Advertisement

Optimization of Insect Cell Based Protein Production Processes - Online Monitoring, Expression Systems, Scale Up

  • Damir Druzinec
  • Denise Salzig
  • Alexander Brix
  • Matthias Kraume
  • Andreas Vilcinskas
  • Christian Kollewe
  • Peter Czermak
Chapter
Part of the Advances in Biochemical Engineering/Biotechnology book series (ABE, volume 136)

Abstract

Due to the increasing use of insect cell based expression systems in research and industrial recombinant protein production, the development of efficient and reproducible production processes remains a challenging task. In this context, the application of online monitoring techniques is intended to ensure high and reproducible product qualities already during the early phases of process development. In the following chapter, the most common transient and stable insect cell based expression systems are briefly introduced. Novel applications of insect cell based expression systems for the production of insect derived antimicrobial peptides/proteins (AMPs) are discussed using the example of G. mellonella derived gloverin. Suitable in situ sensor techniques for insect cell culture monitoring in disposable and common bioreactor systems are outlined with respect to optical and capacitive sensor concepts. Since scale up of production processes is one of the most critical steps in process development, a conclusive overview is given about scale up aspects for industrial insect cell culture processes.

Graphical Abstract

Keywords

BEVS Drosophila S2 FBRM Gloverin In situ monitoring Scale up 

Notes

Acknowledgments

The researchers would like to thank the Hessen State Ministry of Higher Education, Research and Arts for the financial support within the Hessen initiative for scientific and economic excellence (LOEWE).

References

  1. 1.
    Weber W, Fussenegger M (2009) Insect cell-based recombinant protein production. In: Cell and tissue reaction engineering principles and practice. Springer, Berlin, pp 263–277. doi: 10.1007/978-3-540-68182-3
  2. 2.
    Grace TDC (1962) Establishment of four strains of cells from insect tissues grown in vitro. Nature 195(4843):788–789Google Scholar
  3. 3.
    Smagghe G, Goodman C, Stanley D (2009) Insect cell culture and applications to research and pest management. In Vitro Cell Dev Biol Animal 45(3):93–105. doi: 10.1007/s11626-009-9181-x Google Scholar
  4. 4.
    O’Reilly DR, Miller L, Luckow VA (1994) Baculoviruses; genetic vectors; gene expression; genetics; laboratory manuals. Oxford University Press, New YorkGoogle Scholar
  5. 5.
    Vaughn J, Goodwin R, Tompkins G, McCawley P (1977) The establishment of two cell lines from the insect spodoptera frugiperda (lepidoptera; noctuidae). In Vitro Cell Dev Biol Plant 13(4):213–217. doi: 10.1007/bf02615077
  6. 6.
    Wang P, Granados RR, Shuler ML (1992) Studies on serum-free culture of insect cells for virus propagation and recombinant protein production. J Invertebr Pathol 59(1):46–53. doi: 10.1016/0022-2011(92)90110-p Google Scholar
  7. 7.
    Hink WF, Thomsen DR, Davidson DJ, Meyer AL, Castellino FJ (1991) Expression of three recombinant proteins using baculovirus vectors in 23 insect cell lines. Biotechnol Prog 7(1):9–14. doi: 10.1021/bp00007a002 Google Scholar
  8. 8.
    Altmann F, Staudacher E, Wilson IH, März L (1999) Insect cells as hosts for the expression of recombinant glycoproteins. Glycoconj J 16(2):109–123. doi: 10.1023/a:1026488408951 Google Scholar
  9. 9.
    Jarvis DL, Kawar ZS, Hollister JR (1998) Engineering N-glycosylation pathways in the baculovirus-insect cell system. Curr Opin Biotechnol 9(5):528–533. doi: 10.1016/s0958-1669(98)80041-4 Google Scholar
  10. 10.
    Schneider I (1972) Cell lines derived from late embryonic stages of Drosophila melanogaster. J Embryol Exp Morphol 27(2):353–365Google Scholar
  11. 11.
    Echalier G, Ohanessian A (1969) Isolation, in tissue culture, of drosophila melangaster cell lines. Comtes rend hebdomadaires des Seances de L’Academie des Sci 268(13):1771–1773Google Scholar
  12. 12.
    Tian JX, Li CY, Zheng GL, Li GX, Wang P, Granados RR (2004) A new cell clone derived from trichoplusia ni Tn5B1-4 cells. Insect Sci 11(3):165–171. doi: 10.1111/j.1744-7917.2004.tb00236.x Google Scholar
  13. 13.
    Wickham TJ, Davis T, Granados RR, Shuler ML, Wood HA (1992) Screening of insect cell lines for the production of recombinant proteins and infectious virus in the baculovirus expression system. Biotechnol Prog 8(5):391–396. doi: 10.1021/bp00017a003 Google Scholar
  14. 14.
    Luckow VA, Summers MD (1988) Trends in the development of baculovirus expression vectors. Nat Biotech 6(1):47–55Google Scholar
  15. 15.
