Controlled Release of Cold Atmospheric Plasma by Gelatin Scaffold Enhances Wound Healing via Macrophage Modulation

Cold atmospheric plasma (CAP) has emerged as a promising therapeutic tool for wound healing and tissue regeneration. However, the clinical application of CAP faces challenges, particularly the need for repeated treatments to maintain therapeutic efficacy and the difficulty in controlling the release of reactive oxygen and nitrogen species (ROS/RNS), which can cause tissue damage at high concentrations. In this study, we developed a controlled-release system by integrating CAP with a skin bionics gelatin scaffold (CAP-GS), enabling the sustained, localized release of CAP without the need for repeated applications. Our results demonstrate that CAP-GS significantly accelerates skin wound healing by modulating the immune microenvironment and reducing inflammation. The gelatin scaffold effectively regulates the release of ROS/RNS, maintaining levels conducive to M2 macrophage polarization and minimizing oxidative damage. Furthermore, CAP-GS enhances macrophage metabolism, including oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO), metabolic pathways characteristic of M2 polarization. The increased secretion of growth factors by CAP-GS-treated macrophages contributes to cell proliferation, migration, and tissue regeneration. These findings highlight CAP-GS as a promising, clinically applicable system for wound healing and tissue repair, overcoming the limitations of traditional CAP treatments and offering an approach to regenerative medicine.