Engineering Neutrophil Immunomodulatory Hydrogels Promoted Angiogenesis

Timely restoration of blood supply following ischemia is critical to rescue damaged tissue. However, clinical efficacy is hampered by the inflammatory response after ischemia. Whether inflammation fine tunes the angiogenesis and the function of blood vessels via the heterogeneity of neutrophils remain poorly understood. Herein, the objective of this work is to incorporate the growth factors secreted by neutrophils into a porous gelatin methacrylate (GelMA) hydrogel, which subsequently is used as a novel regenerative scaffold with defined architecture for ischemia. We demonstrate that anti-inflammatory neutrophils (N₂-polarized neutrophils) play an important role in promoting the migration of human umbilical vein endothelial cells (HUVECs) and formation of capillary-like networks in vitro. More importantly, vascular anastomosis can be achieved by modulating the neutrophils to N₂ phenotype. In addition, N₂-polarized composite hydrogel scaffolds can regulate inflammation, maintain the survival of exogenous cells, and promote angiogenesis in vivo. Notably, the composite hydrogel scaffolds promote neovascularization during exogenous introduction of endothelial cells by anastomosis. Taken together, this study highlights N₂-polarized neutrophils composite hydrogels can achieve vascularization rapidly by regulating inflammation and promoting vascular anastomosis. This work lays the foundation for research into the treatment of ischemia and may inspire further research into novel treatment options.