Skip to main content
SpringerLink
Log in

Cell therapeutic options in liver diseases: cell types, medical devices and regulatory issues

  • Published:
Journal of Materials Science: Materials in Medicine Aims and scope Submit manuscript

Abstract

Although significant progress has been made in the field of orthotopic liver transplantation, cell-based therapies seem to be a promising alternative to whole-organ transplantation. The reasons are manifold but organ shortage is the main cause for this approach. However, many problems such as the question which cell type should be used or which application site is best for transplantation have been raised. In addition, some clinicians have had success by cultivating liver cells in bioreactors for temporary life support. Besides answering the question which cell type, which injection site or even which culture form should be used for liver support recent international harmonization of legal requirements is needed to be addressed by clinicians, scientists and companies dealing with cellular therapies. We here briefly summarize the possible cell types used to partially or temporarily correct liver diseases, the most recent development of bioreactor technology and important regulatory issues.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Street CN, Rajotte RV, et al. Stem cells: a promising source of pancreatic islets for transplantation in type 1 diabetes. Curr Top Dev Biol. 2003;58:111–36.

    Article  Google Scholar 

  2. Ehnert S, Glanemann M, et al. The possible use of stem cells in regenerative medicine: dream or reality? Langenbecks Arch Surg. 2009;394:985–97.

    Article  Google Scholar 

  3. Sauer IM, Zeilinger K, et al. Extracorporeal liver support based on primary human liver cells and albumin dialysis—treatment of a patient with primary graft non-function. J Hepatol. 2003;39:649–53.

    Article  Google Scholar 

  4. Strom S, Fisher R. Hepatocyte transplantation: new possibilities for therapy. Gastroenterology. 2003;124:568–71.

    Article  Google Scholar 

  5. Nagata H, Ito M, et al. Route of hepatocyte delivery affects hepatocyte engraftment in the spleen. Transplantation. 2003;76:732–4.

    Article  Google Scholar 

  6. Kobayashi N, Ito M, et al. Treatment of carbon tetrachloride and phenobarbital-induced chronic liver failure with intrasplenic hepatocyte transplantation. Cell Transplant. 2000;9:671–3.

    CAS  Google Scholar 

  7. Cai J, Ito M, et al. Treatment of liver failure in rats with end-stage cirrhosis by transplantation of immortalized hepatocytes. Hepatology. 2002;36:386–94.

    Article  CAS  Google Scholar 

  8. Nagata H, Ito M, et al. Treatment of cirrhosis and liver failure in rats by hepatocyte xenotransplantation. Gastroenterology. 2003;124:422–31.

    Article  Google Scholar 

  9. Mito M, Kusano M, et al. Hepatocyte transplantation in man. Transplant Proc. 1992;24:3052–3.

    CAS  Google Scholar 

  10. Strom SC, Chowdhury JR, et al. Hepatocyte transplantation for the treatment of human disease. Semin Liver Dis. 1999;19:39–48.

    Article  CAS  Google Scholar 

  11. Sipe JD. Tissue engineering and reparative medicine. Ann N Y Acad Sci. 2002;961:1–9.

    Article  CAS  Google Scholar 

  12. Barker JN, Wagner JE. Umbilical-cord blood transplantation for the treatment of cancer. Nat Rev Cancer. 2003;3:526–32.

    Article  CAS  Google Scholar 

  13. Thomas ED. Bone marrow transplantation from bench to bedside. Ann N Y Acad Sci. 1995;770:34–41.

    Article  CAS  Google Scholar 

  14. Flohr TR, Bonatti H Jr, et al. The use of stem cells in liver disease. Curr Opin Organ Transplant. 2009;14:64–71.

    Article  Google Scholar 

  15. Sancho-Bru P, Najimi M, et al. Stem and progenitor cells for liver repopulation: can we standardise the process from bench to bedside? Gut. 2009;58:594–603.

    Article  CAS  Google Scholar 

  16. Habibullah CM, Syed IH, et al. Human fetal hepatocyte transplantation in patients with fulminant hepatic failure. Transplantation. 1994;58:951–2.

    Article  CAS  Google Scholar 

  17. Pietrosi G, Vizzini GB, et al. Clinical applications of hepatocyte transplantation. World J Gastroenterol. 2009;15:2074–7.

