A senescent metabolism-modulating hierarchical scaffold restores NAD⁺ homeostasis and redox balance for aged bone repair.

Abstract

Senescence-impaired bone repair poses a significant clinical challenge, primarily due to the metabolic microenvironment imbalance driven by senescent cells. Current biomaterial strategies are largely confined to providing passive mechanical support and/or delivering therapeutic factors, failing to fundamentally reverse this specific pathological microenvironment. Here, we propose a senescent metabolism-reprogramming therapeutic strategy by developing a hierarchical bioceramic scaffold, comprising an outer 3D-printed β-tricalcium phosphate (β-TCP) hollow tube and an inner freeze-casting MnTCP ceramic rod with the loading of nicotinamide mononucleotide (NMN). During aged bone repair, the scaffold enables sustained release of both NMN and manganese (Mn) ions, targeting two core problems of the senescent bone microenvironment: NAD⁺ metabolic imbalance and accumulated oxidative stress. The scaffold was demonstrated to effectively restore intracellular NAD⁺ levels for reversing senescence-induced energy metabolism disorder by improving mitochondrial structure and function, and to scavenge excessive reactive oxygen species (ROS) for regulating cellular redox homeostasis. Therefore, it achieved cellular senescence alleviation by restoring energy metabolism and redox homeostasis. This anti-senescence action together with the inhibition of inflammatory responses collectively promoted osteogenic differentiation and enhanced bone regeneration. Based on the dual regulatory mechanism, the scaffold implantation significantly promoted new bone formation and maturation in aged rats with femoral condyle defects. This work not only provides an efficient biomaterial solution for bone defects in the elderly but, more importantly, pioneers a "material-mediated metabolic modulation" strategy to target tissue senescence, offering a new direction for treating senescence-related diseases in regenerative medicine.