3D Printed Zinc Oxide-Tricalcium Phosphate Scaffolds with Quercetin for Bone Tissue Repair

Successful bone repair requires coordinated regulation of osteogenesis, osteoclast activity, and angiogenesis, yet most bone graft materials address only one or two of these processes. Here, 3D-printed β-tricalcium phosphate scaffolds doped with zinc oxide (ZnO-TCP) and loaded with quercetin (Que) are developed to provide a multifunctional platform for regenerating critical-size defects. ZnO doping enhances densification and mechanical strength, while Zn²⁺ and Que together regulate bone remodeling by suppressing osteoclast activity and promoting osteogenic and angiogenic signaling. In vitro, the combined ZnO-TCP-Que scaffolds significantly reduce Tartrate-Resistant Acid Phosphatase (TRAP) activity, upregulate osteogenic and angiogenic genes, and maintain cytocompatibility. In a rat distal femur model, ZnO-TCP-Que scaffolds increase bone formation by ∼1.5-fold and enhance vascularization by ∼1.8-fold compared to TCP controls. These findings show that co-delivery of Zn²⁺ and Que creates a microenvironment that promotes bone formation, limits resorption, and supports vascular ingrowth. This approach provides a multifunctional ceramic scaffold that can coordinate bone formation, resorption, and vascularization in complex bone defects. STATEMENT OF SIGNIFICANCE: Repairing large bone defects requires coordinated regulation of bone formation, vascularization, and resorption. Most existing biomaterials address only one or two of these processes. Here, we develop a 3D-printed tricalcium phosphate scaffold doped with zinc and loaded with quercetin to simultaneously target these pathways. Zinc improves mechanical strength and supports osteogenic activity, while quercetin provides controlled release and modulates cellular responses. The scaffold reduces osteoclast activity while promoting osteoblast function and endothelial cell behavior. In a rat model, it increased new bone formation by ∼1.5-fold and vascularization by ∼1.8-fold. This work presents a multifunctional approach for designing biomaterials that better support coordinated bone regeneration.