    Article  Google Scholar 

  18. Puppi J, Dhawan A. Human hepatocyte transplantation overview. Methods Mol Biol. 2009;481:1–16.

    Article  CAS  Google Scholar 

  19. Strom SC, Fisher RA, et al. Hepatocyte transplantation as a bridge to orthotopic liver transplantation in terminal liver failure. Transplantation. 1997;63:559–69.

    Article  CAS  Google Scholar 

  20. Fox IJ, Chowdhury JR, et al. Treatment of the Crigler-Najjar syndrome type I with hepatocyte transplantation. N Engl J Med. 1998;338:1422–6.

    Article  CAS  Google Scholar 

  21. Bohnen NI, Charron M, et al. Use of indium-111-labeled hepatocytes to determine the biodistribution of transplanted hepatocytes through portal vein infusion. Clin Nucl Med. 2000;25:447–50.

    Article  CAS  Google Scholar 

  22. Horslen SP, McCowan TC, et al. Isolated hepatocyte transplantation in an infant with a severe urea cycle disorder. Pediatrics. 2003;111:1262–7.

    Article  Google Scholar 

  23. Muraca M, Gerunda G, et al. Hepatocyte transplantation as a treatment for glycogen storage disease type 1a. Lancet. 2002;359:317–8.

    Article  Google Scholar 

  24. Sokal EM, Smets F, et al. Hepatocyte transplantation in a 4-year-old girl with peroxisomal biogenesis disease: technique, safety, and metabolic follow-up. Transplantation. 2003;76:735–8.

    Article  Google Scholar 

  25. Dhawan A, Mitry RR, et al. Hepatocyte transplantation for inherited factor VII deficiency. Transplantation. 2004;78:1812–4.

    Article  Google Scholar 

  26. Allen KJ, Mifsud NA, et al. Cell-mediated rejection results in allograft loss after liver cell transplantation. Liver Transplant. 2008;14:688–94.

    Article  Google Scholar 

  27. Meyburg J, Schmidt J, et al. Liver cell transplantation in children. Clin Transplant. 2009;23(Suppl 21):75–82.

    Article  Google Scholar 

  28. Ambrosino G, Varotto S, et al. Isolated hepatocyte transplantation for Crigler-Najjar syndrome type 1. Cell Transplant. 2005;14:151–7.

    Article  Google Scholar 

  29. Meyburg J, Hoerster F, et al. Use of the middle colic vein for liver cell transplantation in infants and small children. Transplant Proc. 2008;40:936–7.

    Article  CAS  Google Scholar 

  30. Meyburg J, Das AM, et al. One liver for four children: first clinical series of liver cell transplantation for severe neonatal urea cycle defects. Transplantation. 2009;87:636–41.

    Article  Google Scholar 

  31. Puppi J, Tan N, et al. Hepatocyte transplantation followed by auxiliary liver transplantation—a novel treatment for ornithine transcarbamylase deficiency. Am J Transplant. 2008;8:452–7.

    Article  CAS  Google Scholar 

  32. Kreymann B, Seige M, et al. Albumin dialysis: effective removal of copper in a patient with fulminant Wilson disease and successful bridging to liver transplantation: a new possibility for the elimination of protein-bound toxins. J Hepatol. 1999;31:1080–5.

    Article  CAS  Google Scholar 

  33. Patzer JF II, Safta SA, et al. Slow continuous ultrafiltration with bound solute dialysis. ASAIO J. 2006;52:47–58.

    Article  Google Scholar 

  34. Rifai K, Ernst T, et al. Prometheus—a new extracorporeal system for the treatment of liver failure. J Hepatol. 2003;39:984–90.

    Article  CAS  Google Scholar 

  35. Stange J, Hassanein TI, et al. The molecular adsorbents recycling system as a liver support system based on albumin dialysis: a summary of preclinical investigations, prospective, randomized, controlled clinical trial, and clinical experience from 19 centers. Artif Organs. 2002;26:103–10.

    Article  Google Scholar 

  36. Chan C, Berthiaume F, et al. Hepatic tissue engineering for adjunct and temporary liver support: critical technologies. Liver Transplant. 2004;10:1331–42.

    Article  Google Scholar 

  37. Ting PP, Demetriou AA. Clinical experience with artificial liver support systems. Can J Gastroenterol. 2000;14(Suppl D):79D–84D.

