Hydrogel-Mediated Sustained Delivery of Corneal Epithelial Extracellular Vesicles: A Strategy for Enhanced Corneal Regeneration

Extracellular vesicles (EVs) derived from corneal epithelial cells have shown great promise in promoting corneal wound healing and stromal regeneration, but they face challenges with rapid clearance from the eye. This study addresses these challenges by developing a biocompatible collagen-hydrogel sustained delivery system. We successfully isolated, purified, and characterized corneal epithelial EVs (CE-EVs), assessed their efficacy in corneal epithelial healing in vitro, and demonstrated their sustained delivery over 10 days followed by an on-demand release through enzymatic degradation of the hydrogel, which mimics the in vivo scenario. To develop a microscale understanding of the EV diffusion inside the hydrogel matrix, we probed the hydrogel network with several model compounds and nanoparticles by using advanced confocal microscopy analyses, followed by fitting our results to established diffusion models. Our findings suggest this innovative approach offers a safe and effective strategy to promote corneal wound healing. This technology has the potential to revolutionize corneal injury treatment and improve patient outcomes. Moreover, the possibility to tailor EV-release kinetics broadens the scope of EV research in clinical practices, as varying short- and long-term release profiles will be required for diverse medical applications.