3D-Printed and Biofabricated Scaffolds for Osteoporotic Bone Defect Repair: Mechanical Adaptation, Redox Control, Senescence Modulation and Osteoimmunomodulation.

Abstract

Fragility fracture and osteoporotic bone loss represent an increasing global burden in ageing populations: the Global Burden of Disease Study 2021 estimated 172.79 million new fractures, 453.31 million prevalent cases, and 25.18 million years lived with disability in 2021, yet the resulting defects are still managed with grafts and scaffolds validated in healthy bone. Osteoporotic bone is not merely rarefied normal bone but a distinct regenerative microenvironment, in which we propose that oxidative stress, cellular senescence, and loss of osteogenesis-coupled type-H vasculature act as a mutually reinforcing triad, superimposed on an adipogenically biassed progenitor pool, blunted osteocyte mechanotransduction and immunosenescence. Additive manufacturing and biofabrication permit patient-specific geometry and spatial and temporal programming of mechanical and biological cues. This review appraises four interdependent design axes-mechanical adaptation through functionally graded, trabecular-mimetic architectures; redox regulation; senescence modulation; and osteoimmunomodulation coupled to vascularisation-distinguishing study type, disease specificity and author-proposed hypotheses. The most direct clinical signal is mechanical: in a retrospective cohort of 163 lumbar interbody fusion levels, printed porous titanium was associated with subsidence in 5.5% of levels versus 24.4% for solid titanium. By contrast, almost all redox, senescence and immunomodulatory scaffold evidence remains preclinical: osteoporosis-specific evidence relies heavily on ovariectomised rodents, and much of the rest comes from non-osteoporotic models. Within the searches described, we identified no completed clinical evaluation with reported results of a multifunctional scaffold in an osteoporosis-defined cohort. As the authors' proposed conceptual framework rather than an established result, we suggest that these axes be engaged sequentially rather than additively, and that timing, dose and spatial distribution may matter more than the number of bioactivities.