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  • Review Article
  • Published:

Liver support strategies: cutting-edge technologies

Nature Reviews Gastroenterology & Hepatology volume 11, pages 166–176 (2014)Cite this article

Subjects

Key Points

  • Despite almost three decades of research on artificial and bioartificial liver support, appropriate, randomized, controlled, and adequately powered studies are rare

  • Compared with the effect of a suitable orthotopic liver graft on a patient's clinical course, the clinical effects of extracorporeal liver support systems seem to be very limited

  • The main issues for all liver support therapy concepts are the need for tissue vascularization and integration into the host circulation, and a lack of reliable sources of safe and metabolically active cells

  • Strategies to overcome the conceptual limitations of (bio)artificial liver support devices include hepatocyte transplantation and various tissue engineering approaches (for example repopulation of decellularized organs, organ printing and induced organogenesis)

  • Hepatocyte transplantation seems to be at least a temporary alternative treatment strategy in certain metabolic liver disorders, and might have a role in the treatment of acute liver failure and chronic liver disease

  • Translation of regenerative medicine into the clinical routine, especially transplantation of recellularized liver grafts, seems possible but further intense research is needed

Abstract

The treatment of end-stage liver disease and acute liver failure remains a clinically relevant issue. Although orthotopic liver transplantation is a well-established procedure, whole-organ transplantation is invasive and increasingly limited by the unavailability of suitable donor organs. Artificial and bioartificial liver support systems have been developed to provide an alternative to whole organ transplantation, but despite three decades of scientific efforts, the results are still not convincing with respect to clinical outcome. In this Review, conceptual limitations of clinically available liver support therapy systems are discussed. Furthermore, alternative concepts, such as hepatocyte transplantation, and cutting-edge developments in the field of liver support strategies, including the repopulation of decellularized organs and the biofabrication of entirely new organs by printing techniques or induced organogenesis are analysed with respect to clinical relevance. Whereas hepatocyte transplantation shows promising clinical results, at least for the temporary treatment of inborn metabolic diseases, so far data regarding implantation of engineered hepatic tissue have only emerged from preclinical experiments. However, the evolving techniques presented here raise hope for bioengineered liver support therapies in the future.

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Figure 1: Artificial liver support systems.
Figure 2: Bioartifical liver support devices aim to combine detoxification with the synthetic and regulatory functions of hepatocytes.
Figure 3: Concept of recellularization of decellularized livers and consecutive implantation or extracorporeal application.
Figure 4: 3D organ printing.

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References

  1. Dutkowski, P. et al. The model for end-stage liver disease allocation system for liver transplantation saves lives, but increases morbidity and cost: a prospective outcome analysis. Liver Transpl. 17, 674–684 (2011).

    Article  PubMed  Google Scholar 

  2. Axelrod, D. A. Economic and financial outcomes in transplantation: whose dime is it anyway? Curr. Opin. Organ Transplant. 18, 222–228 (2013).

    Article  PubMed  Google Scholar 

  3. Dutkowski, P. et al. Are there better guidelines for allocation in liver transplantation? A novel score targeting justice and utility in the model for end-stage liver disease era. Ann. Surg. 254, 745–753 (2011).

    Article  PubMed  Google Scholar 

  4. Mitzner, S. R. Extracorporeal liver support-albumin dialysis with the Molecular Adsorbent Recirculating System (MARS). Ann. Hepatol. 10 (Suppl. 1), S21–S28 (2011).

    Article  PubMed  Google Scholar 

  5. Rifai, K. Fractionated plasma separation and adsorption: current practice and future options. Liver Int. 31 (Suppl. 3), 13–15 (2011).

    Article  PubMed  Google Scholar 

  6. Sauer, I. M. et al. In vitro comparison of the molecular adsorbent recirculation system (MARS) and single-pass albumin dialysis (SPAD). Hepatology 39, 1408–1414 (2004).

