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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

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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.

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References

  • Auth M.K., Okamoto M., Ishida Y., Keogh A., Auth S.H., Gerlach J., Encke A., McMaster P. and Strain A.J. (1998). Maintained function of primary human hepatocytes by cellular interactions in coculture: implications for liver support systems. Transpl. Int. 11: S439–S443

    Google Scholar 

  • Babensee J.E., De Boni U. and Sefton M.V. (1992). Morphological assessment of hepatoma cells (HepG2) microencapsulated in a HEMA-MMA copolymer with and without Matrigel. J. Biomed. Mater. Res. 26: 1401–1418

    Article  CAS  Google Scholar 

  • Bader A., Fruhauf N., Zech K., Haverich A. and Borlak J.T. (1998). Development of a small-scale bioreactor for drug metabolism studies maintaining hepatospecific functions. Xenobiotica 28: 815–825

    Article  CAS  Google Scholar 

  • Bader A., Knop E., Kern A., Boker K., Fruhauf N., Crome O., Esselmann H., Pape C., Kempka G. and Sewing K.F. (1996). 3-D coculture of hepatic sinusoidal cells with primary hepatocytes-design of an organotypical model. Exp. Cell Res. 226: 223–233

    Article  CAS  Google Scholar 

  • Bader A., Rinkes I.H., Closs E.I., Ryan C.M., Toner M., Cunningham J.M., Tompkins R.G. and Yarmush M.L. (1992). 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. 8: 219–225

    Article  CAS  Google Scholar 

  • Baquerizo A., Mhoyan A., Kearns-Jonker M., Arnaout W.S., Shackleton C., Busuttil R.W., Demetriou A.A. and Cramer D.V. (1999). 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 67: 5–18

    Article  CAS  Google Scholar 

  • Ben-Ze’ev A., Robinson G.S., Bucher N.L. and Farmer S.R. (1988). 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. 85: 2161–2165

    Article  Google Scholar 

  • Black D., Lyman S., Heider T.R. and Behrns K.E. (2004). Molecular and cellular features of hepatic regeneration. J. Surg. Res. 117: 306–315

    Article  CAS  Google Scholar 

  • Blusch J.H., Patience C. and Martin U. (2002). Pig endogenous retroviruses and xenotransplantation. Xenotransplantation 9: 242–251

    Article  Google Scholar 

  • Braet F., Shleper M., Paizi M., Brodsky S., Kopeiko N., Resnick N. and Spira G. (2004). Liver sinusoidal endothelial cell modulation upon resection and shear stress in vitro. Comp. Hepatol. 3: 7

    Article  CAS  Google Scholar 

  • Bucher N.L., Robinson G.S. and Farmer S.R. (1990). Effects of extracellular matrix on hepatocyte growth and gene expression: implications for hepatic regeneration and the repair of liver injury. Semin. Liver Dis. 10: 11–19

    Article  CAS  Google Scholar 

  • Canaple L., Nurdin N., Angelova N., Hunkeler D. and Desvergne B. (2001). Development of a coculture model of encapsulated cells. Ann. NY Acad. Sci. 944: 350–361

    Article  CAS  Google Scholar 

  • Cascio S.M. (2001). Novel strategies for immortalization of human hepatocytes. Artif. Organs 25: 529–538

    Article  CAS  Google Scholar 

  • Costa R.H., Kalinichenko V.V., Holterman A.X. and Wang X. (2003). Transcription factors in liver development differentiation, and regeneration. Hepatology 38: 1331–1347

    CAS  Google Scholar 

  • Curcio E., Barbieri G., Rende M., Giorno L., Morelli S. and Drioli E. (2005). Diffusive and convective transport through hollow fiber membranes for liver cell culture. J. Biotechnol. 117: 309–321

    Article  CAS  Google Scholar 

  • David B., Dore E., Jaffrin M.Y. and Legallais C. (2004). Mass transfers in a fluidized bed bioreactor using alginate beads for a future bioartificial liver. Int. J. Artif. Organs 27: 284–293

    CAS  Google Scholar 

  • De Bartolo L., Bader A. (2001). Review of a flat membrane bioreactor as a bioartificial liver. Ann. Transplant. 6: 40–46

    Google Scholar 

  • De Bartolo L., Jarosch-Von Schweder G., Haverich A. and Bader A. (2000). A novel full-scale flat membrane bioreactor utilizing porcine hepatocytes: cell viability and tissue-specific functions. Biotechnol. Prog. 16: 102–108

