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Journal of Healthcare Engineering
Volume 3, Issue 2, Pages 279-298
http://dx.doi.org/10.1260/2040-2295.3.2.279
Research Article

Addressing the Donor Liver Shortage with EX VIVO Machine Perfusion

Maria-Louisa Izamis,1 Tim a. Berendsen,1 Korkut Uygun,1 and Martin L. Yarmush1,2

1Center for Engineering in Medicine/Surgical Services, Massachusetts General Hospital, Harvard Medical School, and Shriners Burns Hospital, Boston MA, USA
2Department of Biomedical Engineering, Rutgers University, Piscataway, NJ, USA

Received 1 May 2011; Accepted 1 October 2011

Copyright © 2012 Hindawi Publishing Corporation. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. United Network for Organ Sharing, http://www.unos.org/, Accessed 1 May, 2011.
  2. R. M. Merion, “Current status and future of liver transplantation,” Seminars in Liver Disease, vol. 30, no. 4, pp. 411–21, 2010. View at Google Scholar
  3. W. Bernal, G. Auzinger, A. Dhawan, and J. Wendon, “Acute liver failure,” Lancet, vol. 376, no. 9736, pp. 190–201, 2010. View at Google Scholar
  4. L. A. Siminoff, R. M. Arnold, and J. Hewlett, “The process of organ donation and its effect on consent,” Clin Transplant, vol. 15, pp. 39–47, 2001. View at Google Scholar
  5. R. W. Evans, C. E. Orlans, and N. L. Ascher, “The potential supply of organ donors,” JAMA, vol. 267, pp. 239–46, 1992. View at Google Scholar
  6. R. H. Deshpande and N. Heaton, “Can non-heart-beating donors replace cadaveric heart-beating liver donors?” Journal of Hepatology, vol. 45, pp. 499–503, 2006. View at Google Scholar
  7. W. Boettcher, F. Merkle, and H. H. Weitkemper, “History of extracorporeal circulation: the conceptional and developmental period,” J Extra Corpor Technol, vol. 35, no. 3, pp. 172–83, 2003. View at Google Scholar
  8. A. Carrel and C. A. Lindbergh, The culture of organs, ed. P. B. Hoeber, New York, 1938.
  9. R. Hems, B. D. Ross, M. N. Berry, and H. A. Krebs, “Gluconeogenesis in the perfused rat liver,” Biochem J, vol. 101, pp. 284–292, 1966. View at Google Scholar
  10. H. F. Woods, L. V. Eggleston, and H. A. Krebs, “The cause of hepatic accumulation of fructose 1-phosphate on fructose loading,” Biochem J, vol. 119, no. 3, pp. 501–10, 1970. View at Google Scholar
  11. H. F. Woods and H. A. Krebs, “Lactate production in the perfused rat liver,” Biochem J, vol. 125, pp. 129–39, 1971. View at Google Scholar
  12. H. Tolboom, R. Pouw, K. Uygun et al., “A Model for Normothermic Preservation of the Rat Liver,” Tissue Eng, vol. 13, no. 8, pp. 2143–2151, 2007. View at Google Scholar
  13. C. Y. Lee, J. Shailendra, H. M. Duncan et al., “Survival transplantation of preserved non-heart-beating donor rat livers: preservation by hypothermic machine perfusion,” Transplantation, vol. 76, no. 10, pp. 1432–6, 2003. View at Google Scholar
  14. T. A. Berendsen, B. Bruinsma, J. Lee et al., “A simplified sub-normothermic machine perfusion model restores ischemically damaged liver grafts in a rat model of orthotopic liver transplantation,” Tranplantation Research, 2011. Accepted. View at Google Scholar
  15. C. Fondevila, A. J. Hessheimer, M. H. J. Maathuis et al., “Superior preservation of DCD livers with continuous normothermic perfusion,” Ann Surg, vol. 254, pp. 1000–7, 2011. View at Google Scholar
