Optic-nerve-head (ONH) Chips for Glaucomatous Neurodegeneration

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While there is a continuous increase in the incidence of glaucoma, the leading cause of irreversible blindness worldwide, current glaucoma therapies show limited efficacy. As the most prominent causative and prognostic risk factor of glaucoma, elevated intraocular pressure (IOP) could deform the optic nerve head (ONH) and damage the retinal ganglion cell (RGC) axons as they pass through the ONH. Current glaucoma therapies focus on lowering IOP, yet the vision loss continues over time despite a well-controlled IOP. Extensive evidence suggests the ONH astrocyte response to elevated IOP as a mechanism for RGC axonal damage. The astrocytes express mechanosensitive channels, sense the mechanical deformation, and become reactive in response to IOP elevation, which may lead to pathological changes of glaucoma. However, the effects of IOP on ONH biomechanics are not fully understood. Of note, the ONH stiffness changes with age, glaucoma and IOP elevation, and the astrocytes are highly sensitive to microenvironment stiffness and mechanical stimuli. While widely used mouse models are costly, time-consuming and facility limited, most of conventional in vitro ONH models are based on 2-D stiff substrates without incorporating key anatomical and physiological characteristics of native ONH, leading to cellular processes deviated from the in vivo events. We thus hypothesized that the ONH model that closely resembles the physical and mechanical characteristics of native ONH will allow more accurate in vitro glaucoma study. Therefore, the objective of this project is to develop ONH-on-a-chip systems that recapitulate the key structural (co-culture of astrocytes and RGCs), physical (radial aligned RGCs and matrix stiffness), and mechanical (IOP) characteristics of native ONH to delineate the astrocytic mechanisms of glaucoma pathogenesis. An interdisciplinary research team has been assembled to have expertise in organ-on-a-chip technology, glaucoma neurodegeneration, biomechanics and biomaterials, and two Specific Aims are proposed: (1) engineer and validate ONH chips of pathophysiological relevance, and (2) delineate mechanosensing mechanisms underlying glaucoma pathogenesis on the chips. Successful completion of this project will deliver novel, biomimetic ONH chips to provide a reliable, rapid, and inexpensive model to delineate the glaucomatous neurodegeneration. The validated mouse ONH chips will lay the foundation for developing human ONH chip to advance the mechanistic understanding of glaucoma pathogenesis and facilitate the development of disease-modifying therapeutic approaches. The Department of Biomedical Engineering at UNT has a newly ABET-accredited undergraduate program with approximately 254 students (117 women, Hispanic = 77, African American = 33) in 2020. The proposed AREA program will provide research opportunity to undergraduate students, particularly for underrepresented minority and female students and motivate them to pursue their future career in biomedical and health-related areas.