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A tissue-engineered human trabecular meshwork hydrogel for advanced glaucoma disease modeling.

Haiyan Li1, Tyler Bagué2, Alexander Kirschner2

  • 1Department of Ophthalmology and Visual Sciences, SUNY Upstate Medical University, Syracuse, NY, 13210, USA; Department of Cell and Developmental Biology, SUNY Upstate Medical University, Syracuse, NY, 13210, USA; BioInspired Institute, Syracuse University, Syracuse, NY, 13244, USA.

Experimental Eye Research
|January 31, 2021
PubMed
Summary

Researchers developed a novel biomimetic hydrogel to model primary open-angle glaucoma (POAG). This 3D model mimics human trabecular meshwork (HTM) cell-ECM interactions, showing promise for testing POAG treatments.

Keywords:
BioengineeringECM mechanicsIn vitroPOAGTissue stiffening

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Area of Science:

  • Biomaterials Science
  • Ophthalmology
  • Cell Biology

Background:

  • Abnormal human trabecular meshwork (HTM) cell function and extracellular matrix (ECM) remodeling contribute to HTM stiffening in primary open-angle glaucoma (POAG).
  • Existing cellular models lack the complex 3D cell-ECM interface crucial for studying POAG pathology.
  • Tissue-engineered hydrogels offer a promising solution to overcome limitations of current HTM models.

Purpose of the Study:

  • To develop and validate a novel biomimetic HTM hydrogel as a 3D disease model for POAG.
  • To investigate the role of cell-ECM interactions in HTM stiffening under normal and glaucomatous conditions.
  • To assess the utility of the hydrogel model for evaluating therapeutic interventions.

Main Methods:

  • Engineered HTM hydrogels by mixing normal donor-derived HTM cells with collagen I, elastin-like polypeptide, and hyaluronic acid, followed by UV crosslinking.
  • Induced glaucomatous conditions using dexamethasone (DEX) and assessed the effects of the ROCK inhibitor Y27632.
  • Evaluated cytoskeletal organization, tissue-level function, ECM remodeling, and hydrogel biomechanics (contractility, stiffness).
  • Validated the model using confirmed glaucomatous HTM (GTM) cells.

Main Results:

  • DEX exposure increased HTM hydrogel contractility, actin rearrangement, ECM remodeling, and fibronectin deposition, leading to stiffening.
  • Y27632 treatment reversed DEX-induced changes, promoting relaxation and softening of the hydrogels.
  • GTM hydrogels exhibited increased contractility, fibronectin deposition, and stiffness compared to normal HTM hydrogels, despite reduced proliferation.

Conclusions:

  • A biomimetic HTM hydrogel model was successfully developed for investigating 3D cell-ECM interactions in normal and glaucomatous conditions.
  • The model demonstrates bidirectional responsiveness to pharmacological challenges, indicating its potential for screening POAG treatments.
  • This 3D hydrogel platform offers a valuable tool for studying HTM biomechanics and developing novel therapeutic strategies for POAG.