The role of laboratory-scale bioreactors at the semi-continuous and continuous microbiological and biotechnological processes

Tikhomirova, Tatyana S.; Taraskevich, M S; Ponomarenko, O. V.

doi:10.1007/s00253-018-9194-z

Cited by 11 publications

(7 citation statements)

References 85 publications

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“…This is the first study to examine phage yield in a shake flask system and translate the process into a stirred tank bioreactor system. Developing the scaled down model was of critical importance as variable shake flask processes often lead to difficulties in achieving similar yields when the process is moved on into a stirred tank system (Garcia‐Ochoa & Gomez, ; Mitchell, Krieger, Stuart, & Pandey, ; Tikhomirova, Taraskevich, & Ponomarenko, ). The research presented here has shown that by narrowing the conditions used and focussing on those that positively influence phage infection, the titer achieved is reliable and validated at small scale and in a scale‐up system which focuses on larger volumes, automation, and controllable parameters, that is, pH and DO 2 .…”

Section: Resultsmentioning

confidence: 99%

Section: Scale-upmentioning

confidence: 99%

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A scaled‐down model for the translation of bacteriophage culture to manufacturing scale

Ali

Rafiq

Ratcliffe

2019

Biotech & Bioengineering

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Therapeutic bacteriophages are emerging as a potential alternative to antibiotics and synergistic treatment of antimicrobial‐resistant infections. This is reflected by their use in an increasing number of recent clinical trials. Many more therapeutic bacteriophage is being investigated in preclinical research and due to the bespoke nature of these products with respect to their limited infection spectrum, translation to the clinic requires combined understanding of the biology underpinning the bioprocess and how this can be optimized and streamlined for efficient methods of scalable manufacture. Bacteriophage research is currently limited to laboratory scale studies ranging from 1–20 ml, emerging therapies include bacteriophage cocktails to increase the spectrum of infectivity and require multiple large‐scale bioreactors (up to 50 L) containing different bacteriophage–bacterial host reactions. Scaling bioprocesses from the milliliter scale to multi‐liter large‐scale bioreactors is challenging in itself, but performing this for individual phage‐host bioprocesses to facilitate reliable and robust manufacture of phage cocktails increases the complexity. This study used a full factorial design of experiments approach to explore key process input variables (temperature, time of infection, multiplicity of infection, agitation) for their influence on key process outputs (bacteriophage yield, infection kinetics) for two bacteriophage–bacterial host bioprocesses (T4 – Escherichia coli; Phage K – Staphylococcus aureus). The research aimed to determine common input variables that positively influence output yield and found that the temperature at the point of infection had the greatest influence on bacteriophage yield for both bioprocesses. The study also aimed to develop a scaled down shake‐flask model to enable rapid optimization of bacteriophage batch bioprocessing and translate the bioprocess into a scale‐up model with a 3 L working volume in stirred tank bioreactors. The optimization performed in the shake flask model achieved a 550‐fold increase in bacteriophage yield and these improvements successfully translated to the large‐scale cultures.

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Section: Resultsmentioning

confidence: 99%

Section: Scale-upmentioning

confidence: 99%

A scaled‐down model for the translation of bacteriophage culture to manufacturing scale

Ali

Rafiq

Ratcliffe

2019

Biotech & Bioengineering

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“…Instead, a much better reproduction can be obtained at scale‐down simulators with longer circulation times. This suggests that the circulation time distribution plays a major role in the ultimate outcome and therefore population balances must be taken in account (Tikhomirova, Taraskevich, & Ponomarenko, ). Metabolomics analysis also suggests that losses of penicillin production did not show correlation with exposure to the substrate regimes (excess, limitation and starvation), but penicillin productivity showed an inverse relation with the intracellular glucose level (Wang, Zhao, et al, ).…”

Section: Quantitative Metabolomics and Its Application In Systems Metmentioning

confidence: 99%

“…Instead, a much better reproduction can be obtained at scale-down simulators with longer circulation times. This suggests that the circulation time distribution plays a major role in the ultimate outcome and therefore population balances must be taken in account (Tikhomirova, Taraskevich, & Ponomarenko, 2018).…”