    Article  CAS  Google Scholar 

  • De Bartolo L., Morelli S., Bader A. and Drioli E. (2002). Evaluation of cell behaviour related to physico-chemical properties of polymeric membranes to be used in bioartificial organs. Biomaterials 23: 2485–2497

    Article  Google Scholar 

  • De Bartolo L., Morelli S., Lopez L.C., Giorno L., Campana C., Salerno S., Rende M., Favia P., Detomaso L., Gristina R., d’Agostino R. and Drioli E. (2005). Biotransformation and liver-specific functions of human hepatocytes in culture on RGD-immobilized plasma-processed membranes. Biomaterials 26: 4432–4441

    Article  CAS  Google Scholar 

  • De Bartolo L., Morelli S., Rende M., Gordano A. and Drioli E. (2004). New modified polyetheretherketone membrane for liver cell culture in biohybrid systems: adhesion and specific functions of isolated hepatocytes. Biomaterials 25: 3621–3629

    Article  CAS  Google Scholar 

  • De Leeuw A.M., Brouwer A. and Knook D.L. (1990). Sinusoidal endothelial cells of the liver: fine structure and function in relation to age. J. Electron. Microsc. Tech. 14: 218–236

    Article  Google Scholar 

  • De Vos P., De Haan B. and Van Schilfgaarde R. (1997). Effect of the alginate composition on the biocompatibility of alginate-polylysine microcapsules. Biomaterials 18: 273–278

    Article  Google Scholar 

  • 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., 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. and Solomon B.A. (2004). Prospectiverandomizedmulticentercontrolled trial of a bioartificial liver in treating acute liver failure. Ann. Surg. 239: 660–667

    Article  Google Scholar 

  • Dixit V., Darvasi R., Arthur M., Lewin K. and Gitnick G. (1993). Cryopreserved microencapsulated hepatocytes–transplantation studies in Gunn rats. Transplantation 55: 616–622

    Article  CAS  Google Scholar 

  • Dixit V. and Gitnick G. (1998). The bioartificial liver: state-of-the-art. Eur. J. Surg. 582(Suppl.): S71–S76

    Google Scholar 

  • Dore E. and Legallais C. (1999). A new concept of bioartificial liver based on a fluidized bed bioreactor. Ther. Apher. 3: 264–267

    Article  CAS  Google Scholar 

  • Dou M., de Sousa G., Lacarelle B., Placidi M., la Porte P., Domingo M., Lafont H. and Rahmani R. (1992). Thawed human hepatocytes in primary culture. Cryobiology 29: 454–469

    Article  CAS  Google Scholar 

  • Dunn J.C., Tompkins R.G. and Yarmush M.L. (1991). Long-term in vitro function of adult hepatocytes in a collagen sandwich configuration. Biotechnol. Prog. 7: 237–245

    Article  CAS  Google Scholar 

  • Dunn J.C., Tompkins R.G. and Yarmush M.L. (1992). Hepatocytes in collagen sandwich: evidence for transcriptional and translational regulation. J. Cell Biol. 116: 1043–1053

    Article  CAS  Google Scholar 

  • Dunn J.C., Yarmush M.L., Koebe H.G. and Tompkins R.G. (1989). Hepatocyte function and extracellular matrix geometry: long-term culture in a sandwich configuration. Faseb. J. 3: 174–177

    CAS  Google Scholar 

  • Ellis A.J., Hughes R.D., Wendon J.A., Dunne J., Langley P.G., Kelly J.H., Gislason G.T., Sussman N.L. and Williams R. (1996). Pilot-controlled trial of the extracorporeal liver assist device in acute liver failure. Hepatology 24: 1446–1451

    Article  CAS  Google Scholar 

  • Elvevold K.H., Nedredal G.I., Revhaug A. and Smedsrod B. (2004). Scavenger properties of cultivated pig liver endothelial cells. Comp. Hepatol. 3: 4

    Article  CAS  Google Scholar 

  • Enomoto K., Nishikawa Y., Omori Y., Tokairin T., Yoshida M., Ohi N., Nishimura T., Yamamoto Y. and Li Q. (2004). Cell biology and pathology of liver sinusoidal endothelial cells. Med. Electron. Microsc. 37: 208–215

    Article  Google Scholar 

  • Eschbach E., Chatterjee S.S., Noldner M., Gottwald E., Dertinger H., Weibezahn K.F. and Knedlitschek G. (2005). Microstructured scaffolds for liver tissue cultures of high cell density: morphological and biochemical characterization of tissue aggregates. J. Cell Biochem. 95: 243–255

