Immunomodulatory Microgels Support Proregenerative Macrophage Activation and Attenuate Fibroblast Collagen Synthesis

Scars composed of fibrous connective tissues are natural consequences of injury upon incisional wound healing in soft tissues. Hydrogels that feature a sustained presentation of immunomodulatory cytokines are known to modulate wound healing. However, existing immunomodulatory hydrogels lack interconnected micropores to promote cell ingrowth. Other limitations include invasive delivery procedures and harsh synthesis conditions that are incompatible with drug molecules. Here, hybrid nanocomposite microgels containing interleukin‐10 (IL‐10) are reported to modulate tissue macrophage phenotype during wound healing. The intercalation of laponite nanoparticles in the polymer network yields microgels with tissue‐mimetic elasticity (Young's modulus in the range of 2–6 kPa) and allows the sustained release of IL‐10 to promote the differentiation of macrophages toward proregenerative phenotypes. The porous interstitial spaces between microgels promote fibroblast proliferation and fast trafficking (an average speed of ≈14.4 µm h−1). The incorporation of hyaluronic acid further enhances macrophage infiltration. The coculture of macrophages and fibroblasts treated with transforming growth factor‐beta 1 resulted in a twofold reduction in collagen‐I production for microgels releasing IL‐10 compared to the IL‐10 free group. The new microgels show potential toward regenerative healing by harnessing the antifibrotic behavior of host macrophages. This study presents a microgel‐based immunotherapeutic system for attenuation of fibrosis. The microporous structure promotes fibroblast trafficking and proliferation. The incorporation of Laponite enables sustained release of Il‐10, promoting the differentiation of macrophages toward prohealing phenotypes and reducing collagen‐I production by cocultured fibroblasts. This work advances biomaterial‐based immunotherapy and presents a promising cell‐instructive strategy in wound healing applications.