Modulation of macrophages by bioactive glass/sodium alginate hydrogel is crucial in skin regeneration enhancement

Inflammatory response is a critical stage in typical wound healing. Although studies have reported that some bioactive materials can modulate the polarization of macrophages to benefit tissue regeneration, the roles of the inflammatory responses, especially the crucial roles of macrophages, in tissue regeneration stimulated by biomaterials remains unclear. Bioactive glass (BG) and hydrogel containing BG have been reported to be able to promote both hard and soft tissue regeneration. However, the critical roles of macrophages in tissue regeneration enhanced by BG have not been fully elucidated. In this study, the effects of BG/sodium alginate (SA) hydrogel (BG/SA hydrogel) on the behaviors of macrophages as well as on the interactions between macrophages and repairing cells were investigated. In addition, macrophage-depleted mice were used to investigate the necessity of macrophages in the regeneration of full-thickness skin wounds treated with BG/SA hydrogel. Our results indicated that BG/SA hydrogel could polarize macrophages towards M2 phenotype in vitro and in vivo and upregulate the expression of anti-inflammatory genes. In addition, the M2 polarized macrophages could further recruit fibroblasts and endothelial cells as well as enhance the extracellular matrix (ECM) synthesis of fibroblasts and vascularization of endothelial cells in vitro and in vivo. Depletion of macrophages in the wound sites impeded the recruitment of repairing cells and reduced the formation of blood vessels and ECM, slowing down skin regeneration. These results provide an insight into the biomaterial-immune system interactions and demonstrate that modulation of macrophages by BG/SA hydrogel in the inflammatory response is crucial in skin regeneration enhanced by the hydrogel.