Hydrodynamic Stress

During the very early days of mammalian cell culture, it was generally assumed that cell lines would be far more sensitive to shear damage due to the absence of a cell wall. Considerable progress has been made in our understanding of the exact interactions that result in the greatest damage to the cells. It is now clear that it is not the shear forces generated at the impeller tip that are responsible for cell death induced by the hydrodynamic environment of the reactor. Far more damage is caused by the events that take place at the gas head space-liquid interface during bubble disengagement (95).

Despite the importance of the hydrodynamic environment, the biochemical response of the cell to this component of the bioreactor environment has been rather neglected. To address this issue Al-Rubeai et al. (91) investigated the mechanism of cell death following exposure of cells to very high agitation levels. Flow cytometric and morphological analysis indicated that cell death occurred mostly by apoptosis, although levels of necrosis were also significant. Singh et al. (82) found that a Burk-itt's lymphoma cell line that had been routinely passaged in stationary cultures underwent apoptosis when attempts were made to grow the cells in suspension. Bcl-2 transfec-tion of this cell line was found to allow much better cell growth in suspension without the need for adaptation. Simpson et al. (8) reported similar behavior of a hybridoma cell line.

Physiological studies have also investigated the relationship between apoptosis and shear stress. Dimmeler et al. (89) have found that shear stress actually prevents induction of apoptosis in endothelial cells in the presence of the inducer tumor necrosis factor a or following growth factor withdrawal. Clearly, the possibility that a sublethal level of shear stress in the bioreactor protects the cells from apoptosis-inducing agents needs to be investigated.

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