Supramolecular host-guest hyaluronic acid hydrogels enhance corneal wound healing through dynamic spatiotemporal effects

Large abrasions and deeper ulcers of the cornea can lead to corneal scarring, ulceration and thinning if not promptly and adequately treated. Hyaluronic acid (HA) has been investigated for the treatment of corneal wounds due to its remarkable biocompatibility, transparency and mucoadhesive properties. However, intact linear HA has low retention time on the cornea and chemical crosslinkers to synthesize HA hydrogels can cause toxicity limiting their clinical ocular applications. Here, we used supramolecular HA hydrogels formed by non-covalent host-guest interactions between HA-cyclodextrin and HA-adamantane to evaluate the impact of the hydrogels on corneal wound healing. Supramolecular HA hydrogels facilitated adhesion and spreading of encapsulated human corneal epithelial cells ex vivo and improved corneal wound healing in vivo as an in situ-formed, acellular therapeutic membrane. The HA hydrogels were absorbed within the corneal stroma over time, modulated mesenchymal cornea stromal cell secretome production, reduced cellularity and inflammation of the anterior stroma, and significantly mitigated corneal edema compared to treatment with linear HA and untreated control eyes. Taken together, our results demonstrate supramolecular HA hydrogels as a promising and versatile biomaterial platform for corneal wound healing.