    Google Scholar 

  38. Fiegel HC, Kaufmann PM, et al. Hepatic tissue engineering: from transplantation to customized cell-based liver directed therapies from the laboratory. J Cell Mol Med. 2008;12:56–66.

    Article  Google Scholar 

  39. Gerlach JC, Zeilinger K, et al. Bioartificial liver systems: why, what, whither? Regen Med. 2008;3:575–95.

    Article  CAS  Google Scholar 

  40. Kjaergard LL, Liu J, et al. Artificial and bioartificial support systems for acute and acute-on-chronic liver failure: a systematic review. JAMA. 2003;289:217–22.

    Article  Google Scholar 

  41. van de Kerkhove MP, Hoekstra R, et al. Clinical application of bioartificial liver support systems. Ann Surg. 2004;240:216–30.

    Article  Google Scholar 

  42. Ellis AJ, Hughes RD, et al. Pilot-controlled trial of the extracorporeal liver assist device in acute liver failure. Hepatology. 1996;24:1446–51.

    Article  CAS  Google Scholar 

  43. Millis JM, Cronin DC, et al. Initial experience with the modified extracorporeal liver-assist device for patients with fulminant hepatic failure: system modifications and clinical impact. Transplantation. 2002;74:1735–46.

    Article  Google Scholar 

  44. Sussman NL, Chong MG, et al. Reversal of fulminant hepatic failure using an extracorporeal liver assist device. Hepatology. 1992;16:60–5.

    Article  CAS  Google Scholar 

  45. Mazariegos GV, Kramer DJ, et al. Safety observations in phase I clinical evaluation of the Excorp Medical Bioartificial Liver Support System after the first four patients. ASAIO J. 2001;47:471–5.

    Article  CAS  Google Scholar 

  46. Mazariegos GV, Patzer JF II, et al. First clinical use of a novel bioartificial liver support system (BLSS). Am J Transplant. 2002;2:260–6.

    Article  Google Scholar 

  47. Demetriou AA, Brown RS Jr, et al. Prospective, randomized, multicenter, controlled trial of a bioartificial liver in treating acute liver failure. Ann Surg. 2004;239:660–7. discussion 7-70.

    Article  Google Scholar 

  48. Watanabe FD, Mullon CJ, et al. Clinical experience with a bioartificial liver in the treatment of severe liver failure. A phase I clinical trial. Ann Surg. 1997;225:484–91. discussion 91-4.

    Article  CAS  Google Scholar 

  49. van de Kerkhove MP, Di Florio E, et al. Phase I clinical trial with the AMC-bioartificial liver. Int J Artif Organs. 2002;25:950–9.

    Google Scholar 

  50. Morsiani E, Pazzi P, et al. Early experiences with a porcine hepatocyte-based bioartificial liver in acute hepatic failure patients. Int J Artif Organs. 2002;25:192–202.

    CAS  Google Scholar 

  51. Gerlach JC, Botsch M, et al. Experimental evaluation of a cell module for hybrid liver support. Int J Artif Organs. 2001;24:793–8.

    CAS  Google Scholar 

  52. Irgang M, Sauer IM, et al. Porcine endogenous retroviruses: no infection in patients treated with a bioreactor based on porcine liver cells. J Clin Virol. 2003;28:141–54.

    Article  CAS  Google Scholar 

  53. Morsiani E, Brogli M, et al. Biologic liver support: optimal cell source and mass. Int J Artif Organs. 2002;25:985–93.

    CAS  Google Scholar 

  54. Gerlach JC, Zeilinger K, et al. Extracorporeal liver support: porcine or human cell based systems? Int J Artif Organs. 2002;25:1013–8.

    CAS  Google Scholar 

  55. Tsiaoussis J, Newsome PN, et al. Which hepatocyte will it be? Hepatocyte choice for bioartificial liver support systems. Liver Transplant. 2001;7:2–10.

    Article  CAS  Google Scholar 

  56. Kobayashi N, Westerman KA, et al. A reversibly immortalized human hepatocyte cell line as a source of hepatocyte-based biological support. Addict Biol. 2001;6:293–300.

