Flowerbed-inspired biomimetic 3D-printed scaffolds functionalized with urine-derived stem cell exosomes promote alveolar bone regeneration by regulating energy metabolism

<b>Rationale:</b> The anatomical complexity and restricted regenerative potential of alveolar bone defects create a significant clinical challenge and highlight the need for spatially biomimetic and biologically supportive biomaterials. <b>Methods:</b> We developed a bone-mimicking matrix hydrogel scaffold inspired by the features of a "flowerbed," utilizing machine learning-guided three-dimensional bioprinting. Gelatin methacrylate (GelMA), decellularized bone matrix (DBM), and urine-derived stem cell exosomes (USC-Exos) were co-integrated during the printing process to deliver crucial biophysical and biochemical signals for bone regeneration. <b>Results:</b> The GelMA/DBM/USC-Exos scaffold exhibited high printing fidelity, enabling precise fabrication of defect-specific geometries while preserving exosome bioactivity and achieving sustained release (> 16 days). Functionally, the scaffold promoted M2 macrophage polarization and markedly upregulated osteogenic and angiogenic gene expression, which was approximately 2-fold higher than that of the control (p < 0.01). Mechanistically, the scaffold enhanced oxidative phosphorylation by activating the AMP-activated protein kinase pathway, resulting in a nearly 2-fold increase in adenosine triphosphate content and promoting the osteogenic differentiation of jawbone marrow-derived mesenchymal stem cells. <i>In vivo</i> implantation in mandibular defect models induced robust neovascularization and bone formation, resulting in a nearly 3-fold increase in vessel density and 65.6 ± 3.0% new bone volume after 4 and 8 weeks, respectively, effectively promoting coordinated and functional alveolar bone regeneration. <b>Conclusions:</b> This study establishes a biomimetic approach that integrates structural biomimicry, exosome-mediated bioactivity, and energy metabolism regulation, offering a promising and targeted strategy for personalized alveolar bone regeneration.