Copper ion-chelated supramolecular polymer/hyaluronic acid hydrogel promotes wound healing in diabetes

Hydrogel wound dressings have shown promising potential for treating diabetic wounds, but their efficacy is limited by the complex wound microenvironment and the lack of integrated treatment strategies. In this study, a series of multifunctional hydrogel adhesives with anti-inflammatory, antibacterial, and angiogenesis-promoting properties was synthesized using free radical polymerization. The raw materials included methacrylated hyaluronic acid (HAMA), 3-(bis(pyridin-2-ylmethyl)amino)propyl methacrylate (DPAMA), and N-[tris(hydroxymethyl)methyl]acrylamide (THMA). Cu²⁺ ions were incorporated into the hydrogels through their strong affinity for dipicolylamine and carboxylic acid groups. Adhesion strength of the hydrogel ranged from 8 to 14 kPa, and tensile strength was 14.9 kPa. The inhibition zones against Escherichia coli and Staphylococcus aureus were 16.16 mm and 14.5 mm, respectively. ELISA results showed that the HTDC2 hydrogel (containing 3 mg/mL Cu²⁺) significantly reduced TNF-α and IL-1β expression. The HTDC2 hydrogel significantly promoted full-thickness skin wound healing in diabetic mice, achieving over 85 % closure by day 14. Western blot data showed that TNF-α and IL-1β protein levels in HTDC2 group decreased 3.5-fold on day 10 compared with control. Angiogenesis, immunofluorescence, and immunohistochemistry results confirmed that HTDC2 promoted angiogenesis and reduced pro-inflammatory factor expression. In summary, the proposed supramolecular polymer/hyaluronic acid hydrogel is promising as a diabetic wound dressing.