# New Insights on Mechanical Stimulation of Mesenchymal Stem Cells for Cartilage Regeneration
## 3 Influencing the Mechanical Environment
Shear or rotational stress, which could be defined by the change in thickness with respect to the original height, is another force generated by joint movement and is caused by the tangential friction of synovial fluid on the surface. This movement allows synovial fluid to nourish the cartilage, transport waste materials, and keep the chondrocytes metabolically active with a mechanism of diffusion and fluid convection [27]. Under this condition, the collagen network is the viscoelastic component of the tissue that exhibits cushioning ability. The collagen concentration is directly proportional to resistance to shifting [28]. Weight-bearing articular cartilage of the hip and knee daily experience stress amplitudes from 0.5 to 7.7 MPa and average compression of 13% [29; 30; 31]. Chondrocytes show selective responses to various mechanical stimuli. Indeed, dynamic stresses are able to improve the production of ECM components, while static compressions do not lead to great achievements in tissue engineering constructs. Mechanical stimulation triggers those pathways that culminate in maintaining functional ECM in order to provide substantial physical stability against the stresses to which the cartilage is subjected. It is a feedback cycle in which the mechanical stress influences the production of those components which sustain the stress itself. It is not surprising that, in fact, an unbalanced step in this cycle could pave the way to a pathological mechanism which could, in the end, lead to the onset of osteoarthritis features. If physiological stimulation fails, following, for example, sedentary habits, or it exceeds the ability of the tissue to sustain it, e.g., excessive mechanical loading [32], the chondrocytes will miss most of the input to produce the new ECM, resulting in unbalanced homeostasis. It is highly recommended to patients who suffer from early osteoarthritis, who are able to conduct physical exercise, to encourage the movement of the diseased articulation in order to stimulate the restoration of the physiological cycle, which may lead to improvements in biochemical disorders. This dynamic environment should be considered in tissue engineering approaches in order to realize as realistic a construct as possible. The challenge proposed is to move from a purely biological view of the natural cell to an engineered one. Stem cells are studied as structures able to sense and transmit physical stimuli, translating them into biological and mechanical responses, since they have greater mechanical sensitivity than adult cells [33; 34]. As already mentioned, ion channels are paramount in triggering those signaling pathways which lead to matrix turnover and homeostasis, and an intracellular increase of Ca\({}^{2+}\) levels has been considered as one of the stem cell responses to mechanical load. Sequestration of calcium ions and inhibition of VOCCs and other channels have been shown to attenuate the effects of mechanical stimulation. More specifically, during physical stimulation of MSCs, Ca\({}^{2+}\) is known to be involved in the activation of pivotal transcription factors leading to chondrogenic differentiation [20]. In the next section, some interesting works on the topic are presented. In some of those, no exogenous growth factors were added during the experiment. Hence, chondrogenic differentiation was achieved exclusively as a result of load applications. Figure 2 illustrates the different types of mechanical forces applied in these experiments.