Skip to main content
PMC home page
Cytotechnology logoLink to Cytotechnology
. 2006 Jan 3;50(1-3):163–179. doi: 10.1007/s10616-006-6336-4

Present and Future Developments in Hepatic Tissue Engineering for Liver Support Systems

State of the art and future developments of hepatic cell culture techniques for the use in liver support systems

Sonja Diekmann 1,✉, Augustinus Bader 1, Stephanie Schmitmeier 1
PMCID: PMC3476010  PMID: 19003077

Abstract

The liver is the most important organ for the biotransformation of xenobiotics, and the failure to treat acute or acute-on-chronic liver failure causes high mortality rates in affected patients. Due to the lack of donor livers and the limited possibility of the clinical management there has been growing interest in the development of extracorporeal liver support systems as a bridge to liver transplantation or to support recovery during hepatic failure. Earlier attempts to provide liver support comprised non-biological therapies based on the use of conventional detoxification procedures, such as filtration and dialysis. These techniques, however, failed to meet the expected efficacy in terms of the overall survival rate due to the inadequate support of several essential liver-specific functions. For this reason, several bioartificial liver support systems using isolated viable hepatocytes have been constructed to improve the outcome of treatment for patients with fulminant liver failure by delivering essential hepatic functions. However, controlled trials (phase I/II) with these systems have shown no significant survival benefits despite the systems’ contribution to improvements in clinical and biochemical parameters. For the development of improved liver support systems, critical issues, such as the cell source and culture conditions for the long-term maintenance of liver-specific functions in vitro, are reviewed in this article. We also discuss aspects concerning the performance, biotolerance and logistics of the selected bioartificial liver support systems that have been or are currently being preclinically and clinically evaluated.

Key words: Bioartificial liver, Hepatocytes, Liver failure, Liver support systems

References

  1. Auth M.K., Okamoto M., Ishida Y., Keogh A., Auth S.H., Gerlach J., Encke A., McMaster P., Strain A.J. Maintained function of primary human hepatocytes by cellular interactions in coculture: implications for liver support systems. Transpl. Int. 1998;11:S439–S443. doi: 10.1007/s001470050516. [DOI] [PubMed] [Google Scholar]
  2. Babensee J.E., De Boni U., Sefton M.V. Morphological assessment of hepatoma cells (HepG2) microencapsulated in a HEMA-MMA copolymer with and without Matrigel. J. Biomed. Mater. Res. 1992;26:1401–1418. doi: 10.1002/jbm.820261102. [DOI] [PubMed] [Google Scholar]
  3. Bader A., Fruhauf N., Zech K., Haverich A., Borlak J.T. Development of a small-scale bioreactor for drug metabolism studies maintaining hepatospecific functions. Xenobiotica. 1998;28:815–825. doi: 10.1080/004982598239074. [DOI] [PubMed] [Google Scholar]
  4. Bader A., Knop E., Kern A., Boker K., Fruhauf N., Crome O., Esselmann H., Pape C., Kempka G., Sewing K.F. 3-D coculture of hepatic sinusoidal cells with primary hepatocytes-design of an organotypical model. Exp. Cell Res. 1996;226:223–233. doi: 10.1006/excr.1996.0222. [DOI] [PubMed] [Google Scholar]
  5. Bader A., Rinkes I.H., Closs E.I., Ryan C.M., Toner M., Cunningham J.M., Tompkins R.G., Yarmush M.L. A stable long-term hepatocyte culture system for studies of physiologic processes: cytokine stimulation of the acute phase response in rat and human hepatocytes. Biotechnol. Prog. 1992;8:219–225. doi: 10.1021/bp00015a007. [DOI] [PubMed] [Google Scholar]
  6. Baquerizo A., Mhoyan A., Kearns-Jonker M., Arnaout W.S., Shackleton C., Busuttil R.W., Demetriou A.A., Cramer D.V. Characterization of human xenoreactive antibodies in liver failure patients exposed to pig hepatocytes after bioartificial liver treatment: an ex vivo model of pig to human xenotransplantation. Transplantation. 1999;67:5–18. doi: 10.1097/00007890-199901150-00003. [DOI] [PubMed] [Google Scholar]
  7. Ben-Ze’ev A., Robinson G.S., Bucher N.L., Farmer S.R. Cell–cell and cell–matrix interactions differentially regulate the expression of hepatic and cytoskeletal genes in primary cultures of rat hepatocytes. Proc. Natl. Acad. Sci. U.S.A. 1988;85:2161–2165. doi: 10.1073/pnas.85.7.2161. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Black D., Lyman S., Heider T.R., Behrns K.E. Molecular and cellular features of hepatic regeneration. J. Surg. Res. 2004;117:306–315. doi: 10.1016/j.jss.2003.10.026. [DOI] [PubMed] [Google Scholar]
  9. Blusch J.H., Patience C., Martin U. Pig endogenous retroviruses and xenotransplantation. Xenotransplantation. 2002;9:242–251. doi: 10.1034/j.1399-3089.2002.01110.x. [DOI] [PubMed] [Google Scholar]
  10. Braet F., Shleper M., Paizi M., Brodsky S., Kopeiko N., Resnick N., Spira G. Liver sinusoidal endothelial cell modulation upon resection and shear stress in vitro. Comp. Hepatol. 2004;3:7. doi: 10.1186/1476-5926-3-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Bucher N.L., Robinson G.S., Farmer S.R. Effects of extracellular matrix on hepatocyte growth and gene expression: implications for hepatic regeneration and the repair of liver injury. Semin. Liver Dis. 1990;10:11–19. doi: 10.1055/s-2008-1040453. [DOI] [PubMed] [Google Scholar]
