Macrophages play a pivotal role in wound healing and
tissue regeneration,
as they are rapidly recruited to the site of injury or implanted foreign
material. Depending on their interaction with the material, macrophages
can develop different phenotypes, with the M1 pro-inflammatory and
M2 pro-regenerative phenotypes being highly involved in tissue regeneration.
M2 macrophages mitigate inflammation and promote tissue regeneration
and extracellular matrix remodeling. In this study, we engineered
a gelatin-heparin-methacrylate (GelMA-HepMA) hydrogel that gradually
releases interleukin-4 (IL-4), a cytokine that modulates macrophages
to adopt the M2 phenotype. Methacrylation of heparin improved the
retention of both heparin and IL-4 within the hydrogel. The GelMA-HepMA
hydrogel and IL-4 synergistically downregulated M1 gene expression
and upregulated M2 gene expression in macrophages within 48 h of in vitro cell culture. However, the M2-like macrophage phenotype
induced by the GelMA-HepMA-IL-4 hydrogel did not necessarily further
improve endothelial cell proliferation and migration in vitro.