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. 1998 Jul;228(1):1–7. doi: 10.1097/00000658-199807000-00001

Internal bioartificial liver with xenogeneic hepatocytes prevents death from acute liver failure: an experimental study.

V Roger 1, P Balladur 1, J Honiger 1, M Baudrimont 1, R Delelo 1, A Robert 1, Y Calmus 1, J Capeau 1, B Nordlinger 1
PMCID: PMC1191420  PMID: 9671059

Abstract

OBJECTIVE: To demonstrate that a bioartificial liver, using allogeneic or xenogeneic hepatocytes protected from rejection by a semipermeable membrane, could prevent death from acute liver failure. SUMMARY BACKGROUND DATA: An implantable bioartificial liver using isolated hepatocytes could be an alternative to orthotopic liver transplantation to treat patients with acute liver failure. It could serve either as a bridge until liver transplantation or as the main treatment until recovery of the native liver. However, allogeneic or xenogeneic hepatocytes that could be used in clinical applications are spontaneously rejected. METHODS: Acute liver failure was induced in rats by 95% liver resection. Twenty-five million hepatocytes harvested in rats (allogeneic) or guinea pigs (xenogeneic) were encapsulated in a semipermeable membrane to protect them from rejection. The hollow fibers containing hepatocytes were transplanted into the peritoneum of recipient rats. Survival rates were compared between rats transplanted or not with hepatocytes. RESULTS: In groups not transplanted with viable hepatocytes, 73% to 93% of rats died after 95% liver resection. The mortality rate was reduced to 39% in rats transplanted with allogeneic hepatocytes and 36% in rats transplanted with xenogeneic hepatocytes. The bioartificial liver could be removed 1 month after transplantation, when regeneration of the native liver was complete. Allogeneic and xenogeneic hepatocytes remained viable. CONCLUSIONS: The implantable bioartificial liver was able to prevent death in this model of acute liver failure. This could be an important step toward clinical application of the method.

