Computer simulations of the energy dissipation rate in a fluorescence‐activated cell sorter: Implications to cells

Mollet, Mike; Godoy-Silva, Rubén Darío; Berdugo, Claudia; Chalmers, Jeffrey J.

doi:10.1002/bit.21762

Cited by 82 publications

(77 citation statements)

References 32 publications

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“…Mollet et al (2008) experimentally, and through CFD simulations, demonstrated that the EDR in the nozzle of FACS is sufficient to damage a number of different cell lines, including CHO cells. Table 2 and Fig.…”

Section: Cell Damage In Downstream Equipment and Other Bioprocess Equmentioning

confidence: 99%

The potential of hydrodynamic damage to animal cells of industrial relevance: current understanding

Hu¹,

2011

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Suspension animal cell culture is now routinely scaled up to bioreactors on the order of 10,000 L, and greater, to meet commercial demand. However, the concern of the 'shear sensitivity' of animal cells still remains, not only within the bioreactor, but also in the downstream processing. As the productivities continue to increase, titer of ~10 g/L are now reported with cell densities greater than 2 × 10(7) cells/mL. Such high, and potentially higher cell densities will inevitably translate to increased demand in mass transfer and mixing. In addition, achieving productivity gains in both the upstream stage and downstream processes can subject the cells to aggressive environments such as those involving hydrodynamic stresses. The perception of 'shear sensitivity' has historically put an arbitrary upper limit on agitation and aeration in bioreactor operation; however, as cell densities and productivities continue to increase, mass transfer requirements can exceed those imposed by these arbitrary low limits. Therefore, a better understanding of how animal cells, used to produce therapeutic products, respond to hydrodynamic forces in both qualitative and quantitative ways will allow an experimentally based, higher, "upper limit" to be created to guide the design and operation of future commercial, large scale bioreactors. With respect to downstream hydrodynamic conditions, situations have already been achieved in which practical limits with respect to hydrodynamic forces have been experienced. This review mainly focuses on publications from both the academy and industry regarding the effect of hydrodynamic forces on industrially relevant animal cells, and not on the actual scale-up of bioreactors. A summary of implications and remaining challenges will also be presented.

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Section: Cell Damage In Downstream Equipment and Other Bioprocess Equmentioning

confidence: 99%

The potential of hydrodynamic damage to animal cells of industrial relevance: current understanding

Hu¹,

2011

Self Cite

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“…Figure 3 presents the result of these acute exposure studies to five different flow rates (10, 30, 50, 70, and 90 mL min respectively, Mollet et al, 2007). In addition, data from previously published studies using CHO K1 cells, MCF-7, and THP-1 cells are included for comparison (Ma et al, 2002;Mollet et al, 2007Mollet et al, , 2008. As can be observed by inspection of Figure 3, the response of the current CHO cell line is consistent with the response of previously used CHO K1 with respect to the level of EDR at which significant cell lysis occurs.…”

Section: Acute Exposure To High Edrmentioning

confidence: 99%

“…Response of CHO cells used in this study to an acute exposure to the hydrodynamic forces created by the TC and characterized by a specific level of EDR. As reference points, data from previously published studies with CHO K1 cells, MCF-7, and THP1 cells are presented (Ma et al, 2002;Mollet et al, 2007Mollet et al, , 2008. Dashed lines indicate the flow rate for every EDR.…”

Section: à3mentioning

confidence: 99%

Evaluation of the effect of chronic hydrodynamical stresses on cultures of suspensed CHO‐6E6 cells

Godoy-Silva

Mollet

Chalmers

2008

Biotech & Bioengineering

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The effect of hydrodynamic forces on animal cell cultures, while extensively studied, still lacks significant, fundamental understanding. A previous manuscript reported on the acute exposure of CHO cells to hydrodynamic forces in a second generation convergent-divergent microfluidic device (Mollet et al., 2007). In this study, the use of this device is extended in a proof of concept system in which suspended animal cells, grown in a typical bioreactor, are subjected to chronic exposure of moderately high levels of hydrodynamic forces by way of a continuous recycle loop between the bioreactor and the microfluidic device. A strain of CHO cells (CHO-6E6) was grown in a batch culture under controlled pH, temperature, and dissolved oxygen conditions. At mid exponential stage of growth in the bioreactor the recycle flow was initiated. The cells either stopped growing or started dying at EDR values that were significantly lower (one to two orders of magnitude) than those previously reported to kill cells from a single, acute exposure. These observations allow further refinement in the design of bioprocess equipment since it provides a more accurate threshold, above which one does not want to subject animal cells to continuous exposure to specific levels of hydrodynamic forces.

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“…19,31,33 Lokhandwalla and Sturtevant, 31 for example, noted the presence of extensional flow with hemolysis from shock wave lithotripsy. When working with hamster ovary cells, Mollet et al 34 found that high levels of cell damage were seen in areas of high extensional stress. Although ovarian cells are much different from red blood cells, it would not be unreasonable to assume the same mechanisms might affect RBCs and ovarian cells alike.…”

Section: Introductionmentioning

confidence: 99%

Significance of Extensional Stresses to Red Blood Cell Lysis in a Shearing Flow

2011

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Traditionally, an empirical power-law model relating hemolysis to shear stress and exposure time has been used to estimate hemolysis related to flow--however, this basis alone has been insufficient in attempts to predict hemolysis through computational fluid dynamics. Because of this deficiency, we sought to re-examine flow features related to hemolysis in a shearing flow by computationally modeling a set of classic experiments performed in a capillary tube. Simulating 21 different flows of varying entrance contraction ratio, flowrate and viscosity, we identified hemolysis threshold streamlines and analyzed the stresses present. Constant damage thresholds for radial and axial extensional stresses of approximately 3000 Pa for exposure times on the order of microseconds were observed, while no such threshold was found for the maximum shear stress or gradient of the shear stress. The extensional flow seen at the entrance of the capillary appears to be most consistently related to hemolysis. An account of how extensional stresses can lead to lysis of a red cell undergoing tank-tread motion in a shearing flow is provided. This work shows that extensional components of the stress tensor are integral in causing hemolysis for some flows, and should be considered when attempting to predict hemolysis computationally.

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Computer simulations of the energy dissipation rate in a fluorescence‐activated cell sorter: Implications to cells

Cited by 82 publications

References 32 publications

The potential of hydrodynamic damage to animal cells of industrial relevance: current understanding

The potential of hydrodynamic damage to animal cells of industrial relevance: current understanding

Evaluation of the effect of chronic hydrodynamical stresses on cultures of suspensed CHO‐6E6 cells

Significance of Extensional Stresses to Red Blood Cell Lysis in a Shearing Flow

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