    Article  CAS  Google Scholar 

  • Evenepoel P., Laleman W., Wilmer A., Claes K., Maes B., Kuypers D., Bammens B., Nevens F. and Vanrenterghem Y. (2005). Detoxifying capacity and kinetics of prometheus — a new extracorporeal system for the treatment of liver failure. Blood Purif. 23: 349–358

    Article  CAS  Google Scholar 

  • Fishman J.A. and Patience C. (2004). Xenotransplantation: infectious risk revisited. Am. J. Transplant. 4: 1383–1390

    Article  Google Scholar 

  • 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. and Chamuleau R.A. (1999). Significantly improved survival time in pigs with complete liver ischemia treated with a novel bioartificial liver. Int. J. Artif. Organs 22: 701–709

    CAS  Google Scholar 

  • 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. and Chamuleau R.A. (1997). 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

    Article  CAS  Google Scholar 

  • Fremond B., Malandain C., Guyomard C., Chesne C., Guillouzo A. and Campion J.P. (1993). Correction of bilirubin conjugation in the Gunn rat using hepatocytes immobilized in alginate gel beads as an extracorporeal bioartificial liver. Cell Transplant. 2: 453–460

    CAS  Google Scholar 

  • Fruhauf N.R., Oldhafer K.J., Holtje M., Kaiser G.M., Fruhauf J.H., Stavrou G.A., Bader A. and Broelsch C.E. (2004). A bioartificial liver support system using primary hepatocytes: a preclinical study in a new porcine hepatectomy model. Surgery 136: 47–56

    Article  Google Scholar 

  • Gan J.H., Zhou X.Q., Qin A.L., Luo E.P., Zhao W.F., Yu H. and Xu J. (2005). Hybrid artificial liver support system for treatment of severe liver failure. World J. Gastroenterol. 11: 890–894

    Google Scholar 

  • Gerlach J.C. (1996). Development of a hybrid liver support system: a review. Int. J. Artif. Organs 19: 645–654

    CAS  Google Scholar 

  • Gerlach J.C., Kloppel K., Muller C., Schnoy N., Smith M.D. and Neuhaus P. (1993). Hepatocyte aggregate culture technique for bioreactors in hybrid liver support systems. Int. J. Artif. Organs 16: 843–846

    CAS  Google Scholar 

  • 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. and Zeilinger K. (2003). 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 76: 781–786

    Article  Google Scholar 

  • Gimson A.E. (1996). Fulminant and late onset hepatic failure. Br. J. Anaesth. 77: 90–98

    CAS  Google Scholar 

  • Glicklis R., Merchuk J.C. and Cohen S. (2004). Modeling mass transfer in hepatocyte spheroids via cell viability, spheroid sizeand hepatocellular functions. Biotechnol. Bioeng. 86: 672–680

    Article  CAS  Google Scholar 

  • Glicklis R., Shapiro L., Agbaria R., Merchuk J.C. and Cohen S. (2000). Hepatocyte behavior within three-dimensional porous alginate scaffolds. Biotechnol. Bioeng. 67: 344–353

    Article  CAS  Google Scholar 

  • Gregory P.G., Connolly C.K., Toner M. and Sullivan S.J. (2000). In vitro characterization of porcine hepatocyte function. Cell Transplant. 9: 1–10

    CAS  Google Scholar 

  • Guillouzo A., Rialland L., Fautrel A. and Guyomard C. (1999). Survival and function of isolated hepatocytes after cryopreservation. Chem. Biol. Interact. 121: 7–16

    Article  CAS  Google Scholar 

  • Hasegawa H., Shimada M., Gion T., Ijima H., Nakazawa K., Funatsu K. and Sugimachi K. (1999). Modulation of immunologic reactions between cultured porcine hepatocytes and human sera. ASAIO J. 45: 392–396

    Article  CAS  Google Scholar 

  • He Z.P., Tan W.Q., Tang Y.F. and Feng M.F. (2003). 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 71: 281–290

    Article  CAS  Google Scholar 

  • Hengstler J.G., Ringel M., Biefang K., Hammel S., Milbert U., Gerl M., Klebach M., Diener B., Platt K.L., Bottger T., Steinberg P. and Oesch F. (2000). Cultures with cryopreserved hepatocytes: applicability for studies of enzyme induction. Chem. Biol. Interact. 125: 51–73

    Article  CAS  Google Scholar 

  • Hoekstra R. and Chamuleau R.A. (2002). Recent developments on human cell lines for the bioartificial liver. Int. J. Artif. Organs 25: 182–191

    CAS  Google Scholar 

  • Honiger J., Sarkis R., Baudrimont M., Delelo R., Chafai N., Benoist S., Sarkis K., Balladur P., Capeau J. and Nordlinger B. (2000). Semiautomatic macroencapsulation of large numbers of porcine hepatocytes by coextrusion with a solution of AN69 polymer. Biomaterials 21: 1269–1274

