Researchers led by Cornell University and supported by the National Eye Institute have developed a 3D “eye-on-a-chip” platform that replicates ocular fluid dynamics, using it to uncover the signaling mechanism driving steroid-induced glaucoma. Reported in Nature Cardiovascular Research, this work addresses limitations of traditional animal models and 2D cultures, which inadequately capture the human eye’s anatomical complexity and physiological responses.
In the recently published study, the research team developed a 3D ocular fluid outflow chip combining Schlemm’s canal (SC) endothelium and trabecular meshwork (TM) to model fluid drainage in the eye. The system reproduced steroid-induced glaucoma, showing reduced outflow and tighter SC junctions. The “eye-on-a-chip” was treated with the anti-inflammatory steroid dexamethasone, which significantly impaired the drainage.
This allowed the researchers to pinpoint the mechanism: in trabecular meshwork (TM) cells, activation of the receptor ALK5 by steroids suppressed vascular endothelial growth factor C (VEGFC), a protein that normally relaxes Schlemm’s canal (SC) endothelial junctions to facilitate fluid outflow. As a result, ALK5/VEGFC signaling disrupted this junction-loosening function, impairing fluid drainage.
“This communication causes the Schlemm’s canal junction abnormality,” Lee said. “The junctions become really thickened or tightened under the steroid, and that junction change increased the resistance of the outflow, causing this glaucoma.”
The researchers confirmed the role of the mechanism in a mouse model. The finding opens up two paths to treating glaucoma: blocking ALK5 function or providing additional VEGFC to the eye along with the steroid treatment.
“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 two cell types,” Lee said. “It’s complicated and difficult to target one 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.”
Read the full news release from Cornell University.
Source: Cornell University