    Article  Google Scholar 

  57. Alison MR, Islam S, et al. Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly. J Pathol. 2009;217:282–98.

    Article  CAS  Google Scholar 

  58. Cantz T, Manns MP, et al. Stem cells in liver regeneration and therapy. Cell Tissue Res. 2008;331:271–82.

    Article  Google Scholar 

  59. Dan YY, Yeoh GC. Liver stem cells: a scientific and clinical perspective. J Gastroenterol Hepatol. 2008;23:687–98.

    Article  Google Scholar 

  60. Haridass D, Narain N, et al. Hepatocyte transplantation: waiting for stem cells. Curr Opin Organ Transplant. 2008;13:627–32.

    Article  Google Scholar 

  61. Kakinuma S, Nakauchi H, et al. Hepatic stem/progenitor cells and stem-cell transplantation for the treatment of liver disease. J Gastroenterol. 2009;44:167–72.

    Article  Google Scholar 

  62. Weiss TS, Lichtenauer M, et al. Hepatic progenitor cells from adult human livers for cell transplantation. Gut. 2008;57:1129–38.

    Article  CAS  Google Scholar 

  63. Souza BS, Nogueira RC, et al. Current status of stem cell therapy for liver diseases. Cell Transplant. 2009;18:1261–79.

    Article  Google Scholar 

  64. Quante M, Wang TC. Stem cells in gastroenterology and hepatology. Nat Rev Gastroenterol Hepatol. 2009;6:724–37.

    Article  Google Scholar 

  65. Schmelzer E, Wauthier E, et al. The phenotypes of pluripotent human hepatic progenitors. Stem Cells. 2006;24:1852–8.

    Article  CAS  Google Scholar 

  66. Schmelzer E, Zhang L, et al. Human hepatic stem cells from fetal and postnatal donors. J Exp Med. 2007;204:1973–87.

    Article  CAS  Google Scholar 

  67. Wohlers I, Stachelscheid H, et al. The characterization tool: a knowledge-based stem cell, differentiated cell, and tissue database with a web-based analysis front-end. Stem Cell Res. 2009;3:88–95.

    Article  Google Scholar 

  68. Kinoshita T, Sekiguchi T, et al. Hepatic differentiation induced by oncostatin M attenuates fetal liver hematopoiesis. Proc Natl Acad Sci USA. 1999;96:7265–70.

    Article  CAS  Google Scholar 

  69. Stachelscheid H, Urbaniak T, et al. Isolation and characterization of adult human liver progenitors from ischemic liver tissue derived from therapeutic hepatectomies. Tissue Eng A. 2009;15:1633–43.

    Article  CAS  Google Scholar 

  70. Ruhnke M, Nussler AK, et al. Human monocyte-derived neohepatocytes: a promising alternative to primary human hepatocytes for autologous cell therapy. Transplantation. 2005;79:1097–103.

    Article  Google Scholar 

  71. Ruhnke M, Ungefroren H, et al. Differentiation of in vitro-modified human peripheral blood monocytes into hepatocyte-like and pancreatic islet-like cells. Gastroenterology. 2005;128:1774–86.

    Article  CAS  Google Scholar 

  72. Shen CN, Slack JM, et al. Molecular basis of transdifferentiation of pancreas to liver. Nat Cell Biol. 2000;2:879–87.

    Article  CAS  Google Scholar 

  73. Tosh D, Shen CN, et al. Conversion of pancreatic cells to hepatocytes. Biochem Soc Trans. 2002;30:51–5.

    Article  CAS  Google Scholar 

  74. Banas A, Teratani T, et al. Adipose tissue-derived mesenchymal stem cells as a source of human hepatocytes. Hepatology. 2007;46:219–28.

    Article  CAS  Google Scholar 

  75. Najimi M, Khuu DN, et al. Adult-derived human liver mesenchymal-like cells as a potential progenitor reservoir of hepatocytes? Cell Transplant. 2007;16:717–28.

    Google Scholar 

  76. Lee HS, Crane GG, et al. Clonal expansion of adult rat hepatic stem cell lines by suppression of asymmetric cell kinetics (SACK). Biotechnol Bioeng. 2003;83:760–71.

    Article  CAS  Google Scholar 

  77. Schwartz RE, Reyes M, et al. Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells. J Clin Invest. 2002;109:1291–302.

