Researchers use 3-D in-vitro model to identify trigger for steroid-induced glaucoma

Through the power of a 3D in-vitro model, researchers at Cornell University found the mechanism that triggers steroid-induced glaucoma. The “chip-on-eye” platform, which mimics the flow of ocular fluids, found that receptor ALK5 responded to the steroid by downregulating vascular endothelial growth factor C (VEGFC), which enables fluid to pass through the endothelial wall.^1,2

Results from the study that utilized the device were published in Nature Cardiovascular Research, with Renhao Lu, of Nancy E. and Peter C. Meinig School of Biomedical Engineering at Cornell University in Ithaca, New York, serving as first author.¹

“Steroid-induced glaucoma is a major clinical challenge. There’s no targeted therapy. We just say you are unlucky,” said senior author Esak Lee, PhD, assistant professor of biomedical engineering at Cornell Engineering, in a news release. “There is a clear, unmet need to better understand, and prevent, this major side effect of the steroid in the clinics.”

Study authors did note that although previous in vitro models of the trabecular meshwork (TM), Schlemm’s canal (SC) cells, and both TM and SC have been developed, “…these previous in vitro models have not fully recapitulated the native architecture of 3D SC endothelium surrounded by TM, and more notably, they could not examine the aqueous humor outflow mechanisms through the juxtaposed 3D multicellular structure.”²

More specifically, Lee’s laboratory has created these 3D in-vitro models that work to reproduce lymphatic systems in different types of organs that reproduces the systems’ layered structures while isolating biological and biophysical factors. The research team found that since the lymphatics in the eye, called Schlemm’s canal (SC) cells, are surrounded by the trabecular meshwork, the lymphatic system can only flush aqueous humor into the bloodstream when both of the cell layers work in conjunction with one another. Thus, the team developed and administered the “eye-on-a-chip” to female mouse models, then treated the device with anti-the inflammatory steroid dexamethasone. The steroid was found the significantly impair drainage due to the disruption in ALK5/VEGFC signaling.^1,2

“This communication causes the Schlemm’s canal junction abnormality,” Lee said in the release. “The junctions become really thickened or tightened under the steroid, and that junction change increased the resistance of the outflow, causing this glaucoma.”

Lee stated that with the knowledge gained form the study, there are now new possibilities for further studies to assess genes critical to glaucoma research.¹

“We are now aiming to study other targets. There are some genes that people know are important for glaucoma, not just steroid-induced, and we could knock them out in these 2 cell types,” Lee said in the release. “It’s complicated and difficult to target 1 cell type in conventional animal models, but in this system, we could do any genetic modification of these two cell types separately, and then combine them in the device to get a better understanding of these different mechanisms and different types of glaucoma.”

References:

1. Nutt D. “Eye-on-a-chip” reveals trigger for steroid-induced glaucoma. Cornell Chronicle. News release. August 27, 2025. Accessed September 25, 2025. https://news.cornell.edu/stories/2025/08/eye-chip-reveals-trigger-steroid-induced-glaucoma

2. Lu R, Kolarzyk AM, Stamer WD, Lee E. Human ocular fluid outflow on-chip reveals trabecular meshwork-mediated Schlemm’s canal endothelial dysfunction in steroid-induced glaucoma. Nat Cardio Research. 2025;4:1066-1076.https://doi.org/10.1038/s44161-025-00704-3