A hydrogel crosslinked with mixed-valence copper nanoclusters for diabetic wound healing

Abstract

Chronic diabetic wounds affect a significant number of individuals and present considerable challenges in clinical treatment. Ideal diabetic wound dressings should possess antibacterial properties, the ability to regulate redox balance, and the capacity to promote tissue regeneration. Herein, we developed an injectable mixed-valence copper nanocluster-crosslinked hydrogel (HS-Cu) through reductive metal-ligand coordination assembly of Cu²⁺ and thiourea-grafted hyaluronic acid (HA-NCSN) to achieve the above-mentioned requirements in one-step. Density functional theory (DFT) calculations indicated that the bioactive mixed-valence copper nanoclusters exhibited enhanced photothermal properties and conductivity, enabling HS-Cu hydrogel to effectively combat bacteria and accelerate tissue regeneration through combined with photothermal therapy (PTT) and electrical stimulation (ES). Notably, the abundant thiourea groups inside the hydrogel acted as reactive oxygen species (ROS) scavengers to regulate the redox balance at the wound site. Additionally, in vivo experiments indicated that HS-Cu hydrogel promoted hemostasis in wounds. Overall, the HS-Cu hydrogel accelerated the three phases of diabetic wound healing: hemostasis, inflammation, and proliferation, with specific mechanisms including rapid hemostasis, bacterial eradication by PTT, scavenging of ROS, and wound healing acceleration through ES. All the results indicated that mixed-valence copper nanocluster-crosslinked hydrogel demonstrated great potential in the treatment of diabetic wounds. STATEMENT OF SIGNIFICANCE: This study developed an injectable hydrogel through metal-ligand coordination assembly, which showed great potential for accelerating diabetic wound repair in clinic. The hydrogel demonstrated superior antioxidant capacity, photothermal properties, and conductivity due to the internal bioactive mixed-valence copper nanoclusters formed through the reductive coordination between Cu²⁺ ions and thiourea groups. By combining photothermal therapy (PTT) and electrical stimulation (ES), this hydrogel effectively addressed critical challenges in diabetic wound healing, including bacterial infection inhibition, oxidative stress reduction, and tissue regeneration acceleration, thereby significantly enhancing wound healing. The study also provides perspectives for the design and clinical application of ion chelation based functional biomaterials.

Keywords: Diabetic wound; Electrical stimulation; Hydrogel dressing; Mixed-valence copper nanocluster; Photothermal therapy; Ros-scavenging.