    CAS  Google Scholar 

  78. Miyazaki M, Hardjo M, et al. Isolation of a bone marrow-derived stem cell line with high proliferation potential and its application for preventing acute fatal liver failure. Stem Cells. 2007;25:2855–63.

    Article  CAS  Google Scholar 

  79. Aurich H, Sgodda M, et al. Hepatocyte differentiation of mesenchymal stem cells from human adipose tissue in vitro promotes hepatic integration in vivo. Gut. 2009;58:570–81.

    Article  CAS  Google Scholar 

  80. Aurich I, Mueller LP, et al. Functional integration of hepatocytes derived from human mesenchymal stem cells into mouse livers. Gut. 2007;56:405–15.

    Article  CAS  Google Scholar 

  81. Glanemann M, Gaebelein G, et al. Transplantation of monocyte-derived hepatocyte-like cells (NeoHeps) improves survival in a model of acute liver failure. Ann Surg. 2009;249:149–54.

    Article  Google Scholar 

  82. Ehnert S, Nussler AK, et al. Blood monocyte-derived neohepatocytes as in vitro test system for drug metabolism. Drug Metab Dispos. 2008;36:1922–9.

    Article  CAS  Google Scholar 

  83. Lysy PA, Smets F, et al. Human skin fibroblasts: from mesodermal to hepatocyte-like differentiation. Hepatology. 2007;46:1574–85.

    Article  CAS  Google Scholar 

  84. Tosh D, Shen CN, et al. Differentiated properties of hepatocytes induced from pancreatic cells. Hepatology. 2002;36:534–43.

    Article  CAS  Google Scholar 

  85. Burke ZD, Shen CN, et al. Characterization of liver function in transdifferentiated hepatocytes. J Cell Physiol. 2006;206:147–59.

    Article  CAS  Google Scholar 

  86. Sasaki K, Kon J, et al. Proliferation of hepatocyte progenitor cells isolated from adult human livers in serum-free medium. Cell Transplant. 2008;17:1221–30.

    Article  Google Scholar 

  87. Gerlach JC, Mutig K, et al. 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;76:781–6.

    Article  Google Scholar 

  88. Schmelzer E, Mutig K, et al. Effect of human patient plasma ex vivo treatment on gene expression and progenitor cell activation of primary human liver cells in multi-compartment 3D perfusion bioreactors for extra-corporeal liver support. Biotechnol Bioeng. 2009;103:817–27.

    Article  CAS  Google Scholar 

  89. Ring A, Gerlach J, et al. Hepatic maturation of human fetal hepatocytes in four-compartment three-dimensional perfusion culture. Tissue Eng C. 2010;16:835–45.

    Article  CAS  Google Scholar 

  90. Mummery C, Ward-van Oostwaard D, et al. Differentiation of human embryonic stem cells to cardiomyocytes: role of coculture with visceral endoderm-like cells. Circulation. 2003;107:2733–40.

    Article  CAS  Google Scholar 

  91. Nir SG, David R, et al. Human embryonic stem cells for cardiovascular repair. Cardiovasc Res. 2003;58:313–23.

    Article  CAS  Google Scholar 

  92. Rubart M, Field LJ. Cardiac repair by embryonic stem-derived cells. Handb Exp Pharmacol. 2006;174:73–100.

    Article  Google Scholar 

  93. Agarwal S, Holton KL, et al. Efficient differentiation of functional hepatocytes from human embryonic stem cells. Stem Cells. 2008;26:1117–27.

    Article  CAS  Google Scholar 

  94. D’Amour KA, Agulnick AD, et al. Efficient differentiation of human embryonic stem cells to definitive endoderm. Nat Biotechnol. 2005;23:1534–41.

    Article  CAS  Google Scholar 

  95. Hay DC, Zhao D, et al. Efficient differentiation of hepatocytes from human embryonic stem cells exhibiting markers recapitulating liver development in vivo. Stem Cells. 2008;26:894–902.

    Article  CAS  Google Scholar 

  96. Nakagawa M, Koyanagi M, et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol. 2008;26:101–6.

    Article  CAS  Google Scholar 

  97. Ohnuki M, Takahashi K, et al., Generation and characterization of human induced pluripotent stem cells. Curr Protoc Stem Cell Biol 2009;Chapter 4:Unit 4A 2.

