PLCL重编程巨噬细胞代谢和线粒体功能促进皮肤伤口愈合研究

Abstract

Aims This study aimed to compare the therapeutic effects and underlying mechanisms of poly-L-lactic acid (PLLA) and poly-L-lactide-co-ε-caprolactone (PLCL) on large-area skin defects. Specifically, we explored how these two materials differentially regulate inflammatory metabolic pathways and mitochondrial function in macrophages to reprogram the immune microenvironment during skin regeneration. Methods PLLA and PLCL were fabricated and characterized, and the biocompatibility was evaluated with CCK8 assay, cell scratch assay, and mouse subcutaneous implantation models. Full-thickness skin defect mouse models with circular and longitudinal wounds were then established and treated with PLLA and PLCL. Flow cytometry and real-time quantitative PCR were applied to assess immunomodulatory effects of these materials on macrophages. Further, immunofluorescence staining, Seahorse analysis, and untargeted metabolomics were used to detect mitochondrial function and metabolic reprogramming of macrophages. Results PLLA and PLCL exhibited good biocompatibility. Compared to PLLA, PLCL significantly accelerated wound closure, enhanced collagen deposition, and reduced inflammatory cell infiltration. PLCL significantly suppressed M1 macrophage polarization and downregulated the expressions of IL-1β and TNF-α, which in turn promoted fibroblast migration and proliferation. PLCL rescued mitochondrial damage and reversed the metabolic shift from oxidative phosphorylation to glycolysis in inflammatory macrophages. Furthermore, untargeted metabolomics analysis revealed that succinate, prostaglandins, and unsaturated fatty acids were clustered in inflammatory macrophages, whereas PLCL reversed these metabolic alterations. Conclusion Collectively, our findings demonstrate that PLCL reprograms macrophage metabolic pathways, ameliorates mitochondrial dysfunction, and attenuates inflammatory responses, recapitulating aspects of immune modulation to support skin regeneration, compared to PLLA.