Osteogenic Differentiation Triggered by Intracellular Magnetoelectric Stimulation of Core-Shell Nanotransducers under Remotely Applied Magnetic Fields

abstract

Magnetoelectric nanoparticles (MENPs), combining a magnetostrictive core with a piezoelectric shell, offer a promising route for remote-controlled biomedical applications by converting external magnetic fields into electric cues. However, the clinical translation of these materials remains limited due to the toxicity of high-performance piezoelectric materials, which typically contain lead. Previously, we developed lead-free MENPs comprising manganese ferrite oxide (MFO) core nanoparticles (NPs) coated with a Ba0.85Ca0.15Zr0.1Ti0.9O3 (BCZT) piezoelectric shell (MFO@BCZT). While these nanotransducers exhibit robust magnetic responsiveness and piezoelectric performance comparable to lead-based ceramics, their role in producing in situ electrical cues to accelerate bone repair remains unexplored. Given the established role of electrical stimulation in bone remodeling, this study explores the potential of MFO@BCZT MENPs to promote the osteogenic differentiation of human adipose-derived stem cells (hASCs) after internalization, assembly into magnetized 3D spheroids, and subsequent embedding in gelatin methacryloyl hydrogels, to better recapitulate physiologically relevant microenvironments. Differentiation was assessed under static and cyclic magnetic field (CMF) conditions and compared to spheroids containing bare MFO NPs and spheroids without NPs. Results revealed that MFO and MFO@BCZT NPs were cytocompatible; however, MFO@BCZT MENPs significantly enhanced osteogenic marker expression and mineral deposition compared to both controls, with CMF further amplifying these effects. Under CMF stimulation, MFO@BCZT MENPs produced a mineralized matrix with a calcium-to-phosphorus molar ratio of 1.67, aligning precisely with native bone apatite. Overall, by restoring the bioelectric properties of bone at the target region, this study positions MFO@BCZT MENPs as a compelling platform for future smart bone therapies.

keywords

BARIUM-TITANATE; STEM-CELLS; NANOPARTICLES; STATES; NANOCOMPOSITES; PROLIFERATION; SPECTROSCOPY; MORPHOLOGY; TOXICITY; COFE2O4

subject category

Chemistry; Science & Technology - Other Topics; Materials Science

authors

Mendes, MC; Martins, EAG; Chernozem, RV; Chernozem, PV; Custodio, CC; Surmenev, RA; Kholkin, AL; Silva, AS; Mano, JF

Groups

G2 - Photonic, Electronic and Magnetic Materials
G5 - Biomimetic, Biological and Living Materials

Projects

CICECO - Aveiro Institute of Materials (UIDB/50011/2020)

CICECO - Aveiro Institute of Materials (UIDP/50011/2020)

Associated Laboratory CICECO-Aveiro Institute of Materials (LA/P/0006/2020)

Unlocking the scientific excellence and innovation capacity of the University of Aveiro in supramolecular multicomponent biomaterials for enabling advanced biomaterials for healthcare (SUPRALIFE)

acknowledgements

This work was developed within the scope of projects of the CICECO-Aveiro Institute of Materials, UIDB/50011/2020 (DOI 10.54499/UIDB/50011/2020), UIDP/50011/2020 (DOI 10.54499/UIDP/50011/2020), and LA/P/0006/2020 (DOI 10.54499/LA/P/0006/2020), financed by national funds through the FCT/MEC (PIDDAC). The authors would also like to acknowledge the European Research Council through the project "Reborn" (ERC-2019-ADG-883370) and funding from the European Union's Horizon Europe Research and Innovation Program under Grant Agreement No. 101079482 ("SUPRALIFE"). Financial support given by the Portuguese Foundation for Science and Technology (FCT) is also acknowledged, including the doctoral grants SFRH/BD/146740/2019 of M. C. Mendes and SFRH/BD/05665/2021 of E. A. G. Martins, as well as the individual contract 2021.02196. CEECIND (DOI 10.54499/2021.02196.CEECIND/CP1659/CT0002) of A. S. Silva. This work was financially supported by the Ministry of Science and Higher Education of the Russian Federation (no. 075-15-2025-672). The authors are grateful to D.V. Wagner, E. Yu. Gerasimov, K. Romanyuk, D. Koptsev, and M. Surmeneva for the assistance with NP characterization and the discussion of the results. The authors also thank the central laboratories of Tomsk Polytechnic University (Analytical Center) for the XPS measurements (M. Kozadaeva). A. Kholkin acknowledges the projects "FeLow-D" and "Piezo2D" funded under the Horizon Europe programs HORIZON-WIDERA-2023-TALENTS-01 (#101186499) and HORIZON-TMA-MSCA-SE (#101131229), respectively.