    Article  CAS  Google Scholar 

  • Hughes R.D., Nicolaou N., Langley P.G., Ellis A.J., Wendon J.A. and Williams R. (1998). Plasma cytokine levels and coagulation and complement activation during use of the extracorporeal liver assist device in acute liver failure. Artif. Organs 22: 854–858

    Article  CAS  Google Scholar 

  • Irgang M., Sauer I.M., Karlas A., Zeilinger K., Gerlach J.C., Kurth R., Neuhaus P. and Denner J. (2003). Porcine endogenous retroviruses: no infection in patients treated with a bioreactor based on porcine liver cells. J. Clin. Virol. 28: 141–154

    Article  CAS  Google Scholar 

  • Isom H.C., Secott T., Georgoff I., Woodworth C. and Mummaw J. (1985). Maintenance of differentiated rat hepatocytes in primary culture. Proc. Natl. Acad. Sci. U.S.A. 82: 3252–3256

    Article  CAS  Google Scholar 

  • Jasmund I., Langsch A., Simmoteit R. and Bader A. (2002). Cultivation of primary porcine hepatocytes in an OXY-HFB for use as a bioartificial liver device. Biotechnol. Prog. 18: 839–846

    Article  CAS  Google Scholar 

  • Jauregui H.O., Mullon C.J., Trenkler D., Naik S., Santangini H., Press P., Muller T.E. and Solomon B.A. (1995). In vivo evaluation of a hollow fiber liver assist device. Hepatology 21: 460–469

    Article  CAS  Google Scholar 

  • Jauregui H.O., Naik S., Santangini H., Pan J., Trenkler D. and Mullon C. (1994). Primary cultures of rat hepatocytes in hollow fiber chambers. In Vitro Cell Dev Biol. Anim. 30: 23–29

    Article  Google Scholar 

  • Joly A., Desjardins J.F., Fremond B., Desille M., Campion J.P., Malledant Y., Lebreton Y., Semana G., Edwards-Levy F., Levy M.C. and Clement B. (1997). Survival, proliferation, and functions of porcine hepatocytes encapsulated in coated alginate beads: a step toward a reliable bioartificial liver. Transplantation 63: 795–803

    Article  CAS  Google Scholar 

  • Kang Y.H., Berthiaume F., Nath B.D. and Yarmush M.L. (2004). Growth factors and nonparenchymal cell conditioned media induce mitogenic responses in stable long-term adult rat hepatocyte cultures. Exp. Cell Res. 293: 239–247

    Article  CAS  Google Scholar 

  • King A., Strand B., Rokstad A.M., Kulseng B., Andersson A., Skjak-Braek G. and Sandler S. (2003). 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. 64: 533–539

    Article  CAS  Google Scholar 

  • Kjaergard L.L., Liu J., Als-Nielsen B. and Gluud C. (2003). Artificial and bioartificial support systems for acute and acute-on-chronic liver failure: a systematic review. JAMA 289: 217–222

    Article  Google Scholar 

  • Kmieć Z. (2001). 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. and Zilles, K. (eds) Advances in Anatomy Embryology and Cell Biology, Vol. 161, pp 1–149. Springer-Verlag, Berlin, Heidelberg, New York

    Google Scholar 

  • Kobayashi N., Okitsu T., Nakaji S. and Tanaka N. (2003). Hybrid bioartificial liver: establishing a reversibly immortalized human hepatocyte line and developing a bioartificial liver for practical use. J. Artif. Organs 6: 236–244

    Article  Google Scholar 

  • Koide N., Sakaguchi K., Koide Y., Asano K., Kawaguchi M., Matsushima H., Takenami T., Shinji T., Mori M. and Tsuji T. (1990). Formation of multicellular spheroids composed of adult rat hepatocytes in dishes with positively charged surfaces and under other nonadherent environments. Exp. Cell Res. 186: 227–235

    Article  CAS  Google Scholar 

  • Koniaris L.G., McKillop I.H., Schwartz S.I. and Zimmers T.A. (2003). Liver regeneration. J. Am. Coll. Surg. 197: 634–659

    Article  Google Scholar 

  • Krisper P., Haditsch B., Stauber R., Jung A., Stadlbauer V., Trauner M., Holzer H. and Schneditz D. (2005). In vivo quantification of liver dialysis: comparison of albumin dialysis and fractionated plasma separation. J. Hepatol. 43: 451–457

