3D- and 4D-printed scaffolds for osteoporotic bone regeneration: translational insights from in vivo preclinical and human-oriented studies

Abstract

Osteoporosis compromises bone repair through reduced osteogenic capacity, excessive osteoclast activity, oxidative stress, inflammation, impaired angiogenesis, and poor implant fixation. Three-dimensional printing has emerged as a powerful strategy to generate patient-specific scaffolds and implants with controlled porosity, mechanical properties, and bioactive interfaces. In osteoporotic bone, however, passive structural support is often insufficient, prompting the development of drug-loaded, immunomodulatory, antioxidant, osteoanabolic, and stimuli-responsive systems. This mini-review summarizes recent evidence on 3D- and 4D-printed scaffolds for osteoporosis, with emphasis on in vivo preclinical studies and human-oriented translational data. Current studies show that 3D-printed titanium, tantalum, magnesium alloy, calcium phosphate, bioactive glass, polycaprolactone (PCL), polylactic acid (PLA), polyetheretherketone (PEEK), and hybrid hydrogel-integrated scaffolds can enhance osseointegration and bone regeneration in osteoporotic animal models. Functional strategies include local delivery of simvastatin, zoledronic acid, alendronate, teriparatide, bone morphogenic proteins, platelet-rich plasma, strontium, magnesium, lanthanum, cerium, icaritin, and antioxidant or immunomodulatory agents. Emerging 4D-like systems introduce responsiveness to pH, reactive oxygen species (ROS), enzymes, temperature, magnetic fields, microcurrent, or near-infrared irradiation, enabling sequential release, self-healing, photothermal activation, and microenvironment-adaptive repair. Despite strong preclinical progress, true human clinical evidence remains scarce, and most human-oriented work is limited to finite element modeling, patient-specific implant design, biomechanical testing, cadaveric studies, or imaging phantoms. Translation will require large-animal validation, standardized osteoporotic models, long-term safety data, regulatory alignment, and comparative studies against current clinical standards.