    Vlak JM, Schouten A, Usmany M, Belsham GJ, Klinge-Roode EC, Maule AJ, Van Lent JWM, Zuidema D (1990) Expression of cauliflower mosaic virus gene I using a baculovirus vector based upon the p10 gene and a novel selection method. Virology 179(1):312–320. doi: 10.1016/0042-6822(90)90299-7 Google Scholar
  16. 16.
    Jarvis DL, Weinkauf C, Guarino LA (1996) Immediate-early baculovirus vectors for foreign gene expression in transformed or infected insect cells. Protein Expr Purif 8(2):191–203. doi: 10.1006/prep.1996.0092 Google Scholar
  17. 17.
    Luckow VA, Lee SC, Barry GF, Olins PO (1993) Efficient generation of infectious recombinant baculoviruses by site-specific transposon-mediated insertion of foreign genes into a baculovirus genome propagated in E. coli. J virol 67(8):4566–4579Google Scholar
  18. 18.
    Dyring C (2011) Optimising the drosophila S2 expression system for production of therapeutic vaccines. Bioprocess J 10(2):28–35Google Scholar
  19. 19.
    Bunch TA, Grinblat Y, Goldstein LSB (1988) Characterization and use of the drosophila metallothionein promoter in cultured drosophila melanogaster cells. Nucleic acids res 16(3):1043–1061. doi: 10.1093/nar/16.3.1043 Google Scholar
  20. 20.
    Chung YT, Keller EB (1990) Positive and negative regulatory elements mediating transcription from the drosophila melanogaster actin 5C distal promoter. Mol Cell Bio 10(12):6172–6180. doi: 10.1128/mcb.10.12.6172 Google Scholar
  21. 21.
    Pfeifer TA, Hegedus DD, Grigliatti TA, Theilmann DA (1997) Baculovirus immediate-early promoter-mediated expression of the Zeocin TM resistance gene for use as a dominant selectable marker in dipteran and lepidopteran insect cell lines. Gene 188(2):183–190. doi: 10.1016/s0378-1119(96)00756-1 Google Scholar
  22. 22.
    Bernard AR, Kost TA, Overton L, Cavegn C, Young J, Bertrand M, Yahia-Cherif Z, Chabert C, Mills A (1994) Recombinant protein expression in a drosophila cell line: comparison with the baculovirus system. Cytotechnology 15(1):139–144. doi: 10.1007/bf00762388 Google Scholar
  23. 23.
    Verma R, Boleti E, George AJT (1998) Antibody engineering: comparison of bacterial, yeast, insect and mammalian expression systems. J Immunol Methods 216(1–2):165–181. doi: 10.1016/s0022-1759(98)00077-5 Google Scholar
  24. 24.
    Mirzaei M, Xu Y, Elias CB, Prakash S (2009) Nonviral production of human interleukin-7 in spodoptera frugiperda insect cells as a soluble recombinant protein. J Biomed Biot 2009:527. doi: 10.1155/2009/637942 Google Scholar
  25. 25.
    Vilcinskas A (2011) ANTI-infective therapeutics from the lepidopteran model host galleria mellonella. Curr Phar Des 17(13):1240–1245. doi: 10.2174/138161211795703799 Google Scholar
  26. 26.
    Axen A, Carlsson A, Engstrom A, Bennich H (1997) Gloverin, an antibacterial protein from the immune hemolymph of hyalophora pupae. Eur J Biochem 247(2):614–619. doi: 10.1111/j.1432-1033.1997.00614.x Google Scholar
  27. 27.
    Lundstrom A, Liu G, Kang DW, Berzins K, Steiner H (2002) Trichoplusia ni gloverin, an inducible immune gene encoding an antibacterial insect protein. Insect Biochem Mol Biol 32(7):795–801. doi: 10.1016/s0965-1748(01)00162-x Google Scholar
  28. 28.
    Mackintosh JA, Gooley AA, Karuso PH, Beattie AJ, Jardine DR, Veal DA (1998) A gloverin-like antibacterial protein is synthesized in helicoverpa armigera following bacterial challenge. Dev Comp Immunol 22(4):387–399. doi: 10.1016/s0145-305x(98)00025-1 Google Scholar
  29. 29.
    Kawaoka S, Katsuma S, Daimon T, Isono R, Omuro N, Mita K, Shimada T (2008) Functional analysis of four gloverin-like genes in the silkworm, bombyx mori. Arch Insect Biochem Physiol 67(2):87–96. doi: 10.1002/arch.20223 Google Scholar
  30. 30.
    Hwang J, Kim Y (2011) RNA interference of an antimicrobial peptide, gloverin, of the beet armyworm, spodoptera exigua, enhances susceptibility to b. thuringiensis. J Invertebr Patho 108(3):194–200. doi: 10.1016/j.jip.2011.09.003 Google Scholar
  31. 31.
