Mesenchymal stem cell‐inspired microgel scaffolds to control macrophage polarization

There is a desire in regenerative medicine to create biofunctional materials that can control and direct cell function in a precise manner. One particular stem cell of interest, human mesenchymal stem cells (hMSCs), can function as regulators of the immunogenic response and aid in tissue regeneration and wound repair. Here, a porous hydrogel scaffold assembled from microgel subunits was used to recapitulate part of this immunomodulatory behavior. The scaffolds were used to culture a macrophage cell line, while cytokines were delivered exogenously to polarize the macrophages to either a pro‐inflammatory (M1) or alternatively activated (M2a) phenotypes. Using a cytokine array, interleukin 10 (IL‐10) was identified as one key anti‐inflammatory factor secreted by hMSCs in pro‐inflammatory conditions; it was elevated (125 ± 25 pg/ml) in pro‐inflammatory conditions compared to standard medium (6 ± 10 pg/ml). The ability of hMSC laden scaffolds to reverse the M1 phenotype was then examined, even in the presence of exogenous pro‐inflammatory cytokines. Co‐culture of M1 and M2 macrophages with hMSCs reduced the secretion of TNFα, a pro‐inflammatory cytokine even in the presence of pro‐inflammatory stimulatory factors. Next, IL‐10 was supplemented in the medium or tethered directly to the microgel subunits; both methods limited the secretion of pro‐inflammatory cytokines of encapsulated macrophages even in pro‐inflammatory conditions. Cumulatively, these results reveal the potential of biofunctional microgel‐based scaffolds as acellular therapies to present anti‐inflammatory cytokines and control the immunogenic cascade.