Calcium, Cobalt, Strontium, and Cerium-Based Binary Silicate Bioactive Nanoglasses: Rational Comparison in Bioactive Properties for Optimizing Tissue Repair Applications

Abstract Silicate bioactive glass nanoparticles (SBGNs) are promising for tissue repair, but multi-metals doped systems often suffer from compositional complexity, undefined ion-function relationships, and insufficient mechanistic validation. Herein, we established a compositionally simplified binary platform and synthesized four single-ion doped SBGNs (MBGNs: BCa, BCo, BSr, BCe) incorporating representative alkaline-earth, transition, and rare-earth elements. Their tissue repair-relevant bioactivities were systematically compared under unified synthesis and evaluation conditions. All MBGNs exhibited good cytocompatibility but displayed distinct, element-dependent bioactivity profiles. BCa enhanced baseline bioactivity by promoting apatite nucleation in simulated body fluid. BSr showed the strongest anti-inflammatory activity, reducing Il6 and Il1β expression by over 50% and facilitating M2-like macrophage polarization. BCe showed pronounced antioxidant activity, degrading 81.6% of H2O2 and eliminating 90% of intracellular ROS via CeO2-mediated redox cycling. BCo potently promoted angiogenesis, upregulating VEGF and CD31 expression by up to 2.3- and 1.8-fold, and enhancing cell migration and tubular formation. In acute and bacterial infected full-thickness wound models, BSr and BCe accelerated wound closure by 20-40% versus undoped BSi and 3M dressings and more effectively restored vasculature and hair follicles, with BSr exhibiting the greatest healing efficacy. Dose-optimized BCo enhanced hair-follicle regeneration by 123% but was limited by a narrow biosafety window, whereas BCa reduced epidermal thickness by 38% while otherwise resembling BSi. Overall, these data delineate a clear hierarchy of tissue-repair efficacy (BSr > BCe > BCo > BCa ≈ BSi) and show that compositional simplification enables ion-guided design and functional tuning of SBGNs, providing a concise framework for developing simpler yet more potent biomaterials for tissue repair.