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Bioartificial liver devices: Perspectives on the state of the art

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Abstract

Acute liver failure remains a significant cause of morbidity and mortality. Bioartificial liver (BAL) devices have been in development for more than 20 years. Such devices aim to temporarily take over the metabolic and excretory functions of the liver until the patients’ own liver has recovered or a donor liver becomes available for transplant. The important issues include the choice of cell materials and the design of the bioreactor. Ideal BAL cell materials should be of good viability and functionality, easy to access, and exclude immunoreactive and tumorigenic cell materials. Unfortunately, the current cells in use in BAL do not meet these requirements. One of the challenges in BAL development is the improvement of current materials; another key point concerning cell materials is the coculture of different cells. The bioreactor is an important component of BAL, because it determines the viability and function of the hepatocytes within it. From the perspective of bioengineering, a successful and clinically effective bioreactor should mimic the structure of the liver and provide an in vivo-like microenvironment for the growth of hepatocytes, thereby maintaining the cells’ viability and function to the maximum extent. One future trend in the development of the bioreactor is to improve the oxygen supply system. Another direction for future research on bioreactors is the application of biomedical materials. In conclusion, BAL is, in principle, an important therapeutic strategy for patients with acute liver failure, and may also be a bridge to liver transplantation. It requires further research and development, however, before it can enter clinical practice.

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References

  1. Pathikonda M, Munoz S J. Acute liver failure. Ann Hepatol, 2010, 9(1):7–14

    PubMed  Google Scholar 

  2. Gerlach J C, Zeilinger K, Patzer Ii J F. Bioartificial liver systems: why, what, whither? Regen Med, 2008, 3(4):575–595

    Article  PubMed  CAS  Google Scholar 

  3. Chamuleau R A, Deurholt T, Hoekstra R. Which are the right cells to be used in a bioartificial liver? Metab Brain Dis, 2005, 20(4):327–335

    Article  PubMed  Google Scholar 

  4. Poyck P P, Hoekstra R, van Wijk A C, Attanasio C, Calise F, Chamuleau R A, van Gulik T M. Functional and morphological comparison of three primary liver cell types cultured in the AMC bioartificial liver. Liver Transpl, 2007, 13(4):589–598

    Article  PubMed  Google Scholar 

  5. Sauer I M, Zeilinger K, Obermayer N, Pless G, Grünwald A, Pascher A, Mieder T, Roth S, Goetz M, Kardassis D, Mas A, Neuhaus P, Gerlach J C. Primary human liver cells as source for modular extracorporeal liver support—a preliminary report. Int J Artif Organs, 2002, 25(10):1001–1005

    PubMed  CAS  Google Scholar 

  6. Wang H H, Wang Y J, Liu H L, Liu J, Huang Y P, Guo H T, Wang Y M. Detection of PERV by polymerase chain reaction and its safety in bioartificial liver support system. World J Gastroenterol, 2006, 12(8):1287–1291

    PubMed  CAS  Google Scholar 

  7. Hoekstra R, Chamuleau R A. Recent developments on human cell lines for the bioartificial liver. Int J Artif Organs, 2002, 25(3):182–191

    PubMed  CAS  Google Scholar 

  8. Kobayashi N, Okitsu T, Nakaji S, Tanaka N. Hybrid bioartificial liver: establishing a reversibly immortalized human hepatocyte line and developing a bioartificial liver for practical use. J Artif Organs, 2003, 6(4):236–244

    Article  PubMed  Google Scholar 

  9. Fonsato V, Herrera M B, Buttiglieri S, Gatti S, Camussi G, Tetta C. Use of a rotary bioartificial liver in the differentiation of human liver stem cells. Tissue Eng Part C Methods, 2010, 16(1):123–132

    Article  PubMed  CAS  Google Scholar 

  10. Sharma R, Greenhough S, Medine C N, Hay D C. Three-dimensional culture of human embryonic stem cell derived hepatic endoderm and its role in bioartificial liver construction. J Biomed Biotechnol, 2010, doi:10.1155/2010/236147

