Remote-Controlled Magnetic Stimulation of Cell-Based Bioengineered Tissues for In Situ Bone Regeneration

abstract

The native cell microenvironment activates signaling pathways through mechanotransduction mechanisms, influencing cells' physiological and functional outcomes. Magnetic fields are explored to manipulate these environments, and magnetic nanoparticles (MNPs) are highlighted as nano-instructive agents capable of activating key signaling pathways, presenting exciting possibilities in tissue engineering. Still, the ability to precisely control the assembly and differentiation of stem cells within a dynamically responsive microenvironment, crucial for effective tissue regeneration, remains unexplored. This study showcases a novel method wherein MNPs facilitate the precise assembly of magnetically responsive cells into complex 3D tissue structures upon internalization and exposure to temporally defined cyclic magnetic fields. By remotely stimulating these constructs, it is demonstrated for the first time the possibility of remote-controlled modulation of stem cell fate in vivo without biochemical supplementation. Notably, this approach led to ectopic bone formation, highlighting the ability of magnetic actuation to drive osteogenesis in non-bone environments. MNP-driven mechanical stimulation of implanted tissues functions as a bioresponsive system guiding osteogenic differentiation of human adipose-derived stem cells. The in vivo model further illustrates accelerated construct integration, enhanced osteogenic differentiation, and minimal local inflammation, underscoring the potential of this less invasive, remotely controllable platform to advance regenerative strategies for bone engineering.

keywords

PULSED ELECTROMAGNETIC-FIELD; SIGNALING PATHWAYS; STEM-CELLS; MECHANOTRANSDUCTION; DIFFERENTIATION; PROLIFERATION; ACTIVATION; BEHAVIOR; FORCE; BMP-2

subject category

Chemistry; Science & Technology - Other Topics; Materials Science; Physics

authors

Santos, LF; Mendes, MC; Pereira, JA; Dias, IR; Viegas, CA; Amorim, CO; Amaral, JS; Nogueira, LP; Hauge, HJ; Silva, AS; Mano, JF

Groups

G2 - Photonic, Electronic and Magnetic Materials
G5 - Biomimetic, Biological and Living Materials
G6 - Virtual Materials and Artificial Intelligence

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)

Full human-based multi-scale constructs with jammed regenerative pockets for bone engineering. (REBORN)

acknowledgements

This work was developed within the scope of the project CICECO-Aveiro Institute of Materials, UIDB/50011/2020, UIDP/50011/2020 & LA/P/0006/2020, financed by national funds through the FCT/MCTES (PIDDAC). The work was also financed by FCT-Fundacao para a Ciencia e a Tecnologia, in the scope of the project "O2Cells" (2022.04237.PTDC) and was also funded by the European Union's Horizon Europe research and innovation programme under the Grant Agreement No. 101079482 ("SUPRALIFE"). The authors also acknowledge financial support by FCT through a Ph.D. grant of Lucia Santos (SFRH/BD/141523/2018), Maria Mendes (SFRH/BD/146740/2019) and Joao-Abreu Pereira (2022.13351.BD). This work also acknowledges FCT through the individual contract (CEECIND/2021.02196, A. Sofia Silva). The support of the European Research Council for the REBORN project (ERC-2019-ADG-883370) is acknowledged.