss, Colby said. Early results suggest treatment using corneal endothelial cell transplants may be possible. "We're probably talking somewhere between five and 10 years before clinical trials," Joyce said. "We're still in the very early stages." —Judith Montminy |