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Selected References

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  1. Adam R., Reynes M., Johann M., Morino M., Astarcioglu I., Kafetzis I., Castaing D., Bismuth H. The outcome of steatotic grafts in liver transplantation. Transplant Proc. 1991 Feb;23(1 Pt 2):1538–1540. [PubMed] [Google Scholar]
  2. Ascher N. L., Lake J. R., Emond J. C., Roberts J. P. Liver transplantation for fulminant hepatic failure. Arch Surg. 1993 Jun;128(6):677–682. doi: 10.1001/archsurg.1993.01420180079015. [DOI] [PubMed] [Google Scholar]
  3. Balladur P., Crema E., Honiger J., Calmus Y., Baudrimont M., Delelo R., Capeau J., Nordlinger B. Transplantation of allogeneic hepatocytes without immunosuppression: long-term survival. Surgery. 1995 Feb;117(2):189–194. [PubMed] [Google Scholar]
  4. Bernuau J., Rueff B., Benhamou J. P. Fulminant and subfulminant liver failure: definitions and causes. Semin Liver Dis. 1986 May;6(2):97–106. doi: 10.1055/s-2008-1040593. [DOI] [PubMed] [Google Scholar]
  5. Berry M. N., Friend D. S. High-yield preparation of isolated rat liver parenchymal cells: a biochemical and fine structural study. J Cell Biol. 1969 Dec;43(3):506–520. doi: 10.1083/jcb.43.3.506. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bismuth H., Samuel D., Castaing D., Adam R., Saliba F., Johann M., Azoulay D., Ducot B., Chiche L. Orthotopic liver transplantation in fulminant and subfulminant hepatitis. The Paul Brousse experience. Ann Surg. 1995 Aug;222(2):109–119. doi: 10.1097/00000658-199508000-00002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Boudjema K., Cherqui D., Jaeck D., Chenard-Neu M. P., Steib A., Freis G., Becmeur F., Brunot B., Simeoni U., Bellocq J. P. Auxiliary liver transplantation for fulminant and subfulminant hepatic failure. Transplantation. 1995 Jan 27;59(2):218–223. [PubMed] [Google Scholar]
  8. CHANG T. M. SEMIPERMEABLE MICROCAPSULES. Science. 1964 Oct 23;146(3643):524–525. doi: 10.1126/science.146.3643.524. [DOI] [PubMed] [Google Scholar]
  9. Cai Z. H., Shi Z. Q., O'Shea G. M., Sun A. M. Microencapsulated hepatocytes for bioartificial liver support. Artif Organs. 1988 Oct;12(5):388–393. doi: 10.1111/j.1525-1594.1988.tb02793.x. [DOI] [PubMed] [Google Scholar]
  10. Cai Z. H., Shi Z. Q., Sherman M., Sun A. M. Development and evaluation of a system of microencapsulation of primary rat hepatocytes. Hepatology. 1989 Nov;10(5):855–860. doi: 10.1002/hep.1840100518. [DOI] [PubMed] [Google Scholar]
  11. Cuervas-Mons V., Cantón T., Escandón J., Nieto J., Ramos J., Menéndez J., Ortiz J., Castillo-Olivares J. L., Segovia J. M. Monitoring of the rejection of intrasplenic hepatocyte allografts and xenografts in the rat using technetium 99m-imidoacetic acid scanning. Transplant Proc. 1987 Oct;19(5):3850–3851. [PubMed] [Google Scholar]
  12. Darby H., Selden C., Hodgson H. J. Prolonged survival of cyclosporine-treated allogeneic hepatocellular implants. Transplantation. 1986 Sep;42(3):325–326. [PubMed] [Google Scholar]
  13. Demetriou A. A., Reisner A., Sanchez J., Levenson S. M., Moscioni A. D., Chowdhury J. R. Transplantation of microcarrier-attached hepatocytes into 90% partially hepatectomized rats. Hepatology. 1988 Sep-Oct;8(5):1006–1009. doi: 10.1002/hep.1840080505. [DOI] [PubMed] [Google Scholar]
  14. Devictor D., Desplanques L., Debray D., Ozier Y., Dubousset A. M., Valayer J., Houssin D., Bernard O., Huault G. Emergency liver transplantation for fulminant liver failure in infants and children. Hepatology. 1992 Nov;16(5):1156–1162. [PubMed] [Google Scholar]
  15. Dixit V., Darvasi R., Arthur M., Lewin K., Gitnick G. Cryopreserved microencapsulated hepatocytes--transplantation studies in Gunn rats. Transplantation. 1993 Mar;55(3):616–622. doi: 10.1097/00007890-199303000-00028. [DOI] [PubMed] [Google Scholar]