  11. Kobayashi N, Westerman K A, Tanaka N, Fox I J, Leboulch P. A reversibly immortalized human hepatocyte cell line as a source of hepatocyte-based biological support. Addict Biol, 2001, 6(4):293–300

    Article  PubMed  Google Scholar 

  12. Watanabe T, Shibata N, Westerman K A, Okitsu T, Allain J E, Sakaguchi M, Totsugawa T, Maruyama M, Matsumura T, Noguchi H, Yamamoto S, Hikida M, Ohmori A, Reth M, Weber A, Tanaka N, Leboulch P, Kobayashi N. Establishment of immortalized human hepatic stellate scavenger cells to develop bioartificial livers. Transplantation, 2003, 75(11):1873–1880

    Article  PubMed  CAS  Google Scholar 

  13. Totsugawa T, Yong C, Rivas-Carrillo J D, Soto-Gutierrez A, Navarro-Alvarez N, Noguchi H, Okitsu T, Westerman K A, Kohara M, Reth M, Tanaka N, Leboulch P, Kobayashi N. Survival of liver failure pigs by transplantation of reversibly immortalized human hepatocytes with Tamoxifen-mediated self-recombination. J Hepatol, 2007, 47(1):74–82

    Article  PubMed  CAS  Google Scholar 

  14. Enosawa S, Miyashita T, Saito T, Omasa T, Matsumura T. The significant improvement of survival times and pathological parameters by bioartificial liver with recombinant HepG2 in porcine liver failure model. Cell Transplant, 2006, 15(10):873–880

    Article  PubMed  Google Scholar 

  15. Thomas R J, Bennett A, Thomson B, Shakesheff K M. Hepatic stellate cells on poly(DL-lactic acid) surfaces control the formation of 3D hepatocyte co-culture aggregates in vitro. Eur Cell Mater, 2006, 11:16–26, discussion 26

    PubMed  CAS  Google Scholar 

  16. Nedredal G I, Elvevold K, Ytrebø L M, Fuskevåg O M, Pettersen I, Bertheussen K, Langbakk B, Smedsrød B, Revhaug A. Significant contribution of liver nonparenchymal cells to metabolism of ammonia and lactate and cocultivation augments the functions of a bioartificial liver. Am J Physiol Gastrointest Liver Physiol, 2007, 293(1):G75–G83

    Article  PubMed  CAS  Google Scholar 

  17. Gu J, Shi X, Zhang Y, Ding Y. Heterotypic interactions in the preservation of morphology and functionality of porcine hepatocytes by bone marrow mesenchymal stem cells in vitro. J Cell Physiol, 2009, 219(1):100–108

    Article  PubMed  CAS  Google Scholar 

  18. Gu J, Shi X, Chu X, Zhang Y, Ding Y. Contribution of bone marrow mesenchymal stem cells to porcine hepatocyte culture in vitro. Biochem Cell Biol, 2009, 87(4):595–604

    Article  PubMed  CAS  Google Scholar 

  19. Gu J, Shi X, Zhang Y, Chu X, Hang H, Ding Y. Establishment of a three-dimensional co-culture system by porcine hepatocytes and bone marrow mesenchymal stem cells in vitro. Hepatol Res, 2009, 39(4):398–407

    Article  PubMed  CAS  Google Scholar 

  20. Allen J W, Hassanein T, Bhatia S N. Advances in bioartificial liver devices. Hepatology, 2001, 34(3):447–455

    Article  PubMed  CAS  Google Scholar 

  21. Park J K, Lee D H. Bioartificial liver systems: current status and future perspective. J Biosci Bioeng, 2005, 99(4):311–319

