Injectable immunoregulatory hydrogels sequentially drive phenotypic polarization of macrophages for infected wound healing
Yuxiang Wang, Chen Zhou, Zhulian Li, Li Gong, Yaping Zou, Xing Li, Peiyang Gu, Jingyi Liu, Lang Bai, Yan Hong, Jie Liang, Xingdong Zhang, Yujiang Fan, Yong Sun
Abstract
Regulating macrophage phenotypes to reconcile the conflict between bacterial suppression and tissue regeneration is ideal for treating infectious skin wounds. Here, an injectable immunoregulatory hydrogel (SrmE20) that sequentially drives macrophage phenotypic polarization (M0 to M1, then to M2) was constructed by integrating anti-inflammatory components and proinflammatory solvents. In vitro experiments demonstrated that the proinflammatory solvent ethanol stabilized the hydrogel structure, maintained the phenolic hydroxyl group activity, and achieved macrophages' proinflammatory transition (M0 to M1) to enhance antibacterial effects. With ethanol depletion, the hydrogel's cations and phenolic hydroxyl groups synergistically regulated macrophages' anti-inflammatory transition (M1 to M2) to initiate regeneration. In the anti-contraction full-thickness wound model with infection, this hydrogel effectively eliminated bacteria and even achieved anti-inflammatory M2 macrophage accumulation at three days post-surgery, accelerated angiogenesis and collagen deposition. By sequentially driving macrophage phenotypic polarization, this injectable immunoregulatory hydrogel will bring new guidance for the care and treatment of infected wounds. An injectable immunoregulatory hydrogel by integrating anti-inflammatory components (CS-G and SF-D) and proinflammatory solvents (EtOH) has been sequentially drove macrophage phenotypic polarization (M0 to M1, then to M2) to achieved macrophages’ proinflammatory transition (M0 to M1) for enhancing antibacterial effects and anti-inflammatory transition (M1 to M2) for initiating regeneration in infected wounds. • Ethanol balanced the phenolic hydroxyl groups and the oxidative crosslinking in hydrogel. • Hydrogel sequentially drove phenotypic polarization of macrophages. • Hydrogel effectively removed colonized bacteria on the surface and inside of the wound. • Hydrogel enhanced vascularization and matrix structural restoration of regenerated skin.