Alginate-based hydrogels for sustained antimicrobial peptide delivery to enhance wound healing in diabetes

Diabetic foot ulcers (DFUs) are the leading cause of non-traumatic amputations, and its efficient management remains a clinical challenge, particularly in treating severe infections. Current treatment strategies often fail to address the multifactorial nature of DFUs. Combining antimicrobial peptides (AMPs) with the intrinsic properties of alginate hydrogels offers a promising solution for handling the complex etiology of DFUs. In this study, we designed alginate-based hydrogels for delivery of AMPs, namely the AMPs human β-defensin 2 (hBD-2) and PP4-3.1, to enhance diabetic wound healing. The hydrogels exhibited high storage modulus, low swelling ratio, and a nanometric porous structure, enabling sustained AMP release for over three days. Rheology analyses further confirmed their stability across pH 6 to 8. In vitro, hBD-2 hydrogels displayed excellent biocompatibility and promoted better cell migration than PP4-3.1 hydrogels, for up to 48 h. Thus, hBD-2 hydrogels were used in a streptozotocin-induced diabetic mouse model of wound healing. The hBD-2 hydrogels significantly accelerated wound closure and improved wound maturation, enhancing re-epithelialization and tissue remodeling, compared to controls. Furthermore, hBD-2 hydrogels reduced the microbial load from the wounds and attenuated inflammation at the wound site by decreasing the number of M1-like macrophages, M1/M2 ratio, and CD3⁺ cells. Lastly, a pro-reparative environment was promoted through a decrease in reactive oxygen species (ROS) levels, and an increase in neovascularization and collagen deposition. Altogether, these findings suggest that hBD-2 alginate hydrogels hold promise as a novel therapeutic option for managing DFUs, offering a combined anti-inflammatory, ROS-scavenging and tissue-regenerative effect.