  16. S. D. St Peter, C. J. Imber, I. Lopez, D. Hughes, and P. J. Friend, “Extended preservation of non-heart-beating donor livers with normothermic machine perfusion,” Br J Surg, vol. 89, no. 5, pp. 609–16, 2002. View at Google Scholar
  17. S. P. Reddy, S. Bhattachariya, N. Maniakin et al., “Preservation of porcine non-heart-beating donor livers by sequential cold storage and warm perfusion,” Transplantation, vol. 77, no. 9, pp. 1328–32, 2004. View at Google Scholar
  18. J. Brockmann, S. Reddy, C. Coussios et al., “Normothermic perfusion: a new paradigm for organ preservation,” Ann Surg, vol. 250, no. 1, pp. 1–6, 2009. View at Google Scholar
  19. S. Reddy, M. Zilvetti, J. Brockmann, A. McLaren, and P. Friend, “Liver transplantation from non-heart-beating donors - current status and future prospects,” Liver Transplantation, vol. 10, no. 10, pp. 1223–32, 2004. View at Google Scholar
  20. M. Vairetti, A. Ferrigno, F. Carlucci et al., “Subnormothermic machine perfusion protects steatotic livers against preservation injury: a potential for donor pool increase?” Liver Transpl, vol. 15, no. 1, pp. 20–9, 2009. View at Google Scholar
  21. D. Nagrath, H. Xu, Y. Tanimura et al., “Metabolic preconditioning of donor organs: defatting fatty livers by normothermic perfusion ex vivo,” Metab Eng, vol. 11, no. 4-5, pp. 274–83, 2009. View at Google Scholar
  22. J. D. Perkins, “Defatting the fatty liver with normothermic perfusion of the liver allograft,” Liver Transplantation, vol. 15, no. 10, pp. 1366–7, 2009. View at Google Scholar
  23. D. Christoforidis, O. Martinet, F. J. Lejeune, and F. Mosimann, “Isolated liver perfusion for non-resectable liver tumours: a review,” Eur J Surg Oncol, vol. 28, no. 8, pp. 875–90, 2002. View at Google Scholar
  24. T. Pencavel, R. Seth, A. Hayes et al., “Locoregional intravascular viral therapy of cancer: precision guidance for Paris's arrow?” Gene Ther, vol. 17, no. 8, pp. 946–60, 2010. View at Google Scholar
  25. B. van Elten, A. M. Eggermont, S. T. van Tiel, G. Ambagtsheer, J. H. de Wilt, and T. L. ten Hagen, “Gene therapy in in vivo isolated perfusion models,” Curr Gene Ther, vol. 5, no. 2, pp. 195–202, 2005. View at Google Scholar
  26. G. T. Everson and C. C. Kulig, “Antiviral therapy for hepatitis C in the setting of liver transplantation,” Curr Treat Options Gastroenterol, vol. 9, no. 6, pp. 520–9, 2006. View at Google Scholar
  27. S. Kanoria, R. Jalan, A. M. Seifalian, R. Williams, and B. R. Davidson, “Protocols and mechanisms for remote ischemic preconditioning: a novel method for reducing ischemia reperfusion injury,” Transplantation, vol. 84, no. 4, pp. 445–58, 2007. View at Google Scholar
  28. M. R. Schon, O. Kollmar, S. Wolf et al., “Liver transplantation after organ preservation with normothermic extracorporeal perfusion,” Ann Surgery, vol. 233, pp. 114–123, 2001. View at Google Scholar
  29. A. J. Butler, M. A. Rees, D. G. D. Wight et al., “Successful extracorporeal porcine liver perfusion for 72 hr,” Transplantation, vol. 73, no. 8, pp. 1212–1218, 2002. View at Google Scholar
  30. G. L. Riedel, J. L. Scholle, A. P. Shepherd, and W. F. Ward, “Effects of hematocrit on oxygenation of the isolated perfused rat liver,” Am J Physiol, vol. 245, no. 6, pp. G769–74, 1983. View at Google Scholar