    Article  CAS  Google Scholar 

  • Kuddus R., Patzer J.F., Lopez R., Mazariegos G.V., Meighen B., Kramer D.J. and Rao A.S. (2002). Clinical and laboratory evaluation of the safety of a bioartificial liver assist device for potential transmission of porcine endogenous retrovirus. Transplantation 73: 420–429

    Article  CAS  Google Scholar 

  • Lacik I., Brissova M., Anilkumar A.V., Powers A.C. and Wang T. (1998). New capsule with tailored properties for the encapsulation of living cells. J. Biomed. Mater. Res. 39: 52–60

    Article  CAS  Google Scholar 

  • Langsch A. and Bader A. (2001). Longterm stability of phase I and phase II enzymes of porcine liver cells in flat membrane bioreactors. Biotechnol. Bioeng. 76: 115–125

    Article  CAS  Google Scholar 

  • 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. and Joh J.W. (2004). The viability and function of cryopreserved hepatocyte spheroids with different cryopreservation solutions. Transplant. Proc. 36: 2462–2463

    Article  CAS  Google Scholar 

  • Lee W.M. (1993). Acute liver failure. N. Engl. J. Med. 329: 1862–1872

    Article  CAS  Google Scholar 

  • Legallais C., Dore E. and Paullier P. (2000). Design of a fluidized bed bioartificial liver. Artif. Organs 24: 519–525

    Article  CAS  Google Scholar 

  • Lorenti A., Barbich M., de Santibanes M., Ielpi M., Vazquez J.C., Sorroche P. and Argibay P. (2003). Ammonium detoxification performed by porcine hepatocyte spheroids in a bioartificial liver for pediatric use: preliminary report. Artif. Organs 27: 665–670

    Article  CAS  Google Scholar 

  • 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. and Paterlini P. (1997). Spontaneous and iatrogenic spreading of liver-derived cells into peripheral blood of patients with primary liver cancer. Hepatology 26: 998–1005

    Article  CAS  Google Scholar 

  • Lowes K.N., Croager E.J., Olynyk J.K., Abraham L.J. and Yeoh G.C. (2003). Oval cell-mediated liver regeneration: Role of cytokines and growth factors. J. Gastroenterol. Hepatol. 18: 4–12

    Article  CAS  Google Scholar 

  • Mai G., Huy N.T., Morel P., Mei J., Bosco D., Berney T., Majno P., Mentha G., Trono D. and Buhler L.H. (2005). Treatment of fulminant liver failure by transplantation of microencapsulated primary or immortalized xenogeneic hepatocytes. Transplant. Proc. 37: 527–529

    Article  CAS  Google Scholar 

  • Martinez-Hernandez A. and Amenta P.S. (1993). The hepatic extracellular matrix. I. Components and distribution in normal liver. Virchows Arch. A. Pathol. Anat. Histopathol. 423: 1–11

    Article  CAS  Google Scholar 

  • Matsushita T., Yagi T., Hardin J.A., Cragun J.D., Crow F.W., Bergen H.R., Gores G.J. and Nyberg S.L. (2003). Apoptotic cell death and function of cryopreserved porcine hepatocytes in a bioartificial liver. Cell Transplant. 12: 109–121

    Google Scholar 

  • 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. and Patzer J.F. (2001). Safety observations in phase I clinical evaluation of the Excorp Medical Bioartificial Liver Support System after the first four patients. ASAIO J. 47: 471–475

    Article  CAS  Google Scholar 

  • McClelland R.E., MacDonald J.M. and Coger R.N. (2003). Modeling O2 transport within engineered hepatic devices. Biotechnol. Bioeng. 82: 12–27

    Article  CAS  Google Scholar 

  • McLaughlin B.E., Tosone C.M., Custer L.M. and Mullon C. (1999). Overview of extracorporeal liver support systems and clinical results. Ann. NY Acad. Sci. 875: 310–325

    Article  CAS  Google Scholar 

  • Michalopoulos G.K., Bowen W.C., Mule K. and Stolz D.B. (2001). Histological organization in hepatocyte organoid cultures. Am. J. Pathol. 159: 1877–1887

    CAS  Google Scholar 

  • Michalopoulos G.K. and DeFrances M.C. (1997). Liver regeneration. Science 276: 60–66

    Article  CAS  Google Scholar 

  • Mitzner S.R., Stange J., Klammt S., Peszynski P. and Schmidt R. (2001). Albumin dialysis using the molecular adsorbent recirculating system. Curr. Opin. Nephrol. Hypertens. 10: 777–783

