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Understanding cellular and biomechanical aspects of outflow tissue dysfunction in glaucoma

We are interested in determining how trabecular meshwork and Schlemm’s canal cells and their ECM contribute to fibrotic-like tissue contraction and stiffening that are known to play a crucial role in elevated outflow resistance in glaucoma. These biophysical alterations instruct cells to adopt a pathological phenotype over time by activating various mechanotransduction pathways. Despite substantial scientific effort over the past several decades devoted to understanding glaucoma pathogenesis, the precise mechanisms underpinning persistent outflow tissue dysfunction remain elusive.

Image of different biological cells

Trabecular meshwork

We recently showed that our engineered ECM hydrogels provide a biomimetic microenvironment for investigations of 3D trabecular meshwork cell-ECM interactions under normal and simulated glaucomatous conditions. This model system uniquely enables correlative analyses of glaucomatous cell alterations with tissue-level functional changes; i.e., ECM contraction and stiffening. We use the cell-encapsulated ECM hydrogel platform to investigate: 1) how cell contractility is modulated by the glaucomatous stressor TGFβ2 with consideration of the signaling crosstalk balance, 2) how YAP/TAZ mechanotransduction is regulated by varying ECM stiffness and TGFβ2, and 3) how cellular mechanical memory is first formed (YAP signaling) and then stored (epigenetic mechanisms), and how this contributes to the persistence of glaucomatous cellular dysfunction. 

Schlemm’s canal

To expand upon the proven utility of our trabecular meshwork hydrogel platform, we add a monolayer of primary human Schlemm’s canal endothelial cells to effectively create a biomimetic model of the juxtacanalicular trabecular meshwork / Schlemm’s canal inner wall interface. This system enables detailed analyses of reciprocal cell-cell and cell-ECM interactions in 3D under both static and dynamic culture conditions using our custom microfluidics chip. We use this co-culture hydrogel to systematically investigate: 1) how cellular pathology and/or 2) pathologic conversion of the biomechanical environment affect cell-cell communication – both direct and indirect, and 3) how localized immunomodulatory mechanisms contribute to cellular pathobiology (or the reversal thereof).