pH-responsive polydopamine-coated mesoporous silica nanoplatform integrated into 3D-printed PLA/nHA scaffolds for synergistic bone regeneration

Integrating stimuli-responsive nanoplatforms into 3D-printed scaffolds offers a sophisticated approach to mimicking the complex microenvironment of bone healing while minimizing the side effects associated with high-dose growth factor therapy. This study reports the design of a mesoporous silica-based dual-drug delivery system co-loaded with dexamethasone (DEX) and bone morphogenetic protein-2 (BMP-2) to harness their synergistic osteogenic potential while minimizing BMP-2-associated side effects. Mesoporous silica nanoparticles (MSNs) were synthesized to encapsulate DEX, followed by a polydopamine (PDA) coating formed via self-polymerization under mild alkaline conditions. BMP-2 was subsequently immobilized on the PDA layer, yielding pH-responsive DEX@MSNs/PDA/BMP-2 nanoparticles. Characterization confirmed uniform morphology, efficient loading, and controlled release, with accelerated release under acidic conditions, mimicking bone-defect environments. In vitro, dual-drug nanoparticles promoted osteogenic differentiation of preosteoblasts in a concentration-dependent manner, as evidenced by increased alkaline phosphatase activity, enhanced calcium deposition, and upregulated osteogenic genes. The nanoparticles were incorporated into three-dimensionally (3D)-printed polylactic acid/nano-hydroxyapatite scaffolds via freeze-drying, yielding composites with favorable porosity, mechanical properties, hydrophilicity, and biodegradability. In a rat calvarial defect model, implantation of the composite scaffolds significantly improved bone regeneration and neovascularization relative to controls, as demonstrated by micro-computed tomography and histological analyses. The results demonstrate that PDA-coated MSNs co-delivering DEX and BMP-2, integrated into 3D-printed scaffolds, provide a biocompatible and effective platform for bone tissue engineering. This approach combines pH-responsive release, dual-drug synergy, and structural support, offering translational potential for mandibular defect repair.