  12. Canaple L., Nurdin N., Angelova N., Hunkeler D., Desvergne B. Development of a coculture model of encapsulated cells. Ann. NY Acad. Sci. 2001;944:350–361. doi: 10.1111/j.1749-6632.2001.tb03847.x. [DOI] [PubMed] [Google Scholar]
  13. Cascio S.M. Novel strategies for immortalization of human hepatocytes. Artif. Organs. 2001;25:529–538. doi: 10.1046/j.1525-1594.2001.025007529.x. [DOI] [PubMed] [Google Scholar]
  14. Costa R.H., Kalinichenko V.V., Holterman A.X., Wang X. Transcription factors in liver development differentiation, and regeneration. Hepatology. 2003;38:1331–1347. doi: 10.1016/j.hep.2003.09.034. [DOI] [PubMed] [Google Scholar]
  15. Curcio E., Bartolo L., Barbieri G., Rende M., Giorno L., Morelli S., Drioli E. Diffusive and convective transport through hollow fiber membranes for liver cell culture. J. Biotechnol. 2005;117:309–321. doi: 10.1016/j.jbiotec.2005.02.004. [DOI] [PubMed] [Google Scholar]
  16. David B., Dore E., Jaffrin M.Y., Legallais C. Mass transfers in a fluidized bed bioreactor using alginate beads for a future bioartificial liver. Int. J. Artif. Organs. 2004;27:284–293. doi: 10.1177/039139880402700404. [DOI] [PubMed] [Google Scholar]
  17. Bartolo L., Bader A. Review of a flat membrane bioreactor as a bioartificial liver. Ann. Transplant. 2001;6:40–46. [PubMed] [Google Scholar]
  18. Bartolo L., Jarosch-Von Schweder G., Haverich A., Bader A. A novel full-scale flat membrane bioreactor utilizing porcine hepatocytes: cell viability and tissue-specific functions. Biotechnol. Prog. 2000;16:102–108. doi: 10.1021/bp990128o. [DOI] [PubMed] [Google Scholar]
  19. Bartolo L., Morelli S., Bader A., Drioli E. Evaluation of cell behaviour related to physico-chemical properties of polymeric membranes to be used in bioartificial organs. Biomaterials. 2002;23:2485–2497. doi: 10.1016/S0142-9612(01)00383-0. [DOI] [PubMed] [Google Scholar]
  20. Bartolo L., Morelli S., Lopez L.C., Giorno L., Campana C., Salerno S., Rende M., Favia P., Detomaso L., Gristina R., d’Agostino R., Drioli E. Biotransformation and liver-specific functions of human hepatocytes in culture on RGD-immobilized plasma-processed membranes. Biomaterials. 2005;26:4432–4441. doi: 10.1016/j.biomaterials.2004.11.009. [DOI] [PubMed] [Google Scholar]
  21. Bartolo L., Morelli S., Rende M., Gordano A., Drioli E. New modified polyetheretherketone membrane for liver cell culture in biohybrid systems: adhesion and specific functions of isolated hepatocytes. Biomaterials. 2004;25:3621–3629. doi: 10.1016/j.biomaterials.2003.10.042. [DOI] [PubMed] [Google Scholar]
  22. Leeuw A.M., Brouwer A., Knook D.L. Sinusoidal endothelial cells of the liver: fine structure and function in relation to age. J. Electron. Microsc. Tech. 1990;14:218–236. doi: 10.1002/jemt.1060140304. [DOI] [PubMed] [Google Scholar]
  23. Vos P., Haan B., Schilfgaarde R. Effect of the alginate composition on the biocompatibility of alginate-polylysine microcapsules. Biomaterials. 1997;18:273–278. doi: 10.1016/S0142-9612(96)00135-4. [DOI] [PubMed] [Google Scholar]
  24. Demetriou A.A., Brown R.S., Busuttil R.W., Fair J., McGuire B.M., Rosenthal P., Am Esch J.S., Lerut J., Nyberg S.L., Salizzoni M., Fagan E.A., Hemptinne B., Broelsch C.E., Muraca M., Salmeron J.M., Rabkin J.M., Metselaar H.J., Pratt D., La Mata M., McChesney L.P., Everson G.T., Lavin P.T., Stevens A.C., Pitkin Z., Solomon B.A. Prospectiverandomizedmulticentercontrolled trial of a bioartificial liver in treating acute liver failure. Ann. Surg. 2004;239:660–667. doi: 10.1097/01.sla.0000124298.74199.e5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Dixit V., Darvasi R., Arthur M., Lewin K., Gitnick G. Cryopreserved microencapsulated hepatocytes–transplantation studies in Gunn rats. Transplantation. 1993;55:616–622. doi: 10.1097/00007890-199303000-00028. [DOI] [PubMed] [Google Scholar]
  26. Dixit V., Gitnick G. The bioartificial liver: state-of-the-art. Eur. J. Surg. 1998;582(Suppl.):S71–S76. doi: 10.1080/11024159850191481. [DOI] [PubMed] [Google Scholar]
  27. Dore E., Legallais C. A new concept of bioartificial liver based on a fluidized bed bioreactor. Ther. Apher. 1999;3:264–267. doi: 10.1046/j.1526-0968.1999.00152.x. [DOI] [PubMed] [Google Scholar]
  28. Dou M., Sousa G., Lacarelle B., Placidi M., la Porte P., Domingo M., Lafont H., Rahmani R. Thawed human hepatocytes in primary culture. Cryobiology. 1992;29:454–469. doi: 10.1016/0011-2240(92)90048-7. [DOI] [PubMed] [Google Scholar]
  29. Dunn J.C., Tompkins R.G., Yarmush M.L. Long-term in vitro function of adult hepatocytes in a collagen sandwich configuration. Biotechnol. Prog. 1991;7:237–245. doi: 10.1021/bp00009a007. [DOI] [PubMed] [Google Scholar]
  30. Dunn J.C., Tompkins R.G., Yarmush M.L. Hepatocytes in collagen sandwich: evidence for transcriptional and translational regulation. J. Cell Biol. 1992;116:1043–1053. doi: 10.1083/jcb.116.4.1043. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Dunn J.C., Yarmush M.L., Koebe H.G., Tompkins R.G. Hepatocyte function and extracellular matrix geometry: long-term culture in a sandwich configuration. Faseb. J. 1989;3:174–177. doi: 10.1096/fasebj.3.2.2914628. [DOI] [PubMed] [Google Scholar]
