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.

A “T.E.S.T.” hydrogel bioadhesive assisted by corneal cross-linking for in situ sutureless corneal repair

“…A rabbit corneal defect model was established with 3.0 mm in diameter and ∼250 μm in depth, which was a deeper corneal defect when compared with most literature reports [ 20 , 36 ]. The precursor solutions of G8F4 and G8F4C3 were dropped into the lesion with the same volume as the defect.…”

“…At last, as reported in previous literature, a variety of sutureless corneal hydrogels have been developed to promote the regeneration of corneal epithelium and stroma, exhibiting excellent repair effects in vivo , such as IonBAH, LC-COMatrix, LiQD Cornea [ 20 , 37 , 40 , 41 ]. Most of them were based on decellularized corneal matrix.…”

“…Currently, two approaches have been practiced in the literature. On one hand, functional groups including aldehyde group [ 19 ], pyrocatechol functional group [ 20 ], etc. can endow hydrogels with tissue adhesion properties, which have been used in corneal hydrogels.…”

Engineering multifunctional adhesive hydrogel patches for biomedical applications

“…This patch can be applied beneath a contact lens and hence does not require any special surgical intervention. An ion-activated, dual-network hydrogel patch was reported by Zhao et al 147 Here, tetraceptides (Gly-Leu-Lys-Dopamine) were added to an alginate backbone to promote intramolecular bonding. Alongside, transglutaminases were used to stabilize the adhesive property of the material.…”

A Versatile Hydrogel with Antibacterial and Sequential Drug-Releasing Capability for the Programmable Healing of Infectious Keratitis

“…With the advancement of tissue engineering technology, hydrogels have emerged as frontrunners for corneal transplantation, which are mainly attributed to the excellent hydrophilicity, transparency, and biocompatibility, as well as the three-dimensional (3D) porous structures that facilitate cellular activities and metabolite transport. − Generally, hydrogels for corneal replacement can be divided into two categories. , The one consists of natural biomaterials or their derivatives that mimic the extracellular matrix (ECM) composition of corneal stroma, such as collagen, gelatin, and hyaluronic acid. − The other is fabricated from decellularized corneal ECM composed of a balanced composition of collagens, glycoproteins, and sulfated glycosaminoglycans (sGAGs) similar to native cornea, which not only acts as tissue engineering scaffolds but also exhibits regenerative effects compared to purified and denatured natural biomaterials. − Although significant achievements have been achieved, a serious drawback of existing hydrogel designs is their focus on regulating only one stage in corneal regeneration, thus ignoring the integral progression through multiple physiological stages. Accordingly, an ideal hydrogel for cornea replacement in severe IK should not only have physical, chemical, and biological properties similar to those of native corneal tissue but also be capable of accelerating wound healing through precise regulation of their multiple stages.…”