Injectable Self-Healing Oxidized Hyaluronic Acid Hydrogel Remodels the Healing Microenvironment for Efficient Wound Closure.

Abstract

In clinical wound closure, traditional sutures are cumbersome and prone to causing secondary injury, while existing biological adhesives struggle to balance strong adhesion, high safety, and good adaptability within the complex and variable wound microenvironment. Excessive reactive oxygen species (ROS) and persistent inflammation at the wound site are key factors causing imbalance in the healing microenvironment and delaying repair. To address this, this study designed an in-situ injectable self-healing hydrogel adhesive aimed at actively remodeling the wound healing microenvironment. Constructed through dynamic borate ester crosslinking between phenylboronic acid-modified, oxidized-hyaluronic acid and poly(vinyl alcohol) (OHA-PBA/PVA), this material not only exhibits rapid gelation, strong tissue adhesion, and self-healing capabilities to stabilize the physical microenvironment, but also incorporates phenylboronic acid groups that scavenge ROS, thereby alleviating the oxidative stress microenvironment. In a rat full-thickness skin incision model, this hydrogel achieved wound closure comparable to sutures. Mechanistically, it alleviates wound oxidative stress, modulates the immune microenvironment (reducing TNF-α and promoting M2 macrophage polarization), and guides the regenerative microenvironment (promoting organized collagen deposition). This study provides an alternative strategy for actively modulating multiple healing microenvironments through material design to promote high-quality wound repair. STATEMENT OF SIGNIFICANCE: Current clinical wound closure materials face a fundamental challenge: achieving strong tissue adhesion while actively regulating the complex, multi-dimensional microenvironment that governs wound healing. This study addresses this gap by developing an injectable, self-healing hydrogel adhesive (OHA-PBA/PVA) that orchestrates wound repair through three aspects of microenvironment regulation. The hydrogel acts through three mechanisms: (I) stabilizing the physical microenvironment via rapid gelation and strong adhesion; (II) purifying the biochemical microenvironment by scavenging ROS; and (III) modulating the immune microenvironment to promote M2 polarization, reduce TNF‑α, and enhance collagen deposition and angiogenesis. This multidimensional approach achieves wound closure comparable to sutures with reduced inflammation, offering a promising strategy for high-quality tissue regeneration.