An osteoimmunomodulatory Ca2+/Zn2+-doped scaffold promotes M2 macrophage polarization via the src-mediated chemoking signaling pathway to enhance osteoinduction

Abstract

Bone defects disrupt physiological functions of various cells including immune cells, osteoblasts, and osteoclasts. Restoring the coordinative effects of cells between osteogenesis and the immune microenvironment is essential and challenging for bone regeneration. Here, we developed an osteoimmunomodulatory Ca2+/Zn2+ doped polycaprolactone electrospinning scaffold to enhance osteoinduction by modulating the polarization of macrophages. To endow nucleation sites for Ca2+ deposition, epitaxial crystallization was conducted to yield the conformal nano-lamellae on the scaffold surface. The Zn2+ was then embedded into the mineralized scaffold via an ion exchange method. Such an approach remarkably improved the deposition amount of Ca2+ and Zn2+, showing a highly sustained iron release. This hybrid scaffold was capable to regulate the M2-type polarization of macrophages, forming an immune-osteogenic microenvironment. As a result, the osteogenic differentiation of rat bone marrow mesenchymal stem cells (rBMSCs) was enhanced via activating the Src-mediated chemoking signaling pathway as verified by gene sequencing, western blotting, and polymerase chain reaction results. In vivo evaluation further demonstrated that the hybrid scaffold remarkably promoted the bone regeneration in a critical-sized rat cranial defect. Compared to the control group, the bone volume/total volume (BV/TV) of the hybrid scaffold group was increased by 2.6 times. This work provides a feasible strategy for fabricating bone repair substitutes that regulate the bone immune microenvironment and coordinate multicellular functions.