Annals of Biomedical Engineering

, Volume 29, Issue 11, pp 947–955 | Cite as

Analysis of Oxygen Transport to Hepatocytes in a Flat-Plate Microchannel Bioreactor

  • Partha Roy
  • Harihara Baskaran
  • Arno W. Tilles
  • Martin L. Yarmush
  • Mehmet Toner


Oxygen transfer to cultured hepatocytes in microchannel parallel-plate bioreactors with and without an internal membrane oxygenator was investigated with a mathematical model and the results were corroborated with fluorescence imaging experiments. The consumption of oxygen by hepatocytes was assumed to follow Michaelis–Menten kinetics. Our simulations indicate that under conditions of low Péclet (Pe) number (<80) and fixed Damkohler number (=0.14, corresponding to rat hepatocytes) the cells are hypoxic in the bioreactor without an internal membrane oxygenator. Under the same conditions, the bioreactor with an internal membrane oxygenator can avoid cell hypoxia by appropriate selection of membrane Sherwood number and/or the gas phase oxygen partial pressure, thus providing greater control of cell oxygenation. At high Pe, both bioreactors are well oxygenated. Experimentally determined oxygen concentrations within the bioreactors were in good qualitative agreement with model predictions. At low Pe, cell surface oxygen depletion was predicted from analytically derived criteria. Hepatocytes with oxygen dependent functional heterogeneity may exhibit optimal function in the bioreactor with the internal membrane oxygenator. © 2001 Biomedical Engineering Society.