  32. Ellis A.J., Hughes R.D., Wendon J.A., Dunne J., Langley P.G., Kelly J.H., Gislason G.T., Sussman N.L., Williams R. Pilot-controlled trial of the extracorporeal liver assist device in acute liver failure. Hepatology. 1996;24:1446–1451. doi: 10.1002/hep.510240625. [DOI] [PubMed] [Google Scholar]
  33. Elvevold K.H., Nedredal G.I., Revhaug A., Smedsrod B. Scavenger properties of cultivated pig liver endothelial cells. Comp. Hepatol. 2004;3:4. doi: 10.1186/1476-5926-3-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Enomoto K., Nishikawa Y., Omori Y., Tokairin T., Yoshida M., Ohi N., Nishimura T., Yamamoto Y., Li Q. Cell biology and pathology of liver sinusoidal endothelial cells. Med. Electron. Microsc. 2004;37:208–215. doi: 10.1007/s00795-004-0261-4. [DOI] [PubMed] [Google Scholar]
  35. Eschbach E., Chatterjee S.S., Noldner M., Gottwald E., Dertinger H., Weibezahn K.F., Knedlitschek G. Microstructured scaffolds for liver tissue cultures of high cell density: morphological and biochemical characterization of tissue aggregates. J. Cell Biochem. 2005;95:243–255. doi: 10.1002/jcb.20360. [DOI] [PubMed] [Google Scholar]
  36. Evenepoel P., Laleman W., Wilmer A., Claes K., Maes B., Kuypers D., Bammens B., Nevens F., Vanrenterghem Y. Detoxifying capacity and kinetics of prometheus — a new extracorporeal system for the treatment of liver failure. Blood Purif. 2005;23:349–358. doi: 10.1159/000086885. [DOI] [PubMed] [Google Scholar]
  37. Fishman J.A., Patience C. Xenotransplantation: infectious risk revisited. Am. J. Transplant. 2004;4:1383–1390. doi: 10.1111/j.1600-6143.2004.00542.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Flendrig L.M., Calise F., Di Florio E., Mancini A., Ceriello A., Santaniello W., Mezza E., Sicoli F., Belleza G., Bracco A., Cozzolino S., Scala D., Mazzone M., Fattore M., Gonzales E., Chamuleau R.A. Significantly improved survival time in pigs with complete liver ischemia treated with a novel bioartificial liver. Int. J. Artif. Organs. 1999;22:701–709. [PubMed] [Google Scholar]
  39. Flendrig L.M., la Soe J.W., Jorning G.G., Steenbeek A., Karlsen O.T., Bovee W.M., Ladiges N.C., te Velde A.A., Chamuleau R.A. 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. 1997;26:1379–1392. doi: 10.1016/S0168-8278(97)80475-8. [DOI] [PubMed] [Google Scholar]
  40. Fremond B., Malandain C., Guyomard C., Chesne C., Guillouzo A., Campion J.P. Correction of bilirubin conjugation in the Gunn rat using hepatocytes immobilized in alginate gel beads as an extracorporeal bioartificial liver. Cell Transplant. 1993;2:453–460. doi: 10.1177/096368979300200603. [DOI] [PubMed] [Google Scholar]
  41. Fruhauf N.R., Oldhafer K.J., Holtje M., Kaiser G.M., Fruhauf J.H., Stavrou G.A., Bader A., Broelsch C.E. A bioartificial liver support system using primary hepatocytes: a preclinical study in a new porcine hepatectomy model. Surgery. 2004;136:47–56. doi: 10.1016/j.surg.2003.12.017. [DOI] [PubMed] [Google Scholar]
  42. Gan J.H., Zhou X.Q., Qin A.L., Luo E.P., Zhao W.F., Yu H., Xu J. Hybrid artificial liver support system for treatment of severe liver failure. World J. Gastroenterol. 2005;11:890–894. doi: 10.3748/wjg.v11.i6.890. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Gerlach J.C. Development of a hybrid liver support system: a review. Int. J. Artif. Organs. 1996;19:645–654. [PubMed] [Google Scholar]
  44. Gerlach J.C., Kloppel K., Muller C., Schnoy N., Smith M.D., Neuhaus P. Hepatocyte aggregate culture technique for bioreactors in hybrid liver support systems. Int. J. Artif. Organs. 1993;16:843–846. [PubMed] [Google Scholar]
  45. Gerlach J.C., Mutig K., Sauer I.M., Schrade P., Efimova E., Mieder T., Naumann G., Grunwald A., Pless G., Mas A., Bachmann S., Neuhaus P., Zeilinger K. Use of primary human liver cells originating from discarded grafts in a bioreactor for liver support therapy and the prospects of culturing adult liver stem cells in bioreactors: a morphologic study. Transplantation. 2003;76:781–786. doi: 10.1097/01.TP.0000083319.36931.32. [DOI] [PubMed] [Google Scholar]
  46. Gimson A.E. Fulminant and late onset hepatic failure. Br. J. Anaesth. 1996;77:90–98. doi: 10.1093/bja/77.1.90. [DOI] [PubMed] [Google Scholar]
  47. Glicklis R., Merchuk J.C., Cohen S. Modeling mass transfer in hepatocyte spheroids via cell viability, spheroid sizeand hepatocellular functions. Biotechnol. Bioeng. 2004;86:672–680. doi: 10.1002/bit.20086. [DOI] [PubMed] [Google Scholar]
  48. Glicklis R., Shapiro L., Agbaria R., Merchuk J.C., Cohen S. Hepatocyte behavior within three-dimensional porous alginate scaffolds. Biotechnol. Bioeng. 2000;67:344–353. doi: 10.1002/(SICI)1097-0290(20000205)67:3<344::AID-BIT11>3.0.CO;2-2. [DOI] [PubMed] [Google Scholar]
  49. Gregory P.G., Connolly C.K., Toner M., Sullivan S.J. In vitro characterization of porcine hepatocyte function. Cell Transplant. 2000;9:1–10. doi: 10.1177/096368970000900101. [DOI] [PubMed] [Google Scholar]