    Article  CAS  PubMed  Google Scholar 

  7. Al-Chalabi, A. et al. Evaluation of the Hepa Wash® treatment in pigs with acute liver failure. BMC Gastroenterol. 13, 83 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Rozga, J., Umehara, Y., Trofimenko, A., Sadahiro, T. & Demetriou, A. A. A novel plasma filtration therapy for hepatic failure: preclinical studies. Ther. Apher. Dial. 10, 138–144 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Ash, S. R. et al. Push-pull sorbent-based pheresis and hemodiabsorption in the treatment of hepatic failure: preliminary results of a clinical trial with the BioLogic-DTPF System. Ther. Apher. 4, 218–228 (2000).

    Article  CAS  PubMed  Google Scholar 

  10. Otto, J. J., Pender, J. C., Cleary, J. H., Sensenig, D. M. & Welch, C. S. The use of a donor liver in experimental animals with elevated blood ammonia. Surgery 43, 301–309 (1958).

    CAS  PubMed  Google Scholar 

  11. Eiseman, B., Liem, D. S. & Raffucci, F. Heterologous liver perfusion in treatment of hepatic failure. Ann. Surg. 162, 329–345 (1965).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sen, P. K. et al. Use of isolated perfused cadaveric liver in the management of hepatic failure. Surgery 59, 774–781 (1966).

    CAS  PubMed  Google Scholar 

  13. Pascher, A., Sauer, I. M., Hammer, C., Gerlach, J. C. & Neuhaus, P. Extracorporeal liver perfusion as hepatic assist in acute liver failure: a review of world experience. Xenotransplantation 9, 309–324 (2002).

    Article  PubMed  Google Scholar 

  14. Demetriou, A. A. et al. Prospective, randomized, multicenter, controlled trial of a bioartificial liver in treating acute liver failure. Ann. Surg. 239, 660–667 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Ellis, A. J. et al. Pilot-controlled trial of the extracorporeal liver assist device in acute liver failure. Hepatology 24, 1446–1451 (1996).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  17. Sauer, I. M. et al. Clinical extracorporeal hybrid liver support—phase I study with primary porcine liver cells. Xenotransplantation 10, 460–469 (2003).

    Article  CAS  PubMed  Google Scholar 

  18. Sauer, I. M. 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. 39, 649–653 (2003).

    Article  PubMed  Google Scholar 

  19. van de Kerkhove, M. P. et al. Phase I clinical trial with the AMC-bioartificial liver. Int. J. Artif. Organs 25, 950–959 (2002).

    Article  CAS  PubMed  Google Scholar 

  20. Mitzner, S. R. et al. Improvement of hepatorenal syndrome with extracorporeal albumin dialysis MARS: results of a prospective, randomized, controlled clinical trial. Liver Transpl. 6, 277–286 (2000).

    Article  CAS  PubMed  Google Scholar 

  21. Heemann, U. et al. Albumin dialysis in cirrhosis with superimposed acute liver injury: a prospective, controlled study. Hepatology 36, 949–958 (2002).

    Article  CAS  PubMed  Google Scholar 

  22. Sen, S. et al. Pathophysiological effects of albumin dialysis in acute-on-chronic liver failure: a randomized controlled study. Liver Transpl. 10, 1109–1119 (2004).

    Article  PubMed  Google Scholar 

  23. Hassanein, T. I. et al. Randomized controlled study of extracorporeal albumin dialysis for hepatic encephalopathy in advanced cirrhosis. Hepatology 46, 1853–1862 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. Banares, R. et al. Extracorporeal albumin dialysis with the molecular adsorbent recirculating system in acute-on-chronic liver failure: the RELIEF trial. Hepatology 57, 1153–1162 (2013).

    Article  CAS  PubMed  Google Scholar 

  25. US National Library of Medicine. ClinicalTrials.gov[online], (2012).

  26. Kribben, A. et al. Effects of fractionated plasma separation and adsorption on survival in patients with acute-on-chronic liver failure. Gastroenterology 142, 782–789.e783 (2012).

    Article  CAS  PubMed  Google Scholar 

  27. Kortgen, A. et al. Albumin dialysis in liver failure: comparison of molecular adsorbent recirculating system and single pass albumin dialysis—a retrospective analysis. Ther. Apher. Dial. 13, 419–425 (2009).

