3D-Printed GelMA/Hydroxyapatite/Barium Titanate Piezoelectric Hydrogels for Bone Tissue Engineering

Bone defect repair remains a major clinical challenge. This study presents a novel strategy using a 3D-printed piezoelectric hydrogel scaffold—composed of gelatin methacrylate (GelMA), hydroxyapatite (HA), and barium titanate (BTO)—for functional bone tissue engineering. The GelMA/HA/BTO (GelHABT) scaffold exhibited a well-defined porous structure, enhanced mechanical stability, and, crucially, reliable piezoelectric responsiveness. This key feature enables the material to convert external mechanical stimuli, such as low-intensity pulsed ultrasound (LIPUS), into endogenous electrical signals. In vitro, the scaffold promoted BMSCs adhesion, proliferation, and osteogenic differentiation, with performance significantly enhanced under LIPUS stimulation. Mechanistic insights revealed that the piezoelectric microenvironment remodeled the cellular miRNA expression profile, particularly up-regulating osteogenesis-related miR-29b-3p and activating the AMPK signaling pathway. Collectively, this ultrasound-responsive, gene-regulating scaffold represents a promising approach for treating bone defects by leveraging piezoelectricity to actively stimulate bone regeneration. Overall design: Based on the results of previous in vitro experiments of materials, GelHA group, as a classical bone repair material, has been widely studied, and its miRNAs expression pattern is relatively mature, which is suitable for use as the control group, and GelHABT group as the experimental group. Both groups of materials were treated under LIPUS conditions to enhance the piezoelectric effect. Each group of BMSCs was seeded on the surface of the material with a density of 1×105 cells/mL, 48-well plate with 500 µL per well, and cultured in a 37°C 5% CO2 incubator for 24 h. Then, the medium was replaced by osteogenic induction medium for 14 days, and the medium was changed every two days. LIPUS stimulation was given once a day for 10 min.