  16. Ebata H., Oikawa I., Mito M. Rejection of allogeneic hepatocytes and fetal hepatic tissue transplanted into the rat spleen. Transplantation. 1985 Feb;39(2):221–223. [PubMed] [Google Scholar]
  17. Emond J., Capron-Laudereau M., Meriggi F., Bernuau J., Reynes M., Houssin D. Extent of hepatectomy in the rat. Evaluation of basal conditions and effect of therapy. Eur Surg Res. 1989;21(5):251–259. doi: 10.1159/000129034. [DOI] [PubMed] [Google Scholar]
  18. Gaub J., Iversen J. Rat liver regeneration after 90% partial hepatectomy. Hepatology. 1984 Sep-Oct;4(5):902–904. doi: 10.1002/hep.1840040519. [DOI] [PubMed] [Google Scholar]
  19. Gomez N., Balladur P., Calmus Y., Baudrimont M., Honiger J., Delelo R., Myara A., Crema E., Trivin F., Capeau J. Evidence for survival and metabolic activity of encapsulated xenogeneic hepatocytes transplanted without immunosuppression in Gunn rats. Transplantation. 1997 Jun 27;63(12):1718–1723. doi: 10.1097/00007890-199706270-00003. [DOI] [PubMed] [Google Scholar]
  20. Gugenheim J., Samuel D., Reynes M., Bismuth H. Liver transplantation across ABO blood group barriers. Lancet. 1990 Sep 1;336(8714):519–523. doi: 10.1016/0140-6736(90)92082-s. [DOI] [PubMed] [Google Scholar]
  21. Gunsalus J. R., Brady D. A., Coulter S. M., Gray B. M., Edge A. S. Reduction of serum cholesterol in Watanabe rabbits by xenogeneic hepatocellular transplantation. Nat Med. 1997 Jan;3(1):48–53. doi: 10.1038/nm0197-48. [DOI] [PubMed] [Google Scholar]
  22. Gupta S., Chowdhary J. R. Hepatocyte transplantation: back to the future. Hepatology. 1992 Jan;15(1):156–162. doi: 10.1002/hep.1840150126. [DOI] [PubMed] [Google Scholar]
  23. Honiger J., Balladur P., Mariani P., Calmus Y., Vaubourdolle M., Delelo R., Capeau J., Nordlinger B. Permeability and biocompatibility of a new hydrogel used for encapsulation of hepatocytes. Biomaterials. 1995 Jul;16(10):753–759. doi: 10.1016/0142-9612(95)99637-2. [DOI] [PubMed] [Google Scholar]
  24. Kato K., Matsuda M., Kusano M., Onodera K., Kato J., Kasai S., Mito M., Hodgson W. J. The immunostimulant OK-432 enhances liver regeneration after 90% hepatectomy in rats. Hepatology. 1994 May;19(5):1241–1244. [PubMed] [Google Scholar]
  25. Lee W. M. Acute liver failure. N Engl J Med. 1993 Dec 16;329(25):1862–1872. doi: 10.1056/NEJM199312163292508. [DOI] [PubMed] [Google Scholar]
  26. Lim F., Sun A. M. Microencapsulated islets as bioartificial endocrine pancreas. Science. 1980 Nov 21;210(4472):908–910. doi: 10.1126/science.6776628. [DOI] [PubMed] [Google Scholar]
  27. Makowka L., Lee G., Cobourn C. S., Farber E., Falk J. A., Falk R. E. Allogeneic hepatocyte transplantation in the rat spleen under cyclosporine immunosuppression. Transplantation. 1986 Nov;42(5):537–541. doi: 10.1097/00007890-198611000-00020. [DOI] [PubMed] [Google Scholar]
  28. Makowka L., Rotstein L. E., Falk R. E., Falk J. A., Zuk R., Langer B., Blendis L. M., Phillips M. J. Studies into the mechanism of reversal of experimental acute hepatic failure by hepatocyte transplantation. 1. Can J Surg. 1981 Jan;24(1):39–44. [PubMed] [Google Scholar]
  29. Matsumura K. N., Guevara G. R., Huston H., Hamilton W. L., Rikimaru M., Yamasaki G., Matsumura M. S. Hybrid bioartificial liver in hepatic failure: preliminary clinical report. Surgery. 1987 Jan;101(1):99–103. [PubMed] [Google Scholar]
  30. Miyazaki M., Makowka L., Falk R. E., Falk J. A., Falk W., Venturi D. Reversal of lethal, chemotherapeutically induced acute hepatic necrosis in rats by regenerating liver cytosol. Surgery. 1983 Aug;94(2):142–150. [PubMed] [Google Scholar]
  31. Nyberg S. L., Peshwa M. V., Payne W. D., Hu W. S., Cerra F. B. Evolution of the bioartificial liver: the need for randomized clinical trials. Am J Surg. 1993 Nov;166(5):512–521. doi: 10.1016/s0002-9610(05)81146-8. [DOI] [PubMed] [Google Scholar]
  32. Ohkawa M., Hayashi H., Chaudry I. H., Clemens M. G., Baue A. E. Effects of regenerating liver cytosol on drug-induced hepatic failure. Surgery. 1985 Apr;97(4):455–462. [PubMed] [Google Scholar]
