Macrophages are innate immune cells that play important roles in wound healing. Particularly, M1 macrophages are considered pro‐inflammatory and promote initial phases of inflammation. Long-term exposure to inflammatory stimuli causes an increase in M1 macrophages, which contributes to chronic inflammation. Activated M1 macrophages have been shown to upregulate integrin α2β1 expression. To interfere with α2β1 binding, we designed a biofunctional hydrogel utilizing a collagen I-derived peptide, DGEA (Asp-Gly-Glu-Ala). We hypothesize that M1 macrophage activation can be reduced in the presence of DGEA. Effects of DGEA on M1 macrophages were studied via soluble delivery and immobilization within poly(ethylene glycol) (PEG) hydrogels. We demonstrate that M1 macrophage activation is reduced both via soluble delivery of DGEA in 2D and via immobilized DGEA in a 3D PEG-DGEA hydrogel. This novel biomaterial can manipulate inflammatory macrophage activation and can be applied to prevent chronic inflammatory conditions via macrophage manipulation. Graphical abstract

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Macrophages modulate the wound healing cascade by adopting different phenotypes such as pro‐inflammatory (M1) or pro‐wound healing (M2). To reduce M1 activation, the JAK/STAT pathway can be targeted by using suppressors of cytokine signaling (SOCS1) proteins. Recently a peptide mimicking the kinase inhibitory region (KIR) of SOCS1 has been utilized to manipulate the adaptive immune response. However, the utilization of SOCS1‐KIR to reduce pro‐inflammatory phenotype in macrophages is yet to be investigated in a biomaterial formulation. This study introduces a PEGDA hydrogel platform to investigate SOCS1‐KIR as a macrophage phenotype manipulating peptide. Immunocytochemistry, cytokine secretion assays, and gene expression analysis for pro‐inflammatory macrophage markers in 2D and 3D experiments demonstrate a reduction in M1 activation due to SOCS1‐KIR treatment. The retention of SOCS1‐KIR in the hydrogel through release assays and diffusion tests is demonstrated. The swelling ratio of the hydrogel also remains unaffected with the entrapment of SOCS1‐KIR. This study elucidates how SOCS1‐KIR peptide in PEGDA hydrogels can be utilized as an effective therapeutic for macrophage manipulation.