    Article  CAS  PubMed  Google Scholar 

  28. Ringe, H. et al. Continuous veno-venous single-pass albumin hemodiafiltration in children with acute liver failure. Pediatr. Crit. Care Med. 12, 257–264 (2011).

    Article  PubMed  Google Scholar 

  29. Karvellas, C. J. et al. A case-control study of single-pass albumin dialysis for acetaminophen-induced acute liver failure. Blood Purif. 28, 151–158 (2009).

    Article  CAS  PubMed  Google Scholar 

  30. US National Library of Medicine. ClinicalTrials.gov[online], (2012).

  31. US National Library of Medicine. ClinicalTrials.gov[online], (2012).

  32. Millis, J. M. et al. Initial experience with the modified extracorporeal liver-assist device for patients with fulminant hepatic failure: system modifications and clinical impact. Transplantation 74, 1735–1746 (2002).

    Article  PubMed  Google Scholar 

  33. van de Kerkhove, M. P. et al. Bridging a patient with acute liver failure to liver transplantation by the AMC-bioartificial liver. Cell Transplant. 12, 563–568 (2003).

    Article  PubMed  Google Scholar 

  34. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  35. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

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

    Article  PubMed  Google Scholar 

  37. Liu, J. P., Gluud, L. L., Als-Nielsen, B. & Gluud, C. Artificial and bioartificial support systems for liver failure. Cochrane Database of Systematic Reviews, Issue 1. Art. No.: CD003628. http://dx.doi.org/10.1002/14651858.CD003628.pub2.

  38. Stutchfield, B. M., Simpson, K. & Wigmore, S. J. Systematic review and meta-analysis of survival following extracorporeal liver support. Br. J. Surg. 98, 623–631 (2011).

    Article  CAS  PubMed  Google Scholar 

  39. Pascher, A., Sauer, I. M. & Neuhaus, P. Analysis of allogeneic versus xenogeneic auxiliary organ perfusion in liver failure reveals superior efficacy of human livers. Int. J. Artif. Organs 25, 1006–1012 (2002).

    Article  CAS  PubMed  Google Scholar 

  40. Iwata, H. & Ueda, Y. Pharmacokinetic considerations in development of a bioartificial liver. Clin. Pharmacokinet. 43, 211–25 (2004).

    Article  PubMed  Google Scholar 

  41. Dhawan, A., Strom, S. C., Sokal, E. & Fox, I. J. Human hepatocyte transplantation. Methods Mol. Biol. 640, 525–534 (2010).

    Article  PubMed  Google Scholar 

  42. Gupta, S. et al. Entry and integration of transplanted hepatocytes in rat liver plates occur by disruption of hepatic sinusoidal endothelium. Hepatology 29, 509–519 (1999).

    Article  CAS  PubMed  Google Scholar 

  43. Laconi, E. et al. Long-term, near-total liver replacement by transplantation of isolated hepatocytes in rats treated with retrorsine. Am. J. Pathol. 153, 319–329 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Hughes, R. D., Mitry, R. R. & Dhawan, A. Current status of hepatocyte transplantation. Transplantation 93, 342–347 (2012).

    Article  CAS  PubMed  Google Scholar 

  45. Jorns, C. et al. Hepatocyte transplantation for inherited metabolic diseases of the liver. J. Intern. Med. 272, 201–223 (2012).

    Article  CAS  PubMed  Google Scholar 

  46. Mito, M. et al. Studies on ectopic liver utilizing hepatocyte transplantation into the rat spleen. Transplant. Proc. 11, 585–591 (1979).

    CAS  PubMed  Google Scholar 

  47. Saito, R. et al. Transplantation of liver organoids in the omentum and kidney. Artif. Organs 35, 80–83 (2011).

    Article  CAS  PubMed  Google Scholar 

  48. Meyburg, J. et al. One liver for four children: first clinical series of liver cell transplantation for severe neonatal urea cycle defects. Transplantation 87, 636–641 (2009).

    Article  PubMed  Google Scholar 

  49. Meyburg, J., Schmidt, J. & Hoffmann, G. F. Liver cell transplantation in children. Clin. Transplant. 23, 75–82 (2009).

