Assembly of bioinspired multifunctional microspheres for enhanced alveolar bone regeneration

Regeneration of the alveolar bone remains a major clinical challenge due to the complex oral microenvironment and the need for coordinated restoration of multiple tissue types. To overcome these hurdles, biomaterials designed for periodontal regeneration must meet a rigorous set of criteria, including excellent injectability, mechanical stability, selective cell repopulation, and strong osteoinductive capacity. In this study, we developed a bioinspired, multifunctional microsphere system that fulfills these requirements. The system is injectable, mechanically robust, selectively binds bone marrow-derived stem cells (BMSCs), and exhibits potent osteoinductivity. These multifunctional properties were achieved by UV-assembling nanofibrous hollow microspheres (NFH-MS), conjugating the BMSC-specific E7 peptide to the nanofibrous shell, and encapsulating a bone-forming peptide (BFP) within the hollow core. UV-assembly enhanced the scaffold's mechanical integrity, generated interconnected macropores to support cell infiltration, and promoted intercellular communication. Notably, it significantly upregulated Connexin 43 and N-cadherin-mediated junctions, further facilitating cellular interactions. In synergy with E7 and BFP, the UV-assembled NFH-MS scaffold markedly improved BMSC adhesion, osteogenic differentiation, and biomineralization. This bioinspired multifunctional NFH-MS platform demonstrated superior alveolar bone regeneration in a rat fenestration defect model, offering a promising and minimally invasive strategy for periodontal tissue engineering. • Injectable nanofibrous microsphere-based 3D scaffolds are UV-assembled in situ in defect sites. • Interconnected macropores and high scaffold modulus accelerate 3D cell infiltration and multicellular communication. • The assembled 3D scaffold promotes CX43/N-cadherin coupling and p-STAT3/RUNX2 signaling. • A synergistic microenvironment within the scaffold promotes periodontal tissue regeneration.