    Xu X–X, Zhong X, Yi H-Y, Yu X-Q (2012) Manduca sexta gloverin binds microbial components and is active against bacteria and fungi. Dev Comp Immunol 38(2):275–284. doi: 10.1016/j.dci.2012.06.012 Google Scholar
  32. 32.
    Moreno-Habel DA, Biglang-awa IM, Dulce A, Luu DD, Garcia P, Weers PMM, Haas-Stapleton EJ (2012) Inactivation of the budded virus of autographa californica M nucleopolyhedrovirus by gloverin. J Invertebr Pathol 110(1):92–101. doi: 10.1016/j.jip.2012.02.007 Google Scholar
  33. 33.
    Czermak P, Pörtner R, Brix A (2009) Special engineering aspects. In: Cell and tissue reaction engineering. principles and practice, Springer, Heidelberg, pp 83–172. doi: 10.1007/978-3-540-68182-3
  34. 34.
    Vojinovic V, Cabral JMS, Fonseca LP (2006) Real-time bioprocess monitoring part I: In situ sensors. Sens Actuators B-Chem 114(2):1083–1091. doi: 10.1016/j.snb.2005.07.059 Google Scholar
  35. 35.
    Sommerfeld S, Strube J (2005) Challenges in biotechnology production—generic processes and process optimization for monoclonal antibodies. Chem Eng Process 44(10):1123–1137. doi: 10.1016/j.cep.2005.03.006 Google Scholar
  36. 36.
    Teixeira AP, Oliveira R, Alves PM, Carrondo MJT (2009) Advances in on-line monitoring and control of mammalian cell cultures: supporting the PAT initiative. Biotechnol Adv 27(6):726–732. doi: 10.1016/j.biotechadv.2009.05.003 Google Scholar
  37. 37.
    Eibl R, Löffelholz C, Eibl D (2010) Single-use bioreactors—an overview. In: Single-use technology in biopharmaceutical manufacture. Wiley J & Sons, Inc., pp 33–51, chapter 4, doi: 10.1002/9780470909997
  38. 38.
    Beutel S, Henkel S (2011) In situ sensor techniques in modern bioprocess monitoring. Appl Microbiol Biotechnol 91(6):1493–1505. doi: 10.1007/s00253-011-3470-5 Google Scholar
  39. 39.
    Landgrebe D, Haake C, Hoepfner T, Beutel S, Hitzmann B, Scheper T, Rhiel M, Reardon KF (2010) On-line infrared spectroscopy for bioprocess monitoring. Appl Microbiol Biotechnol 88(1):11–22. doi: 10.1007/s00253-010-2743-8 Google Scholar
  40. 40.
    Maranga L, Brazao TF, Carrondo MJT (2003) Virus-like particle production at low multiplicities of infection with the baculovirus insect cell system. Biotechnol Bioeng 84(2):245–253. doi: 10.1002/bit.10773 Google Scholar
  41. 41.
    Lindner P, Endres C, Bluma A, Höpfner T, Glindkamp A, Haake C, Landgrebe D, Riechers D, Baumfalk R, Hitzmann B, Scheper T, Reardon KF (2010) Disposable sensor systems. In: single-use technology in biopharmaceutical manufacture. Wiley, pp 67–81, chapter 6. doi: 10.1002/9780470909997
  42. 42.
    Lindner P, Endres C, Bluma A, Höpfner T, Glindkamp A, Haake C, Landgrebe D, Riechers D, Baumfalk R, Hitzmann B, Scheper T, Reardon KF (2011) Disposable sensor systems. In: Eibl R, Eibl D (eds) Single-use technology in biopharmaceutical manufacture. Wiley, Hoboken, pp 67–81. doi: 10.1002/9780470909997, ch6
  43. 43.
    Stuart BH (2004) Infrared spectroscopy: fundamentals and applications. Wiley,Google Scholar
  44. 44.
    Haake C, Landgrebe D, Scheper T, Rhiel M, Rhiel M (2009) Online-infrarotspektroskopie in der bioprozessanalytik. Chem Ing Tech 81(9):1385–1396. doi: 10.1002/cite.200900042 Google Scholar
  45. 45.
    Roychoudhury P, O’Kennedy R, McNeil B, Harvey LM (2007) Multiplexing fibre optic near infrared (NIR) spectroscopy as an emerging technology to monitor industrial bioprocesses. Anal Chim Acta 590(1):110–117. doi: 10.1016/j.aca.2007.03.011 Google Scholar
  46. 46.
    Arnold SA, Crowley J, Woods N, Harvey LM, McNeill B (2003) In-situ near infrared spectroscopy to monitor key analytes in mammalian cell cultivation. Biotechnol Bioeng 84(1):13–19. doi: 10.1002/bit.10738 Google Scholar
  47. 47.
    Rhiel M, Ducommun P, Bolzonella I, Marison I, von Stockar U (2002) Real-time in situ monitoring of freely suspended and immobilized cell cultures based on mid-infrared spectroscopic measurements. Biotechnol Bioeng 77(2):174–185. doi: 10.1002/bit.10134 Google Scholar
  48. 48.
