4D Biofabrication of Magnetically Augmented Callus Assembloid Implants Enables Rapid Endochondral Ossification via Activation of Mechanosensitive Pathways
Konstantinos Ioannidis, Andreas Dimopoulos, Isaak Decoene, Maya Guilliams, Hanna Svitina, Liudmyla Storozhuk, Rodrigo de Oliveira Silva, Sergey A. Basov, T. K. T. Nguyen, Stefanos Mourdikoudis, M. J. Van Bael, Bart Smeets, Dimitrios Sakellariou, Ioannis Papantoniou
Abstract
The use of magnetic-driven strategies for non-contact manipulation of engineered living modules opens up new possibilities for tissue engineering. The integration of magnetic nanoparticles (MNPs) with cartilaginous microtissues enables model-driven 4D bottom-up biofabrication of remotely actuated assembloids, providing unique properties to mechanoresponsive tissues, particularly skeletal constructs. However, for clinical use, the long-term effects of magnetic stimulation on phenotype and in vivo functionality need further exploration. Magnetic-driven biofabrication includes both rapid processes, such as guided microtissue assembly, and slower biological processes, like extracellular matrix secretion. This work explores the interplay between magnetic fields and MNP-loaded cartilaginous microtissues through mathematical modeling and experimental approaches, investigating long-term stimulation effects on ECM maturation and chondrogenic hypertrophy. Transcriptomic analysis reveal that magnetic stimulation activated mechanosensitive pathways and catabolic processes, driving accelerated cartilage-to-bone transitions via endochondral ossification, outcomes not observed in non-stimulated controls. This study paves the way for pre-programmed, remotely actuated skeletal assembloids with superior bone-forming capacity for regenerating challenging bone fractures.