Mechanically adaptive injectable hydrogels with dual-role oxidized cyclodextrin for pH-responsive drug delivery in chronic infected wound healing

Abstract

The management of chronically infected wounds remains challenging due to persistent bacterial colonization and unresolved inflammation. To address this, an injectable double-network hydrogel was developed to facilitate wound healing. Formation of the hydrogel occurred via a reversible Schiff base reaction between oxidized β-cyclodextrin (OCD) and α-lipoic acid–modified chitosan (LACS), imparting high injectability for thorough coverage of irregular wound sites. Notably, OCD played a dual role: encapsulating hydrophobic resveratrol via its hydrophobic inner cavity for pH-responsive release triggered by Schiff base bond cleavage, while also serving as a crosslinker by providing aldehyde groups for primary network formation. Upon UV exposure, a secondary disulfide bond network formed, enhancing mechanical stability and adaptability post-injection. The mechanical properties were tunable by adjusting OCD content to modulate Schiff base network density. In vitro, LCOD exhibited strong antibacterial, antioxidant, and biocompatible properties. In vivo results in a murine infected wound model showed that resveratrol-loaded LCOD promoted healing by reducing inflammation, enhancing collagen deposition, stimulating angiogenesis, and accelerating re-epithelialization. The multifunctional hydrogel combines ease of injection, tunable mechanical properties, and pH-triggered drug release, representing a promising therapeutic approach for managing chronic wounds.