3D‐Printable and Bioelectronic‐Compatible Graphene‐Reinforced PLA Nanocomposites Rejuvenate Aged Bone Regeneration Through Glycolytic Reprogramming

Abstract

Age‐related metabolic dysregulation, chronic inflammation, and impaired vascularization severely compromise critical‐sized bone healing. Building upon G‐PLA nanocomposites previously established for bioelectronic encapsulation, we herein investigate their potential as a bio‐instructive interface for guided bone regeneration. Fabricated via in situ graphite exfoliation, G‐PLA provides enhanced hydrophilicity, mechanical robustness, and bioactivity while preserving excellent 3D‐printability. In rat cranial defects, G‐PLA significantly accelerated regeneration, as demonstrated by micro‐CT, histological, and immunohistochemical analyses. Comparative evaluations in young and aged animals revealed that G‐PLA effectively mitigates age‐dependent declines in reparative capacity. Proteomic profiling indicated that G‐PLA orchestrates a pro‐regenerative microenvironment by inducing glycolytic reprogramming to meet the elevated energy demands of regeneration. In aged defects, G‐PLA upregulated glycolytic enzymes (e.g., ALDOA and HK2), enhanced angiogenesis (CD31/CD34), and suppressed inflammation‐ and senescence‐associated markers (e.g., P21 and SIRT2). In vitro studies validated that G‐PLA augments glycolytic flux in endothelial cells, enhances osteogenic differentiation of mesenchymal stem cells, and promotes macrophage polarization toward an anti‐inflammatory M2 phenotype. Therefore, G‐PLA nanocomposites transcend passive structural support to act as a bio‐instructive interface that revitalizes the aging‐associated vascular‐bone coupling, offering a versatile framework for next‐generation multifunctional implantable hybrid systems.