Jun Wang,1,* Yanxia Lin,1,2,* Huijing Fan,1 Jianfeng Cui,1 Yuanxiang Wang,1 Zilan Wang1 

1The Department of Rehabilitation Medicine, Shenzhen Qianhai Shekou Free Trade Zone Hospital, Shenzhen, 518067, People’s Republic of China; 2Guangzhou Myers Biotechnology Co., Ltd, Guangzhou, 510660, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Yanxia Lin, The Department of Rehabilitation Medicine, Shenzhen Qianhai Shekou Free Trade Zone Hospital, No. 128, 7th Road, Shekou Industrial Zone, Shenzhen, Guangdong, 518067, People’s Republic of China, Email 540147960@qq.com Jun Wang, The Department of Rehabilitation Medicine, Shenzhen Qianhai Shekou Free Trade Zone Hospital, No. 128, 7th Road, Shekou Industrial Zone, Shenzhen, Guangdong, 518067, People’s Republic of China, Email wangjun0743@163.com

Background: Bacterial infections in wounds have emerged as an increasingly significant healthcare concern. The toxins secreted by bacteria cause persistent inflammation and excessive oxidative stress, resulting in serious tissue damage and ultimately delay wound healing.
Methods: Herein, a ROS/pH dual-responsive hydrogel dressing loaded with amphiphilic structured nano micelles was developed for efficiently promoting infected wound healing. First, chitosan-grafted α-lipoic acid (CSLA) and curcumin (Cur) formed stable amphiphilic nano micelles (CSLA@Cur) through ultrasonic self-assembly. Subsequently, CSLA@Cur was incorporated into a hydrogel formed from 4-carboxyphenylboronic acid-modified gelatin methacrylate (GelMA-CPBA) and oxidized chondroitin sulfate (OCS) via Schiff base formation, boronate ester bonding, and free radical polymerization to obtain GC/OCS-CL@Cur hydrogel dressing. The mechanical properties, antimicrobial, antioxidant, and ROS/pH responsiveness of GC/OCS-CL@Cur were evaluated. Cellular assays were performed to investigate the biocompatibility of GC/OCS-CL@Cur and its role in promoting angiogenesis, scavenging intracellular ROS and regulating macrophage polarization. A full-thickness skin defect rat model with bacterial infection was established to investigate the ability of GC/OCS-CL@Cur to enhance wound repair in vivo.
Results: The unique cross-linked structure of GC/OCS-CL@Cur significantly improves the mechanical properties of hydrogels. Importantly, GC/OCS-CL@Cur exhibited sensitive ROS/pH dual responsiveness, which enabled the controlled release of CSLA@Cur and efficient delivery of Cur. Moreover, GC/OCS-CL@Cur possessed excellent antimicrobial activity and efficient ROS scavenging ability. In vitro cellular assays demonstrated that GC/OCS-CL@Cur could effectively scavenge intracellular ROS (up to 90% scavenging ratio), promote macrophage polarization to M2 phenotype, and enhance angiogenesis. In vivo experiments showed that GC/OCS-CL@Cur significantly regulated the expression level of inflammatory cytokines, and healed more than 95% of wounds in 14 days, showing excellent wound healing ability.
Conclusion: These results demonstrate the successful development of a dual-responsive (ROS/pH) hydrogel dressing with integrated antibacterial, antioxidant, and anti-inflammatory properties, showcasing significant potential for treating infected wounds.

Keywords: nano micelles, microenvironment response, antioxidant, anti-inflammatory, infected wound