  31. K. Cheung, P. E. Hickman, J. M. Potter et al., “An optimized model for rat liver perfusion studies,” J Surg Res, vol. 66, no. 1, pp. 81–9, 1996. View at Google Scholar
  32. J. V. Guarrera, S. D. Henry, B. Samstein et al., “Hypothermic machine preservation in human liver transplantation: the first clinical series,” Am J Transplant, vol. 10, no. 2, pp. 372–81, 2009. View at Google Scholar
  33. J. V. Guarrera, J. Estevez, J. Boykin et al., “Hypothermic machine perfusion of liver grafts for transplantation: technical development in human discard and miniature swine models,” Transplant Proc, vol. 37, pp. 323–25, 2005. View at Google Scholar
  34. A. Ferrigno, V. Rizzo, E. Boncompagni et al., “Machine perfusion at 20C reduces preservation damage to livers from non-heart beating donors,” Cryobiology, vol. 62, pp. 152–8, 2011. View at Google Scholar
  35. M. Vairetti, A. Ferrigno, V. Rizzo et al., “Subnormothermic machine perfusion protects against rat liver preservation injury: a comparative evaluation with conventional cold storage,” Transplant Proc, vol. 39, no. 6, pp. 1765–1767, 2007. View at Google Scholar
  36. J. B. Hanks, W. C. Meyers, C. L. Wellman, R. C. Hill, and R. S. Jones, “The effect of cell-free and erythrocyte-containing perfusion in rat livers,” Journal of Surgical Research, vol. 29, no. 2, 1979. View at Google Scholar
  37. H. Xu, T. Berendsen, K. Kim et al., “Extracorporeal normothermic machine perfusion resuscitates pig DCD livers with extended warm ischemia,” J Surg Res, 2011. View at Google Scholar
  38. J. D. Perkins, “Another comparison between University of Wisconsin solution and histidine-tryptophan-ketoglutarate solution for liver preservation,” Liver Transpl, vol. 15, no. 4, pp. 443–4, 2009. View at Google Scholar
  39. J. F. McAnulty, “Hypothermic organ preservation by static storage methods: Current status and a view to the future,” Cryobiology, vol. 60, pp. S13–S19, 2010. View at Google Scholar
  40. B. Gonzalez-Flecha, J. C. Cutrin, and A. Boveris, “Time course and mechanism of oxidative stress and tissue damage in rat liver subjected to in vivo ischemia-reperfusion,” J Clin Invest, vol. 91, pp. 456–64, 1993. View at Google Scholar
  41. R. Adam, H. Bismuth, T. Diamond et al., “Effect of extended cold ischaemia with UW solution on graft function after liver transplantation,” Lancet, vol. 340, no. 8832, 1992. View at Google Scholar
  42. N. Cuende, B. Miranda, J. F. Cañón, G. Garrido, and R. Matesanz, “Donor characteristics associated with liver graft survival,” Transplantation, vol. 79, no. 10, 2005. View at Google Scholar
  43. F. O. Belzer and J. H. Southard, “Principles of solid-organ preservation by cold storage,” Transplantation, vol. 45, no. 4, pp. 673–676, 1988. View at Google Scholar
  44. R. Y. Calne, D. E. Pegg, J. Pryse-Davies, and F. L. Brown, “Renal preservation by ice-cooling. An experimental study relating to kidney transplantation from cadavers,” Br Med J, vol. 2, no. 5358, pp. 651–5, 1963. View at Google Scholar
  45. J. A. Fridell, R. S. Mangus, and A. J. Tector, “Clinical experience with histidine-tryptophan-ketoglutarate solution in abdominal organ preservation: a review of recent literature,” Clin Transpl, vol. 23, no. 3, pp. 305–12, 2009. View at Google Scholar
