Spatiotemporal Synergistic Effects of Injectable Biomaterials With Two Typical 3D Geometries on Macrophage Modulation for Enhanced Tissue Regeneration

Injectable biomaterials with immunomodulatory functions have become a promising strategy to facilitate tissue regeneration. Material geometry is known to influence macrophage attachment and phenotype, providing opportunities for the rational design of "immune-instructive" topographies to modulate macrophage function. Here, we developed a biomaterial systems consisting of two different "immune-instructives" 3D geometries: sphere-shaped microspheres (MSs) and rod-shaped short microfibers (MFs) to modulate macrophage function for tissue regeneration. In the injectable biomaterials, we found that varying ratios of MSs to MFs in the composites significantly influence macrophage recruitment and M2 polarization, with high ratios of MFs potentially inducing scar formation. Through a systematic comparison of the promotive effects on tissue regeneration between MSs and MFs, we discovered that MSs and MFs exhibited a spatiotemporal synergistic effect on immunomodulation for tissue regeneration. Specially, MS rapidly triggered the foreign body reaction after implantation and enhance macrophage infiltration. Subsequently, the recruited macrophages underwent morphological changes upon contact with MFs, activating autophagy and polarizing toward the M2 phenotype, thereby accelerating collagen deposition. The developed immunomodulatory composites provide a promising strategy for engineering injectable biomaterials with immunomodulatory function that demonstrates desirable stimulation for tissue regeneration.