  98. Takahashi K, Tanabe K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131:861–72.

    Article  CAS  Google Scholar 

  99. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–76.

    Article  CAS  Google Scholar 

  100. Okita K, Ichisaka T, et al. Generation of germline-competent induced pluripotent stem cells. Nature. 2007;448:313–7.

    Article  CAS  Google Scholar 

  101. Yu J, Vodyanik MA, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318:1917–20.

    Article  CAS  Google Scholar 

  102. Huangfu D, Osafune K, et al. Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nat Biotechnol. 2008;26:1269–75.

    Article  CAS  Google Scholar 

  103. Wernig M, Meissner A, et al. In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature. 2007;448:318–24.

    Article  CAS  Google Scholar 

  104. Feng B, Jiang J, et al. Reprogramming of fibroblasts into induced pluripotent stem cells with orphan nuclear receptor Esrrb. Nat Cell Biol. 2009;11:197–203.

    Article  CAS  Google Scholar 

  105. Park IH, Zhao R, et al. Reprogramming of human somatic cells to pluripotency with defined factors. Nature. 2008;451:141–6.

    Article  CAS  Google Scholar 

  106. Lowry WE, Richter L, et al. Generation of human induced pluripotent stem cells from dermal fibroblasts. Proc Natl Acad Sci USA. 2008;105:2883–8.

    Article  CAS  Google Scholar 

  107. Park IH, Lerou PH, et al. Generation of human-induced pluripotent stem cells. Nat Protoc. 2008;3:1180–6.

    Article  CAS  Google Scholar 

  108. Kim JB, Sebastiano V, et al. Oct4-induced pluripotency in adult neural stem cells. Cell. 2009;136:411–9.

    Article  CAS  Google Scholar 

  109. Kim JB, Zaehres H, et al. Pluripotent stem cells induced from adult neural stem cells by reprogramming with two factors. Nature. 2008;454:646–50.

    Article  CAS  Google Scholar 

  110. Carey BW, Markoulaki S, et al. Reprogramming of murine and human somatic cells using a single polycistronic vector. Proc Natl Acad Sci USA. 2009;106:157–62.

    Article  CAS  Google Scholar 

  111. Ishii T, Fukumitsu K, et al. Effects of extracellular matrixes and growth factors on the hepatic differentiation of human embryonic stem cells. Am J Physiol Gastrointest Liver Physiol. 2008;295:G313–21.

    Article  CAS  Google Scholar 

  112. Hay DC, Fletcher J, et al. Highly efficient differentiation of hESCs to functional hepatic endoderm requires ActivinA and Wnt3a signaling. Proc Natl Acad Sci USA. 2008;105:12301–6.

    Article  CAS  Google Scholar 

  113. Momose Y, Matsunaga T, et al. Differentiation of monkey embryonic stem cells into hepatocytes and mRNA expression of cytochrome p450 enzymes responsible for drug metabolism: comparison of embryoid body formation conditions and matrices. Biol Pharm Bull. 2009;32:619–26.

    Article  CAS  Google Scholar 

  114. Sullivan GJ, Hay DC, et al. Generation of functional human hepatic endoderm from human induced pluripotent stem cells. Hepatology. 2009;51:329–35.

    Google Scholar 

  115. MacDonald JM, Wolfe SP, et al. Effect of flow configuration and membrane characteristics on membrane fouling in a novel multicoaxial hollow-fiber bioartificial liver. Ann N Y Acad Sci. 2001;944:334–43.

    Article  CAS  Google Scholar 

  116. De Bartolo L, Jarosch-Von Schweder G, et al. A novel full-scale flat membrane bioreactor utilizing porcine hepatocytes: cell viability and tissue-specific functions. Biotechnol Prog. 2000;16:102–8.

    Article  CAS  Google Scholar 

  117. Shito M, Kim NH, et al. In vitro and in vivo evaluation of albumin synthesis rate of porcine hepatocytes in a flat-plate bioreactor. Artif Organs. 2001;25:571–8.

    Article  CAS  Google Scholar 

  118. Shito M, Tilles AW, et al. Efficacy of an extracorporeal flat-plate bioartificial liver in treating fulminant hepatic failure. J Surg Res. 2003;111:53–62.