  46. L. Feng, N. Zhao, X. Yao et al., “Histidine-tryptophan-ketoglutarate solution vs. University of Wisonsin solution for liver transplantation: a systematic review,” Liver Transpl, vol. 13, no. 8, pp. 1125–36, 2007. View at Google Scholar
  47. H. Janssen, P. H. Janssen, and C. E. Broelsch, “UW is superior to Celsior and HTK in the protection of human liver endothelial cells against preservation injury,” Liver Transpl, vol. 10, no. 12, pp. 1514–23, 2004. View at Google Scholar
  48. N. V. Jamieson, R. Sundberg, S. Lindell et al., “Preservation of the canine liver for 24–48 hours using simple cold storage with UW solution,” Transplantation, vol. 46, no. 4, pp. 517–22, 1988. View at Google Scholar
  49. J. Moen, K. Claesson, H. Pienaar et al., “Preservation of dog liver, kidney, and pancreas using the Belzer-UW solution with a high-sodium and low-potassium content,” Transplantation, vol. 47, no. 6, pp. 940–5, 1989. View at Google Scholar
  50. M. Kalayoglu, R. M. Hoffmann, A. M. D'Alessandro, J. D. Pirsch, H. W. Sollinger, and F. O. Belzer, “Results of extended preservation of the liver for clinical transplantation,” Lancet, vol. 1, no. 8586, pp. 617–9, 1988. View at Google Scholar
  51. S. Todo, J. Nery, K. Yanaga, L. Podesta, R. D. Gordon, and T. E. Starzl, “Extended preservation of human liver grafts with UW solution,” JAMA, vol. 261, no. 5, pp. 711–4, 1989. View at Google Scholar
  52. K. Tekin, C. J. Imber, M. Atli et al., “A simple scoring system to evaluate the effects of cold ischemia on marginal liver donors,” Transplantation, vol. 77, no. 3, pp. 411–6, 2004. View at Google Scholar
  53. R. J. Porte, R. J. Ploeg, B. Hansen et al., “Long-term graft survival after liver transplantation in the UW era: late effects of cold ischemia and primary dysfunction. European Multicentre Study Group,” Transpl Int, vol. 11, Suppl 1, pp. S164–7, 1998. View at Google Scholar
  54. R. J. Stratta, R. P. Wood, A. N. Langnas et al. et al., “The impact of extended preservation on clinical liver transplantation,” Transplantation, vol. 50, no. 3, pp. 438–43, 1990. View at Google Scholar
  55. F. O. Belzer, A. M. D'Alessandro, R. M. Hoffmann et al., “The use of UW solution in clinical transplantation. A 4-year experience,” Ann Surg, vol. 215, no. 6, pp. 579–83, 1992. View at Google Scholar
  56. B. J. Fuller and C. Y. Lee, “Hypothermic perfusion preservation: The future of organ preservation revisited?” Cryobiology, vol. 54, pp. 129–145, 2007. View at Google Scholar
  57. C. Moers, J. Pirenne, A. Paul, R. J. Ploeg, and Machine Preservation Trial Study Group, “Machine perfusion or cold storage in deceased-donor kidney transplantation,” N Engl J Med, vol. 360, no. 1, pp. 7–19, 2009. View at Google Scholar
  58. LH. Toledo-Pereyra, “Pulsatile perfusion is still indicated for kidney preservation,” Tranplantation, vol. 34, no. 2, p. 110, 1982. View at Google Scholar
  59. RM. Merion, H. K. Oh, F. K. Port, L. H. Toledo-Pereyra, and J. G. Turcotte, “A prospective controlled trial of coldstorage versus machine-perfusion preservation in cadaveric renal transplantation,” Transplantation, vol. 50, no. 2, pp. 230–3, 1990. View at Google Scholar