  50. Guillouzo A., Rialland L., Fautrel A., Guyomard C. Survival and function of isolated hepatocytes after cryopreservation. Chem. Biol. Interact. 1999;121:7–16. doi: 10.1016/S0009-2797(99)00087-3. [DOI] [PubMed] [Google Scholar]
  51. Hasegawa H., Shimada M., Gion T., Ijima H., Nakazawa K., Funatsu K., Sugimachi K. Modulation of immunologic reactions between cultured porcine hepatocytes and human sera. ASAIO J. 1999;45:392–396. doi: 10.1097/00002480-199909000-00005. [DOI] [PubMed] [Google Scholar]
  52. He Z.P., Tan W.Q., Tang Y.F., Feng M.F. Differentiation of putative hepatic stem cells derived from adult rats into mature hepatocytes in the presence of epidermal growth factor and hepatocyte growth factor. Differentiation. 2003;71:281–290. doi: 10.1046/j.1432-0436.2003.7104505.x. [DOI] [PubMed] [Google Scholar]
  53. Hengstler J.G., Ringel M., Biefang K., Hammel S., Milbert U., Gerl M., Klebach M., Diener B., Platt K.L., Bottger T., Steinberg P., Oesch F. Cultures with cryopreserved hepatocytes: applicability for studies of enzyme induction. Chem. Biol. Interact. 2000;125:51–73. doi: 10.1016/S0009-2797(99)00141-6. [DOI] [PubMed] [Google Scholar]
  54. Hoekstra R., Chamuleau R.A. Recent developments on human cell lines for the bioartificial liver. Int. J. Artif. Organs. 2002;25:182–191. doi: 10.1177/039139880202500304. [DOI] [PubMed] [Google Scholar]
  55. Honiger J., Sarkis R., Baudrimont M., Delelo R., Chafai N., Benoist S., Sarkis K., Balladur P., Capeau J., Nordlinger B. Semiautomatic macroencapsulation of large numbers of porcine hepatocytes by coextrusion with a solution of AN69 polymer. Biomaterials. 2000;21:1269–1274. doi: 10.1016/S0142-9612(00)00012-0. [DOI] [PubMed] [Google Scholar]
  56. Hughes R.D., Nicolaou N., Langley P.G., Ellis A.J., Wendon J.A., Williams R. Plasma cytokine levels and coagulation and complement activation during use of the extracorporeal liver assist device in acute liver failure. Artif. Organs. 1998;22:854–858. doi: 10.1046/j.1525-1594.1998.06162.x. [DOI] [PubMed] [Google Scholar]
  57. Irgang M., Sauer I.M., Karlas A., Zeilinger K., Gerlach J.C., Kurth R., Neuhaus P., Denner J. Porcine endogenous retroviruses: no infection in patients treated with a bioreactor based on porcine liver cells. J. Clin. Virol. 2003;28: 141–154. doi: 10.1016/S1386-6532(02)00275-5. [DOI] [PubMed] [Google Scholar]
  58. Isom H.C., Secott T., Georgoff I., Woodworth C., Mummaw J. Maintenance of differentiated rat hepatocytes in primary culture. Proc. Natl. Acad. Sci. U.S.A. 1985;82:3252–3256. doi: 10.1073/pnas.82.10.3252. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Jasmund I., Langsch A., Simmoteit R., Bader A. Cultivation of primary porcine hepatocytes in an OXY-HFB for use as a bioartificial liver device. Biotechnol. Prog. 2002;18:839–846. doi: 10.1021/bp025501y. [DOI] [PubMed] [Google Scholar]
  60. Jauregui H.O., Mullon C.J., Trenkler D., Naik S., Santangini H., Press P., Muller T.E., Solomon B.A. In vivo evaluation of a hollow fiber liver assist device. Hepatology. 1995;21:460–469. doi: 10.1002/hep.1840210230. [DOI] [PubMed] [Google Scholar]
  61. Jauregui H.O., Naik S., Santangini H., Pan J., Trenkler D., Mullon C. Primary cultures of rat hepatocytes in hollow fiber chambers. In Vitro Cell Dev Biol. Anim. 1994;30:23–29. doi: 10.1007/BF02631414. [DOI] [PubMed] [Google Scholar]
  62. Joly A., Desjardins J.F., Fremond B., Desille M., Campion J.P., Malledant Y., Lebreton Y., Semana G., Edwards-Levy F., Levy M.C., Clement B. Survival, proliferation, and functions of porcine hepatocytes encapsulated in coated alginate beads: a step toward a reliable bioartificial liver. Transplantation. 1997;63:795–803. doi: 10.1097/00007890-199703270-00002. [DOI] [PubMed] [Google Scholar]
  63. Kang Y.H., Berthiaume F., Nath B.D., Yarmush M.L. Growth factors and nonparenchymal cell conditioned media induce mitogenic responses in stable long-term adult rat hepatocyte cultures. Exp. Cell Res. 2004;293:239–247. doi: 10.1016/j.yexcr.2003.10.011. [DOI] [PubMed] [Google Scholar]
  64. King A., Strand B., Rokstad A.M., Kulseng B., Andersson A., Skjak-Braek G., Sandler S. Improvement of the biocompatibility of alginate/poly-l-lysine/alginate microcapsules by the use of epimerized alginate as a coating. J. Biomed. Mater. Res. (Part) A. 2003;64:533–539. doi: 10.1002/jbm.a.10276. [DOI] [PubMed] [Google Scholar]
  65. Kjaergard L.L., Liu J., Als-Nielsen B., Gluud C. Artificial and bioartificial support systems for acute and acute-on-chronic liver failure: a systematic review. JAMA. 2003;289:217–222. doi: 10.1001/jama.289.2.217. [DOI] [PubMed] [Google Scholar]
  66. Kmieć Z. Cooperation of liver cells in health and disease. In: Beck F., Christ B., Kriz W., Kummer W., Marani E., Putz R., Sano Y., Schiebler T.H., Schoenwolf G.C., Zilles K., editors. Advances in Anatomy Embryology and Cell Biology, Vol. 161. Berlin, Heidelberg, New York: Springer-Verlag; 2001. pp. 1–149. [DOI] [PubMed] [Google Scholar]
  67. Kobayashi N., Okitsu T., Nakaji S., Tanaka N. Hybrid bioartificial liver: establishing a reversibly immortalized human hepatocyte line and developing a bioartificial liver for practical use. J. Artif. Organs. 2003;6:236–244. doi: 10.1007/s10047-003-0235-7. [DOI] [PubMed] [Google Scholar]
