Beeswax-based nanoconstructs enriched dual responsive hydrogel for diabetic foot ulcers in streptozotocin-induced diabetic rats.

Diabetic foot ulcer (DFU) is a complicated pathophysiological process, and there is now no recognized treatment. Hyperglycemia, neuropathy, impaired angiogenesis, reactive oxygen species, and advanced glycation end products construct the distinctive wound environment of diabetic wounds. This study aimed to develop naringenin-ferulic acid beeswax-based nanoconstructs enriched dual-responsive hydrogel (NAR-FA NLC HG) for topical application for DFU. The pH- and temperature-responsive hydrogel was formulated via a chemical cross-linking reaction of carboxymethyl chitosan and poloxamer 407 and loaded with NAR-FA NLC using the swelling-loading method. SEM, FTIR, and XRD observed the morphology and characterization of the prepared hydrogel. The in vitro release study showed controlled release during 48 h. Antibacterial activity significantly inhibits B. subtilis and E. coli compared to NLC and control groups (p < 0.05). Cell line studies show that hydrogel is compatible with HaCaT cells and 92.4 ± 4.9 % of wound contraction after 48 h of scratch wound assay. The wound closure rate with NAR FA NLC HG in STZ-induced diabetic rats reached 93.2 ± 3.4 % by day 15 with significant (p < 0.001) increases in the VEGF level and decreasing ICAM-1 level. Hence, the smart hydrogel established in this study has the potential to serve as a promising topical therapy for DFU with inherent antimicrobial activity components, including beeswax, NAR, and FA.