PAC01: 8717Aa, 8780-y

Bioartificial liver Oxygen transport Membrane Mathematical modeling 


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  1. 1.
    Arias, I. M., J. L. Boyer, N. Fausto, W. B. Jakoby, D. Schacter, and D. A. Shafritz. (tiThe Liver: Biology and Pathobiology). New York, NY: Raven, 1994.Google Scholar
  2. 2.
    Balis, U. J., K. Behnia, B. Dwarakanath, S. N. Bhatia, S. J. Sullivan, M. L. Yarmush, and M. Toner. Oxygen consumption characteristics of porcine hepatocytes. Metab. Eng.1:49–62, 1999.Google Scholar
  3. 3.
    Bartolo, L. D., G. J. Schweder, A. Haverich, and A. Bader. A novel full-scale flat membrane bioreactor utilizing porcine hepatocytes: Cell viability and tissue-specific functions. Biotechnol. Prog.16:102–108, 2000.PubMedGoogle Scholar
  4. 4.
    Batchelor, G. K. An Introduction to Fluid Dynamics. Cambridge, U.K.: Cambridge University Press, 1967.Google Scholar
  5. 5.
    Bhatia, S. N., M. Toner, B. D. Foy, A. Rotem, K. M. O'Neil, R. G. Tompkins, and M. L. Yarmush. Zonal liver cell heterogeneity: Effects of oxygen on metabolic functions of hepatocytes. Cell. Eng.1:125–135, 1996.Google Scholar
  6. 6.
    Busse, B., M. D. Smith, and J. C. Gerlach. Treatment of acute liver failure: Hybrid liver support—A critical overview. Langenbecks Arch. Surg.384:588–599, 1999.Google Scholar
  7. 7.
    Catapano, G.Mass transfer limitations to the performance of membrane bioartificial liver support devices. Artif. Organs19:18–35, 1996.Google Scholar
  8. 8.
    Colton, C. K., K. A. Smith, P. Stroeve, and E. W. Merrill. Laminar flow mass transfer in a flat duct with permeable walls. AIChE J.17:773–780, 1971.Google Scholar
  9. 9.
    Dunn, J. C., R. G. Tompkins, and M. L. Yarmush. Long-term in vitro function of adult hepatocytes in a collagen sandwich configuration. Biotechnol. Prog.7:237–245, 1991.PubMedGoogle Scholar
  10. 10.
    Ellis, A. J., R. D. Hughes, J. A. Wendon, J. Dunne, P. G. Langley, J. H. Kelly, G. T. Gislason, N. L. Sussman, and R. Williams. Pilot-controlled trial of the extracorporeal liver assist device in acute liver failure. Hepatology24:1446–1451, 1996.Google Scholar
  11. 11.
    Flendrig, L. M., J. W. La Soe, G. G. A. Jorning, A. Steenbeek, O. T. Karlsen, W. M. M. J. Bovee, N. C. J. J. Ladiges, A. A. Te Velde, and R. A. F. M. Chamuleau. In vitro evaluation of a novel bioreactor based on an integral oxygenator and a spirally wound nonwoven polyester matrix for hepatocyte culture as small aggregates. J. Hepatol.26:1379–1392, 1997.Google Scholar
  12. 12.
    Foy, B. D., A. Rotem, M. Toner, R. G. Tompkins, and M. L. Yarmush. A device to measure the oxygen-uptake rate of attached cells—Importance in bioartificial organ design. Cell Transplant.3:515–527, 1994.Google Scholar
  13. 13.
    Hay, P. D., A. R. Veitch, M. D. Smith, R. B. Cousins, and J. D. S. Gaylor. Oxygen transfer in a diffusion-limited hollow fiber bioartificial liver. Artif. Organs24:278–288, 2000.Google Scholar
  14. 14.
    Jungermann, K., and N. Katz. Functional specialization of different hepatocyte populations. Physiol. Rev.69:708–764, 1989.PubMedGoogle Scholar
  15. 15.
    Kennichi, Y., and N. Ohshima. Improvement of metabolic performance of cultured hepatocytes by high oxygen tension in the atmosphere. Artif. Organs25:1–6, 2001.Google Scholar
  16. 16.
    Kihak, M. K., and M. R. Shahriari. Highly sensitive, all solid state fiber optic oxygen sensor based on the sol-gel coating technique. Electron. Lett.32:240–242, 1996.Google Scholar
  17. 17.
    Kobayashi, N., M. Miyazaki, K. Fukaya, Y. Inoue, M. Sakaguchi, T. Uemura, H. Noguchi, A. Kondo, N. Tanaka, and M. Namba. Transplantation of highly differentiated immortalized human hepatocytes to treat acute liver failure. Transplantation69:202–207, 2000.Google Scholar
  18. 18.
    Kreyszig, E. Advanced Engineering Mathematics, 5th ed., New Delhi, India: Wiley Eastern Limited, 1983.Google Scholar
  19. 19.
    Krihak, M., and M. R. Shahriari. Active sol–gel materials for fiber optic chemical sensors. Proc. SPIE2293:88–98, 1994.Google Scholar
  20. 20.
    Ledezma, G. A., A. Folch, S. N. Bhatia, M. L. Yarmush, and M. Toner. Numerical model of fluid flow and oxygen transport in a radial-flow microchannel containing hepatocytes. J. Biomech. Eng.121:58–64, 1999.Google Scholar
  21. 21.
    Millward, H. R., B. J. Bellhouse, and I. J. Sobey. The vortex wave membrane bioreactor: Hydrodynamics and mass transfer. Chem. Eng. J. Biochem. Eng. J.62:175–181, 1996.Google Scholar
  22. 22.
    Peng, C.-A., and B. O. Palsson. Importance of nonhomogeneous concentration distributions near walls in bioreactors for primary-cell cultures. Ind. Eng. Chem. Res.34:3239–3245, 1995.Google Scholar
  23. 23.
    Probstein, R. F. Physicochemical Hydrodynamics. Stoneham, MA: Butterworth, 1989.Google Scholar
  24. 24.
    Rotem, A., M. Toner, R. G. Tompkins, and M. L. Yarmush. Oxygen-uptake rates in cultured rat hepatocytes. Biotechnol. Bioeng.40:1286–1291, 1992.Google Scholar
  25. 25.
    Rozga, J., L. Podesta, E. LePage, E. Morsiani, A. D. Moscioni, A. Hoffman, L. Sher, F. Villamil, G. Woolf, M. McGrath, L. Kong, H. Rosen, T. Lanman, J. Vierling, L. Makowka, and A. A. Demetriou. A bioartificial liver to treat severe acute liver failure. Ann. Surg.219:538–546, 1994.Google Scholar
  26. 26.
    Seglen, P. O.Preparation of isolated rat liver cells. Methods Cell Biol.13:29–83, 1976.PubMedGoogle Scholar
  27. 27.
    Smith, M. D. A hybrid artificial liver with integral membrane oxygenation: Theory, developmental studies and prototype testing. Ph.D., University of Strathclyde, 1997.Google Scholar
  28. 28.
    Smith, M. D., D. Cairns, J. D. S. Gaylor, and A. R. Veitch. Analysis of oxygen transfer in hollow fiber hepatocyte bioreactors. Artif. Organs21:531–542, 1997.Google Scholar
  29. 29.
    Smithson, J. E., and J. M. Neuberger. Acute liver failure—Overview. Eur. J. Gastroenterol. Hepatol.11:943–947, 1999.Google Scholar
  30. 30.
    Sussman, N. L., G. T. Gislason, C. A. Conlin, and J. H. Kelly. The hepatix extracorporeal liver assist device: Initial clinical experience. Artif. Organs18:390–396, 1994.Google Scholar
  31. 31.
    Tilles, A. W., U. J. Balis, H. Baskaran, M. L. Yarmush, and M. Toner. Internal membrane oxygenation removes substrate oxygen limitations in a small-scale flat-plate hepatocyte bioreactor. In: Tissue Engineering for Therapeutic Use 5, edited by Y. Ikada and N. Ohshima. Amsterdam: Elsevier, 2001.Google Scholar
  32. 32.
    Tilles, A. W., H. Baskaran, P. Roy, M. L. Yarmush, and M. Toner. Effects of oxygenation and flow on the viability and function of rat hepatocytes co-cultured in a microchannel flat-plate bioreactor. Biotechnol. Bioeng.73:379–389, 2001.Google Scholar
  33. 33.
    Tzanakakis, E. S., D. J. Hess, T. D. Sielaff, and W.-S. Hu. Extracorporeal tissue engineered liver-assist devices. Ann. Rev. Biomed. Eng.2:607–632, 2000.Google Scholar
  34. 34.
    Wang, W., C. E. Reimers, S. C. Wainright, and M. R. Shariari. Applying fiber-optic sensors for monitoring dissolved oxygen. Sea Technol.40:69–74, 1999.Google Scholar
  35. 35.
    Yarmush, M. L., J. C. Y. Dunn, and R. G. Tompkins. Assesment of artificial liver support technology. Cell Transplant.1:323–341, 1992.Google Scholar
  36. 36.
    Yarmush, M. L., M. Toner, J. C. Y. Dunn, A. Rotem, A. Hubel, and R. G. Tompkins. Hepatic tissue engineering—Development of critical technologies. Ann. N.Y. Acad. Sci.665:238–252, 1992.Google Scholar

Copyright information

© Biomedical Engineering Society 2001

Authors and Affiliations

  • Partha Roy
    • 1
  • Harihara Baskaran
    • 1
  • Arno W. Tilles
    • 1
  • Martin L. Yarmush
    • 1
  • Mehmet Toner
    • 1
  1. 1.Center for Engineering in Medicine and Surgical ServicesMassachusetts General Hospital, Harvard Medical School, and Shriners Hospitals for ChildrenBoston

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