Injectable and degradable methacrylic acid hydrogel alters macrophage response in skeletal muscle

After severe trauma, skeletal muscle cannot repair itself leading to scar tissue formation and functional impairment. A novel approach to overcome this issue is to alter the fibrotic response in muscle using regenerative biomaterials, such as those containing methacrylic acid (MAA). In the skin, MAA-based materials have been shown to promote wound healing and new vessel formation, through endogenous mechanisms, including macrophage polarization; however, MAA has yet to be studied outside the skin. To study the innate immune response to MAA in skeletal muscle, MAA-poly(ethylene glycol) (MAA-PEG) hydrogels were synthesized with degradation rates of either 2 (fast-degrading) or 7 days (slow-degrading). When injected into the tibialis anterior muscle of mice, both slow- and fast-degrading MAA hydrogels increased the expression of Il-10, Tnfα and M2 macrophage markers (Fizz1 and Arg for slow-and fast-degrading, respectively). Moreover, the slow degrading MAA hydrogel decreased the number of pro-inflammatory MHCII+ macrophages. An unbiased t-distributed stochastic neighbor embedding (tSNE) analysis suggested the involvement of other immune cells beyond just macrophages in the effect of MAA on skeletal muscle. Overall, this study shows that MAA hydrogels bias macrophages towards a pro-regenerative phenotype.