    Article  CAS  Google Scholar 

  • Miura Y., Akimoto T. and Yagi K. (1988). Liver functions in hepatocytes entrapped within calcium alginate. Ann. NY Acad. Sci. 542: 521–532

    Article  CAS  Google Scholar 

  • Morsiani E., Brogli M., Galavotti D., Bellini T., Ricci D., Pazzi P. and Puviani A.C. (2001). Long-term expression of highly differentiated functions by isolated porcine hepatocytes perfused in a radial–flow bioreactor. Artif. Organs 25: 740–748

    Article  CAS  Google Scholar 

  • Morsiani E., Brogli M., Galavotti D., Pazzi P., Puviani A.C. and Azzena G.F. (2002a). Biologic liver support: optimal cell source and mass. Int. J. Artif. Organs 25: 985–993

    CAS  Google Scholar 

  • 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. and Cassai E. (2002b). Early experiences with a porcine hepatocyte-based bioartificial liver in acute hepatic failure patients. Int. J. Artif. Organs 25: 192–202

    CAS  Google Scholar 

  • Muraca M., Vilei M.T., Zanusso E., Ferraresso C., Granato A., Doninsegna S., Dal Monte R., Carraro P. and Carturan G. (2000). Encapsulation of hepatocytes by SiO(2). Transplant Proc. 32: 2713–2714

    Article  CAS  Google Scholar 

  • Muto Y., Nouri-Aria K.T., Meager A., Alexander G.J., Eddleston A.L. and Williams R. (1988). Enhanced tumour necrosis factor and interleukin-1 in fulminant hepatic failure. Lancet 2: 72–74

    Article  CAS  Google Scholar 

  • Nagy A. (2000). Cre recombinase: the universal reagent for genome tailoring. Genesis 26: 99–109

    Article  CAS  Google Scholar 

  • Nyberg S.L., Hibbs J.R., Hardin J.A., Germer J.J. and Persing D.H. (1999). Transfer of porcine endogenous retrovirus across hollow fiber membranes: significance to a bioartificial liver. Transplantation 67: 1251–1255

    Article  CAS  Google Scholar 

  • Nyberg S.L., Mann H.J., Hu M.Y., Payne W.D., Hu W.S., Cerra F.B. and Remmel R.P. (1996). Extrahepatic metabolism of 4-methylumbelliferone and lidocaine in the anhepatic rabbit. Drug Metab. Dispos. 24: 643–648

    CAS  Google Scholar 

  • Nyberg S.L., Platt J.L., Shirabe K., Payne W.D., Hu W.S. and Cerra F.B. (1992a). Immunoprotection of xenocytes in a hollow fiber bioartificial liver. ASAIO J. 38: M463–M467

    Article  CAS  Google Scholar 

  • Nyberg S.L., Shatford R.A., Hu W.S., Payne W.D. and Cerra F.B. (1992b). Hepatocyte culture systems for artificial liver support: implications for critical care medicine (bioartificial liver support). Crit. Care Med. 20: 1157–1168

    Article  CAS  Google Scholar 

  • Nyberg S.L., Shatford R.A., Payne W.D., Hu W.S. and Cerra F.B. (1992c). 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 10: 205–215

    Article  CAS  Google Scholar 

  • 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. and Cerra F.B. (1993). Extracorporeal application of a gel-entrapmentbioartificial liver: demonstration of drug metabolism and other biochemical functions. Cell Transplant. 2: 441–452

    CAS  Google Scholar 

  • 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. and Pedraz J.L. (2003). Cell encapsulation: promise and progress. Nat. Med. 9: 104–107

    Article  CAS  Google Scholar 

  • Orive G., Hernandez R.M., Rodriguez Gascon A., Calafiore R., Chang T.M., de Vos P., Hortelano G., Hunkeler D., Lacik I. and Pedraz J.L (2004). History, challenges and perspectives of cell microencapsulation. Trends Biotechnol. 22: 87–92

    Article  CAS  Google Scholar 

  • Pahernik S.A., Thasler W.E., Doser M., Gomez-Lechon M.J., Castell M.J., Planck H. and Koebe H.G. (2001). High density culturing of porcine hepatocytes immobilized on nonwoven polyurethane-based biomatrices. Cells Tissues Organs 168: 170–177

    Article  CAS  Google Scholar 

  • Pitkin Z. and Mullon C. (1999). Evidence of absence of porcine endogenous retrovirus (PERV) infection in patients treated with a bioartificial liver support system. Artif. Organs 23: 829–833

