Alginate-based hydrogels loaded with human β-defensin-2 promote healing of MRSA-infected wounds in a diabetic model: a preclinical proof-of-concept study.

Diabetic foot infections (DFIs), resulting from microbial colonization and proliferation in non-healing diabetic wounds, are among the most serious and common complications in patients with diabetes. As antimicrobial resistance continues to rise, the clinical management of DFI persists as a major challenge, emphasizing the need for novel therapeutic approaches. In this study, we aimed to combine the dual antimicrobial and pro-healing properties of antimicrobial peptides (AMPs) with the intrinsic characteristics of the alginate polymer as an encouraging strategy to address the multifactorial etiology of chronic wounds. Using ionic cross-linking with calcium sulfate, we developed alginate-based hydrogels with a nanometric porous structure for the sustained delivery of the AMP human β-defensin-2 (hBD-2) to promote wound healing in conditions of diabetes. The effects of the produced hBD-2 hydrogels were assessed in a streptozotocin-induced diabetic mouse model with wounds infected by methicillin-resistant Staphylococcus aureus (MRSA). Overall, hBD-2 hydrogels improved wound closure, by promoting re-epithelialization and tissue remodeling, ultimately restoring normal epidermal thickness. Moreover, hBD-2 hydrogels attenuated the wound MRSA load, while decreasing the inflammatory state. Lastly, hBD-2 hydrogels increased the number of Ki67 cells and CD31 cells, indicating improved cellular proliferation and angiogenesis, ultimately supporting the evidence of an early progression toward the final phases of wound healing. Despite the difficult MRSA-infected wound conditions, the findings underline the potential of hBD-2 hydrogels as a promising treatment for chronic wounds such as DFUs, owing to antimicrobial, anti-inflammatory, and tissue-regenerative properties.