Production Process for Stem Cell Based Therapeutic Implants: Expansion of the Production Cell Line and Cultivation of Encapsulated Cells

  • C. Weber
  • S. Pohl
  • R. Poertner
  • Pablo Pino-Grace
  • D. Freimark
  • C. Wallrapp
  • P. Geigle
  • P. Czermak
Part of the Advances in Biochemical Engineering / Biotechnology book series (ABE, volume 123)


Cell based therapy promises the treatment of many diseases like diabetes mellitus, Parkinson disease or stroke. Microencapsulation of the cells protects them against host-vs-graft reactions and thus enables the usage of allogenic cell lines for the manufacturing of cell therapeutic implants. The production process of such implants consists mainly of the three steps expansion of the cells, encapsulation of the cells, and cultivation of the encapsulated cells in order to increase their vitality and thus quality. This chapter deals with the development of fixed-bed bioreactor-based cultivation procedures used in the first and third step of production. The bioreactor system for the expansion of the stem cell line (hMSC-TERT) is based on non-porous glass spheres, which support cell growth and harvesting with high yield and vitality. The cultivation process for the spherical cell based implants leads to an increase of vitality and additionally enables the application of a medium-based differentiation protocol.


Cell therapy Mesenchymal stem cells Encapsulation Fixed bed bioreactor Glass carrier 



The authors would like to thank the Federal Ministry of Economics and Technology for financial support as well as the CellMed AG for providing the production cell line hMSC-TERT and the CellBeads®.