    Article  CAS  Google Scholar 

  • Quek C.H., Li J., Sun T., Chan M.L., Mao H.Q., Gan L.M., Leong K.W. and Yu H. (2004). Photo-crosslinkable microcapsules formed by polyelectrolyte copolymer and modified collagen for rat hepatocyte encapsulation. Biomaterials 25: 3531–3540

    Article  CAS  Google Scholar 

  • Rahman T. and Hodgson H. (2001). Clinical management of acute hepatic failure. Intensive Care Med. 27: 467–476

    Article  CAS  Google Scholar 

  • Ramadori G. and Armbrust T. (2001). Cytokines in the liver. Eur. J. Gastroenterol. Hepatol. 13: 777–784

    Article  CAS  Google Scholar 

  • Rifai K., Bahr M., Schneider A., Ott M. and Mann M. (2003). Neue Verfahren in der Leberersatztherapie. Medizinische Klinik 98: 750–753

    Article  Google Scholar 

  • 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. and Michalopoulos G.K. (2000). Serum-freelong-term cultures of human hepatocytes: maintenance of cell morphology, transcription factors, and liver-specific functions. Biochem. Biophys. Res. Commun. 269: 46–53

    Article  CAS  Google Scholar 

  • Saad B., Scholl F.A., Thomas H., Schawalder H., Streit V., Waechter F. and Maier P. (1993). 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. 213: 805–814

    Article  CAS  Google Scholar 

  • Sakai Y., Naruse K., Nagashima I., Muto T. and Suzuki M. (1996). Large-scale preparation and function of porcine hepatocyte spheroids. Int. J. Artif. Organs 19: 294–301

    CAS  Google Scholar 

  • Sato Y., Tsukada K. and Hatakeyama K. (1999). Role of shear stress and immune responses in liver regeneration after a partial hepatectomy. Surg. Today 29: 1–9

    Article  CAS  Google Scholar 

  • Sauer I.M. and Gerlach J.C. (2002). Modular extracorporeal liver support. Artif. Organs 26: 703–706

    Article  Google Scholar 

  • 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. and Gerlach J.C. (2003). Clinical extracorporeal hybrid liver support–phase I study with primary porcine liver cells. Xenotransplantation 10: 460–469

    Article  CAS  Google Scholar 

  • Sauer I.M., Obermeyer N., Kardassis D., Theruvath T. and Gerlach J.C. (2001). Development of a hybrid liver support system. Ann. NY Acad. Sci. 944: 308–319

    Article  CAS  Google Scholar 

  • 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. and Gerlach J.C. (2002). Primary human liver cells as source for modular extracorporeal liver support–a preliminary report. Int. J. Artif. Organs 25: 1001–1005

    CAS  Google Scholar 

  • Schoen J.M., Wang H.H., Minuk G.Y. and Lautt W.W. (2001). Shear stress-induced nitric oxide release triggers the liver regeneration cascade. Nitric Oxide 5: 453–464

    Article  CAS  Google Scholar 

  • Schuetz E.G., Li D., Omiecinski C.J., Muller-Eberhard U., Kleinman H.K., Elswick B. and Guzelian P.S. (1988). Regulation of gene expression in adult rat hepatocytes cultured on a basement membrane matrix. J. Cell Physiol. 134: 309–323

    Article  CAS  Google Scholar 

  • Semino C.E., Merok J.R., Crane G.G., Panagiotakos G. and Zhang S. (2003). Functional differentiation of hepatocyte-like spheroid structures from putative liver progenitor cells in three-dimensional peptide scaffolds. Differentiation 71: 262–270

    Article  CAS  Google Scholar 

  • Seo S.J., Akaike T., Choi Y.J., Shirakawa M., Kang I.K. and Cho C.S. (2005). Alginate microcapsules prepared with xyloglucan as a synthetic extracellular matrix for hepatocyte attachment. Biomaterials 26: 3607–3615

    Article  CAS  Google Scholar 

  • Serandour A.L., Loyer P., Garnier D., Courselaud B., Theret N., Glaise D., Guguen-Guillouzo C. and Corlu A. (2005). TNFα-mediated extracellular matrix remodeling is required for multiple division cycles in rat hepatocytes. Hepatology 41: 478–486

    Article  CAS  Google Scholar 

  • Shito M., Tilles A.W., Tompkins R.G., Yarmush M.L. and Toner M. (2003). Efficacy of an extracorporeal flat-plate bioartificial liver in treating fulminant hepatic failure. J. Surg. Res. 111: 53–62

    Article  CAS  Google Scholar 

  • Sielaff T.D., Hu M.Y., Rao S., Groehler K., Olson D., Mann H.J., Remmel R.P., Shatford R.A., Amiot B. and Hu W.S. (1995). A technique for porcine hepatocyte harvest and description of differentiated metabolic functions in static culture. Transplantation 59: 1459–1463

