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. 2011;2011:620247.
doi: 10.4061/2011/620247. Epub 2011 Aug 23.

Bioprocess Forces and Their Impact on Cell Behavior: Implications for Bone Regeneration Therapy

Free PMC article

Bioprocess Forces and Their Impact on Cell Behavior: Implications for Bone Regeneration Therapy

David Brindley et al. J Tissue Eng. .
Free PMC article


Bioprocess forces such as shear stress experienced during routine cell culture are considered to be harmful to cells. However, the impact of physical forces on cell behavior is an area of growing interest within the tissue engineering community, and it is widely acknowledged that mechanical stimulation including shear stress can enhance osteogenic differentiation. This paper considers the effects of bioprocess shear stress on cell responses such as survival and proliferation in several contexts, including suspension-adapted cells used for recombinant protein and monoclonal antibody manufacture, adherent cells for therapy in suspension, and adherent cells attached to their growth substrates. The enhanced osteogenic differentiation that fluid flow shear stress is widely found to induce is discussed, along with the tissue engineering of mineralized tissue using perfusion bioreactors. Recent evidence that bioprocess forces produced during capillary transfer or pipetting of cell suspensions can enhance osteogenic responses is also discussed.


Figure 1
Figure 1
Different circumstances in which mammalian cells become exposed to shear stress that can impact on their behavior. (a) During the manufacture of biopharmaceuticals such as recombinant proteins or monoclonal antibodies, shear stress encountered by suspension-adapted cells in stirred tank bioreactors is often considered harmful. (b) Adherent cells can experience shear stress as a mechanical stimulus that promotes osteogenic differentiation and this can be exploited in perfusion bioreactors, where active transport of oxygen and nutrients throughout 3D scaffolds exposes cells to shear stress. (c) Bioprocess forces produced during manual processing of multipotent cell populations can also enhance osteogenic differentiation potential.
Figure 2
Figure 2
The application method and magnitude of shear stress can both impact on cell survival, proliferation and osteogenic differentiation. (a) Cells cultured in 2D and subjected to fluid flow shear stress, for example using parallel plate perfusion systems, are exposed to shear stress in one plane at the exposed surface of the cells and relatively high shear stress drives osteogenic differentiation. (b) In 3D perfusion culture, typically used when seeding cells throughout biomaterial scaffolds, cell dynamics are different: some cells are flattened and adhered firmly to the scaffold surface. These cells (shown in purple) experience shear stress at their exposed surface similar to those cultured in 2D culture. Other cells bridge between scaffold components and these cells (shown in green) experience shear stress as a 3D stimulus. Consequently, lower levels of shear stress than those required in 2D culture can drive osteogenic differentiation. (c) Bioprocess forces experienced during pipetting and capillary transfer of adherent cells in suspension provide non-uniform shear stress stimuli in the form of wall shear stress as the cells randomly hit the capillary walls during transport (red stars). Furthermore, shear stress and extensional forces upon entry to the capillary may provide further positive mechanical stimulus (green star). Red arrows indicate initial direction of fluid flow.

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