  1. 1.
    Lanza RP, Hayes JL, Chick WL (1996) Encapsulated cell technology. Nature Biotech 14:1107–1111CrossRefGoogle Scholar
  2. 2.
    Freimark D, Czermak P (2009) Cell-based regeneration of intervertebral disc defects: review and concepts. Int J Artif Organs 32:197–203Google Scholar
  3. 3.
    Baksh D, Song L, Tuan RS (2004) Adult mesenchymal stem cells: characterization, differentiation, and application in cell and gene therapy. J Cell Mol Med 8:301–316CrossRefGoogle Scholar
  4. 4.
    Chiu RCJ (2003) Bone-marrow stem cells as a source for cell therapy. Heart Failure Rev 8:247–251CrossRefGoogle Scholar
  5. 5.
    Fraser JK et al (2004) Adult stem cell therapy for the heart. Int J Biochem Cell Biol 36:658–666CrossRefGoogle Scholar
  6. 6.
    Mimeault M, Hauke R, Batra SK (2007) Stem cells: a revolution in therapeutics–recent advances in stem cell biology and their therapeutic applications in regenerative medicine and cancer therapies. Clin Pharmacol Ther 82:252–264CrossRefGoogle Scholar
  7. 7.
    Simonsen JL et al (2002) Telomerase expression extends the proliferative life-span and maintains the osteogenic potential of human bone marrow stromal cells. Nat Biotechnol 20:592–596CrossRefGoogle Scholar
  8. 8.
    Heile AMB et al (2009) Cerebral Q1 transplantation of encapsulated mesenchymal stem cells improves cellular pathology after experimental traumatic brain injury. Neurosci LettGoogle Scholar
  9. 9.
    Aris R (1975) The mathematical theory of diffusion and reaction impermeable catalysts. Clarendon, OxfordGoogle Scholar
  10. 10.
    Bailey J, Ollis DF (1986) Biochemical engineering fundamentals. McGraw-Hill, New YorkGoogle Scholar
  11. 11.
    Froment GF, Bischoff KB (1979) Chemical reactor analysis and design. Wiley, New YorkGoogle Scholar
  12. 12.
    Fassnacht D (2001) Fixed-bed reactors for the cultivation of animal cells. Fortschritt-Berichte VDI, vol. 17, VDI-Verlag, DüsseldorfGoogle Scholar
  13. 13.
    Willaert RG, Baron GV, de Backer L (1996) Modelling of immobilised bioprocesses. In: Willaert RG, Baron GV, de Backer L (eds) Immobilised living cell systems. Wiley, New York, pp 237–254Google Scholar
  14. 14.
    Perry RH, Green DW (2007) Perry’s chemical engineers’ handbook. McGraw-HillGoogle Scholar
  15. 15.
    Weber C, Gokorsch S, Czermak P (2007) Expansion and chondrogenic differentiation of human mesenchymal stem cells. Int J Artif Organs 30:611–618Google Scholar
  16. 16.
    Schop D et al (2009) Growth, metabolism, and growth inhibitors of mesenchymal stem cells. Tissue Eng A 15:1877–1886CrossRefGoogle Scholar
  17. 17.
    Higuera G et al (2009) Qvantifying in vitro growth and metabolism kinetics of human mesenchymal stem cells using a mathematical model. Tissue Eng Part A 15:1–11CrossRefGoogle Scholar
  18. 18.
    Schop D et al (2008) Expansion of mesenchymal stem cells using a microcarrier-based cultivation system: growth and metabolism. J Tissue Eng Regen Med 2:126–135CrossRefGoogle Scholar
  19. 19.
    Lonergan T, Brenner C, Bavister B (2006) Differentiation-related changes in mitochondrial properties as indicators of stem cell competence. J Cell Phys 208:149–153CrossRefGoogle Scholar
  20. 20.
    Conget P, Minguell JJ (1999) Phenotypical and functional properties of human bone marrow mesenchymal progenitor cells. J Cell Phys 181:67–73CrossRefGoogle Scholar
  21. 21.
    Guo Z et al (2001) Biological features of mesenchymal stem cells from human bone marrow. Chin Med J 114:950–953Google Scholar
  22. 22.
    Soukup T et al (2006) Mesenchymal stem cells isolated from human bone marrow: cultivation, phenotypic analysis and changes in proliferation kinetics. Acta Med 49:27–33Google Scholar
  23. 23.
    Peng CA, Palson BA (1996) Determination of specific oxygen uptake rates in human hematopoietic cultures and implications for bioreactor design. Ann Biomed Eng 24:373–381CrossRefGoogle Scholar
  24. 24.
    Pörtner R et al (2005) Bioreactor design for tissue engineering. J Biosci Bioeng 100:235–245CrossRefGoogle Scholar
  25. 25.
    Acevedo CA et al (2008) A mathematical model for the design of fibrin microcapsules with skin cells. Bioprocess Biosyst Eng 32(3):341–351CrossRefGoogle Scholar
  26. 26.
    De Leon A, Mayani H, Ramırez OT (1998) Design, characterization and application of a minibioreactor for the culture of human hematopoietic cells under controlled conditions. Cytotechnol 28:127–138CrossRefGoogle Scholar
  27. 27.
    Youn BS, Sen A, Behie LA (2006) Scale-up of breast cancer stem cell aggregate cultures to suspension bioreactors. Biotechnol Prog 22:801–810CrossRefGoogle Scholar
  28. 28.
    Weber C et al (2007) Cultivation and differentiation of encapsulated hMSC-TERT in a disposable small-scale syringe-like fixed bed reactor. Open Biomed Eng J 1:64–70Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  • C. Weber
    • 1
  • S. Pohl
    • 1
  • R. Poertner
    • 2
  • Pablo Pino-Grace
    • 1
  • D. Freimark
    • 1
  • C. Wallrapp
    • 3
  • P. Geigle
    • 3
  • P. Czermak
    • 1
    • 4
  1. 1.Institute of Biopharmaceutical TechnologyUniversity of Applied Sciences Giessen-FriedbergGiessenGermany
  2. 2.Institute of Bioprocess and Biosystem TechnologyUniversity of Hamburg-HarburgHamburgGermany
  3. 3.CellMed AGAlzenauGermany
  4. 4.Department of Chemical EngineeringKansas State UniversityManhattanUSA

Personalised recommendations