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Living with heterogeneities in bioreactors

Understanding the effects of environmental gradients on cells

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Abstract

The presence of spatial gradients in fundamental culture parameters, such as dissolved gases, pH, concentration of substrates, and shear rate, among others, is an important problem that frequently occurs in large-scale bioreactors. This problem is caused by a deficient mixing that results from limitations inherent to traditional scale-up methods and practical constraints during large-scale bioreactor design and operation. When cultured in a heterogeneous environment, cells are continuously exposed to fluctuating conditions as they travel through the various zones of a bioreactor. Such fluctuations can affect cell metabolism, yields, and quality of the products of interest. In this review, the theoretical analyses that predict the existence of environmental gradients in bioreactors and their experimental confirmation are reviewed. The origins of gradients in common culture parameters and their effects on various organisms of biotechnological importance are discussed. In particular, studies based on the scale-down methodology, a convenient tool for assessing the effect of environmental heterogene ities, are surveyed.

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Abbreviations

C * :

Dissolved oxygen concentration at saturation with air

CFD:

Computational fluid dynamics

CHO:

Chinese hamster ovary

dCO2 :

Dissolved carbon dioxide

dH2 :

Dissolved hydrogen

Di :

Impeller diameter

DO:

Dissolved oxygen concentration

dw:

Dry weight

GFP:

Green fluorescent protein

HGH:

Human growth hormone

k La:

Volumetric oxygen transfer coefficient

N :

Impeller rotation speed

PFR:

Plug-flow reactor

P o :

Power input

Q :

Pump rate

SD:

Scale-down

SDS:

Scale-down system

STR:

Stirred-tank reactor

t c :

Circulation time

TCA:

Tricarboxylic acid

tm :

Mixing time

t MT :

Characteristic time for mass transfer

tO2u :

Characteristic time for oxygen uptake

V :

Volume

’:

Density

μ:

Viscosity

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  1. Departamento de Medicina Molecular y Bioprocessos, Instituto de Biotecnologia Universidad Nacioral Autónoma de México (UNAM), Apde. Postal 510-3, CP. 62250, Cuerravaca, Morelos, México

    Alvaro R. Lara, Octavio T. Ramírez & Laura A. Palomares

  2. Departamento de Ingeniería Celular y Biocatálisis, Instituto de Biotecnologia Universidad Nacioral Autónoma de México (UNAM), Apde. Postal. 510-3, CP. 62250, Cuerravaca, Morelos, México

    Enrique Galindo

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Lara, A.R., Galindo, E., Ramírez, O.T. et al. Living with heterogeneities in bioreactors. Mol Biotechnol 34, 355–381 (2006). https://doi.org/10.1385/MB:34:3:355

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