Microporous annealed particle scaffolds avoid foreign body response by down regulating complement-fibroblast-macrophage signaling loop

SUMMARY Biomaterial implantation can trigger a foreign body response (FBR) that impedes tissue-implant integration. To investigate how implant porosity influences this response, we compared the immune response to subcutaneous implants of microporous annealed particle (MAP) scaffolds and nanoporous hydrogels using mass cytometry, single-cell RNA sequencing, and multiplex cytokine assays. MAP scaffolds promoted vascularization and tissue integration, marked by increased endothelial and regulatory T cells, and reduced proinflammatory immune cells and cytokines. In contrast, nanoporous hydrogels demonstrated enrichment of basophils, natural killer cells, and macrophage populations associated with fibrosis. Transcriptomic and proteomic analyses revealed that MAP scaffolds suppressed activation of the complement-fibroblast-macrophage signaling loop, particularly the C5a signaling crosstalk pathway. This was confirmed using C5-deficient mice, where complement-driven cytokine production was significantly reduced only in nanoporous implants. These findings demonstrate that scaffold porosity modulates immune and complement responses, identifying a key mechanism by which MAP scaffolds reduce FBR and improve biomaterial integration.