Engineered mesenchymal stem cells-laden chondroitin sulfate hydrogel promotes diabetic wound healing through ROS scavenging and macrophage polarization

The treatment of diabetic wound complications has long been a formidable challenge in the clinic, and a multifunctional biomaterial dressing holds great promise as an ideal approach for promoting diabetic wound healing. In this study, we designed a crosslinked chondroitin sulfate (CS) and polyethylene glycol (PEG) hydrogel (CS gel) as a reservoir via a Michael addition reaction. To further enhance the biological functions, surface-engineered mesenchymal stem cells (MSCs) modified with bilirubin-modified chondroitin sulfate-mediated mixed micellar backpacks possessing ROS scavenging/responsive and CD44-targeting abilities (DCMMs) were incorporated into the hydrogel system. The hydrogel served as a physical carrier, providing a sustained-release platform that ensured the long-term presence and controlled delivery of MSCs-tethered micellar backpacks at the wound site. In vitro experiments revealed the remarkable capacity of the hydrogel for ROS scavenging and regulating macrophage polarization. In vivo investigations in diabetic mouse models further confirmed the therapeutic potential, revealing a significant acceleration of wound closure, attenuation of inflammation, and augmentation of angiogenesis. Overall, this innovative hydrogel system that encapsulates surface-engineered mesenchymal stem cells (MSCs-DCMMs) represents a promising remedy and a framework for stem-cell-based therapeutic systems to treat diabetic wounds.