  68. Koide N., Sakaguchi K., Koide Y., Asano K., Kawaguchi M., Matsushima H., Takenami T., Shinji T., Mori M., Tsuji T. Formation of multicellular spheroids composed of adult rat hepatocytes in dishes with positively charged surfaces and under other nonadherent environments. Exp. Cell Res. 1990;186:227–235. doi: 10.1016/0014-4827(90)90300-Y. [DOI] [PubMed] [Google Scholar]
  69. Koniaris L.G., McKillop I.H., Schwartz S.I., Zimmers T.A. Liver regeneration. J. Am. Coll. Surg. 2003;197:634–659. doi: 10.1016/S1072-7515(03)00374-0. [DOI] [PubMed] [Google Scholar]
  70. Krisper P., Haditsch B., Stauber R., Jung A., Stadlbauer V., Trauner M., Holzer H., Schneditz D. In vivo quantification of liver dialysis: comparison of albumin dialysis and fractionated plasma separation. J. Hepatol. 2005;43:451–457. doi: 10.1016/j.jhep.2005.02.038. [DOI] [PubMed] [Google Scholar]
  71. Kuddus R., Patzer J.F., Lopez R., Mazariegos G.V., Meighen B., Kramer D.J., Rao A.S. Clinical and laboratory evaluation of the safety of a bioartificial liver assist device for potential transmission of porcine endogenous retrovirus. Transplantation. 2002;73:420–429. doi: 10.1097/00007890-200202150-00017. [DOI] [PubMed] [Google Scholar]
  72. Lacik I., Brissova M., Anilkumar A.V., Powers A.C., Wang T. New capsule with tailored properties for the encapsulation of living cells. J. Biomed. Mater. Res. 1998;39:52–60. doi: 10.1002/(SICI)1097-4636(199801)39:1<52::AID-JBM7>3.0.CO;2-H. [DOI] [PubMed] [Google Scholar]
  73. Langsch A., Bader A. Longterm stability of phase I and phase II enzymes of porcine liver cells in flat membrane bioreactors. Biotechnol. Bioeng. 2001;76:115–125. doi: 10.1002/bit.1151. [DOI] [PubMed] [Google Scholar]
  74. Lee K.W., Park J.B., Yoon J.J., Lee J.H., Kim S.Y., Jung H.J., Lee S.K., Kim S.J., Lee H.H., Lee D.S., Joh J.W. The viability and function of cryopreserved hepatocyte spheroids with different cryopreservation solutions. Transplant. Proc. 2004;36:2462–2463. doi: 10.1016/j.transproceed.2004.08.069. [DOI] [PubMed] [Google Scholar]
  75. Lee W.M. Acute liver failure. N. Engl. J. Med. 1993;329:1862–1872. doi: 10.1056/NEJM199312163292508. [DOI] [PubMed] [Google Scholar]
  76. Legallais C., Dore E., Paullier P. Design of a fluidized bed bioartificial liver. Artif. Organs. 2000;24:519–525. doi: 10.1046/j.1525-1594.2000.06510.x. [DOI] [PubMed] [Google Scholar]
  77. Lorenti A., Barbich M., de Santibanes M., Ielpi M., Vazquez J.C., Sorroche P., Argibay P. Ammonium detoxification performed by porcine hepatocyte spheroids in a bioartificial liver for pediatric use: preliminary report. Artif. Organs. 2003;27:665–670. doi: 10.1046/j.1525-1594.2003.07098.x. [DOI] [PubMed] [Google Scholar]
  78. Louha M., Poussin K., Ganne N., Zylberberg H., Nalpas B., Nicolet J., Capron F., Soubrane O., Vons C., Pol S., Beaugrand M, Berthelot P., Franco D., Trinchet J.C., Brechot C., Paterlini P. Spontaneous and iatrogenic spreading of liver-derived cells into peripheral blood of patients with primary liver cancer. Hepatology. 1997;26:998–1005. doi: 10.1002/hep.510260430. [DOI] [PubMed] [Google Scholar]
  79. Lowes K.N., Croager E.J., Olynyk J.K., Abraham L.J., Yeoh G.C. Oval cell-mediated liver regeneration: Role of cytokines and growth factors. J. Gastroenterol. Hepatol. 2003;18:4–12. doi: 10.1046/j.1440-1746.2003.02906.x. [DOI] [PubMed] [Google Scholar]
  80. Mai G., Huy N.T., Morel P., Mei J., Bosco D., Berney T., Majno P., Mentha G., Trono D., Buhler L.H. Treatment of fulminant liver failure by transplantation of microencapsulated primary or immortalized xenogeneic hepatocytes. Transplant. Proc. 2005;37:527–529. doi: 10.1016/j.transproceed.2005.01.017. [DOI] [PubMed] [Google Scholar]
  81. Martinez-Hernandez A., Amenta P.S. The hepatic extracellular matrix. I. Components and distribution in normal liver. Virchows Arch. A. Pathol. Anat. Histopathol. 1993;423:1–11. doi: 10.1007/BF01606425. [DOI] [PubMed] [Google Scholar]
  82. Matsushita T., Yagi T., Hardin J.A., Cragun J.D., Crow F.W., Bergen H.R., Gores G.J., Nyberg S.L. Apoptotic cell death and function of cryopreserved porcine hepatocytes in a bioartificial liver. Cell Transplant. 2003;12:109–121. doi: 10.3727/000000003108746696. [DOI] [PubMed] [Google Scholar]
  83. Mazariegos G.V., Kramer D.J., Lopez R.C., Shakil A.O., Rosenbloom A.J., DeVera M., Giraldo M., Grogan T.A., Zhu Y., Fulmer M.L., Amiot B.P., Patzer J.F. Safety observations in phase I clinical evaluation of the Excorp Medical Bioartificial Liver Support System after the first four patients. ASAIO J. 2001;47:471–475. doi: 10.1097/00002480-200109000-00015. [DOI] [PubMed] [Google Scholar]
  84. McClelland R.E., MacDonald J.M., Coger R.N. Modeling O2 transport within engineered hepatic devices. Biotechnol. Bioeng. 2003;82:12–27. doi: 10.1002/bit.10531. [DOI] [PubMed] [Google Scholar]
  85. McLaughlin B.E., Tosone C.M., Custer L.M., Mullon C. Overview of extracorporeal liver support systems and clinical results. Ann. NY Acad. Sci. 1999;875:310–325. doi: 10.1111/j.1749-6632.1999.tb08514.x. [DOI] [PubMed] [Google Scholar]