    Henriques JG, Buziol S, Stocker E, Voogd A, Menezes JC (2009) Monitoring mammalian cell cultivations for monoclonal antibody production using near-infrared spectroscopy. Optical Sens Syst Biotechnol 116:73–97. doi: Google Scholar
  49. 49.
    Sellick CA, Hansen R, Jarvis RM, Maqsood AR, Stephens GM, Dickson AJ, Goodacre R (2010) Rapid monitoring of recombinant antibody production by mammalian cell cultures using Fourier transform infrared spectroscopy and chemometrics. Biotechnol Bioeng 106(3):432–442. doi: 10.1002/bit.22707 Google Scholar
  50. 50.
    Petiot E, Bernard-Moulin P, Magadoux T, Geny C, Pinton H, Marc A (2010) In situ quantification of microcarrier animal cell cultures using near-infrared spectroscopy. Process Biochem 45(11):1832–1836. doi: 10.1016/j.procbio.2010.08.010 Google Scholar
  51. 51.
    Riley MR, Rhiel M, Zhou XJ, Arnold MA, Murhammer DW (1997) Simultaneous measurement of glucose and glutamine in insect cell culture media by near infrared spectroscopy. Biotechnol Bioeng 55(1):11–15. doi:10.1002/(sici)1097-0290(19970705)55:1<11::aid-bit2>3.0.co;2-#Google Scholar
  52. 52.
    Zabriskie DW, Humphrey AE (1978) Estimation of fermentation biomass concentration by measuring culture fluorescence. Appl Environ Microbiol 35(2):337–343Google Scholar
  53. 53.
    Li JK, Humphrey AE (1991) Use of fluorometry for monitoring and control of a bioreactor. Biotechnol Bioeng 37(11):1043–1049. doi: 10.1002/bit.260371109 Google Scholar
  54. 54.
    Konstantinov KB, Dhurjati P, Van Dyk T, Majarian W, Larossa R (1993) Real-time compensation of the inner filter effect in high-density bioluminescent cultures. Biotechnol Bioeng 42(10):1190–1198. doi: 10.1002/bit.260421009 Google Scholar
  55. 55.
    Srinivas SP, Mutharasan R (1987) Inner filter effects and their interferences in the interpretation of culture fluorescence. Biotechnol Bioeng 30(6):769–774. doi: 10.1002/bit.260300609 Google Scholar
  56. 56.
    Teixeira AP, Portugal CAM, Carinhas N, Dias JML, Crespo JP, Alves PM, Carrondo MJT, Oliveira R (2009) In situ 2D fluorometry and chemometric monitoring of mammalian cell cultures. Biotechnol Bioeng 102(4):1098–1106. doi: 10.1002/bit.22125 Google Scholar
  57. 57.
    Vivian JT, Callis PR (2001) Mechanisms of tryptophan fluorescence shifts in proteins. Biophys J 80(5):2093–2109Google Scholar
  58. 58.
    Anders K-D, Akhnoukh R, Scheper T, Kretzmer G (1992) Messung der Kulturfluoreszenz zur Überwachung und Charakterisierung von Insektenzellkultivierungen in Bioreaktoren. Chem Ing Tech 64(6):572–573. doi: 10.1002/cite.330640625 Google Scholar
  59. 59.
    Hisiger S, Jolicoeur M (2005) A multiwavelength fluorescence probe: Is one probe capable for on-line monitoring of recombinant protein production and biomass activity? J Biotechnol 117(4):325–336. doi: 10.1016/j.jbiotec.2005.03.004 Google Scholar
  60. 60.
    Teixeira AP, Duarte TM, Carrondo MJT, Alves PM (2011) Synchronous fluorescence spectroscopy as a novel tool to enable pat applications in bioprocesses. Biotechnol Bioeng 108(8):1852–1861. doi: 10.1002/bit.23131 Google Scholar
  61. 61.
    Becker T, Hitzmann B, Muffler K, Poertner R, Reardon KF, Stahl F, Ulber R (2007) Future aspects of bioprocess monitoring. In: Ulber RSD (ed) White biotechnology. Advances in biochemical engineering-biotechnology, vol 105, pp 249–293, doi: Google Scholar
  62. 62.
    Abu-Absi NR, Kenty BM, Cuellar ME, Borys MC, Sakhamuri S, Strachan DJ, Hausladen MC, Li ZJ (2011) Real time monitoring of multiple parameters in mammalian cell culture bioreactors using an in-line Raman spectroscopy probe. Biotechnol Bioeng 108(5):1215–1221. doi: 10.1002/bit.23023 Google Scholar
  63. 63.
    Ulber R, Frerichs JG, Beutel S (2003) Optical sensor systems for bioprocess monitoring. Anal Bioanal Chem 376(3):342–348. doi: 10.1007/s00216-003-1930-1 Google Scholar
  64. 64.
