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.