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Model-based analysis and optimization of bioreactor for hematopoietic stem cell cultivation

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Abstract

One of the problems to be solved in attaining the full potentials of hematopoietic stem cell (HSC) applications is the limited availability of the cells. Growing HSCs in a bioreactor offers an alternative solution to this problem. Besides, it also offers the advantages of eliminating labour intensive process as well as the possible contamination involved in the periodic nutrient replenishments in the traditional T-flask stem cell cultivation. In spite of this, the optimization of HSC cultivation in a bioreactor has been barely explored. This manuscript discusses the development of a mathematical model to describe the dynamics in nutrient distribution and cell concentration of an ex vivo HSC cultivation in a microchannel perfusion bioreactor. The model was further used to optimize the cultivation by proposing three alternative feeding strategies in order to prevent the occurrence of nutrient limitation in the bioreactor. The evaluation of these strategies, the periodic step change increase in the inlet oxygen concentration, the periodic step change increase in the media inflow, and the feedback control of media inflow, shows that these strategies can successfully improve the cell yield of the bioreactor. In general, the developed model is useful for the design and optimization of bioreactor operation.

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References

  1. Cai Y, Rodriguez S, Hebel H (2009) DNA vaccine manufacture: scale and quality. Expert Rev Vaccines 8:1277–1291

    Article  Google Scholar 

  2. Birch JR, Racher AJ (2006) Antibody production. Adv Drug Deliv Rev 58:671–685

    Article  CAS  Google Scholar 

  3. Nilsson J, Jonasson P, Samuelsson E, Stahl S, Uhlen M (1996) Integrated production of human insulin and its C-peptide. J Biotechnol 48:241–250

    Article  CAS  Google Scholar 

  4. Buynak JD (2004) The discovery and development of modified penicillin- and cephalosporin-derived β-lactamase inhibitors. Curr Med Chem 11:1951–1964

    CAS  Google Scholar 

  5. Saran S, Isar J, Saxena RK (2007) Statistical optimization of conditions for protease production from Bacillus sp. and its scale-up in a bioreactor. Appl Biochem Biotechnol 141:229–239

    Article  CAS  Google Scholar 

  6. Shu ZY, Jiang H, Lin RF, Jiang YM, Lin L, Huang JZ (2010) Technical methods to improve yield, activity and stability in the development of microbial lipases. J Mol Catal B Enzym 62:1–8

    Article  CAS  Google Scholar 

  7. Banerjee S, Mudliar S, Sen R, Giri B, Satpute D, Chakrabarti T, Pandey RA (2010) Commercializing lignocellulosic bioethanol: technology bottlenecks and possible remedies. Biofuels Bioprod Biorefin 4:77–93

    Article  CAS  Google Scholar 

  8. Sauer M, Porro D, Mattanovich D, Branduardi P (2008) Microbial production of organic acids: expanding the markets. Trends Biotechnol 26:100–108

    Article  CAS  Google Scholar 

  9. Koller MR, Emerson SG, Palsson BO (1993) Large-scale expansion of human stem and progenitor cells from bone marrow mononuclear cells in continuous perfusion cultures. Blood 82:378–384

    CAS  Google Scholar 

  10. De León A, Mayani H, Ramírez O (1998) Design, characterization and application of a minibioreactor for the culture of human hematopoietic cells under controlled conditions. Cytotechnology 28:127–138

    Article  Google Scholar 

  11. Highfill JG, Haley SD, Kompala DS (1996) Large-scale production of murine bone marrow cells in an airlift packed bed bioreactor. Biotechnol Bioeng 50:514–520

    Article  CAS  Google Scholar 

  12. Meissner P, Schröder B, Herfurth C, Biselli M (1999) Development of a fixed bed bioreactor for the expansion of human hematopoietic progenitor cells. Cytotechnology 30:227–234

    Article  CAS  Google Scholar 

  13. Sardonini CA, Wu YJ (1993) Expansion and differentiation of human hematopoietic cells from static cultures through small-scale bioreactors. Biotechnol Progr 9:131–137

    Article  CAS  Google Scholar 

  14. Mehta K, Linderman JJ (2006) Model-based analysis and design of a microchannel reactor for tissue engineering. Biotechnol Bioeng 94:596–609

    Article  CAS  Google Scholar 

  15. Koller MR, Bender JG, Miller WM, Papoutsakis ET (1993) Expansion of primitive human hematopoietic progenitors in a perfusion bioreactor system with IL-3, IL-6, and stem cell factor. Bio/Technology 11:358–363