    Article  PubMed  Google Scholar 

  50. Dhawan, A., Puppi, J., Hughes, R. D. & Mitry, R. R. Human hepatocyte transplantation: current experience and future challenges. Nat. Rev. Gastroenterol. Hepatol. 7, 288–298 (2010).

    Article  PubMed  Google Scholar 

  51. Bosma, P. J. Inherited disorders of bilirubin metabolism. J. Hepatol. 38, 107–117 (2003).

    Article  CAS  PubMed  Google Scholar 

  52. Fox, I. J. et al. Treatment of the Crigler–Najjar syndrome type I with hepatocyte transplantation. N. Engl. J. Med. 338, 1422–1427 (1998).

    Article  CAS  PubMed  Google Scholar 

  53. Darwish, A. A. et al. Permanent access to the portal system for cellular transplantation using an implantable port device. Liver Transpl. 10, 1213–1215 (2004).

    Article  PubMed  Google Scholar 

  54. Ambrosino, G. et al. Isolated hepatocyte transplantation for Crigler–Najjar syndrome type 1. Cell Transplant. 14, 151–157 (2005).

    Article  PubMed  Google Scholar 

  55. Dhawan, A., Mitry, R. R. & Hughes, R. D. Hepatocyte transplantation for liver-based metabolic disorders. J. Inherit. Metab. Dis. 29, 431–435 (2006).

    Article  PubMed  Google Scholar 

  56. Allen, K. J., Mifsud, N. A., Williamson, R., Bertolino, P. & Hardikar, W. Cell-mediated rejection results in allograft loss after liver cell transplantation. Liver Transpl. 14, 688–694 (2008).

    Article  PubMed  Google Scholar 

  57. Lysy, P. A. et al. Liver cell transplantation for Crigler-Najjar syndrome type I: update and perspectives. World J. Gastroenterol. 14, 3464 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Mitry, R. R. et al. One liver, three recipients: segment IV from split-liver procedures as a source of hepatocytes for cell transplantation. Transplantation 77, 1614–1616 (2004).

    Article  PubMed  Google Scholar 

  59. Strom, S. C. et al. Transplantation of human hepatocytes. Transplant. Proc. 29, 2103–2106 (1997).

    Article  CAS  PubMed  Google Scholar 

  60. Horslen, S. P. et al. Isolated hepatocyte transplantation in an infant with a severe urea cycle disorder. Pediatrics 111, 1262–1267 (2003).

    Article  PubMed  Google Scholar 

  61. Stephenne, X. et al. Cryopreserved liver cell transplantation controls ornithine transcarbamylase deficient patient while awaiting liver transplantation. Am. J. Transplant. 5, 2058–2061 (2005).

    Article  PubMed  Google Scholar 

  62. Puppi, J. et al. Hepatocyte transplantation followed by auxiliary liver transplantation—a novel treatment for ornithine transcarbamylase deficiency. Am. J. Transplant. 8, 452–457 (2008).

    Article  CAS  PubMed  Google Scholar 

  63. Stéphenne, X. et al. Sustained engraftment and tissue enzyme activity after liver cell transplantation for argininosuccinate lyase deficiency. Gastroenterology 130, 1317–1323 (2006).

    Article  PubMed  Google Scholar 

  64. Fisher, R. A. & Strom, S. C. Human hepatocyte transplantation: worldwide results. Transplantation 82, 441–449 (2006).

    Article  PubMed  Google Scholar 

  65. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  66. US National Library of Medicine. ClinicalTrials.gov[online], (2012).

  67. US National Library of Medicine. ClinicalTrials.gov[online], (2011).

  68. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  69. US National Library of Medicine. ClinicalTrials.gov[online], (2011).

  70. Bilir, B. M. et al. Hepatocyte transplantation in acute liver failure. Liver Transpl. 6, 32–40 (2000).

    Article  CAS  PubMed  Google Scholar 

  71. Strom, S. C. et al. Hepatocyte transplantation as a bridge to orthotopic liver transplantation in terminal liver failure. Transplantation 63, 559–569 (1997).