    Article  PubMed  CAS  Google Scholar 

  22. Park J, Li Y, Berthiaume F, Toner M, Yarmush M L, Tilles A W. Radial flow hepatocyte bioreactor using stacked microfabricated grooved substrates. Biotechnol Bioeng, 2008, 99(2):455–467

    Article  PubMed  CAS  Google Scholar 

  23. Kinasiewicz A, Smietanka A, Gajkowska B, Werynski A. Impact of oxygenation of bioartificial liver using perfluorocarbon emulsion perftoran on metabolism of human hepatoma C3A cells. Artif Cells Blood Substit Immobil Biotechnol, 2008, 36(6):525–534

    Article  PubMed  CAS  Google Scholar 

  24. Sauer I M, Kardassis D, Zeillinger K, Pascher A, Gruenwald A, Pless G, Irgang M, Kraemer M, Puhl G, Frank J, Müller A R, Steinmüller T, Denner J, Neuhaus P, Gerlach J C. Clinical extracorporeal hybrid liver support—phase I study with primary porcine liver cells. Xenotransplantation, 2003, 10(5):460–469

    Article  PubMed  CAS  Google Scholar 

  25. Poyck P P, Mareels G, Hoekstra R, van Wijk A C, van der Hoeven T V, van Gulik T M, Verdonck P R, Chamuleau R A. Enhanced oxygen availability improves liver-specific functions of the AMC bioartificial liver. Artif Organs, 2008, 32(2):116–126

    Article  PubMed  CAS  Google Scholar 

  26. De Bartolo L, Jarosch-Von Schweder G, Haverich A, Bader A. A novel full-scale flat membrane bioreactor utilizing porcine hepatocytes: cell viability and tissue-specific functions. Biotechnol Prog, 2000, 16(1):102–108

    Article  PubMed  Google Scholar 

  27. Sullivan J P, Gordon J E, Palmer A F. Simulation of oxygen carrier mediated oxygen transport to C3A hepatoma cells housed within a hollow fiber bioreactor. Biotechnol Bioeng, 2006, 93(2):306–317

    Article  PubMed  CAS  Google Scholar 

  28. Sullivan J P, Gordon J E, Bou-Akl T, Matthew H W, Palmer A F. Enhanced oxygen delivery to primary hepatocytes within a hollow fiber bioreactor facilitated via hemoglobin-based oxygen carriers. Artif Cells Blood Substit Immobil Biotechnol, 2007, 35(6):585–606

    Article  PubMed  CAS  Google Scholar 

  29. Sullivan J P, Harris D R, Palmer A F. Convection and hemoglobinbased oxygen carrier enhanced oxygen transport in a hepatic hollow fiber bioreactor. Artif Cells Blood Substit Immobil Biotechnol, 2008, 36(4):386–402

    Article  PubMed  CAS  Google Scholar 

  30. Chu X H, Shi X L, Feng Z Q, Gu Z Z, Ding Y T. Chitosan nanofiber scaffold enhances hepatocyte adhesion and function. Biotechnol Lett, 2009, 31(3):347–352

    Article  PubMed  CAS  Google Scholar 

  31. Feng Z Q, Chu X, Huang N P, Wang T, Wang Y, Shi X, Ding Y, Gu Z Z. The effect of nanofibrous galactosylated chitosan scaffolds on the formation of rat primary hepatocyte aggregates and the maintenance of liver function. Biomaterials, 2009, 30(14):2753–2763

    Article  PubMed  CAS  Google Scholar 

  32. Chu X H, Shi X L, Feng Z Q, Gu J Y, Xu H Y, Zhang Y, Gu Z Z, Ding Y T. In vitro evaluation of a multi-layer radial-flow bioreactor based on galactosylated chitosan nanofiber scaffolds. Biomaterials, 2009, 30(27):4533–4538

    Article  PubMed  CAS  Google Scholar 

  33. Park J, Berthiaume F, Toner M, Yarmush M L, Tilles A W. Microfabricated grooved substrates as platforms for bioartificial liver reactors. Biotechnol Bioeng, 2005, 90(5):632–644