    Article  CAS  Google Scholar 

  16. Andrade-Zaldívar H, Santos L, De León Rodríguez A (2008) Expansion of human hematopoietic stem cells for transplantation: trends and perspectives. Cytotechnology 56:151–160

    Article  Google Scholar 

  17. Poulsom R, Alison MR, Forbes SJ, Wright NA (2002) Adult stem cell plasticity. J Pathol 197:441–456

    Article  Google Scholar 

  18. Ulloa-Montoya F, Verfaillie CM, Hu WS (2005) Culture systems for pluripotent stem cells. J Biosci Bioeng 100:12–27

    Article  CAS  Google Scholar 

  19. Chen BY, You JW, Hsieh YT, Chang JS (2008) Feasibility study of exponential feeding strategy in fed-batch cultures for phenol degradation using Cupriavidus taiwanensis. Biochem Eng J 41:175–180

    Article  CAS  Google Scholar 

  20. Babaeipour V, Shojaosadati SA, Khalilzadeh R, Maghsoudi N, Tabandeh F (2008) A proposed feeding strategy for the overproduction of recombinant proteins in Escherichia coli. Biotechnol Appl Biochem 49:141–147

    Article  CAS  Google Scholar 

  21. Ting TE, Thoma GJ, Beitle RR Jr, Davis RK, Perkins R, Karim K, Liu HM (2008) A simple substrate feeding strategy using a pH control trigger in fed-batch fermentation. Appl Biochem Biotechnol 149:89–98

    Article  CAS  Google Scholar 

  22. Velut S, de Maré L, Hagander P (2007) Bioreactor control using a probing feeding strategy and mid-ranging control. Control Eng Pract 15:135–147

    Article  Google Scholar 

  23. Nguang SK, Chen XD (1997) Simple substrate feeding rate control mechanism for optimizing the steady state productivity of a class of continuous fermentation processes. Biotechnol Progr 13:200–204

    Article  CAS  Google Scholar 

  24. Ruan L, Chen XD (1996) Comparison of several periodic operations of a continuous fermentation process. Biotechnol Progr 12:286–288

    Article  CAS  Google Scholar 

  25. de Maré L, Cimander C, Elfwing A, Hagander P (2007) Feeding strategies for E. coli fermentations demanding an enriched environment. Bioprocess Biosyst Eng 30:13–25

    Article  Google Scholar 

  26. Ivanova G, Serafim LS, Lemos PC, Ramos AM, Reis MAM, Cabrita EJ (2009) Influence of feeding strategies of mixed microbial cultures on the chemical composition and microstructure of copolyesters P(3HB-co-3HV) analyzed by NMR and statistical analysis. Magn Reson Chem 47:497–504

    Article  CAS  Google Scholar 

  27. Patel SD, Papoutsakis ET, Winter JN, Miller WM (2000) The lactate issue revisited: novel feeding protocols to examine inhibition of cell proliferation and glucose metabolism in hematopoietic cell cultures. Biotechnol Progr 16:885–892

    Article  CAS  Google Scholar 

  28. Allen JW, Bhatia SN (2003) Formation of steady-state oxygen gradients in vitro: application to liver zonation. Biotechnol Bioeng 82:253–262

    Article  CAS  Google Scholar 

  29. Pathi P, Ma T, Locke BR (2005) Role of nutrient supply on cell growth in bioreactor design for tissue engineering of hematopoietic cells. Biotechnol Bioeng 89:743–758

    Article  CAS  Google Scholar 

  30. Horner M, Miller WM, Ottino JM, Papoutsakis ET (1998) Transport in a grooved perfusion flat-bed bioreactor for cell therapy applications. Biotechnol Progr 14:689–698

    Article  CAS  Google Scholar 

  31. Chow DC, Wenning LA, Miller WM, Papoutsakis ET (2001) Modeling pO2 distributions in the bone marrow hematopoietic compartment. I. Krogh’s model. Biophys J 81:675–684

    Article  CAS  Google Scholar 

  32. Peng CA, Koller MR, Palsson BO (1996) Unilineage model of hematopoiesis predicts self-renewal of stem and progenitor cells based on ex vivo growth data. Biotechnol Bioeng 52:24–33

    Article  CAS  Google Scholar 

  33. Nielsen LK, Papoutsakis ET, Miller WM (1998) Modeling ex vivo hematopoiesis using chemical engineering metaphors. Chem Eng Sci 53:1913–1925

