Human ocular fluid outflow on-chip reveals trabecular meshwork-mediated Schlemm's canal endothelial dysfunction in steroid-induced glaucoma.

Glaucoma is a leading cause of blindness, featuring elevated intraocular pressure and consequential optic nerve damage1. While elevated intraocular pressure is due to impaired ocular fluid outflow through both the trabecular meshwork (TM) and the lymphatic-like Schlemm's canal (SC) endothelium, the mechanism by which SC endothelium regulates fluid outflow in cooperation with the TM in healthy and glaucomatous conditions remains unclear. Here we create a human ocular fluid outflow on-chip, composed of a three-dimensional lymphatic or SC endothelium surrounded by TM and draining interstitial fluid. Using the system, we recapitulate steroid-induced glaucoma, characterized by decreased fluid outflow and tightened SC endothelial junctions. We further reveal that the glaucoma phenotypes are induced by an ALK5/VEGFC-mediated SC endothelial dysfunction in the presence of TM. The ocular fluid outflow on-chip provides a unique platform for bridging traditional in vitro and in vivo models of ocular lymphatic physiology and disease.