41. Dörr M, Fibinger MPC, Last D, Schmidt S, Santos-Aberturas J, Böttcher D, Hummel A,
Vickers C, Voss M, Bornscheuer UT (2016) Fully automatized high-throughput enzyme
library screening using a robotic platform. Biotechnol Bioeng 113:1421–1432
42. Haby B, Hans S, Anane E, Sawatzki A, Krausch N, Neubauer P, Cruz Bournazou MN (2019)
Integrated robotic mini bioreactor platform for automated, parallel microbial cultivation with
online data handling and process control. SLAS Technol 24:569–582
43. Unthan S, Radek A, Wiechert W, Oldiges M, Noack S (2015) Bioprocess automation on a
mini pilot plant enables fast quantitative microbial phenotyping. Microb Cell Factories 14:32
44. Lattermann C, Büchs J (2015) Microscale and miniscale fermentation and screening. Curr
Opin Biotechnol 35:1–6
45. Hemmerich J, Noack S, Wiechert W, Oldiges M (2018) Microbioreactor systems for accelerated bioprocess development. Biotechnol J 13:1–9
46. Lara AR, Galindo E, Ramírez OT, Palomares LA (2006) Living with heterogeneities in
bioreactors: understanding the effects of environmental gradients on cells. Mol Biotechnol
34:355–382
47. Oldshue JY (1966) Fermentation mixing scale-up techniques. Biotechnol Bioeng 8:3–24
48. Oosterhuis NMG (1984) Scale-up of bioreactors. TU Delft 162
49. Enfors SO, Jahic M, Rozkov A, Xu B, Hecker M, Jürgen B, Krüger E, Schweder T, Hamer G,
O’Beirne D, Noisommit-Rizzi N, Reuss M, Boone L, Hewitt C, McFarlane C, Nienow A,
Kovacs T, Trägårdh C, Fuchs L, Revstedt J, Friberg PC, Hjertager B, Blomsten G,
Skogman H, Hjort S, Hoeks F, Lin HY, Neubauer P, Van der Lans R, Luyben K, Vrabel P,
Manelius A, Manelius Å (2001) Physiological responses to mixing in large scale bioreactors. J
Biotechnol 85:175–185
50. Larsson G, Törnkvist M, Ståhl Wernersson E, Trägårdh C, Noorman H, Enfors SO (1996)
Substrate gradients in bioreactors: origin and consequences. Bioprocess Eng 14:281–289
51. Brand E, Junne S, Anane E, Cruz-Bournazou MN, Neubauer P (2018) Importance of the
cultivation history for the response of Escherichia coli to oscillations in scale-down experiments. Bioprocess Biosyst Eng 41:1305–1313
52. Sweere APJ, Luyben KCAM, Kossen NWF (1987) Regime analysis and scale-down: tools to
investigate the performance of bioreactors. Enzym Microb Technol 9:386–398
53. Lin HY, Mathiszik B, Xu B, Enfors SO, Neubauer P (2001) Determination of the maximum
specific uptake capacities for glucose and oxygen in glucose-limited fed-batch cultivations of
Escherichia coli. Biotechnol Bioeng 73:347–357
54. Bylund F, Collet E, Larsson G, Enfors SO, Larsson G (1998) Substrate gradient formation in
the large-scale bioreactor lowers cell yield and increases by-product formation. Bioprocess
Eng 18:171–180
55. Neubauer P, Häggström L, Enfors SO (1995) Influence of substrate oscillations on acetate
formation and growth yield in Escherichia coli glucose limited fed-batch cultivations.
Biotechnol Bioeng 47:139–146
56. Xu B, Jahic M, Blomsten G, Enfors SO (1999) Glucose overflow metabolism and mixed-acid
fermentation in aerobic large-scale fed-batch processes with Escherichia coli. Appl Microbiol
Biotechnol 51:564–571
57. Nienow AW (2006) Reactor engineering in large scale animal cell culture. Cytotechnology
50:9–33
58. Simen JD, Löffler M, Jäger G, Schäferhoff K, Freund A, Matthes J, Müller J, Takors R,
Feuer R, von Wulffen J, Lischke J, Ederer M, Knies D, Kunz S, Sawodny O, Riess O,
Sprenger G, Trachtmann N, Nieß A, Broicher A (2017) Transcriptional response of
Escherichia coli to ammonia and glucose fluctuations. Microb Biotechnol 10:858–872
59. Spann R, Glibstrup J, Pellicer-Alborch K, Junne S, Neubauer P, Roca C, Kold D, Lantz AE,
Sin G, Gernaey KV, Krühne U (2019) CFD predicted pH gradients in lactic acid bacteria
cultivations. Biotechnol Bioeng 116:769–780
Potential of Integrating Model-Based Design of Experiments Approaches and. . .