    Weber C, Pohl S, Portner R, Wallrapp C, Kassem M, Geigle P, Czermak P (2007) Cultivation and differentiation of encapsulated hMSC-TERT in a disposable small-scale syringe-like fixed bed reactor. Open Biomed Eng J 1:64–70. doi: 10.2174/187412070701016407 Google Scholar
  65. 65.
    Weber C, Freimark D, Portner R, Pino-Grace P, Pohl S, Wallrapp C, Geigle P, Czermak P (2010) Expansion of human mesenchymal stem cells in a fixed-bed bioreactor system based on non-porous glass carrier–part A: inoculation, cultivation, and cell harvest procedures. Int J Artif Organs 33(8):512–525Google Scholar
  66. 66.
    Weber C, Freimark D, Portner R, Pino-Grace P, Pohl S, Wallrapp C, Geigle P, Czermak P (2010) Expansion of human mesenchymal stem cells in a fixed-bed bioreactor system based on non-porous glass carrier—Part B: modeling and scale up of the system. Int J Artif Organs 33(11):782–795Google Scholar
  67. 67.
    Freimark D, Pino-Grace P, Pohl S, Weber C, Wallrapp C, Geigle P, Portner R, Czermak P (2010) Use of encapsulated stem cells to overcome the bottleneck of cell availability for cell therapy approaches. Transfus Med Hemother 37(2):66–73. doi: 10.1159/000285777 Google Scholar
  68. 68.
    Weber C, Pohl S, Poertner R, Pino-Grace P, Freimark D, Wallrapp C, Geigle P, Czermak P (2010) Production process for stem cell based therapeutic implants: expansion of the production cell line and cultivation of encapsulated cells. Adv Biochem Eng Biotechnol 123:143–162. doi: Google Scholar
  69. 69.
    Weber C (2010) Festbettbasierte Kultivierungsverfahren für die Herstellung zelltherapeutischer Implantate. Ausgabe 278 von Fortschrittberichte VDI/17: Biotechnik, Medizintechnik. VDI-VerlagGoogle Scholar
  70. 70.
    Köneke R, Comte A, Jurgens H, Kohls O, Lam H, Scheper T (1998) Faseroptische Sauerstoffsensoren für Biotechnologie Umwelt- und Lebensmitteltechnik. Chem Ing Tech 70(12):1611–1617. doi: 10.1002/cite.330701224 Google Scholar
  71. 71.
    Kohls O, Scheper T (2000) Setup of a fiber optical oxygen multisensor-system and its applications in biotechnology. Sens Actuators B 70(1–3):121–130. doi: 10.1016/s0925-4005(00)00581-5 Google Scholar
  72. 72.
    Severinghaus JW, Bradley AF (1958) Electrodes for blood pO2 and pCO2 determination. J Appl Physiol 13(3):515–520Google Scholar
  73. 73.
    Cajlakovic M, Bizzarri A, Ribitsch V (2006) Luminescence lifetime-based carbon dioxide optical sensor for clinical applications. Anal Chim Acta 573:57–64. doi: 10.1016/j.aca.2006.05.085 Google Scholar
  74. 74.
    Weigl BH, Wolfbeis OS (1995) Sensitivity studies on optical carbon dioxide sensors based on ion pairing. Sens Actuators, B 28(2):151–156. doi: 10.1016/0925-4005(95)80041-7 Google Scholar
  75. 75.
    Edmonds TE, Flatters NJ, Jones CF, Miller JN (1988) Determination of pH with acid-base indicators: implications for optical fibre probes. Talanta 35(2):103–107. doi: 10.1016/0039-9140(88)80046-8 Google Scholar
  76. 76.
    Li CY, Zhang XB, Han ZX, Akermark B, Sun LC, Shen GL, Yu RQ (2006) A wide pH range optical sensing system based on a sol-gel encapsulated amino-functionalised corrole. Analyst 131(3):388–393. doi: 10.1039/b514510d Google Scholar
  77. 77.
    Dremel BAA, Schmid RD (1992) Optische Sensoren für die Bioprozeß-Kontrolle. Chem Ing Tech 64(6):510–517. doi: 10.1002/cite.330640607 Google Scholar
  78. 78.
    Tan W, Shi Z-R, Kopelman R (1992) Development of submicron chemical fiber optic sensors. Anal Chem 64:2985–2990Google Scholar
  79. 79.
    Kermis HR, Kostov Y, Rao G (2003) Rapid method for the preparation of a robust optical pH sensor. Analyst 128(9):1181–1186. doi: 10.1039/b304902g Google Scholar
  80. 80.
    Glindkamp A, Riechers D, Rehbock C, Hitzmann B, Scheper T, Reardon KF (2010) Sensors in disposable bioreactors status and trends. Advances Biochem Eng biotechnol 115:145–169Google Scholar
  81. 81.