    Article  CAS  PubMed  Google Scholar 

  72. Mito, M., Kusano, M. & Kawaura, Y. Hepatocyte transplantation in man. Transplant. Proc. 24, 3052–3053 (1992).

    CAS  PubMed  Google Scholar 

  73. Soltys, K. A. et al. Barriers to the successful treatment of liver disease by hepatocyte transplantation. J. Hepatol. 53, 769 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Quaglia, A. et al. Liver after hepatocyte transplantation for liver-based metabolic disorders in children. Cell Transplant. 17, 1403–1414 (2008).

    Article  PubMed  Google Scholar 

  75. Puppi, J. & Modo, M. Use of magnetic resonance imaging contrast agents to detect transplanted liver cells. Top. Magn. Reson. Imaging 20, 113–120 (2009).

    Article  PubMed  Google Scholar 

  76. Hughes, R. D. et al. Isolation of hepatocytes from livers from non-heart-beating donors for cell transplantation. Liver Transpl. 12, 713–717 (2006).

    Article  PubMed  Google Scholar 

  77. Erker, L. et al. Therapeutic liver reconstitution with murine cells isolated long after death. Gastroenterology 139, 1019–1029 (2010).

    Article  PubMed  Google Scholar 

  78. Nagata, H. et al. Prolonged survival of porcine hepatocytes in cynomolgus monkeys. Gastroenterology 132, 321–329 (2007).

    Article  CAS  PubMed  Google Scholar 

  79. Gupta, S. Hog heaven on the road to liver cell therapy. Gastroenterology 132, 450–453 (2007).

    Article  CAS  PubMed  Google Scholar 

  80. Yamanouchi, K. et al. Hepatic irradiation augments engraftment of donor cells following hepatocyte transplantation. Hepatology 49, 258–267 (2009).

    Article  PubMed  Google Scholar 

  81. Dagher, I. et al. Efficient hepatocyte engraftment and long-term transgene expression after reversible portal embolization in nonhuman primates. Hepatology 49, 950–959 (2009).

    Article  PubMed  Google Scholar 

  82. Zhou, H. et al. Single liver lobe repopulation with wildtype hepatocytes using regional hepatic irradiation cures jaundice in gunn rats. PLoS ONE 7, e46775 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Mei, J. et al. Improved survival of fulminant liver failure by transplantation of microencapsulated cryopreserved porcine hepatocytes in mice. Cell Transplant. 18, 101–110 (2009).

    Article  PubMed  Google Scholar 

  84. Zhou, P. et al. Decellularized liver matrix as a carrier for the transplantation of human fetal and primary hepatocytes in mice. Liver Transpl. 17, 418–427 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Yovchev, M. I., Xue, Y., Shafritz, D. A., Locker, J. & Oertel, M. Repopulation of the fibrotic/cirrhotic rat liver by transplanted hepatic stem/progenitor cells and mature hepatocytes. Hepatology http://dx.doi.org/10.1002/hep.26615.

  86. Hoppo, T., Komori, J., Manohar, R., Stolz, D. B. & Lagasse, E. Rescue of lethal hepatic failure by hepatized lymph nodes in mice. Gastroenterology 140, 656–666 (2011).

    Article  CAS  PubMed  Google Scholar 

  87. Komori, J., Boone, L., DeWard, A., Hoppo, T. & Lagasse, E. The mouse lymph node as an ectopic transplantation site for multiple tissues. Nat. Biotechnol. 30, 976–983 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Baptista, P. M. et al. The use of whole organ decellularization for the generation of a vascularized liver organoid. Hepatology 53, 604–617 (2011).

    Article  CAS  PubMed  Google Scholar 

  89. Folkman, J. & Hochberg, M. Self-regulation of growth in three dimensions. J. Exp. Med. 138, 745–753 (1973).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Bernard, M. P. et al. Nucleotide sequences of complementary deoxyribonucleic acids for the pro alpha 1 chain of human type I procollagen. Statistical evaluation of structures that are conserved during evolution. Biochemistry 22, 5213–5223 (1983).