    Article  CAS  Google Scholar 

  119. Flendrig LM, la Soe JW, et al. 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;26:1379–92.

    Article  CAS  Google Scholar 

  120. Bhatia SN, Yarmush ML, et al. Controlling cell interactions by micropatterning in co-cultures: hepatocytes and 3T3 fibroblasts. J Biomed Mater Res. 1997;34:189–99.

    Article  CAS  Google Scholar 

  121. Kim SS, Utsunomiya H, et al. Survival and function of hepatocytes on a novel three-dimensional synthetic biodegradable polymer scaffold with an intrinsic network of channels. Ann Surg. 1998;228:8–13.

    Article  CAS  Google Scholar 

  122. Powers MJ, Domansky K, et al. A microfabricated array bioreactor for perfused 3D liver culture. Biotechnol Bioeng. 2002;78:257–69.

    Article  CAS  Google Scholar 

  123. Powers MJ, Janigian DM, et al. Functional behavior of primary rat liver cells in a three-dimensional perfused microarray bioreactor. Tissue Eng. 2002;8:499–513.

    Article  Google Scholar 

  124. Ambrosino G, Varotto S, et al. ALEX (artificial liver for extracorporeal xenoassistance): a new bioreactor containing a porcine autologous biomatrix as hepatocyte support. Preliminary results in an ex vivo experimental model. Int J Artif Organs. 2002;25:960–5.

    CAS  Google Scholar 

  125. Linti C, Zipfel A, et al. Cultivation of porcine hepatocytes in polyurethane nonwovens as part of a biohybrid liver support system. Int J Artif Organs. 2002;25:994–1000.

    CAS  Google Scholar 

  126. Gerlach JC, Kloppel K, et al. Hepatocyte aggregate culture technique for bioreactors in hybrid liver support systems. Int J Artif Organs. 1993;16:843–6.

    CAS  Google Scholar 

  127. Gerlach JC, Schnoy N, et al. Improved hepatocyte in vitro maintenance in a culture model with woven multicompartment capillary systems: electron microscopy studies. Hepatology. 1995;22:546–52.

    CAS  Google Scholar 

  128. Zeilinger K, Holland G, et al. Time course of primary liver cell reorganization in three-dimensional high-density bioreactors for extracorporeal liver support: an immunohistochemical and ultrastructural study. Tissue Eng. 2004;10:1113–24.

    CAS  Google Scholar 

  129. Gerlach JC, Brayfield C, et al. Lidocaine/monoethylglycinexylidide test, galactose elimination test, and sorbitol elimination test for metabolic assessment of liver cell bioreactors. Artif Organs. 2010;34:462–72.

    Article  CAS  Google Scholar 

  130. Pless G, Steffen I, et al. Evaluation of primary human liver cells in bioreactor cultures for extracorporeal liver support on the basis of urea production. Artif Organs. 2006;30:686–94.

    Article  CAS  Google Scholar 

  131. Zeilinger K, Sauer IM, et al. Three-dimensional co-culture of primary human liver cells in bioreactors for in vitro drug studies: effects of the initial cell quality on the long-term maintenance of hepatocyte-specific functions. Altern Lab Anim. 2002;30:525–38.

    CAS  Google Scholar 

  132. Sauer IM, Zeilinger K, et al. Primary human liver cells as source for modular extracorporeal liver support—a preliminary report. Int J Artif Organs. 2002;25:1001–5.

    CAS  Google Scholar 

  133. McCuskey RS. Morphological mechanisms for regulating blood flow through hepatic sinusoids. Liver. 2000;20:3–7.

    Article  CAS  Google Scholar 

  134. McCuskey RS. The hepatic microvascular system in health and its response to toxicants. Anat Rec (Hoboken). 2008;291:661–71.

    Google Scholar 

  135. Saxena R, Theise ND, et al. Microanatomy of the human liver-exploring the hidden interfaces. Hepatology. 1999;30:1339–46.

    Article  CAS  Google Scholar 

  136. Kamegaya Y, Oda M, et al., Evidence for the spontaneous contractility of ITO cells by time-lapse cinematographic and computerized image analysis. In: Wisse E, et al., editors, Cells of the hepatic sinusoid. Leiden: Kupffer Cell Foundation; 1995.

