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.

Efficient strategies for the production of recombinant proteins are gaining increasing importance, as more applications that require high amounts of high-quality proteins reach the market. Higher production efficiencies and, consequently, lower costs of the final product are needed for obtaining a commercially viable process. In this chapter, common problems in recombinant protein production are reviewed and strategies for their solution are discussed. Such strategies include molecular biology techniques, as well as manipulation of the culture environment. Finally, specific problems relevant to different hosts are discussed.

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Biomedical applications increasingly require fully characterized new nanomaterials. There is strong evidence showing that nanomaterials not only interact with cells passively but also actively, mediating essential molecular processes for the regulation of cellular functions, but we are only starting to understand the mechanisms of those interactions. Systematic studies about cell behavior as a response to specific nanoparticle properties are scarce in the literature even when they are necessary for the rational design of medical nanodevices. Information in the literature shows that the physicochemical properties determine the bioactivity, biocompatibility, and safety of nanomaterials. The information available regarding the interaction and responses of cells to nanomaterials has not been analyzed and discussed in a single document. Hence, in this review, we present the latest advances about cellular responses to nanomaterials and integrate the available information into concrete considerations for the development of innovative, efficient, specific and, more importantly, safe biomedical nanodevices. We focus on how physicochemical nanoparticle properties (size, chemical surface, shape, charge, and topography) influence cell behavior in a first attempt to provide a practical guide for designing medical nanodevices, avoiding common experimental omissions that may lead to data misinterpretation. Finally, we emphasize the importance of the systematic study of nano-bio interactions to acquire sufficient reproducible information that allows accurate control of cell behavior based on tuning of nanomaterial properties. This information is useful to guide the design of specific nanodevices and nanomaterials to elicit desired cell responses, like targeting, drug delivery, cell attachment, differentiation, etc, or to avoid undesired side effects.

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