  33. Ribeiro J., Nordlinger B., Ballet F., Cynober L., Coudray-Lucas C., Baudrimont M., Legendre C., Delelo R., Panis Y. Intrasplenic hepatocellular transplantation corrects hepatic encephalopathy in portacaval-shunted rats. Hepatology. 1992 Jan;15(1):12–18. doi: 10.1002/hep.1840150104. [DOI] [PubMed] [Google Scholar]
  34. Roger V., Balladur P., Honiger J., Baudrimont M., Delelo R., Calmus Y., Capeau J., Nordlinger B. A good model of experimental acute hepatic failure: 95% hepatectomy; treatment by transplantation of hepatocytes. Transplant Proc. 1995 Aug;27(4):2504–2505. [PubMed] [Google Scholar]
  35. Rozga J., Holzman M. D., Ro M. S., Griffin D. W., Neuzil D. F., Giorgio T., Moscioni A. D., Demetriou A. A. Development of a hybrid bioartificial liver. Ann Surg. 1993 May;217(5):502–511. doi: 10.1097/00000658-199305010-00010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Rozga J., Podesta L., LePage E., Morsiani E., Moscioni A. D., Hoffman A., Sher L., Villamil F., Woolf G., McGrath M. A bioartificial liver to treat severe acute liver failure. Ann Surg. 1994 May;219(5):538–546. doi: 10.1097/00000658-199405000-00012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Rozga J., Williams F., Ro M. S., Neuzil D. F., Giorgio T. D., Backfisch G., Moscioni A. D., Hakim R., Demetriou A. A. Development of a bioartificial liver: properties and function of a hollow-fiber module inoculated with liver cells. Hepatology. 1993 Feb;17(2):258–265. [PubMed] [Google Scholar]
  38. Scharp D. W., Swanson C. J., Olack B. J., Latta P. P., Hegre O. D., Doherty E. J., Gentile F. T., Flavin K. S., Ansara M. F., Lacy P. E. Protection of encapsulated human islets implanted without immunosuppression in patients with type I or type II diabetes and in nondiabetic control subjects. Diabetes. 1994 Sep;43(9):1167–1170. doi: 10.2337/diab.43.9.1167. [DOI] [PubMed] [Google Scholar]
  39. Seglen P. O. Preparation of isolated rat liver cells. Methods Cell Biol. 1976;13:29–83. doi: 10.1016/s0091-679x(08)61797-5. [DOI] [PubMed] [Google Scholar]
  40. Soon-Shiong P., Heintz R. E., Merideth N., Yao Q. X., Yao Z., Zheng T., Murphy M., Moloney M. K., Schmehl M., Harris M. Insulin independence in a type 1 diabetic patient after encapsulated islet transplantation. Lancet. 1994 Apr 16;343(8903):950–951. doi: 10.1016/s0140-6736(94)90067-1. [DOI] [PubMed] [Google Scholar]
  41. Strain A. J. Isolated hepatocytes: use in experimental and clinical hepatology. Gut. 1994 Apr;35(4):433–436. doi: 10.1136/gut.35.4.433. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Strom S. C., Fisher R. A., Thompson M. T., Sanyal A. J., Cole P. E., Ham J. M., Posner M. P. Hepatocyte transplantation as a bridge to orthotopic liver transplantation in terminal liver failure. Transplantation. 1997 Feb 27;63(4):559–569. doi: 10.1097/00007890-199702270-00014. [DOI] [PubMed] [Google Scholar]
  43. Sun A. M., Cai Z., Shi Z., Ma F., O'Shea G. M., Gharapetian H. Microencapsulated hepatocytes as a bioartificial liver. ASAIO Trans. 1986 Jul-Sep;32(1):39–41. [PubMed] [Google Scholar]
  44. Sussman N. L., Chong M. G., Koussayer T., He D. E., Shang T. A., Whisennand H. H., Kelly J. H. Reversal of fulminant hepatic failure using an extracorporeal liver assist device. Hepatology. 1992 Jul;16(1):60–65. doi: 10.1002/hep.1840160112. [DOI] [PubMed] [Google Scholar]
  45. Terblanche J., Porter K. A., Starzl T. E., Moore J., Patzelt L., Hayashida N. Stimulation of hepatic regeneration after partial hepatectomy by infusion of a cytosol extract from regenerating dog liver. Surg Gynecol Obstet. 1980 Oct;151(4):538–544. [PMC free article] [PubMed] [Google Scholar]
  46. Terpstra O. T. Auxiliary liver grafting: a new concept in liver transplantation. Lancet. 1993 Sep 25;342(8874):758–758. doi: 10.1016/0140-6736(93)91537-v. [DOI] [PubMed] [Google Scholar]

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