Microlitre/millilitre shaken bioreactors in fermentative and biotransformation processes – a review

Fernandes, Pedro; Cabral, Joaquim M. S.

doi:10.1080/10242420600667684

Cited by 48 publications

(39 citation statements)

References 88 publications

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“…To reduce the quantity of material required, and enable a more comprehensive study of the bioprocess, smaller scale models have been investigated. To date, models that make good predictions at the 10-100 mL scale exist (Betts and Baganz, 2006;Gill et al, 2008;Pampel et al, 2008), however, in recent years there has been an increased interest in models that are based on microtiter plate technology (Duetz, 2007;Fernandes and Cabral, 2006;Islam et al, 2007Islam et al, , 2008. These systems have the advantage that only milliliters of material are required to predict large-scale operation and that a wider range of operating parameters can rapidly be investigated in parallel.…”

Section: Introductionmentioning

confidence: 97%

Ultra scale‐down prediction using microwell technology of the industrial scale clarification characteristics by centrifugation of mammalian cell broths

Tait

Aucamp

Bugeon

et al. 2009

Biotech & Bioengineering

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This article describes how a combination of an ultra scale-down (USD) shear device feeding a microwell centrifugation plate may be used to provide a prediction of how mammalian cell broth will clarify at scale. In particular a method is described that is inherently adaptable to a robotic platform and may be used to predict how the flow rate and capacity (equivalent settling area) of a centrifuge and the choice of feed zone configuration may affect the solids carry over in the supernatant. This is an important consideration as the extent of solids carry over will determine the required size and lifetime of a subsequent filtration stage or the passage of fine particulates and colloidal material affecting the performance and lifetime of chromatography stages. The extent of solids removal observed in individual wells of a microwell plate during centrifugation is shown to correlate with the vertical and horizontal location of the well on the plate. Geometric adjustments to the evaluation of the equivalent settling area of individual wells (Sigma(M)) results in an improved prediction of solids removal as a function of centrifuge capacity. The USD centrifuge settling characteristics need to be as for a range of equivalent flow rates as may be experienced at an industrial scale for a machine of different shear characteristics in the entry feed zone. This was shown to be achievable with two microwell-plate based measurements and the use of varying fill volumes in the microwells to allow the rapid study of a fivefold range of equivalent flow rates (i.e., at full scale for a particular industrial centrifuge) and the effect of a range of feed configurations. The microwell based USD method was used to examine the recovery of CHO-S cells, prepared in a 5 L reactor, at different points of growth and for different levels of exposure to shear post reactor. The combination of particle size distribution measurements of the cells before and after shear and the effect of shear on the solids remaining after centrifugation rate provide insight into the state of the cells throughout the fermentation and the ease with which they and accumulated debris may be removed by continuous centrifugation. Hence bioprocess data are more readily available to help better integrate cell culture and cell removal stages and resolve key bioprocess design issues such as choice of time of harvesting and the impact on product yield and contaminant carry over. Operation at microwell scale allows data acquisition and bioprocess understanding over a wide range of operating conditions that might not normally be achieved during bioprocess development.

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Section: Introductionmentioning

confidence: 97%

Ultra scale‐down prediction using microwell technology of the industrial scale clarification characteristics by centrifugation of mammalian cell broths

Tait

Aucamp

Bugeon

et al. 2009

Biotech & Bioengineering

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“…The current challenge in the further development of high throughput microreactor systems is the increase of the measurement and control possibilities. [1][2][3][4][5] During this moment, there is a strong inverse relationship between the level of experimental throughput and the amount of information that can be obtained. 6 Cultivations performed in bench scale bioreactors yield reliable and information rich data, especially because these bioreactors are equipped with sophisticated measurement and control devices.…”

Section: Introductionmentioning

confidence: 98%

Aerobic batch cultivation in micro bioreactor with integrated electrochemical sensor array

Leeuwen

Krommenhoek

Heijnen

et al. 2009

Biotechnology Progress

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Aerobic batch cultivations of Candida utilis were carried out in two micro bioreactors with a working volume of 100 muL operated in parallel. The dimensions of the micro bioreactors were similar as the wells in a 96-well microtiter plate, to preserve compatibility with the current high-throughput cultivation systems. Each micro bioreactor was equipped with an electrochemical sensor array for the online measurement of temperature, pH, dissolved oxygen, and viable biomass concentration. Furthermore, the CO(2) production rate was obtained from the online measurement of cumulative CO(2) production during the cultivation. The online data obtained by the sensor array and the CO(2) production measurements appeared to be very reproducible for all batch cultivations performed and were highly comparable to measurement results obtained during a similar aerobic batch cultivation carried out in a conventional 4L bench-scale bioreactor. Although the sensor chip certainly needs further improvement on some points, this work clearly shows the applicability of electrochemical sensor arrays for the monitoring of parallel micro-scale fermentations, e.g. using the 96-well microtiterplate format.

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“…Nowadays, a huge variety of miniaturized bioreactors has been described that addresses the aforementioned challenges (reviewed in Betts and Baganz, 2006;Fernandes and Cabral, 2006;Kumar et al, 2004;Schäpper et al, 2009;Weuster-Botz, 2005). Among these systems are also parallelized microbioractors such as arrays of miniaturized stirred tanks in which process control is realized by liquid dosing via a pipetting robot (Puskeiler et al, 2005) or modified 24-well MTPs in which the pH-value can be controlled by dispensing NH 3 and CO 2 via a sparge membrane (Isett et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Microfluidic biolector—microfluidic bioprocess control in microtiter plates

Funke

Buchenauer

Schnakenberg

et al. 2010

Biotech & Bioengineering

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In industrial-scale biotechnological processes, the active control of the pH-value combined with the controlled feeding of substrate solutions (fed-batch) is the standard strategy to cultivate both prokaryotic and eukaryotic cells. On the contrary, for small-scale cultivations, much simpler batch experiments with no process control are performed. This lack of process control often hinders researchers to scale-up and scale-down fermentation experiments, because the microbial metabolism and thereby the growth and production kinetics drastically changes depending on the cultivation strategy applied. While small-scale batches are typically performed highly parallel and in high throughput, large-scale cultivations demand sophisticated equipment for process control which is in most cases costly and difficult to handle. Currently, there is no technical system on the market that realizes simple process control in high throughput. The novel concept of a microfermentation system described in this work combines a fiber-optic online-monitoring device for microtiter plates (MTPs)--the BioLector technology--together with microfluidic control of cultivation processes in volumes below 1 mL. In the microfluidic chip, a micropump is integrated to realize distinct substrate flow rates during fed-batch cultivation in microscale. Hence, a cultivation system with several distinct advantages could be established: (1) high information output on a microscale; (2) many experiments can be performed in parallel and be automated using MTPs; (3) this system is user-friendly and can easily be transferred to a disposable single-use system. This article elucidates this new concept and illustrates applications in fermentations of Escherichia coli under pH-controlled and fed-batch conditions in shaken MTPs.

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Microlitre/millilitre shaken bioreactors in fermentative and biotransformation processes – a review

Cited by 48 publications

References 88 publications

Ultra scale‐down prediction using microwell technology of the industrial scale clarification characteristics by centrifugation of mammalian cell broths

Ultra scale‐down prediction using microwell technology of the industrial scale clarification characteristics by centrifugation of mammalian cell broths

Aerobic batch cultivation in micro bioreactor with integrated electrochemical sensor array

Microfluidic biolector—microfluidic bioprocess control in microtiter plates

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