New 3d Eye Model Reveals Causes Of Steroid-related Glaucoma

The eye, for illustration astir organs, has an intricate plumbing system. Pressure builds erstwhile drainage is impaired, and this information – glaucoma – tin origin irreversible imagination loss. Certain celebrated anti-inflammatory oculus medications that incorporate steroids tin successful immoderate cases compound nan problem, though scientists person been astatine a nonaccomplishment to understand why.

Now, Cornell researchers person identified nan signaling system that triggers steroid-induced glaucoma by creating a 3D "eye-on-a-chip" platform that mimics nan travel of ocular fluids.

The findings were published Aug. 27 successful Nature Cardiovascular Research. The lead writer is Renhao Lu, Ph.D. '24.

Steroid-induced glaucoma is simply a awesome objective challenge. There's nary targeted therapy. We conscionable opportunity you are unlucky. There is simply a clear, unmet request to amended understand, and prevent, this awesome broadside effect of nan steroid successful nan clinics."

Esak (Isaac) Lee, senior author, assistant professor of biomedical engineering astatine Cornell Engineering

Glaucoma is typically studied successful animal models and elemental 2D compartment cultures, but those approaches often neglect to seizure nan anatomical complexity and responsiveness of nan quality eye. 

The solution from Lee's lab, which studies lymphatic systems successful different types of organs, has been to create 3D in-vitro models that tin reproduce nan systems' layered structures while isolating biologic and biophysical factors, each successful a highly reproducible and controlled manner. Lee previously co-designed specified a instrumentality that revealed a macromolecule that jams up nan basal drainage successful quality tegument lymphatic vessels, causing nan achy swelling known arsenic lymphedema.

The eye's lymphatic vessels are responsible for draining aqueous humor, a clear, water-like fluid that provides oxygen and nutrients but, erstwhile not removed, tin origin intraocular unit (IOP) to build, damaging neurons successful nan retina that are captious for transmitting ray signals to nan brain.

Lee's squad realized nan lymphatics successful nan eye, known arsenic Schlemm's canal (SC) cells, are rather different from those successful nan skin, lungs and different organs. These are surrounded by different compartment type: trabecular meshwork (TM). Only pinch some compartment layers moving successful conjunction tin nan lymphatic strategy flush nan overproduced aqueous joke backmost into nan bloodstream.

The squad built a 3D in-vitro device, known arsenic a microphysiological strategy (MPS), pinch a double furniture of TM and SC cells, pinch a curvature that mimicked nan conduit building of lymphatic vessels successful nan eye. The researchers treated nan "eye-on-a-chip" pinch nan anti-inflammatory steroid dexamethasone, which importantly impaired nan drainage.

This enabled nan researchers to place nan culprit: A cardinal receptor successful TM cells, ALK5, responded to nan steroid by downregulating a protein, vascular endothelial maturation facet C (VEGFC), which usually loosens nan endothelial junctions successful SC cells, enabling fluid to walk done nan endothelial wall. But that usability was disrupted by ALK5/VEGFC signaling.

"This connection causes nan Schlemm's canal junction abnormality," Lee said. "The junctions go really thickened aliases tightened nether nan steroid, and that junction alteration accrued nan guidance of nan outflow, causing this glaucoma."

The researchers confirmed nan domiciled of nan system successful a rodent model. The uncovering opens up 2 paths to treating glaucoma: blocking ALK5 function; aliases providing further VEGFC to nan oculus on pinch nan steroid treatment.

"We are now aiming to study different targets. There are immoderate genes that group cognize are important for glaucoma, not conscionable steroid-induced, and we could sound them retired successful these 2 compartment types," Lee said. "It's analyzable and difficult to target 1 compartment type successful accepted animal models, but successful this system, we could do immoderate familial modification of these 2 compartment types separately, and past harvester them successful nan instrumentality to get a amended knowing of these different mechanisms and different types of glaucoma."

Co-authors see postdoctoral interrogator Anna Kolarzyk, Ph.D. '25, and W. Daniel Stamer, professor of ophthalmology astatine Duke University.

The researchers made usage of nan Cornell NanoScale Science and Technology Facility and was supported by nan National Institutes of Health and nan BrightFocus Foundation.