    Article  CAS  PubMed  Google Scholar 

  91. Bernard, M. P. et al. Structure of a cDNA for the pro alpha 2 chain of human type I procollagen. Comparison with chick cDNA for pro alpha 2(I) identifies structurally conserved features of the protein and the gene. Biochemistry 22, 1139–1145 (1983).

    Article  CAS  PubMed  Google Scholar 

  92. Badylak, S. F., Taylor, D. & Uygun, K. Whole-organ tissue engineering: decellularization and recellularization of three-dimensional matrix scaffolds. Annu. Rev. Biomed. Eng. 13, 27–53 (2011).

    Article  CAS  PubMed  Google Scholar 

  93. Bissell, M. J. & Aggeler, J. Dynamic reciprocity: how do extracellular matrix and hormones direct gene expression? Prog. Clin. Biol. Res. 249, 251–262 (1987).

    CAS  PubMed  Google Scholar 

  94. Sellaro, T. L. et al. Maintenance of human hepatocyte function in vitro by liver-derived extracellular matrix gels. Tissue Eng. Part A 16, 1075–1082 (2010).

    Article  CAS  PubMed  Google Scholar 

  95. Wang, Y. et al. Lineage restriction of human hepatic stem cells to mature fates is made efficient by tissue-specific biomatrix scaffolds. Hepatology 53, 293–305 (2011).

    Article  CAS  PubMed  Google Scholar 

  96. Wang, X. et al. Decellularized liver scaffolds effectively support the proliferation and differentiation of mouse fetal hepatic progenitors. J. Biomed. Mater. Res. A http://doi.dx.org/10.1002/jbm.a.34764.

  97. Cortiella, J. et al. Influence of acellular natural lung matrix on murine embryonic stem cell differentiation and tissue formation. Tissue Eng. Part A 16, 2565–2580 (2010).

    Article  CAS  PubMed  Google Scholar 

  98. Badylak, S. F., Weiss, D. J., Caplan, A. & Macchiarini, P. Engineered whole organs and complex tissues. Lancet 379, 943–952 (2012).

    Article  PubMed  Google Scholar 

  99. Crapo, P. M., Gilbert, T. W. & Badylak, S. F. An overview of tissue and whole organ decellularization processes. Biomaterials 32, 3233–3243 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Nagata, S., Hanayama, R. & Kawane, K. Autoimmunity and the clearance of dead cells. Cell 140, 619–630 (2010).

    Article  CAS  PubMed  Google Scholar 

  101. Zheng, M. H. et al. Porcine small intestine submucosa (SIS) is not an acellular collagenous matrix and contains porcine DNA: possible implications in human implantation. J. Biomed. Mater. Res. B Appl. Biomater. 73, 61–67 (2005).

    Article  CAS  PubMed  Google Scholar 

  102. Park, K. M., Park, S. M., Yang, S. R., Hong, S. H. & Woo, H. M. Preparation of immunogen-reduced and biocompatible extracellular matrices from porcine liver. J. Biosci. Bioeng. 115, 207–215 (2012).

    Article  CAS  PubMed  Google Scholar 

  103. Shirakigawa, N., Ijima, H. & Takei, T. Decellularized liver as a practical scaffold with a vascular network template for liver tissue engineering. J. Biosci. Bioeng. 114, 546–551 (2012).

    Article  CAS  PubMed  Google Scholar 

  104. Uygun, B. E. et al. Organ reengineering through development of a transplantable recellularized liver graft using decellularized liver matrix. Nat. Med. 16, 814–820 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Barakat, O. et al. Use of decellularized porcine liver for engineering humanized liver organ. J. Surg. Res. 173, e11–e25 (2012).

    Article  CAS  PubMed  Google Scholar 

  106. Soto-Gutierrez, A. et al. A whole-organ regenerative medicine approach for liver replacement. Tissue Eng. Part C Methods 17, 677–686 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Ott, H. C. et al. Perfusion-decellularized matrix: using nature's platform to engineer a bioartificial heart. Nat. Med. 14, 213–221 (2008).

