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Magnetic approaches for Tissue Mechanics and Engineering

Periodic Reporting for period 4 - MaTissE (Magnetic approaches for Tissue Mechanics and Engineering)

Reporting period: 2020-01-01 to 2020-12-31

While magnetic nanomaterials are increasingly used as clinical agents for imaging and therapy, their use as a tool for tissue engineering opens up challenging perspectives that have rarely been explored. Lying at the interface between biophysics and nanomedicine, and based on magnetic techniques, the MaTissE project aimed to magnetically design functional tissues while exploring the long-term intracellular fate of nanoparticles.
A major challenge for the regenerative medicine and biophysics communities is to assemble individual cells into 3D tissue-like structure that can be matured and stimulated at will. This was one the central issue being addressed in the MaTissE project through the development of a set of innovative magnetic approaches based on initial cell magnetization, followed by the use of magnetic micro-attractor arrays for 3D cell assembly and micro-controlled attractors network to manipulate the model tissue without direct contact. Such approach would be unique in that the same device will be used to create the model tissue and to stimulate it, for example in a cyclical manner to stimulate cardiomyogenesis, or in a stretching configuration suited to skeletal muscle geometry. Besides, such technique could be applied to the controversial issue of the role of purely mechanical factors in tissue differentiation.
In parallel, another important concern in nanomedicine is the fate of the nanoparticles in the biological environment. Meaning what do the nanoparticles become after achieving their biomedical intracellular mission. There is currently a need for reliable methodologies to measure in real time the fate and persistence of nanoparticles in bio-tissular systems.
The MaTissE project provided magnetic solutions to all these issues, by (i) creating 3D tissues, (ii) applying controlled stimulation to such tissular constructs, and (iii) exploring in situ using nanomagnetic methods the nanoparticles fate.
Within the MaTissE project three prototypes of magnetic tissue bioreactors, stretcher, cyclic stimulator, and aligner, were produced and successfully tested, either with skeletal muscle precursors to force the stretched muscle geometry, or with embryonic stem cells with the demonstration of a remote magnetic control of stem cells differentiation, or with cardiomyocytes to align them in a 3D gel. We also tested different protocols to allow a better cartilage differentiation, implemented magnetic cartilage tissue engineering in scaffolds, and explored the role of extracellular vesicles in this differentiation. Concerning the nanofate of nanoparticles, we have implemented new methods to track the long-term intracellular and tissular fate of nanoparticles, and we have demonstrated a massive intracellular biodegradation, which could be prevented by a gold shell or a polymeric coating. We also demonstrated that a bench-top size magnetic sensor could be used to monitor in operando, in situ, on living environment, the magnetism of cells or engineered tissues. Remarkably, all these magnetic measurements at the tissue scale allowed to evidence that nanoparticles can have a true intracellular destruction/(re)synthesis cycle and offered the first experimental evidence that magnetic nanoparticles can be synthesized endogenously in human stem cells. Finally, we have also exported the innovative methodologies introduced to other metallic nanoparticles, embedded in a tissue construct.
All devices developed for magnetic tissue formation and stimulation were unique in that they provide an "all-in-one" solution: the same device was used to create the model tissue and to stimulate it throughout its maturation, for example in a cyclical manner that mimics cardiac muscle contraction. Such innovative approach has already allowed to gain insights into the role of mechanical factors in embryonic stem cells differentiation. Their use also led to the production of unprecedented tissue replacement structures.
In parallel, the first multimethod, multiscale, and quantitative, studies of intracellular nanoparticles degradation implemented in the project showed many results beyond the state of the art. First, it evidenced an unexpected near-total magnetic or silver nanoparticles intracellular degradation during long-term maturation of a stem cell model tissue. Second, it unraveled that it was possible to monitor this degradation in situ on living cells using a magnetic sensor. Then, it showed that nanoscale features (gold or polymeric shell) could be enough to shield the nanoparticles core from degradation. Finally, we were able to demonstrate that iron ions released over the degradation of magnetic nanoparticles can be used by the cells for the biosynthesis of new magnetic nanoparticles. Such first evidence of magnetic biosynthesis in human stem cells is an initial step in understanding the presence of magnetic nanoparticles in humans.