    Hoepfner T, Bluma A, Rudolph G, Lindner P, Scheper T (2010) A review of non-invasive optical-based image analysis systems for continuous bioprocess monitoring. Bioprocess Biosyst Eng 33(2):247–256. doi: 10.1007/s00449-009-0319-8 Google Scholar
  82. 82.
    Bluma A, Hoepfner T, Lindner P, Rehbock C, Beutel S, Riechers D, Hitzmann B, Scheper T (2010) In-situ imaging sensors for bioprocess monitoring: state of the art. Anal Bioanal Chem 398(6):2429–2438. doi: 10.1007/s00216-010-4181-y Google Scholar
  83. 83.
    Frerichs JG, Joeris K, Konstantinov K, Scheper T (2002) Use of an in situ microscope for on-line observation of animal cell cultures. Chem Ing Tech 74(11):1629–1633. doi: 10.1002/1522-2640(20021115)74:11<1629:aid-cite1629>3.0.co;2-7 Google Scholar
  84. 84.
    Joeris K, Frerichs JG, Konstantinov K, Scheper T (2002) In-situ microscopy: Online process monitoring of mammalian cell cultures. Cytotechnology 38(1–2):129–134. doi: 10.1023/a:1021170502775 Google Scholar
  85. 85.
    Anton F, Burzlaff A, Kasper C, Brueckerhoff T, Scheper T (2007) Preliminary study towards the use of in situ microscopy for the online analysis of microcarrier cultivations. Eng Life Sci 7(1):91–96. doi: 10.1002/elsc.200620172 Google Scholar
  86. 86.
    Rudolph G, Lindner P, Gierse A, Bluma A, Martinez G, Hitzmann B, Scheper T (2008) Online monitoring of microcarrier based fibroblast cultivations with in situ microscopy. Biotechnol Bioeng 99(1):136–145. doi: 10.1002/bit.21523 Google Scholar
  87. 87.
    Guez JS, Cassar JP, Wartelle F, Dhulster P, Suhr H (2004) Real time in situ microscopy for animal cell-concentration monitoring during high density culture in bioreactor. J Biotechnol 111(3):335–343. doi: 10.1016/j.jbiotec.2004.04.028 Google Scholar
  88. 88.
    Suhr H, Wehnert G, Schneider K, Bittner C, Scholz T, Geissler P, Jahne B, Scheper T (1995) In situ Microscopy for online characterisation of cell-populations in bioreactors, including cell-concentration measurements by depth from focus. Biotechnol Bioeng 47(1):106–116. doi: 10.1002/bit.260470113 Google Scholar
  89. 89.
    Wei N, You J, Friehs K, Flaschel E, Nattkemper TW (2007) An in situ probe for on-line monitoring of cell density and viability on the basis of dark field microscopy in conjunction with image processing and supervised machine learning. Biotechnol Bioeng 97(6):1489–1500. doi: 10.1002/bit.21368 Google Scholar
  90. 90.
    Wei N, You J, Friehs K, Flaschel E, Nattkemper TW (2007) In situ dark field microscopy for on-line monitoring of yeast cultures. Biotechnol Lett 29(3):373–378. doi: 10.1007/s10529-006-9245-x Google Scholar
  91. 91.
    Sparks RG, Dobbs CL (1993) The use of laser backscatter instumentation for the online measurement of the particle-size distribution of emulsions. Part Part Syst Charact 10:279–289Google Scholar
  92. 92.
    Barrett P, Glennon B (1999) In-line FBRM monitoring of particle size in dilute agitated suspensions. Part Part Syst Charact 16(5):207–211. doi: 10.1002/(sici)1521-4117(199910)16:5<207:aid-ppsc207>3.0.co;2-u Google Scholar
  93. 93.
    Tadayyon A, Rohani S (1998) Determination of particle size distribution by par-tec (R) 100: modeling and experimental results. Part Part Syst Charact 15(3):127–135. doi: 10.1002/(sici)1521-4117(199817)15:3<127:aid-ppsc127>3.0.co;2-b Google Scholar
  94. 94.
    Heath AR, Fawell PD, Bahri PA, Swift JD (2002) Estimating average particle size by focused beam reflectance measurement (FBRM). Part Part Syst Charact 19(2):84–95. doi: 10.1002/1521-4117(200205)19:2<84:aid-ppsc84>3.0.co;2-1 Google Scholar
  95. 95.
    Pearson AP, Glennon B, Kieran PM (2003) Comparison of morphological characteristics of Streptomyces natalensis by image analysis and focused beam reflectance measurement. Biotechnol Prog 19(4):1342–1347. doi: 10.1021/bp025734p Google Scholar
  96. 96.
    Pearson AP, Glennon B, Kieran PM (2004) Monitoring of cell growth using the focused beam reflectance method. J Chem Technol Biotechnol 79(10):1142–1147. doi: 10.1002/jctb.1105 Google Scholar
  97. 97.