    Article  CAS  PubMed  Google Scholar 

  108. Bao, J. et al. Construction of a portal implantable functional tissue-engineered liver using perfusion-decellularized matrix and hepatocytes in rats. Cell Transplant. 20, 753–766 (2011).

    Article  PubMed  Google Scholar 

  109. Olausson, M. et al. Transplantation of an allogeneic vein bioengineered with autologous stem cells: a proof-of-concept study. Lancet 380, 230–237 (2012).

    Article  PubMed  Google Scholar 

  110. Macchiarini, P. et al. Clinical transplantation of a tissue-engineered airway. Lancet 372, 2023–2030 (2008).

    Article  PubMed  Google Scholar 

  111. Elliott, M. J. et al. Stem-cell-based, tissue engineered tracheal replacement in a child: a 2-year follow-up study. Lancet 380, 994–1000 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  112. Baiguera, S., Birchall, M. A. & Macchiarini, P. Tissue-engineered tracheal transplantation. Transplantation 89, 485–491 (2010).

    Article  PubMed  Google Scholar 

  113. Horst, M. et al. Engineering functional bladder tissues. J. Tissue Eng. Regen. Med. 7, 515–522 (2013).

    Article  CAS  PubMed  Google Scholar 

  114. Mase, V. J. Jr et al. Clinical application of an acellular biologic scaffold for surgical repair of a large, traumatic quadriceps femoris muscle defect. Orthopedics 33, 511 (2010).

    PubMed  Google Scholar 

  115. Vogel, G. Trachea transplants test the limits. Science 340, 266–268 (2013).

    Article  CAS  PubMed  Google Scholar 

  116. Katsuda, T., Sakai, Y. & Ochiya, T. Induced pluripotent stem cell-derived hepatocytes as an alternative to human adult hepatocytes. J. Stem Cells 7, 1–17 (2012).

    PubMed  Google Scholar 

  117. Wu, X. B. & Tao, R. Hepatocyte differentiation of mesenchymal stem cells. Hepatobiliary Pancreat. Dis. Int. 11, 360–371 (2012).

    Article  CAS  PubMed  Google Scholar 

  118. Espejel, S. et al. Induced pluripotent stem cell-derived hepatocytes have the functional and proliferative capabilities needed for liver regeneration in mice. J. Clin. Invest. 120, 3120 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Quante, M. & Wang, T. C. Stem cells in gastroenterology and hepatology. Nat. Rev. Gastroenterol. Hepatol. 6, 724–737 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  120. Guillemot, F., Mironov, V. & Nakamura, M. Bioprinting is coming of age: Report from the International Conference on Bioprinting and Biofabrication in Bordeaux (3B'09). Biofabrication 2, 010201 (2010).

    Article  PubMed  Google Scholar 

  121. Klebe, R. Cytoscribing: A method for micropositioning cells and the construction of two- and three-dimensional synthetic tissues. Exp. Cell Res. 179, 362–373 (1988).

    Article  CAS  PubMed  Google Scholar 

  122. Derby, B. Printing and prototyping of tissues and scaffolds. Science 338, 921–926 (2012).

    Article  CAS  PubMed  Google Scholar 

  123. Villar, G., Graham, A. D. & Bayley, H. A tissue-like printed material. Science 340, 48–52 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Mironov, V. et al. Organ printing: tissue spheroids as building blocks. Biomaterials 30, 2164–2174 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Norotte, C., Marga, F. S., Niklason, L. E. & Forgacs, G. Scaffold-free vascular tissue engineering using bioprinting. Biomaterials 30, 5910–5917 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Visconti, R. P. et al. Towards organ printing: engineering an intra-organ branched vascular tree. Expert Opin. Biol. Ther. 10, 409–420 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Pérez-Pomares, J. M. & Foty, R. A. Tissue fusion and cell sorting in embryonic development and disease: biomedical implications. Bioessays 28, 809–821 (2006).

