title: Living with heterogeneities in bioreactors: understanding the effects of environmental gradients on cells.
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 heterogeneities, are surveyed.
authors.affiliation: Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnología Universidad Nacional Autónoma de México (UNAM), Apdo. Postal. 510-3. Cuernavaca, Morelos, CP. 62250, México.
authors.forename: Alvaro R
authors.initials: AR
authors.lastname: Lara
authors.forename: Enrique
authors.initials: E
authors.lastname: Galindo
authors.forename: Octavio T
authors.initials: OT
authors.lastname: Ramírez
authors.forename: Laura A
authors.initials: LA
authors.lastname: Palomares
mesh_terms: D000332:Aerobiosis; D000818:Animals; D001419:Bacteria / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D001431:Bacteriological Techniques / Q000295:instrumentation; D019149:Bioreactors; D016466:CHO Cells / Q000166:cytology / Q000378:metabolism; D002245:Carbon Dioxide / Q000378:metabolism; D018929:Cell Culture Techniques / Q000295:instrumentation / Q000379:methods; D002478:Cells, Cultured / Q000166:cytology / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D003470:Culture Media / Q000737:chemistry / Q000494:pharmacology; D004058:Diffusion; D004777:Environment; D004867:Equipment Design; D005285:Fermentation; D005658:Fungi / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D006801:Humans; D006859:Hydrogen / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D009172:Mycology / Q000295:instrumentation / Q000379:methods; D010100:Oxygen / Q000378:metabolism; D059828:Plant Cells; D010944:Plants / Q000378:metabolism; D013314:Stress, Mechanical; D013696:Temperature
chemical_list: D003470:Culture Media; D002245:Carbon Dioxide; D006859:Hydrogen; D010100:Oxygen