Natural Dual‐Crosslinking Bioadhesive Hydrogel for Corneal Regeneration in Large‐Size Defects

Abstract Corneal injectable hydrogels represent a promising alternative to alleviate donor shortage and simplify traditional surgeries. However, most hydrogels focus on repairing focal corneal defects (≤3.5 mm) and leave many clinical requirements unmet. Herein, a novel ion‐activated bioadhesive hydrogel (IonBAH) is designed and its long‐term performance of repairing large corneal defects (6 mm) is evaluated in rabbits for 6 months. The IonBAH is a dual‐network hydrogel composed of natural corneal extracellular matrix and peptide‐modified alginate, which enables its desirable transparency and biocompatibility, tunable mechanics, and robust adhesion. Moreover, the IonBAH maintains the secretory phenotype of quiescent keratocytes, while preventing their myofibroblastic differentiation in vitro. Upon application in situ, it rapidly seals the 6 mm corneal defect and forms normal curvature through the coverage of a contact lens impregnated with calcium ions. During the 6 months follow‐up, the IonBAH promotes rapid regeneration of corneal epithelium, stroma, and nerves with restored transparency, equivalent to the outcome of donor corneal transplantation. In addition, the suitability of IonBAH as an adhesive and patch for various clinical requirements are also evaluated with a pleasing outcome. Collectively, IonBAH may provide a clinically applicable scaffold for corneal surgeries, especially in large defect repair.