An immune-adaptive 3D-printed scaffold promotes endogenous osteogenesis by engineered macrophage capture traps.

Abstract

Macrophages serve as central units in immune regulation, with their polarization influencing distinct stages of the bone healing process. Here, we report an immune-adaptive 3D-printed scaffold that integrates engineered macrophage capture traps, an HA network-mediated macrophage anchoring interface, onto a poly(lactic-co-glycolic acid)/hydroxyapatite microsphere composite framework. These traps selectively enrich macrophages via CD44 receptor-mediated recognition and dynamically guide their polarization. Intramuscular implantation experiments demonstrated a sequential shift in polarization of scaffold-enriched macrophages from M1 at 3 days to M2 at 7 days. Omics analysis of the short-term rabbit calvarial defect model revealed that HA released from this scaffold is phagocytosed by macrophages, gradually enters lysosomes, and activates antioxidant pathways, including negative regulator of reactive oxygen species (NRROS), sestrin 2 (SESN2), and glucose-6-phosphate dehydrogenase (G6PD), thereby reducing intracellular levels of reactive oxygen and nitrogen species. These processes collectively drive the shift in macrophage polarization from M1 to M2, and accelerate angiogenesis and bone matrix deposition. These findings provide new insights for the design of immunomodulatory bone regenerative materials.