Nanostructured Quercetin-Lipid Carrier on 3D Printed Scaffolds for Improved Bone Regeneration

Musculoskeletal defects remain difficult to treat because current grafts often have limited supply, donor-site morbidity, risk of immune reaction, or insufficient local biological stimulation. To address this problem, this study developed 3D-printed β-tricalcium phosphate (TCP) scaffolds loaded with quercetin-loaded nanostructured lipid carriers (Que-NLCs) to combine an osteoconductive ceramic structure with local delivery of a natural osteogenic and anti-resorptive compound. Que-NLCs provided controlled release for up to 21 days and reduced the initial burst release compared with free Que at both pH 5.0 and 7.4. At pH 5.0, release was ∼40% for Que and ∼33% for Que-NLCs, while at pH 7.4, release was ∼32% for Que and ∼26% for Que-NLCs. In vitro studies showed that Que-NLC-loaded scaffolds increased osteoblast viability by ∼28.6%, increased alkaline phosphatase activity by 33% by day 11, and reduced osteoclastic activity by 56% by day 21. RT-qPCR further showed up to 4-fold increases in osteogenic markers and up to 60% reduction in osteoclastogenesis-related genes. In a 6-week rat distal femur model, Que-NLC scaffolds increased new bone formation by ∼1.9-fold compared with TCP. These results show that Que-NLC-TCP scaffolds provide a localized, controlled drug-delivery platform to improve bone regeneration in non-load-bearing defects.