Reprogramming Wound Healing: GAG-Based Bioactive Scaffold Drives Pro-Regenerative Cellular Cross-Talk

The study investigates the use of a glycosaaminoglycan (GAG)-based bioactive scaffold composed of chitosan, chondroitin sulfate, and hyaluronic acid (CH-(CS-HA)) to enhance wound healing by modulating fibroblast-macrophage cross-talk. In vitro studies showed that the scaffold promoted significant phenotypic changes, including increased α-SMA and fibronectin expression in fibroblasts and M2 polarization in macrophages, indicating antifibrotic ECM remodeling and an anti-inflammatory phenotype. In a rat wound model, the scaffold achieved 91% wound closure by day 17, compared to 63% in controls, and supported early hair follicle regeneration. These results suggest that CH-(CS-HA) effectively orchestrates immune-stromal interactions to promote inflammation resolution, balanced ECM remodeling, and functional tissue regeneration.