Naringenin Loaded Hydrogel Supports Wound Repair in a Cell Model of Diabetic Skin

Abstract

Introduction: Diabetic foot ulcers are a major complication of diabetes, driven by inflammation, oxidative stress, and poor vascular function. Naringenin, a citrus flavonoid, addresses these factors but has low solubility and stability. We developed a Na-AMPS hydrogel dressing to enhance its delivery under diabetic-like conditions. Methods: A Na-AMPS hydrogel containing 0.02%(w/w) naringenin was formulated and assessed for rheological and adhesive properties, drug release, and biological activity in HUVEC and HDFa cells. Cytotoxicity (XTT), reactive oxygen species (ROS), mitochondrial membrane potential (TMRM), cytokine levels (IL-6, IL-8, MMP-9, TGF-β), and wound closure (scratch assay) were measured. Results/Discussion: Naringenin modestly reduced the hydrogel elastic modulus (15,791.5 ± 1965 Pa at 30 Hz) without affecting adhesion. Release studies showed rapid drug release from solution but sustained release from hydrogels (17.88 ± 2.61% over 24 h). Under hyperglycaemic and pro-inflammatory conditions, naringenin significantly decreased ROS in HUVECs (41,030.58 ± 2737 to 31,778.74 ± 1822 AU; p < 0.001) and HDFa cells (38,188.13 ± 4593 to 29,950.94 ± 1426 AU; p < 0.05). Naringenin improved mitochondrial membrane potential in both cell types (p < 0.05–0.01) and attenuated pro-inflammatory cytokines. IL-6 decreased in HUVECs (39.40 ± 5.02 to 27.15 ± 3.10 pg/mL; p < 0.01) and HDFa cells (40.05 ± 2.23 to 16.41 ± 1.27 pg/mL; p < 0.0001). In HDFa’s, MMP-9 was reduced (403.43 ± 18.70 to 195.33 ± 11.02 pg/mL; p < 0.0001), while in HUVECs, wound closure was enhanced. Conclusion: Naringenin-loaded Na-AMPS hydrogels demonstrated sustained release, suitable mechanical properties, and significant antioxidant, anti-inflammatory, and wound healing effects. These findings highlight their therapeutic potential for diabetic wounds treatment.