    Article  PubMed  Google Scholar 

  128. Forgacs, G., Foty, R. A., Shafrir, Y. & Steinberg, M. S. Viscoelastic properties of living embryonic tissues: a quantitative study. Biophys. J. 74, 2227–2234 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Cui, X. & Boland, T. Human microvasculature fabrication using thermal inkjet printing technology. Biomaterials 30, 6221–6227 (2009).

    Article  CAS  PubMed  Google Scholar 

  130. Khatiwala, C., Law, R., Shepherd, B., Dorfman, S. & Csete, M. 3D cell bioprinting for regenerative medicine research and therapies. Gene Ther. Regul. 7, 1230004 (2012).

    Article  CAS  Google Scholar 

  131. Robbins, J. B., Gorgen, V., Min, P., Shepherd, B. R. & Presnell, S. C. A novel in vitro three-dimensional bioprinted liver tissue system for drug development [abstract 7979]. Presented at Experimental Biology, 2013, Boston, MA.

  132. Chang, R., Emami, K., Wu, H. & Sun, W. Biofabrication of a three-dimensional liver micro-organ as an in vitro drug metabolism model. Biofabrication 2, 045004 (2010).

    Article  CAS  PubMed  Google Scholar 

  133. Snyder, J. et al. Bioprinting cell-laden matrigel for radioprotection study of liver by pro-drug conversion in a dual-tissue microfluidic chip. Biofabrication 3, 034112 (2011).

    Article  CAS  PubMed  Google Scholar 

  134. Butcher, J. T., Sedmera, D., Guldberg, R. E. & Markwald, R. R. Quantitative volumetric analysis of cardiac morphogenesis assessed through micro-computed tomography. Dev. Dyn. 236, 802–809 (2007).

    Article  PubMed  Google Scholar 

  135. Little, T. S. et al. Engineering a 3D, biological construct: representative research in the South Carolina Project for Organ Biofabrication. Biofabrication 3, 030202 (2011).

    Article  PubMed  Google Scholar 

  136. Neagu, A., Jakab, K., Jamison, R. & Forgacs, G. Role of physical mechanisms in biological self-organization. Phys. Rev. Lett. 95, 178104 (2005).

    Article  CAS  PubMed  Google Scholar 

  137. Yang, X., Mironov, V. & Wang, Q. Modeling fusion of cellular aggregates in biofabrication using phase field theories. J. Theor. Biol. 303, 110–118 (2012).

    Article  PubMed  Google Scholar 

  138. Khan, F. & Ahmand, S. in Biomaterials and Stem Cells in Regenerative Medicine (eds Ramalingam, M., Ramakrishna, S. & Best, S.) 101–122 (CRC Press, 2012).

    Book  Google Scholar 

  139. Parsa, S., Gupta, M., Loizeau, F. & Cheung, K. C. Effects of surfactant and gentle agitation on inkjet dispensing of living cells. Biofabrication 2, 025003 (2010).

    Article  CAS  PubMed  Google Scholar 

  140. Guillotin, B. & Guillemot, F. Cell patterning technologies for organotypic tissue fabrication. Trends Biotechnol. 29, 183–190 (2011).

    Article  CAS  PubMed  Google Scholar 

  141. Miller, J. S. et al. Rapid casting of patterned vascular networks for perfusable engineered three-dimensional tissues. Nat. Mater. 11, 768–774 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Takebe, T. et al. Vascularized and functional human liver from an iPSC-derived organ bud transplant. Nature 499, 481–484 (2013).

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. General, Visceral, and Transplant Surgery, Experimental Surgery and Regenerative Medicine, Charité–Universitaetsmedizin Berlin, Campus Virchow, Augustenburger Platz 1, Berlin, 13353, Germany

    Benjamin Struecker, Nathanael Raschzok & Igor M. Sauer

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  1. Benjamin Struecker
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  2. Nathanael Raschzok
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  3. Igor M. Sauer
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All authors contributed equally to all aspects of this manuscript.

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Correspondence to Igor M. Sauer.

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Struecker, B., Raschzok, N. & Sauer, I. Liver support strategies: cutting-edge technologies. Nat Rev Gastroenterol Hepatol 11, 166–176 (2014). https://doi.org/10.1038/nrgastro.2013.204

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