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.