    Article  CAS  Google Scholar 

  34. Chow DC, Wenning LA, Miller WM, Papoutsakis ET (2001) Modeling pO2 distributions in the bone marrow hematopoietic compartment. II. Modified Kroghian models. Biophys J 81:685–696

    Article  CAS  Google Scholar 

  35. Peng CA, Palsson BO (1996) Determination of specific oxygen uptake rates in human hematopoietic cultures and implications for bioreactor design. Ann Biomed Eng 24:373–381

    Article  CAS  Google Scholar 

  36. Liao JC, Lightfoot NE (1988) Lumping analysis of biochemical reaction systems with time scale separation. Biotechnol Bioeng 31:869–879

    Article  CAS  Google Scholar 

  37. Ma CYJ, Kumar R, Xu XY, Mantalaris A (2007) A combined fluid dynamics, mass transport and cell growth model for a three-dimensional perfused biorector for tissue engineering of haematopoietic cells. Biochem Eng J 35:1–11

    Google Scholar 

  38. Bailey JE (1998) Mathematical modeling and analysis in biochemical engineering: past accomplishments and future opportunities. Biotechnol Progr 14:8–20

    Article  CAS  Google Scholar 

  39. Bradley TR, Hodgson GS, Rosendaal M (1978) The effect of oxygen tension on haemopoietic and fibroblast cell proliferation in vitro. J Cell Physiol 97:517–522

    Article  CAS  Google Scholar 

  40. Koller MR, Bender JG, Miller WM, Papoutsakis ET (1992) Reduced oxygen tension increases hematopoiesis in long-term culture of human stem and progenitor cells from cord blood and bone marrow. Exp Hematol 20:264–270

    CAS  Google Scholar 

  41. Cipolleschi MG, Sbarba PD, Olivotto M (1993) The role of hypoxia in the maintenance of hematopoietic stem cells. Blood 82:2031–2037

    CAS  Google Scholar 

  42. Hevehan DL, Papoutsakis ET, Miller WM (2000) Physiologically significant effects of pH and oxygen tension on granulopoiesis. Exp Hematol 28:267–275

    Article  CAS  Google Scholar 

  43. Mostafa SS, Miller WM, Terry Papoutsakis E (2000) Oxygen tension influences the differentiation, maturation and apoptosis of human megakaryocytes. Br J Haematol 111:879–889

    Article  CAS  Google Scholar 

  44. Koller MR, Bender JG, Papoutsakis ET, Miller WM (1992) Beneficial effects of reduced oxygen tension and perfusion in long-term hematopoietic cultures. Ann N Y Acad Sci 665:105–116

    Article  CAS  Google Scholar 

  45. Lobato da Silva C, Gonçalves R, Lemos F, Lemos MANDA, Zanjani ED, Almeida-Porada G, Cabral JMS (2003) Modelling of ex vivo expansion/maintenance of hematopoietic stem cells. Bioprocess Biosyst Eng 25:365–369

    Google Scholar 

  46. Koller MR, Palsson BO (1993) Tissue engineering: reconstitution of human hematopoiesis ex vivo. Biotechnol Bioeng 42:909–930

    Article  CAS  Google Scholar 

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Acknowledgments

The author thanks the UNESCO-L’Oreal Women in Science Programme for the Fellowship.

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Authors and Affiliations

  1. Bioprocess and Microbiology Laboratory, Department of Chemical Engineering, Faculty of Industrial Technology, Bandung Institute of Technology, Ganesha 10, Bandung, 40132, Indonesia

    M. T. A. P. Kresnowati

  2. Bio Engineering Laboratory (BEL), Department of Chemical Engineering, Monash University, Clayton, VIC, 3800, Australia

    M. T. A. P. Kresnowati & G. M. Forde

  3. Biotechnology and Food Engineering Group, Department of Chemical Engineering, Monash University, Clayton, VIC, 3800, Australia

    X. D. Chen

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  1. M. T. A. P. Kresnowati
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  2. G. M. Forde
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  3. X. D. Chen
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Correspondence to M. T. A. P. Kresnowati.

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Kresnowati, M.T.A.P., Forde, G.M. & Chen, X.D. Model-based analysis and optimization of bioreactor for hematopoietic stem cell cultivation. Bioprocess Biosyst Eng 34, 81–93 (2011). https://doi.org/10.1007/s00449-010-0449-z

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  • DOI: https://doi.org/10.1007/s00449-010-0449-z

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