Section: Metabolomics-assisted Systems Biology and Synthetic Biologmentioning

confidence: 99%

Coupled metabolic‐hydrodynamic modeling enabling rational scale‐up of industrial bioprocesses

Wang

Haringa

Tang

et al. 2019

Biotech & Bioengineering

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Metabolomics aims to address what and how regulatory mechanisms are coordinated to achieve flux optimality, different metabolic objectives as well as appropriate adaptations to dynamic nutrient availability. Recent decades have witnessed that the integration of metabolomics and fluxomics within the goal of synthetic biology has arrived at generating the desired bioproducts with improved bioconversion efficiency. Absolute metabolite quantification by isotope dilution mass spectrometry represents a functional readout of cellular biochemistry and contributes to the establishment of metabolic (structured) models required in systems metabolic engineering. In industrial practices, population heterogeneity arising from fluctuating nutrient availability frequently leads to performance losses, that is reduced commercial metrics (titer, rate, and yield). Hence, the development of more stable producers and more predictable bioprocesses can benefit from a quantitative understanding of spatial and temporal cell-to-cell heterogeneity within industrial bioprocesses. Quantitative metabolomics analysis and metabolic modeling applied in computational fluid dynamics (CFD)-assisted scale-down simulators that mimic industrial heterogeneity such as fluctuations in nutrients, dissolved gases, and other stresses can procure informative clues for coping with issues during bioprocessing scale-up. In previous studies, only limited insights into the hydrodynamic conditions inside the industrial-scale bioreactor have been obtained, which makes case-by-case scale-up far from straightforward. Tracking the flow paths of cells circulating in large-scale bioreactors is a highly valuable tool for evaluating cellular performance in production tanks. The "lifelines" or "trajectories" of cells in industrial-scale bioreactors can be captured using Euler-Lagrange CFD simulation. This novel methodology can be further coupled with metabolic (structured) models to provide not only a statistical analysis of cell lifelines triggered by the environmental fluctuations but also a global assessment of the metabolic response to heterogeneity inside an industrial bioreactor. For the future, the industrial design should be dependent on the computational framework, and this integration work will allow bioprocess scale-up to the industrial scale with an end in mind. K E Y W O R D SCFD, Euler-Langrange, metabolic model, metabolomics, population heterogeneity, scale down

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“…(Schmidt 2005 ). In contrast, semi-continuous and continuous processes can be operated in a reduced-sized bioreactor with good productivity (Tikhomirova et al 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Evaluating the potential of semi-continuous itaconic acid fermentation by Aspergillus terreus: operational profile and experiences

Hülber-Beyer,

Bélafi-Bakó,

Rózsenberszki

et al. 2023

World J Microbiol Biotechnol

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Itaconic acid is an important bio-based chemical. The present study aims to evaluate the applicability of semi-continuous fermentation technique for itaconic acid production by Aspergillus terreus. The fermentation is planned to be connected with bipolar membrane electrodialysis unit for acid recovery. This process allows the reuse of residual glucose from the effluent. Our particular attention was focused on the effect of glucose concentration. Two different glucose supplementation strategies were tested: constant glucose concentration in the refilling medium and adjusted glucose concentration in order to maintain a continuously high – 120 g/L – glucose concentration in the fermentor. The itaconic acid titre, yield and productivity for the 24 h time periods between draining/refilling interventions were investigated. The constantly high glucose concentration in the fermentor resulted in doubled biomass formation. The average itaconic acid titre was 32.9 ± 2.7 g/L. The producing strain formed numerous spores during semi-continuous fermentation that germinated continuously. Yield and volumetric productivity showed a periodic pattern during the procedure.

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The role of laboratory-scale bioreactors at the semi-continuous and continuous microbiological and biotechnological processes

Cited by 11 publications

References 85 publications

A scaled‐down model for the translation of bacteriophage culture to manufacturing scale

A scaled‐down model for the translation of bacteriophage culture to manufacturing scale

Coupled metabolic‐hydrodynamic modeling enabling rational scale‐up of industrial bioprocesses

Evaluating the potential of semi-continuous itaconic acid fermentation by Aspergillus terreus: operational profile and experiences

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