Highly stable fibronectin-mimetic-peptide-based supramolecular hydrogel to accelerate corneal wound healing

Without timely treatment, poor wound healing in corneal injuries can seriously impair vision and lead to blindness. Thus, it is vital to develop a therapeutic strategy to accelerate corneal re-epithelialization. The conjugation of self-assembled motifs with a fibronectin-mimetic peptide sequence (PHSRN) drastically improves the chemical stability of PHSRN against protease hydrolysis and minimally affects its biological activity to promote the migration of corneal epithelial cells. The optimized Nap-FFPHSRN self-assembled into bioactive supramolecular hydrogels increases cell motility by remolding F-actin and boosts the tight junction of the corneal epithelium by increasing the expression of zonula occludens-1 (ZO-1). An in vivo experiment showed that a Nap-FFPHSRN hydrogel provided extended precorneal retention with good ocular tolerance after topical instillation. An animal model of corneal scrape showed that a single daily dose of Nap-FFPHSRN hydrogel had a superior therapeutic effect in facilitating corneal re-epithelialization with complete morphological and architectural recovery. With a rational approach to mimic bioactive proteins, this study presents a new strategy to demonstrate the potential of peptide-based supramolecular hydrogels for use in clinical treatment of corneal injury. STATEMENT OF SIGNIFICANCE: Here we systematically investigate the self-assembly behavior and chemical stability of designed peptide amphiphiles (Nap-FPHRSN, Nap-FFPHSRN and Nap-FFFPHSRN). The introduction of self-assembled motifs (Nap-F, Nap-FF and Nap-FFF) drastically enhances the chemical stability of fibronectin-mimetic peptide (PHSRN). Moreover, topical instillation of Nap-FFPHSRN hydrogel once daily, exhibits a better in vivo effect than PHSRN and the same in vivo effect as fibronectin, both of which are instilled three times daily, for promoting full morphological and architectural recovery after corneal re-epithelialization. As a rational design of conjugating bioactive peptides with self-assembled motifs to mimic bioactive proteins, this work may lead to a new approach that improves the in vivo therapeutic effect for treating corneal injury in clinic settings.