    Ge XM, Zhao XQ, Bai FW (2005) Online monitoring and characterization of flocculating yeast cell flocs during continuous ethanol fermentation. Biotechnol Bioeng 90(5):523–531. doi: 10.1002/bit.20391 Google Scholar
  98. 98.
    Grimm LH, Kelly S, Hengstler J, Gobel A, Krull R, Hempel DC (2004) Kinetic studies on the aggregation of aspergillus niger conidia. Biotechnol Bioeng 87(2):213–218. doi: 10.1002/bit.20130 Google Scholar
  99. 99.
    McDonald KA, Jackman AP, Hurst S (2001) Characterization of plant suspension cultures using the focused beam reflectance technique. Biotechnol Lett 23(4):317–324. doi: 10.1023/a:1005646826204 Google Scholar
  100. 100.
    Jeffers P, Raposo S, Lima-Costa ME, Connolly P, Glennon B, Kieran PM (2003) Focussed beam reflectance measurement (FBRM) monitoring of particle size and morphology in suspension cultures of morinda citrifolia and centaurea calcitrapa. Biotechnol Lett 25(23):2023–2028. doi: 10.1023/B:BILE.0000004396.97796.0c Google Scholar
  101. 101.
    Uduman N, Qi Y, Danquah MK, Hoadley AFA (2010) Marine microalgae flocculation and focused beam reflectance measurement. Chem Eng J 162(3):935–940. doi: 10.1016/j.cej.2010.06.046 Google Scholar
  102. 102.
    Davey CL, Davey HM, Kell DB, Todd RW (1993) Introduction to the dielectric estimation of cellular biomass in real time, with special emphasis on measurements at high volume fractions. Anal Chim Acta 279(1):155–161. doi: 10.1016/0003-2670(93)85078-X Google Scholar
  103. 103.
    Stoicheva NG, Davey CL, Markx GH, Kell DB (1989) Dielectric spectroscopy: a rapid method for the determination of solvent biocompatibility during biotransformations. Biocatal Biotransform 2(4):245–255. doi:8992034
  104. 104.
    Degouys V, Cerckel I, Garcia A, Harfield J, Dubois D, Fabry L, Miller AOA (1993) Dielectric spectroscopy of mammalian cells. Cytotechnology 13(3):195–202. doi: 10.1007/bf00749815 Google Scholar
  105. 105.
    Justice C, Leber J, Freimark D, Pino Grace P, Kraume M, Czermak P (2011) Online- and offline- monitoring of stem cell expansion on microcarrier. Cytotechnology 63 (4):325-335. doi: 10.1007/s10616-011-9359-4 Google Scholar
  106. 106.
    Cannizzaro C, Gugerli R, Marison I, von Stockar U (2003) On-line biomass monitoring of CHO perfusion culture with scanning dielectric spectroscopy. Biotechnol Bioeng 84(5):597–610. doi: 10.1002/bit.10809 Google Scholar
  107. 107.
    Justice C, Brix A, Freimark D, Kraume M, Pfromm P, Eichenmueller B, Czermak P (2011) Process control in cell culture technology using dielectric spectroscopy. Biotechnol Adv 29(4):391–401. doi: 10.1016/j.biotechadv.2011.03.002 Google Scholar
  108. 108.
    Zeiser A, Bedard C, Voyer R, Jardin B, Tom R, Kamen AA (1999) On-line monitoring of the progress of infection in Sf-9 insect cell cultures using relative permittivity measurements. Biotechnol Bioeng 63(1):122–126. doi: 10.1002/(sici)1097-0290(19990405)63:1<122:aid-bit13>3.0.co;2-i Google Scholar
  109. 109.
    Zeiser A, Elias CB, Voyer R, Jardin B, Kamen AA (2000) On-line monitoring of physiological parameters of insect cell cultures during the growth and infection process. Biotechnol Prog 16(5):803–808. doi: 10.1021/bp000092w Google Scholar
  110. 110.
    Elias CB, Zeiser A, Bedard C, Kamen AA (2000) Enhanced growth of Sf-9 cells to a maximum density of 5.2 × 10(7) cells per mL and production of beta-galactosidase at high cell density by fed batch culture. Biotechnol Bioeng 68(4):381–388. doi: 10.1002/(sici)1097-0290(20000520)68:4<381::aid-bit3>3.0.co;2-d Google Scholar
  111. 111.
    Negrete A, Esteban G, Kotin RM (2007) Process optimization of large-scale production of recombinant adeno-associated vectors using dielectric spectroscopy. Appl Microbiol Biotechnol 76(4):761–772. doi: 10.1007/s00253-007-1030-9 Google Scholar
  112. 112.
    Ansorge S, Esteban G, Schmid G (2007) On-line monitoring of infected Sf-9 insect cell cultures by scanning permittivity measurements and comparison with off-line biovolume measurements. Cytotechnology 55(2–3):115–124. doi: 10.1007/s10616-007-9093-0 Google Scholar
  113. 113.
