BIOENGINEERED, STEM CELL DERIVED OCULAR OUTFLOW TISSUE

Abstract

Glaucoma is one of the leading causes of irreversible blindness in the world. Despite decades of research, intraocular pressure (IOP) is the only known treatable risk factor. IOP is affected by the timely removal of aqueous humor through the conventional outflow track, which is made up of the trabecular meshwork and adjacent Schlemm’s canal. Dysfunction in these tissues due to aging, oxidative stress, metabolic or pathological changes lead to increased flow resistance, elevated IOP, and ultimately glaucoma. Recent advances in ocular regenerative therapy have the potential to rescue glaucomatous tissue function and restore its delicate microenvironment. The possibility of using stem cell-derived trabecular meshwork and Schlemm’s canal cells to recreate a functional outflow tissue are explored in this thesis. Previously, our lab developed a well-defined, micro-porous substrate that promotes in vivo-like physiology and outflow function in primary trabecular meshwork and Schlemm’s canal cell cultures. Using these primary cell cultures as controls, we have created 3D stem cell-derived outflow tissues, evaluated and compared their morphology, expression, outflow facility, and drug responsiveness. To explore the importance of the dynamic microenvironment in outflow function, we developed a dual-flow microfluidic chamber that mimics the basal-to-apical and shear flow of aqueous humor through the conventional outflow track. Overall, this dissertation demonstrates the promising application of stem cells in future glaucoma drug screening and treatment.