  86. Michalopoulos G.K., Bowen W.C., Mule K., Stolz D.B. Histological organization in hepatocyte organoid cultures. Am. J. Pathol. 2001;159:1877–1887. doi: 10.1016/S0002-9440(10)63034-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  87. Michalopoulos G.K., DeFrances M.C. Liver regeneration. Science. 1997;276:60–66. doi: 10.1126/science.276.5309.60. [DOI] [PubMed] [Google Scholar]
  88. Mitzner S.R., Stange J., Klammt S., Peszynski P., Schmidt R. Albumin dialysis using the molecular adsorbent recirculating system. Curr. Opin. Nephrol. Hypertens. 2001;10:777–783. doi: 10.1097/00041552-200111000-00008. [DOI] [PubMed] [Google Scholar]
  89. Miura Y., Akimoto T., Yagi K. Liver functions in hepatocytes entrapped within calcium alginate. Ann. NY Acad. Sci. 1988;542:521–532. doi: 10.1111/j.1749-6632.1988.tb25881.x. [DOI] [PubMed] [Google Scholar]
  90. Morsiani E., Brogli M., Galavotti D., Bellini T., Ricci D., Pazzi P., Puviani A.C. Long-term expression of highly differentiated functions by isolated porcine hepatocytes perfused in a radial–flow bioreactor. Artif. Organs. 2001;25:740–748. doi: 10.1046/j.1525-1594.2001.06669.x. [DOI] [PubMed] [Google Scholar]
  91. Morsiani E., Brogli M., Galavotti D., Pazzi P., Puviani A.C., Azzena G.F. Biologic liver support: optimal cell source and mass. Int. J. Artif. Organs. 2002a;25:985–993. doi: 10.1177/039139880202501013. [DOI] [PubMed] [Google Scholar]
  92. Morsiani E., Pazzi P., Puviani A.C., Brogli M., Valieri L., Gorini P., Scoletta P., Marangoni E., Ragazzi R., Azzena G., Frazzoli E., Di Luca D., Cassai E. Early experiences with a porcine hepatocyte-based bioartificial liver in acute hepatic failure patients. Int. J. Artif. Organs. 2002b;25:192–202. doi: 10.1177/039139880202500305. [DOI] [PubMed] [Google Scholar]
  93. Muraca M., Vilei M.T., Zanusso E., Ferraresso C., Granato A., Doninsegna S., Dal Monte R., Carraro P., Carturan G. Encapsulation of hepatocytes by SiO(2) Transplant Proc. 2000;32:2713–2714. doi: 10.1016/S0041-1345(00)01852-2. [DOI] [PubMed] [Google Scholar]
  94. Muto Y., Nouri-Aria K.T., Meager A., Alexander G.J., Eddleston A.L., Williams R. Enhanced tumour necrosis factor and interleukin-1 in fulminant hepatic failure. Lancet. 1988;2:72–74. doi: 10.1016/S0140-6736(88)90006-2. [DOI] [PubMed] [Google Scholar]
  95. Nagy A. Cre recombinase: the universal reagent for genome tailoring. Genesis. 2000;26:99–109. doi: 10.1002/(SICI)1526-968X(200002)26:2<99::AID-GENE1>3.0.CO;2-B. [DOI] [PubMed] [Google Scholar]
  96. Nyberg S.L., Hibbs J.R., Hardin J.A., Germer J.J., Persing D.H. Transfer of porcine endogenous retrovirus across hollow fiber membranes: significance to a bioartificial liver. Transplantation. 1999;67:1251–1255. doi: 10.1097/00007890-199905150-00009. [DOI] [PubMed] [Google Scholar]
  97. Nyberg S.L., Mann H.J., Hu M.Y., Payne W.D., Hu W.S., Cerra F.B., Remmel R.P. Extrahepatic metabolism of 4-methylumbelliferone and lidocaine in the anhepatic rabbit. Drug Metab. Dispos. 1996;24:643–648. [PubMed] [Google Scholar]
  98. Nyberg S.L., Platt J.L., Shirabe K., Payne W.D., Hu W.S., Cerra F.B. Immunoprotection of xenocytes in a hollow fiber bioartificial liver. ASAIO J. 1992a;38:M463–M467. doi: 10.1097/00002480-199207000-00077. [DOI] [PubMed] [Google Scholar]
  99. Nyberg S.L., Shatford R.A., Hu W.S., Payne W.D., Cerra F.B. Hepatocyte culture systems for artificial liver support: implications for critical care medicine (bioartificial liver support) Crit. Care Med. 1992b;20:1157–1168. doi: 10.1097/00003246-199208000-00016. [DOI] [PubMed] [Google Scholar]
  100. Nyberg S.L., Shatford R.A., Payne W.D., Hu W.S., Cerra F.B. Primary culture of rat hepatocytes entrapped in cylindrical collagen gels: an in vitro system with application to the bioartificial liver. Rat hepatocytes cultured in cylindrical collagen gels. Cytotechnology. 1992c;10:205–215. doi: 10.1007/BF00146671. [DOI] [PubMed] [Google Scholar]
  101. Nyberg S.L., Shirabe K., Peshwa M.V., Sielaff T.D., Crotty P.L., Mann H.J., Remmel R.P., Payne W.D., Hu W.S., Cerra F.B. Extracorporeal application of a gel-entrapmentbioartificial liver: demonstration of drug metabolism and other biochemical functions. Cell Transplant. 1993;2:441–452. doi: 10.1177/096368979300200602. [DOI] [PubMed] [Google Scholar]
  102. Orive G., Hernandez R.M., Gascon A.R., Calafiore R., Chang T.M., De Vos P., Hortelano G., Hunkeler D., Lacik I., Shapiro A.M., Pedraz J.L. Cell encapsulation: promise and progress. Nat. Med. 2003;9:104–107. doi: 10.1038/nm0103-104. [DOI] [PubMed] [Google Scholar]
  103. Orive G., Hernandez R.M., Rodriguez Gascon A., Calafiore R., Chang T.M., de Vos P., Hortelano G., Hunkeler D., Lacik I., Pedraz J.L. History, challenges and perspectives of cell microencapsulation. Trends Biotechnol. 2004;22:87–92. doi: 10.1016/j.tibtech.2003.11.004. [DOI] [PubMed] [Google Scholar]
  104. Pahernik S.A., Thasler W.E., Doser M., Gomez-Lechon M.J., Castell M.J., Planck H., Koebe H.G. High density culturing of porcine hepatocytes immobilized on nonwoven polyurethane-based biomatrices. Cells Tissues Organs. 2001;168:170–177. doi: 10.1159/000047832. [DOI] [PubMed] [Google Scholar]