    Carvell JP, Dowd JE (2006) On-line measurements and control of viable cell density in cell culture manufacturing processes using radio-frequency impedance. Cytotechnology 50(1–3):35–48. doi: 10.1007/s10616-005-3974-x Google Scholar
  114. 114.
    Cox MMJ (2012) Recombinant protein vaccines produced in insect cells. Vaccine 30(10):1759. doi: 10.1016/j.vaccine.2012.01.016 Google Scholar
  115. 115.
    Vicente T, Roldao A, Peixoto C, Carrondo MJT, Alves PM (2011) Large-scale production and purification of VLP-based vaccines. J Invertebr Pathol 107:S42. doi: 10.1016/j.jip.2011.05.004 Google Scholar
  116. 116.
    Schmidt FR (2005) Optimization and scale up of industrial fermentation processes. Appl Microbiol Biotechnol 68(4):425. doi: 10.1007/s00253-005-0003-0 Google Scholar
  117. 117.
    Shen CF, Lanthier S, Jacob D, Montes J, Beath A, Beresford A, Kamen A (2012) Process optimization and scale up for production of rabies vaccine live adenovirus vector (AdRG1.3). Vaccine 30(2), doi: 10.1016/j.vaccine.2011.10.095
  118. 118.
    Chu L, Robinson DK (2001) Industrial choices for protein production by large-scale cell culture. Curr Opin Biotechnol 12(2):180. doi: 10.1016/s0958-1669(00)00197-x Google Scholar
  119. 119.
    Feng S-Z, Jiao P-R, Qi W-B, Fan H-Y, Liao M (2011) Development and strategies of cell-culture technology for influenza vaccine. Appl Microbiol Biotechnol 89(4):893. doi: 10.1007/s00253-010-2973-9 Google Scholar
  120. 120.
    Catapano G, Czermak P, Eibl R, Eibl D, Pörtner R (2009) Bioreactor design and scale up. In: Cell and tissue reaction engineering: Principles and Practice. Springer, Heidelberg, pp 173–259, doi: 10.1007/978-3-540-68182-3
  121. 121.
    Shuler ML, Kargi F (2001) Bioprocess engineering: Basic concepts, vol 2. Prentice HallGoogle Scholar
  122. 122.
    Kotin RM (2011) Large-scale recombinant adeno-associated virus production. Hum Mol Genet 20(R1):R2. doi: 10.1093/hmg/ddr141 Google Scholar
  123. 123.
    Kost TA, Condreay JP, Jarvis DL (2005) Baculovirus as versatile vectors for protein expression in insect and mammalian cells. Nat Biotechnol 23(5):567. doi: 10.1038/nbt1095 Google Scholar
  124. 124.
    Nienow AW (2006) Reactor engineering in large scale animal cell culture. Cytotechnology 50(1–3):9. doi: 10.1007/s10616-006-9005-8 Google Scholar
  125. 125.
    Marks DM (2003) Equipment design considerations for large scale cell culture. Cytotechnology 42(1):21. doi: 10.1023/a:1026103405618 Google Scholar
  126. 126.
    Ikonomou L, Schneider YJ, Agathos SN (2003) Insect cell culture for industrial production of recombinant proteins. Appl Microbiol Biotechnol 62(1):1. doi: 10.1007/s00253-003-1223-9 Google Scholar
  127. 127.
    Weber W, Weber E, Geisse S, Memmert K (2002) Optimisation of protein expression and establishment of the wave bioreactor for baculovirus/insect cell culture. Cytotechnology 38(1–2):77. doi: 10.1023/a:1021102015070 Google Scholar
  128. 128.
    Singh V (1999) Disposable bioreactor for cell culture using wave-induced agitation. Cytotechnology 30(1–3):149. doi: 10.1023/a:1008025016272 Google Scholar
  129. 129.
    Eibl R, Kaiser S, Lombriser R, Eibl D (2010) Disposable bioreactors: the current state-of-the-art and recommended applications in biotechnology. Appl Microbiol Biotechnol 86(1):41. doi: 10.1007/s00253-009-2422-9 Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Damir Druzinec
    • 1
  • Denise Salzig
    • 1
  • Alexander Brix
    • 2
  • Matthias Kraume
    • 3
  • Andreas Vilcinskas
    • 4
  • Christian Kollewe
    • 4
  • Peter Czermak
    • 1
    • 5
    • 6
  1. 1.Institute of Bioprocess Engineering and Pharmaceutical TechnologyUniversity of Applied Sciences MittelhessenGiessenGermany
  2. 2.Boehringer Ingelheim Vetmedica IncSt. JosephMissouriUSA
  3. 3.Department of Chemical EngineeringUniversity of Technology BerlinBerlinGermany
  4. 4.Fraunhofer Institute of Molecular Biology and Applied EcologyGiessenGermany
  5. 5.Department of Chemical EngineeringKansas State UniversityManhattanUSA
  6. 6.Faculty of Biology and ChemistryJustus-Liebig-University of GiessenGiessenGermany

Personalised recommendations