Chitosan-based hydrogels loaded with repaglinide and difluorinated curcumin: impact on structural integrity, drug release, and antibacterial activity.

Diabetic foot ulcers (DFUs) are chronic, hard-to-heal wounds requiring dressings that can address infection, oxidative stress, and impaired tissue regeneration simultaneously. This study aimed to develop chitosan-based thermoresponsive hydrogels co-loaded with repaglinide (Ripa) and difluorinated curcumin (dfCur) and evaluate their physicochemical properties, antibacterial activity, and cytocompatibility. Hydrogels were synthesized using chitosan and β-glycerophosphate, loaded with Ripa (3% w/v), dfCur (1% w/v), or both. Morphology, chemistry, swelling, porosity, degradation, and drug release were characterized using FESEM, ATR-FTIR, gravimetric methods, and UV-Vis spectrophotometry. Cytocompatibility was assessed via MTT assay with NIH3T3 fibroblasts, and antibacterial activity was tested against Staphylococcus aureus and Escherichia coli. Data were analyzed using one-way ANOVA with p < 0.05 considered significant. Dual-drug hydrogels exhibited the highest swelling capacity (~ 115%) and fastest degradation (46-48% mass retained at day 28), with sustained release of both drugs over 7 days. Fibroblast viability was significantly enhanced for dual-drug hydrogels (128.4 ± 3.2%, p < 0.001 vs. control), and antibacterial activity was strongest in dfCur-containing formulations, showing inhibition zones of 21.6 ± 1.4 mm for S. aureus and 19.3 ± 1.2 mm for E. coli. The co-loading of Ripa and dfCur into a thermoresponsive chitosan hydrogel produced a synergistic platform with enhanced biocompatibility, potent antibacterial effects, and controlled drug release. This multifunctional dressing shows promise for advanced DFU management and warrants further in vivo evaluation.