Sr2+ doped HA@PCL scaffold regulating reprogramming of macrophage to enhance osteogenesis and angiogenesis via ameliorating endoplasmic reticulum stress

The induction of angiogenesis and osteogenesis of bone defects still poses a challenge by bioactive materials without any growth factor. Modulating the bone immune microenvironment might be an effective approach to ameliorate the regeneration of vessels and bone. In this study, we construct SrHA@PCL scaffolds and find that Sr 2+ doped HA@PCL scaffolds performed better role of immune modulation to induce the formation of M2-like macrophage and the effect is better as the increasing concentration of Sr 2+ . Besides, the Sr 2+ doped scaffolds performed better effect of angiogenesis and osteogenesis wherever in vitro and in vivo experiments. However, the specific mechanism of how Sr 2+ regulates the polarization of M2-like macrophage is unclear. According to RNA sequencing, we find that the genes of IRE1α, XBP-1 and GRP78, markers of endoplasmic reticulum stress, perform lower expression in Sr 2+ doped scaffolds, but the expression of CaSR is higher. Hence, we speculate and verify that the Sr 2+ can activate CaSR to induce the phosphorylation of p38MAPK, then the IRE1α-XBP-1 signaling pathway is inhibited, finally inhibiting endoplasmic reticulum stress, resulting the polarization of M2-like macrophage to regulate bone immune microenvironment. Collectively, the composite SrHA@PCL scaffolds developed here with role of inhibiting endoplasmic reticulum stress to induce M2-like macrophage polarization may represent a promising implant for expediting in situ angiogenesis and osteogenesis. • A novel Sr 2+ -doped PCL/HA scaffold was fabricated via cryogenic 3D printing. • Sr 2+ regulates immune via inhibiting the IRE1α-XBP1 axis. • Sr2+ enhances osteogenesis and angiogenesis via immune regulation.