    Article  PubMed  CAS  Google Scholar 

  34. Park J, Berthiaume F, Toner M, Yarmush M L, Tilles A W. Microfabricated grooved substrates as platforms for bioartificial liver reactors. Biotechnol Bioeng, 2005, 90(5):632–644

    Article  PubMed  CAS  Google Scholar 

  35. Hochleitner B, Hengster P, Bucher H, Ladurner R, Schneeberger S, Krismer A, Kleinsasser A, Barnas U, Klima G, Margreiter R. Significant survival prolongation in pigs with fulminant hepatic failure treated with a novel microgravity-based bioartificial liver. Artif Organs, 2006, 30(12):906–914

    Article  PubMed  CAS  Google Scholar 

  36. Hochleitner B, Hengster P, Duo L, Bucher H, Klima G, Margreiter R. A novel bioartificial liver with culture of porcine hepatocyte aggregates under simulated microgravity. Artif Organs, 2005, 29(1):58–66

    Article  PubMed  CAS  Google Scholar 

  37. Shinohara H, Shimada M, Ikemoto T, Morine Y, Imura S, Fujii M, Imaizumi T, Murayama M, Aiba Y. New type of artificial liver support system (ALSS) using the photocatalytic effect of titanium oxide. Dig Dis Sci, 2007, 52(9):2271–2275

    Article  PubMed  CAS  Google Scholar 

  38. Sussman N L, Gislason G T, Conlin C A, Kelly J H. The Hepatix extracorporeal liver assist device: initial clinical experience. Artif Organs, 1994, 18(5):390–396

    Article  PubMed  CAS  Google Scholar 

  39. Watanabe F D, Mullon C J, Hewitt W R, Arkadopoulos N, Kahaku E, Eguchi S, Khalili T, Arnaout W, Shackleton C R, Rozga J, Solomon B, Demetriou A A. Clinical experience with a bioartificial liver in the treatment of severe liver failure. A phase I clinical trial. Ann Surg, 1997, 225(5):484–491, discussion 491–494

    Article  PubMed  CAS  Google Scholar 

  40. Patzer J F, Mazariegos G V, Lopez R. Preclinical evaluation of the Excorp Medical, Inc., bioartifical liver support system. Am Coll Surg, 2002, 195:299–310

    Article  Google Scholar 

  41. Morsiani E, Pazzi P, Puviani A C, Brogli M, Valieri L, Gorini P, Scoletta P, Marangoni E, Ragazzi R, Azzena G, Frazzoli E, Di Luca D, Cassai E, Lombardi G, Cavallari A, Faenza S, Pasetto A, Girardis M, Jovine E, Pinna A D. Early experiences with a porcine hepatocyte-based bioartificial liver in acute hepatic failure patients. Int J Artif Organs, 2002, 25(3):192–202

    PubMed  CAS  Google Scholar 

  42. Ding Y T, Qiu Y D, Chen Z, Xu Q X, Zhang H Y, Tang Q, Yu D C. The development of a new bioartificial liver and its application in 12 acute liver failure patients. World J Gastroenterol, 2003, 9(4):829–832

    PubMed  CAS  Google Scholar 

  43. Xu Q, Yu D, Qiu Y, Zhang H, Ding Y. Function of a new internal bioartificial liver: an in vitro study. Ann Clin Lab Sci, 2003, 33(3):306–312

    PubMed  CAS  Google Scholar 

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  1. Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of the Nanjing University Medical School, Nanjing, 210008, China

    Yi-Tao Ding & Xiao-Lei Shi

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  1. Yi-Tao Ding
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  2. Xiao-Lei Shi
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Correspondence to Yi-Tao Ding.

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Ding, YT., Shi, XL. Bioartificial liver devices: Perspectives on the state of the art. Front. Med. 5, 15–19 (2011). https://doi.org/10.1007/s11684-010-0110-x

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