Single-use stirred tank bioreactors on a 10-mL scale operated in a magnetic-inductive bioreaction block for 48 bioreactors were equipped with individual stirrer-speed tracing, as well as individual DO- and pH-monitoring and control. A Hall-effect sensor system was integrated into the bioreaction block to measure individually the changes in magnetic field density caused by the rotating permanent magnets. A restart of the magnetic inductive drive was initiated automatically each time a Hall-effect sensor indicates one non-rotating gas-inducing stirrer. Individual DO and pH were monitored online by measuring the fluorescence decay time of two chemical sensors immobilized at the bottom of each single-use bioreactor. Parallel DO measurements were shown to be very reliable and independently from the fermentation media applied in this study for the cultivation of Escherichia coli and Saccharomyces cerevisiae. The standard deviation of parallel pH measurements was pH 0.1 at pH 7.0 at the minimum and increased to a standard deviation of pH 0.2 at pH 6.0 or at pH 8.5 with the complex medium applied for fermentations with S. cerevisiae. Parallel pH-control was thus shown to be meaningful with a tolerance band around the pH set-point of +/- pH 0.2 if the set-point is pH 6.0 or lower.
Based on electromagnetic simulations as well as on computational fluid dynamics simulations gas-inducing impellers and their magnetic inductive drive were optimized for stirred-tank reactors on a 10 ml-scale arranged in a bioreaction block with 48 bioreactors. High impeller speeds of up to 4,000 rpm were achieved at very small electrical power inputs (63 W with 48 bioreactors). The maxima of local energy dissipation in the reaction medium were estimated to be up to 50 W L(-1) at 2,800 rpm. Total power input and local energy dissipation are thus well comparable to standard stirred-tank bioreactors. A prototype fluorescence reader for 8 bioreactors with immobilized fluorometric sensor spots was applied for online measurement of dissolved oxygen concentration making use of the phase detection method. A self-optimizing scheduling software was developed for parallel control of 48 bioreactors with a liquid-handling system for automation of titration and sampling. It was shown on the examples of simple parallel batch cultivations of Escherichia coli with different media compositions that high cell densities of up to 16.5 g L(-1) dry cell mass can be achieved without pH-control within 5 h with a high parallel reproducibility (standard deviation<3.5%, n=48) due to the high oxygen transfer capability of the gas-inducing stirred-tank bioreactors.
There have been two errors in the last two paragraphs of the Introduction. The correct version of these paragraphs is listed in the following:Compared to the fully controlled laboratory stirredtank bioreactor all of these approaches lack important features. The reported maximum oxygen transfer coefficients are rather low (<0.11 s À1 ), no closed-loop control of pH and or DO is available and fed-batch operation is not possible. This paper presents new methods and devices for high-throughput bioprocess design on a 10-ml scale. Forty-eight bioreactors equipped with a magnetically driven gas-inducing impeller ensuring high oxygen transfer coefficients of up to 0.4 s À1 [15][16][17] are operated sterile in a bioreaction block providing an electromagnetic drive, heat exchangers and sterile gas supply. A prototype sensor block is applied for individual DO-measurements via fluorescence lifetime of fluorophors immobilized inside the milliliter-scale bioreactors. The automation of titration, feeding and sampling is realized by a liquid-handling system. The development of a self-optimizing scheduling system for effective parallel control and data acquisition of 48 bioreactors is outlined. Forty-eight parallel operation of E. coli batch processes with different media compositions are studied on a 10-ml scale. Figure 9 was printed without y-axis title. The complete figure is printed below:The online version of the original article can be found at http:// dx
To verify the reproducibility of cultivations of Escherichia coli in novel millilitre-scale bioreactors, fully automated fed-batch cultivation was performed in seven parallel-operated ml-scale bioreactors with an initial volume of 10 ml/reactor. The process was automatically controlled by a liquid-handling system responsible for glucose feeding, titration and sampling. Atline analysis (carried out externally of the reaction vessel with a short time delay) comprised automated pH and attenuance measurements. The partial pressure of oxygen (pO2) was measured online by a novel fluorimetric sensor block measuring the fluorescence lifetime of fluorophors immobilized inside the millilitre-scale bioreactors. Within a process time of 14.6 h, the parallel cultivation yielded a dry cell weight of 36.9+/-0.9 g.l(-1). Atline pH measurements were characterized by an S.D. of <1.1% throughout the process. Computational-fluid-dynamics simulation of single-phase flow yields a mean power input of 21.9 W.l(-1) at an impeller speed of 2800 rev./min corresponding to a power number (NP) of 3.7.
bedingungen parallel zu testen. Durch die Modulform der Membranfestbettreaktoren ist in der weiteren Prozessentwicklung ein einfaches Scale-up möglich.Aufgrund der gewählten Immobilisierungsbedingungen und der verwendeten Membranen werden die Enzyme reversibel gebunden. Bei einem Verlust der Enzymaktivität oder bei einem gewünschten Wechsel der Enzymaktivität, kann das bereits immobilisierte Enzym schnell und vollständig von der Membran eluiert werden. Nach der Reaktivierung der Membran kann die erneute Enzymbindung erfolgen. Die eingesetzten Membranen zeigen sich für nachfolgende Immobilisierungen gleiche Bindungskapazitäten. Das vorgestellte Verfahren ermöglicht eine zeitsparende Prozessentwicklung.
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