Location of Flow Resistance in Glaucoma Found

Glaucoma, a leading cause of blindness that affects 3 million Americans, is a disease of flow: when fluid builds up in the eye, the increased pressure damages the optic nerve.

Northwestern Engineering researchers have now found the area in the eye that generates this elevated pressure, located within one micrometer of the surface of Schlemm’s canal, where fluid drains from the eye. In eyes with glaucoma, this tiny region is 20 times stiffer than in healthy eyes.

Knowing this exact location could lead to better therapies to treat or even prevent glaucoma, said Mark Johnson, professor of biomedical engineering and mechanical engineering at Northwestern’s McCormick School of Engineering and Applied Science who led the research.

“People have been looking for this location for the past 150 years, and now that we know what we need to change within the tissue, it will be much easier to find treatments for it,” said Johnson, who is also a professor of ophthalmology at Northwestern’s Feinberg School of Medicine. The results were published this month in the Proceedings of the National Academy of Sciences.

In healthy eyes, a clear liquid called aqueous humor nourishes and maintains the pressure of the eye. When it drains back into the body’s vascular system, it flows through Schlemm’s canal. But if the canal’s surface cells — called endothelial cells — are too stiff, they have difficulty forming pores that allow the fluid to drain. The resulting pressure in the eye can eventually damage the optic nerve and cause blindness.

Johnson and his collaborators discovered that these endothelial cells were the cause of this fluid back-up in 2014, but they weren’t sure of the cause. Using atomic force microscopy, they found that immediately beneath these cells in glaucomatous eyes, within 1 micrometer of the surface, was an ultrathin region with greatly elevated stiffness. They believe this layer is causing the elevated stiffness of the endothelial cells, thereby decreasing pore formation and elevating flow resistance.

To prove this, they also measured flow resistance in this extremely narrow region. These endothelial cells are unique in that when they are exposed to a pressure difference, they develop bubbles called giant vacuoles. The researchers then used these vacuoles as micropressure sensors within the eye —the more vacuoles, the higher the pressure drop in this layer. They found that the increased flow resistance in glaucoma was in this layer.

“We knew five years ago that these endothelial cells were important, but now we know just how they are controlling stiffness in this tiny region,” Johnson said.

These findings could result in better therapies. A new treatment for glaucoma, the use of rho kinase inhibitors, works by softening these endothelial cells in the eye to increase flow. But this treatment softens many cell types in the entire eye, leading to side effects. Johnson and his collaborators are now working to develop therapies that could change the gene expression of this narrow region of cells. That would soften just this area to lower flow resistance, without affecting the rest of the eye.

“Now that we know everything is happening in this very narrow region, we can imagine delivering drugs directly to the site to change the local environment,” Johnson said.

Other authors on the paper include Cheng Sun, associate professor of mechanical engineering, and Hao Zhang, professor of biomedical engineering, as well as collaborators from Boston University, Duke University, and the University of Regensburg.