Reposted from the College of Engineering.
A new grant from the National Institutes of Health will accelerate University of Utah research using biomedical chip technology to better understand keratoconus, a potentially blinding disease that causes the eye's cornea to thin and bulge.
What starts as a small protrusion on the cornea, the clear dome at the front of the eye, can continue to steepen until vision blurs beyond what eyeglasses and treatments designed to slow the damage can correct. Little is known about why keratoconus progresses, and up to one in five patients eventually needs a cornea transplant, making the disease one of the leading reasons for cornea transplant surgery worldwide.
The four-year, $2.4 million grant from the National Eye Institute will allow Jungkyu "Jay" Kim, an associate professor of mechanical engineering, to test a hypothesis that could provide the first detailed explanation of disease progression: A feedback loop caused by the shape of the cornea itself.
"We think the new shape becomes the problem," explained Kim, who holds joint appointments in biomedical engineering and the John A. Moran Eye Center. "The cone shape creates stress, the stress damages cells, the damage thins the tissue, and thinner tissue bulges more. Each turn makes the next one worse. At some point the disease stops needing its original cause."
Until now, testing that hypothesis has been nearly impossible.
"There's no animal model that truly reproduces keratoconus," Kim said. "And you can't take a donated cornea, reshape it, and see how the cells respond over time."
With natural corneas out of the question, Kim's lab has been building one. The cornea-on-a-chip is a small transparent device holding living human corneal cells on a thin membrane that can be curved on demand by hydraulic pressure-from the gentle dome of a healthy eye to the steep geometries of keratoconus. Curvature is now a dial the researchers can turn across all three corneal cell layers in a single chip.
In work published in Nature Communications last year, Kim's group used that dial and reported an unexpected result. Curvature alone-no chemical trigger, no injury, nothing but a change in shape-was enough to push healthy corneal cells toward a fibrotic, scar-forming state and switch on inflammatory genes.
"That was the moment this became more than just an engineering project," Kim said.
The grant seeks answers to two interdependent questions. The first asks what is happening: the researchers need to know at what curvature ordinary mechanical stress tips into damage, how that damage spreads between the cornea's layers, and whether there is a point at which the cycle can be disrupted.
The second asks what to do about it. Once the lab knows which molecular pathways carry the damage, researchers can test drugs developed to block them by applying them to the chip both before the cornea steepens and after damage is underway.
"Knowing the mechanism isn't the finish line," Kim said. "A drug that works before the disease takes hold and a drug that works after are different problems, and patients see ophthalmologists at every stage."
The research spans two departments in the Price College of Engineering and the Moran Eye Center. Jiyoung Chang, associate professor of mechanical engineering, fabricates the ultrathin membranes that stand in for the cornea's internal layers. Michael Yu, a professor of biomedical engineering, analyzes collagen damage and the proteins that shift under mechanical stress. Moran Eye Center cornea surgeon Amy Lin will provide Kim with a key resource for the research: corneal tissue from keratoconus patients undergoing corneal transplants and data on the tissue's curvature and thickness.
The chip belongs to a category regulators call "New Approach Methodologies": human-based laboratory models meant to answer questions that currently require animal studies. Federal interest in them has grown under the FDA Modernization Act, and eye research is a prime candidate since animal eyes differ significantly from human eyes in many ways.
"Every one of these chips is a question we can answer without an animal," Kim said. "In eye research that matters more than most, because for a lot of what we need to know, there isn't a good animal model to begin with."
The lab is pursuing a related line of inquiry abroad. A separate award from the Korea Health Industry Development Institute supports a collaboration with Asan Medical Center in Seoul studying how corneal nerves regrow after transplant surgery-a process that leaves many patients with reduced sensation in the eye, for reasons that remain poorly understood.
Banner image: Conceptual rendering of the cornea-on-a-chip device. Human corneal cells grow on a flexible dome that mimics the eye's shape and stretch, helping researchers study keratoconus, a disease in which the cornea thins and bulges into a cone. Image credits: Kim Group, University of Utah.