  137. Van Der Smissen P, Breat F, et al., The cytoskeleton of the liver sieve in situ: a TEM study. In: Wisse E, et al., editors, Cells of the hepatic sinusoid. Leiden: Kupffer Cell Foundation; 1995.

  138. Tiniakos DG, Lee JA, et al. Innervation of the liver: morphology and function. Liver. 1996;16:151–60.

    CAS  Google Scholar 

  139. Halme DG, Kessler DA. FDA regulation of stem-cell-based therapies. N Engl J Med. 2006;355:1730–5.

    Article  CAS  Google Scholar 

  140. von Tigerstrom BJ. The challenges of regulating stem cell-based products. Trends Biotechnol. 2008;26:653–8.

    Article  CAS  Google Scholar 

  141. Schneider CK, Salmikangas P, et al. Challenges with advanced therapy medicinal products and how to meet them. Nat Rev Drug Discov. 2010;9:195–201.

    Article  CAS  Google Scholar 

  142. Schneider CK, Schaffner-Dallmann G. Typical pitfalls in applications for marketing authorization of biotechnological products in Europe. Nat Rev Drug Discov. 2008;7:893–9.

    Article  CAS  Google Scholar 

  143. Rayment EA, Williams DJ. Concise review: mind the gap: challenges in characterizing and quantifying cell- and tissue-based therapies for clinical translation. Stem Cells. 2010;28:996–1004.

    Google Scholar 

  144. Daar AS, Bhatt A, et al. Stem cell research and transplantation: science leading ethics. Transplant Proc. 2004;36:2504–6.

    Article  CAS  Google Scholar 

  145. Daar J. Sliding the slope toward human cloning. Am J Bioeth. 2001;1:23–4.

    CAS  Google Scholar 

  146. Daar JF. The prospect of human cloning: improving nature or dooming the species? Seton Hall Law Rev. 2003;33:511–72.

    Google Scholar 

  147. Daar AS. Paid organ procurement: pragmatic and ethical viewpoints. Transplant Proc. 2004;36:1876–7.

    Article  CAS  Google Scholar 

  148. de Vries RB, Oerlemans A, et al. Ethical aspects of tissue engineering: a review. Tissue Eng B. 2008;14:367–75.

    Article  Google Scholar 

  149. Thasler WE, Weiss TS, et al. Charitable state-controlled foundation human tissue and cell research: ethic and legal aspects in the supply of surgically removed human tissue for research in the academic and commercial sector in Germany. Cell Tissue Bank. 2003;4:49–56.

    Article  Google Scholar 

Download references

Acknowledgments

The present work has been partially supported by BMBF—0315208E (EmbryoTox, AKN), BMBF—01GN0984 (RegMed, AKN), BMBF—0315741 (Virtual Liver, AKN/MG), BMBF—0315753 (Virtual Liver, TSW), supported grant from the Medical Faculty of the University of Regensburg (ReForM-C, TSW).

Author information

Authors and Affiliations

  1. Department of Traumatology, MRI, Klinikum rechts der Isar, Technische Universität München, Ismaningerstr. 22, 81675, Munich, Germany

    Andreas K. Nussler, Lilianna Schyschka, Sabrina Ehnert & Xueying Yan

  2. Berlin-Brandenburg Center for Regenerative Therapies, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany

    Katrin Zeilinger

  3. McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Jörg C. Gerlach

  4. Center for Liver Cell Research, Department of Surgery, Grosshadern Hospital, Ludwig Maximilians University, Munich, Germany

    Serene M. L. Lee, Maren Ilowski & Wolfgang E. Thasler

  5. Department of Pediatrics and Juvenile Medicine, University Medical Center Regensburg, Regensburg, Germany

    Thomas S. Weiss

Authors
  1. Andreas K. Nussler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Katrin Zeilinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lilianna Schyschka
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sabrina Ehnert
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jörg C. Gerlach
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xueying Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Serene M. L. Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Maren Ilowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Wolfgang E. Thasler
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Thomas S. Weiss
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andreas K. Nussler.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nussler, A.K., Zeilinger, K., Schyschka, L. et al. Cell therapeutic options in liver diseases: cell types, medical devices and regulatory issues. J Mater Sci: Mater Med 22, 1087–1099 (2011). https://doi.org/10.1007/s10856-011-4306-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10856-011-4306-7

Keywords

Search

Navigation