# Tuning the Cell and Biological Tissue Environment through Magneto-Active Materials
## 2 Mechanically Mediated Biological Processes
### Mechanical Effects on Bone Development and Healing
These interactions result into a complex system of physicochemical cues that, in turn, travel within the cellular aggregate and lead to a cellular continuum that moves together. Among the physicochemical signals, mechanical waves constitute one of the most relevant vehicles in transmitting the information between cells and guiding the collective migration process. In this regard, mechanical waves help with coordinating the cellular behaviour by sharing, within the whole continuum, cellular crosstalk, cell-cell and cell-ECM adhesive interactions, and active responses from cell contractility [41]. Interestingly, during morphogenesis, mesoderm tissue stiffening initiates an epithelial-to-mesenchymal transition in neural crest cells and triggers their collective migration. More broadly, tissue mechanics combine with molecular effectors to coordinate morphogenesis [42]. When looking at cells from a mechano-structural point of view, they are usually modelled as a combination of viscous and elastic substances, similar to non-Newtonian fluids, meaning that stresses tend to relax with time. This viscoelastic behaviour allows the cell to adapt to the stress over time. Moreover, the ECM contains proteins such as collagen, elastin, laminin and perlecan. These greatly vary from relatively soft, such as in brain tissue with a shear modulus in the order of 1 kPa, to cartilage with a respective value closer to 1 MPa. These elements tend to be orders of magnitude tougher and impassable for cells, but are neither perfectly packed nor distributed, having inner gaps that are large enough for the cells to pass through. Other forces keeping them attached to the extracellular matrix, mainly those exerted by actin and myosin, are subject to substantial contractile forces, generating elevated internal stress. This dampens movement but does not outright impede it. Surprisingly, the migration mechanism can be reduced to purely mechanical phenomena. In simple terms, cells move when there are unbalanced forces driving the movement in a particular direction. For example, the closure of epithelial gaps in the absence of cell injury is governed by the collective migration of cells through the activation of lamellipodium protrusion [43]. Traction forces are constantly being altered, and the cells move in the proper direction to minimise the newly achieved stress, in a process mimicking diffusion. Therefore, the controlled tuning of the ECM seems a powerful idea to, at some instance, influence the cell migration process and it has been explored as an emerging therapy [44]. Numerous studies have been conducted to date to elucidate the specific effects of ECM's mechanical properties on cell migration. Anisotropic ECM promotes the heterogeneous distribution of mechanical forces acting within the cell continuum [8]. The resulting interplay between external forces and cellular stresses modulates changes in the cellular shape and provides preferred directions for collective migration. More concretely, cells tend to migrate along gradients of substrate stiffness [45]. This behaviour is termed as durotaxis and is postulated as one of the main promoters of cell movement to stiffer regions [46]. Experiments conducted by [PERSON] et al. [7] corroborate these premises and demonstrate that stiffness gradients within the substrate induce collective cell migration towards the stiffer regions. Collective invasion is prevalent in cancer [5,6]. However, because cancer is a slow, long-term process that is not amenable to direct microscopy observation, to date the mechanisms of collective cell migration are less understood compared with morphogenesis and regeneration [40]. In histopathological sections, most epithelial cancers display the hallmarks of collective invasion into surrounding tissues, including intact cell-cell junctions, the expression of cadherins and other cell-cell adhesion receptors. Moreover, structural ECM degradation and remodelling due to the engagement of cell surface proteases is an early event in collective cancer cell movement.