  105. Pitkin Z., Mullon C. Evidence of absence of porcine endogenous retrovirus (PERV) infection in patients treated with a bioartificial liver support system. Artif. Organs. 1999;23:829–833. doi: 10.1046/j.1525-1594.1999.06444.x. [DOI] [PubMed] [Google Scholar]
  106. Quek C.H., Li J., Sun T., Chan M.L., Mao H.Q., Gan L.M., Leong K.W., Yu H. Photo-crosslinkable microcapsules formed by polyelectrolyte copolymer and modified collagen for rat hepatocyte encapsulation. Biomaterials. 2004;25:3531–3540. doi: 10.1016/j.biomaterials.2003.09.112. [DOI] [PubMed] [Google Scholar]
  107. Rahman T., Hodgson H. Clinical management of acute hepatic failure. Intensive Care Med. 2001;27:467–476. doi: 10.1007/s001340100873. [DOI] [PubMed] [Google Scholar]
  108. Ramadori G., Armbrust T. Cytokines in the liver. Eur. J. Gastroenterol. Hepatol. 2001;13:777–784. doi: 10.1097/00042737-200107000-00004. [DOI] [PubMed] [Google Scholar]
  109. Rifai K., Bahr M., Schneider A., Ott M., Mann M. Neue Verfahren in der Leberersatztherapie. Medizinische Klinik. 2003;98:750–753. doi: 10.1007/s00063-003-1321-6. [DOI] [PubMed] [Google Scholar]
  110. Runge D., Runge D.M., Jager D., Lubecki K.A., Beer Stolz D., Karathanasis S., Kietzmann T., Strom S.C., Jungermann K., Fleig W.E., Michalopoulos G.K. Serum-freelong-term cultures of human hepatocytes: maintenance of cell morphology, transcription factors, and liver-specific functions. Biochem. Biophys. Res. Commun. 2000;269:46–53. doi: 10.1006/bbrc.2000.2215. [DOI] [PubMed] [Google Scholar]
  111. Saad B., Scholl F.A., Thomas H., Schawalder H., Streit V., Waechter F., Maier P. Crude liver membrane fractions and extracellular matrix components as substrata regulate differentially the preservation and inducibility of cytochrome P-450 isoenzymes in cultured rat hepatocytes. Eur. J. Biochem. 1993;213:805–814. doi: 10.1111/j.1432-1033.1993.tb17823.x. [DOI] [PubMed] [Google Scholar]
  112. Sakai Y., Naruse K., Nagashima I., Muto T., Suzuki M. Large-scale preparation and function of porcine hepatocyte spheroids. Int. J. Artif. Organs. 1996;19:294–301. [PubMed] [Google Scholar]
  113. Sato Y., Tsukada K., Hatakeyama K. Role of shear stress and immune responses in liver regeneration after a partial hepatectomy. Surg. Today. 1999;29:1–9. doi: 10.1007/BF02482962. [DOI] [PubMed] [Google Scholar]
  114. Sauer I.M., Gerlach J.C. Modular extracorporeal liver support. Artif. Organs. 2002;26:703–706. doi: 10.1046/j.1525-1594.2002.06931_1.x. [DOI] [PubMed] [Google Scholar]
  115. Sauer I.M., Kardassis D., Zeillinger K., Pascher A., Gruenwald A., Pless G., Irgang M., Kraemer M., Puhl G., Frank J., Muller A.R., Steinmuller T., Denner J., Neuhaus P., Gerlach J.C. Clinical extracorporeal hybrid liver support–phase I study with primary porcine liver cells. Xenotransplantation. 2003;10:460–469. doi: 10.1034/j.1399-3089.2003.00062.x. [DOI] [PubMed] [Google Scholar]
  116. Sauer I.M., Obermeyer N., Kardassis D., Theruvath T., Gerlach J.C. Development of a hybrid liver support system. Ann. NY Acad. Sci. 2001;944:308–319. doi: 10.1111/j.1749-6632.2001.tb03843.x. [DOI] [PubMed] [Google Scholar]
  117. Sauer I.M., Zeilinger K., Obermayer N., Pless G., Grunwald A., Pascher A., Mieder T., Roth S., Goetz M., Kardassis D., Mas A., Neuhaus P., Gerlach J.C. Primary human liver cells as source for modular extracorporeal liver support–a preliminary report. Int. J. Artif. Organs. 2002;25:1001–1005. doi: 10.1177/039139880202501015. [DOI] [PubMed] [Google Scholar]
  118. Schoen J.M., Wang H.H., Minuk G.Y., Lautt W.W. Shear stress-induced nitric oxide release triggers the liver regeneration cascade. Nitric Oxide. 2001;5:453–464. doi: 10.1006/niox.2001.0373. [DOI] [PubMed] [Google Scholar]
  119. Schuetz E.G., Li D., Omiecinski C.J., Muller-Eberhard U., Kleinman H.K., Elswick B., Guzelian P.S. Regulation of gene expression in adult rat hepatocytes cultured on a basement membrane matrix. J. Cell Physiol. 1988;134:309–323. doi: 10.1002/jcp.1041340302. [DOI] [PubMed] [Google Scholar]
  120. Semino C.E., Merok J.R., Crane G.G., Panagiotakos G., Zhang S. Functional differentiation of hepatocyte-like spheroid structures from putative liver progenitor cells in three-dimensional peptide scaffolds. Differentiation. 2003;71:262–270. doi: 10.1046/j.1432-0436.2003.7104503.x. [DOI] [PubMed] [Google Scholar]
  121. Seo S.J., Akaike T., Choi Y.J., Shirakawa M., Kang I.K., Cho C.S. Alginate microcapsules prepared with xyloglucan as a synthetic extracellular matrix for hepatocyte attachment. Biomaterials. 2005;26:3607–3615. doi: 10.1016/j.biomaterials.2004.09.025. [DOI] [PubMed] [Google Scholar]
  122. Serandour A.L., Loyer P., Garnier D., Courselaud B., Theret N., Glaise D., Guguen-Guillouzo C., Corlu A. TNFα-mediated extracellular matrix remodeling is required for multiple division cycles in rat hepatocytes. Hepatology. 2005;41:478–486. doi: 10.1002/hep.20602. [DOI] [PubMed] [Google Scholar]
  123. Shito M., Tilles A.W., Tompkins R.G., Yarmush M.L., Toner M. Efficacy of an extracorporeal flat-plate bioartificial liver in treating fulminant hepatic failure. J. Surg. Res. 2003;111:53–62. doi: 10.1016/S0022-4804(03)00048-9. [DOI] [PubMed] [Google Scholar]