25
Vickers C, Voss M, Bornscheuer UT (2016) Fully automatized high-throughput enzyme
library screening using a robotic platform. Biotechnol Bioeng 113:1421–1432
42. Haby B, Hans S, Anane E, Sawatzki A, Krausch N, Neubauer P, Cruz Bournazou MN (2019)
Integrated robotic mini bioreactor platform for automated, parallel microbial cultivation with
online data handling and process control. SLAS Technol 24:569–582
43. Unthan S, Radek A, Wiechert W, Oldiges M, Noack S (2015) Bioprocess automation on a
mini pilot plant enables fast quantitative microbial phenotyping. Microb Cell Factories 14:32
44. Lattermann C, Büchs J (2015) Microscale and miniscale fermentation and screening. Curr
Opin Biotechnol 35:1–6
45. Hemmerich J, Noack S, Wiechert W, Oldiges M (2018) Microbioreactor systems for accelerated bioprocess development. Biotechnol J 13:1–9
46. Lara AR, Galindo E, Ramírez OT, Palomares LA (2006) Living with heterogeneities in
bioreactors: understanding the effects of environmental gradients on cells. Mol Biotechnol
34:355–382
47. Oldshue JY (1966) Fermentation mixing scale-up techniques. Biotechnol Bioeng 8:3–24
48. Oosterhuis NMG (1984) Scale-up of bioreactors. TU Delft 162
49. Enfors SO, Jahic M, Rozkov A, Xu B, Hecker M, Jürgen B, Krüger E, Schweder T, Hamer G,
O’Beirne D, Noisommit-Rizzi N, Reuss M, Boone L, Hewitt C, McFarlane C, Nienow A,
Kovacs T, Trägårdh C, Fuchs L, Revstedt J, Friberg PC, Hjertager B, Blomsten G,
Skogman H, Hjort S, Hoeks F, Lin HY, Neubauer P, Van der Lans R, Luyben K, Vrabel P,
Manelius A, Manelius Å (2001) Physiological responses to mixing in large scale bioreactors. J
Biotechnol 85:175–185
50. Larsson G, Törnkvist M, Ståhl Wernersson E, Trägårdh C, Noorman H, Enfors SO (1996)
Substrate gradients in bioreactors: origin and consequences. Bioprocess Eng 14:281–289
51. Brand E, Junne S, Anane E, Cruz-Bournazou MN, Neubauer P (2018) Importance of the
cultivation history for the response of Escherichia coli to oscillations in scale-down experiments. Bioprocess Biosyst Eng 41:1305–1313
52. Sweere APJ, Luyben KCAM, Kossen NWF (1987) Regime analysis and scale-down: tools to
investigate the performance of bioreactors. Enzym Microb Technol 9:386–398
53. Lin HY, Mathiszik B, Xu B, Enfors SO, Neubauer P (2001) Determination of the maximum
specific uptake capacities for glucose and oxygen in glucose-limited fed-batch cultivations of
Escherichia coli. Biotechnol Bioeng 73:347–357
54. Bylund F, Collet E, Larsson G, Enfors SO, Larsson G (1998) Substrate gradient formation in
the large-scale bioreactor lowers cell yield and increases by-product formation. Bioprocess
Eng 18:171–180
55. Neubauer P, Häggström L, Enfors SO (1995) Influence of substrate oscillations on acetate
formation and growth yield in Escherichia coli glucose limited fed-batch cultivations.
Biotechnol Bioeng 47:139–146
56. Xu B, Jahic M, Blomsten G, Enfors SO (1999) Glucose overflow metabolism and mixed-acid
fermentation in aerobic large-scale fed-batch processes with Escherichia coli. Appl Microbiol
Biotechnol 51:564–571
57. Nienow AW (2006) Reactor engineering in large scale animal cell culture. Cytotechnology
50:9–33
58. Simen JD, Löffler M, Jäger G, Schäferhoff K, Freund A, Matthes J, Müller J, Takors R,
Feuer R, von Wulffen J, Lischke J, Ederer M, Knies D, Kunz S, Sawodny O, Riess O,
Sprenger G, Trachtmann N, Nieß A, Broicher A (2017) Transcriptional response of
Escherichia coli to ammonia and glucose fluctuations. Microb Biotechnol 10:858–872
59. Spann R, Glibstrup J, Pellicer-Alborch K, Junne S, Neubauer P, Roca C, Kold D, Lantz AE,
Sin G, Gernaey KV, Krühne U (2019) CFD predicted pH gradients in lactic acid bacteria
cultivations. Biotechnol Bioeng 116:769–780
Potential of Integrating Model-Based Design of Experiments Approaches and. . .
25