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.