  124. Sielaff T.D., Hu M.Y., Rao S., Groehler K., Olson D., Mann H.J., Remmel R.P., Shatford R.A., Amiot B., Hu W.S., et al. A technique for porcine hepatocyte harvest and description of differentiated metabolic functions in static culture. Transplantation. 1995;59:1459–1463. doi: 10.1097/00007890-199505270-00017. [DOI] [PubMed] [Google Scholar]
  125. Stange J., Mitzner S. Hepatocyte encapsulation–initial intentions and new aspects for its use in bioartificial liver support. Int. J. Artif. Organs. 1996;19:45–48. [PubMed] [Google Scholar]
  126. Sussman N.L., Chong M.G., Koussayer T., He D.E., Shang T.A., Whisennand H.H., Kelly J.H. Reversal of fulminant hepatic failure using an extracorporeal liver assist device. Hepatology. 1992;16:60–65. doi: 10.1002/hep.1840160112. [DOI] [PubMed] [Google Scholar]
  127. Sussman N.L., Kelly J.H. Improved liver function following treatment with an extracorporeal liver assist device. Artif. Organs. 1993;17:27–30. doi: 10.1111/j.1525-1594.1993.tb00381.x. [DOI] [PubMed] [Google Scholar]
  128. Suzuki A., Iwama A., Miyashita H., Nakauchi H., Taniguchi H. Role for growth factors and extracellular matrix in controlling differentiation of prospectively isolated hepatic stem cells. Development. 2003;130:2513–2524. doi: 10.1242/dev.00459. [DOI] [PubMed] [Google Scholar]
  129. Taub R. Liver regeneration: from myth to mechanism. Nat. Rev. Mol. Cell Biol. 2004;5:836–847. doi: 10.1038/nrm1489. [DOI] [PubMed] [Google Scholar]
  130. te Velde A.A., Ladiges N.C., Flendrig L.M., Chamuleau R.A. Functional activity of isolated pig hepatocytes attached to different extracellular matrix substrates. Implication for application of pig hepatocytes in a bioartificial liver. J. Hepatol. 1995;23:184–192. doi: 10.1016/0168-8278(95)80333-5. [DOI] [PubMed] [Google Scholar]
  131. Tong J.Z., Sarrazin S., Cassio D., Gauthier F., Alvarez F. Application of spheroid culture to human hepatocytes and maintenance of their differentiation. Biol. Cell. 1994;81:77–81. doi: 10.1016/0248-4900(94)90058-2. [DOI] [PubMed] [Google Scholar]
  132. Tsiaoussis J., Newsome P.N., Nelson L.J., Hayes P.C., Plevris J.N. Which hepatocyte will it be? Hepatocyte choice for bioartificial liver support systems. Liver Transpl. 2001;7:2–10. doi: 10.1053/jlts.2001.20845. [DOI] [PubMed] [Google Scholar]
  133. Uludag H., De Vos P., Tresco P.A. Technology of mammalian cell encapsulation. Adv. Drug Deliv. Rev. 2000;42:29–64. doi: 10.1016/S0169-409X(00)00053-3. [DOI] [PubMed] [Google Scholar]
  134. van de Kerkhove M.P., Germans M.R., Deurholt T., Hoekstra R., Joziasse D.H., van Wijk A.C., van Gulik T.M., Chamuleau R.A., Roos A. Evidence for Galα (1–3)Gal expression on primary porcine hepatocytes: implications for bioartificial liver systems. J. Hepatol. 2005a;42:541–547. doi: 10.1016/j.jhep.2004.11.041. [DOI] [PubMed] [Google Scholar]
  135. van de Kerkhove M.P., Hoekstra R., Chamuleau R.A., van Gulik T.M. Clinical application of bioartificial liver support systems. Ann. Surg. 2004;240:216–230. doi: 10.1097/01.sla.0000132986.75257.19. [DOI] [PMC free article] [PubMed] [Google Scholar]
  136. van de Kerkhove M.P., Poyck P.P., Deurholt T., Hoekstra R., Chamuleau R.A., van Gulik T.M. Liver support therapy: an overview of the AMC-bioartificial liver research. Dig. Surg. 2005b;22:254–264. doi: 10.1159/000088055. [DOI] [PubMed] [Google Scholar]
  137. Wake K. Cell-cell organization and functions of ‘sinusoids’ in liver microcirculation system. J. Electron. Microsc. (Tokyo) 1999;48:89–98. doi: 10.1093/oxfordjournals.jmicro.a023666. [DOI] [PubMed] [Google Scholar]
  138. Werner A., Duvar S., Muthing J., Buntemeyer H., Kahmann U., Lunsdorf H., Lehmann J. Cultivation and characterization of a new immortalized human hepatocyte cell lineHepZ, for use in an artificial liver support system. Ann. NY Acad. Sci. 1999;875:364–368. doi: 10.1111/j.1749-6632.1999.tb08518.x. [DOI] [PubMed] [Google Scholar]
  139. Wilkening S., Stahl F., Bader A. Comparison of primary human hepatocytes and hepatoma cell line HepG2 with regard to their biotransformation properties. Drug Metab. Dispos. 2003;31:1035–1042. doi: 10.1124/dmd.31.8.1035. [DOI] [PubMed] [Google Scholar]
  140. Xu J., Ma M., Purcell W.M. Biochemical and functional changes of rat liver spheroids during spheroid formation and maintenance in culture: II. nitric oxide synthesis and related changes. J. Cell Biochem. 2003;90:1176–1185. doi: 10.1002/jcb.10731. [DOI] [PubMed] [Google Scholar]
  141. Yamada K., Kamihira M., Iijima S. Self-organization of liver constitutive cells mediated by artificial matrix and improvement of liver functions in long-term culture. Biochem. Eng. J. 2001;8:135–143. doi: 10.1016/S1369-703X(01)00095-X. [DOI] [Google Scholar]
  142. Yamashita Y., Shimada M., Tsujita E., Shirabe K., Ijima H., Nakazawa K., Sakiyama R., Fukuda J., Funatsu K., Sugimachi K. Efficacy of a larger version of the hybrid artificial liver support system using a polyurethane foam/spheroid packed-bed module in a warm ischemic liver failure pig model for preclinical experiments. Cell Transplant. 2003;12:101–107. doi: 10.3727/000000003108746687. [DOI] [PubMed] [Google Scholar]

Articles from Cytotechnology are provided here courtesy of Springer Science+Business Media B.V.

RESOURCES