    Article  CAS  Google Scholar 

  • Stange J. and Mitzner S. (1996). Hepatocyte encapsulation–initial intentions and new aspects for its use in bioartificial liver support. Int. J. Artif. Organs 19: 45–48

    CAS  Google Scholar 

  • Sussman N.L., Chong M.G., Koussayer T., He D.E., Shang T.A., Whisennand H.H. and Kelly J.H. (1992). Reversal of fulminant hepatic failure using an extracorporeal liver assist device. Hepatology 16: 60–65

    Article  CAS  Google Scholar 

  • Sussman N.L. and Kelly J.H. (1993). Improved liver function following treatment with an extracorporeal liver assist device. Artif. Organs 17: 27–30

    Article  CAS  Google Scholar 

  • Suzuki A., Iwama A., Miyashita H., Nakauchi H. and Taniguchi H. (2003). Role for growth factors and extracellular matrix in controlling differentiation of prospectively isolated hepatic stem cells. Development 130: 2513–2524

    Article  CAS  Google Scholar 

  • Taub R. (2004). Liver regeneration: from myth to mechanism. Nat. Rev. Mol. Cell Biol. 5: 836–847

    Article  CAS  Google Scholar 

  • te Velde A.A., Ladiges N.C., Flendrig L.M. and Chamuleau R.A. (1995). Functional activity of isolated pig hepatocytes attached to different extracellular matrix substrates. Implication for application of pig hepatocytes in a bioartificial liver. J. Hepatol. 23: 184–192

    CAS  Google Scholar 

  • Tong J.Z., Sarrazin S., Cassio D., Gauthier F. and Alvarez F. (1994). Application of spheroid culture to human hepatocytes and maintenance of their differentiation. Biol. Cell 81: 77–81

    Article  CAS  Google Scholar 

  • Tsiaoussis J., Newsome P.N., Nelson L.J., Hayes P.C. and Plevris J.N. (2001). Which hepatocyte will it be? Hepatocyte choice for bioartificial liver support systems. Liver Transpl. 7: 2–10

    Article  CAS  Google Scholar 

  • Uludag H., De Vos P. and Tresco P.A. (2000). Technology of mammalian cell encapsulation. Adv. Drug Deliv. Rev. 42: 29–64

    Article  CAS  Google Scholar 

  • 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. and Roos A. (2005a). Evidence for Galα (1–3)Gal expression on primary porcine hepatocytes: implications for bioartificial liver systems. J. Hepatol. 42: 541–547

    Article  CAS  Google Scholar 

  • van de Kerkhove M.P., Hoekstra R., Chamuleau R.A. and van Gulik T.M. (2004). Clinical application of bioartificial liver support systems. Ann. Surg. 240: 216–230

    Article  Google Scholar 

  • van de Kerkhove M.P. and Poyck P.P. (2005b). Liver support therapy: an overview of the AMC-bioartificial liver research. Dig. Surg. 22: 254–264

    Article  CAS  Google Scholar 

  • (1999). Cell-cell organization and functions of ‘sinusoids’ in liver microcirculation system. J. Electron. Microsc. (Tokyo) 48: 89–98

    CAS  Google Scholar 

  • (1999). Cultivation and characterization of a new immortalized human hepatocyte cell lineHepZ, for use in an artificial liver support system. Ann. NY Acad. Sci. 875: 364–368

    Article  CAS  Google Scholar 

  • (2003). Comparison of primary human hepatocytes and hepatoma cell line HepG2 with regard to their biotransformation properties. Drug Metab. Dispos. 31: 1035–1042

    Article  CAS  Google Scholar 

  • (2003). 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. 90: 1176–1185

    Article  CAS  Google Scholar 

  • (2001). Self-organization of liver constitutive cells mediated by artificial matrix and improvement of liver functions in long-term culture. Biochem. Eng. J. 8: 135–143

    Article  CAS  Google Scholar 

  • (2003). 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. 12: 101–107

    Google Scholar 

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  1. Center for Biotechnology and Biomedicine, Cell Techniques and Applied Stem Cell Biotechnology, University of Leipzig, Deutscher Platz 5, 04103, Leipzig, Germany

    Sonja Diekmann, Augustinus Bader & Stephanie Schmitmeier

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Diekmann, S., Bader, A. & Schmitmeier, S. Present and Future Developments in Hepatic Tissue Engineering for Liver Support Systems. Cytotechnology 50, 163–179 (2006). https://doi.org/10.1007/s10616-006-6336-4

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