Injectable hydrogel microsphere orchestrates immune regulation and bone regeneration via sustained release of calcitriol.

Repairing bone defects in inflammatory conditions remains a significant clinical challenge. An ideal scaffold material for such situations should enable minimally invasive implantation and integrate capabilities for immunomodulation, anti-infection therapy, and enhanced bone regeneration. In this study, we developed injectable calcitriol@polydopamine@gelatin methacryloyl hydrogel microspheres (CAL@PDA@GMs) using microfluidic technology. This system facilitates the sustained release of calcitriol, which features excellent biocompatibility and biodegradability, promotes osteogenesis, scavenges excessive reactive oxygen species (ROS), and induces the polarization of macrophages from the M1 to M2 phenotype, thereby mitigating lipopolysaccharide (LPS)-induced inflammation. These mechanisms work synergistically to create an optimal immune microenvironment for bone regeneration in inflammatory conditions. RNA sequencing (RNA-Seq) analyses revealed that immunomodulation is achieved by regulating macrophage phenotypes, inhibiting the nuclear transcription factor-kappa B (NF-κB) and ROS signaling pathways, and reducing the secretion of pro-inflammatory cytokines. This study proposes a novel method to enhance tissue regeneration by remediating the damaged tissue microenvironment and presents a potential clinical therapeutic strategy for large-scale bone injuries.