  60. S. D. St Peter, C. J. Imber, and P. J. Friend, “Liver and kidney preservation by perfusion,” The Lancet, vol. 359, pp. 604–13, 2002. View at Google Scholar
  61. S. Jain, C. Y. Lee, S. Baicu et al., “Hepatic function in hypothermically stored porcine livers: Comparison of hypothermic machine perfusion vs cold storage,” Transpl Proc, vol. 37, pp. 340–1, 2005. View at Google Scholar
  62. N. Yamamoto, Y. Konishi, S. Wakashiro et al., “Seventy-two-hour preservation of porcine liver by continuous hypothermic perfusion with UW solution in comparison with simple cold storage,” J Surg Res, vol. 51, no. 4, pp. 288–92, 1991. View at Google Scholar
  63. B. H. Pienaar, S. L. Lindell, T. Van Gulik, J. H. Southard, and F. O. Belzer, “Seventy two hour preservation of the canine liver by machine perfusion,” Transplantation, vol. 49, pp. 258–60, 1990. View at Google Scholar
  64. J. Benichou, C. G. Halgrimson, R. Weil 3rd, L. J. Koep, and T. E. Starzl, “Canine and human liver preservation for 6 to 18 hr by cold infusion,” Transplantation, vol. 24, no. 6, pp. 407–11, 1977. View at Google Scholar
  65. L. Brettschneider, J. Kolff, G. V. Smith, A. J. Martin, P. Taylor, and T. E. Starzl, “An evaluation of perfusion constituents in liver preservation,” Surg. Forum, vol. 19, pp. 354–6, 1968. View at Google Scholar
  66. J. V. Guarrera, S. D. Henry, S. W. Chen et al., “Hypothermic machine preservation attenuates ischemia/reperfusion markers after liver transplantation: preliminary results,” J Surg Res, vol. 167, no. 2, pp. e365–73, 2010. View at Google Scholar
  67. L. Matsuoka, T. Shah, S. Aswad et al., “Pulsatile perfusion reduces the incidence of delayed graft function in expanded criteria donor kidney transplantation,” Am J Transplant, vol. 6, no. 6, 2006. View at Google Scholar
  68. K. Hashimoto and C. Miller, “The use of marginal grafts in liver transplantation,” J Hepatobiliary Pancreat Sci, vol. 15, pp. 92–101, 2008. View at Google Scholar
  69. “A definition of irreversible coma. Report of the Ad Hoc Committe of the Harvard Medical School to Examine the Definition of Brain Death,” JAMA, vol. 205, pp. 337–40, 1968.
  70. J. W. Daemen, G. Kootstra, R. M. Wijnen, M. Yin, and E. Heineman, “Nonheart-beating donors: the Maastricht experience,” Clin Transpl, pp. 303–16, 1994. View at Google Scholar
  71. N. Matsuno, M. Uchiyama, H. Iwamoto et al., “Machine perfusion preservation for liver transplantation from non-heart-beating donors with agonal stage,” Transpl Proc, vol. 34, pp. 2610–11, 2002. View at Google Scholar
  72. H. Iwamoto, N. Matsuno, Y. Narumi et al., “Beneficial effect of machine perfusion preservation on liver transplantation from non-heart-beating donors,” Transpl Proc, vol. 32, no. 7, pp. 1645–6, 2000. View at Google Scholar
  73. P. Dutkowski, O. de Rougemont, and P. A. Clavien, “Machine perfusion for, “marginal” liver grafts,” Am J Transplant, vol. 8, no. 5, pp. 917–24, 2008. View at Google Scholar
  74. B. Lüer, M. Koetting, P. Efferz, and T. Minor, “Role of oxygen during hypothermic machine perfusion preservation of the liver,” Transpl Int, vol. 23, no. 9, pp. 944–50, 2010. View at Google Scholar
  75. C. Y. Lee, S. Jain, H. M. Duncan et al., “Survival transplantation of preserved non-heartbeating donor rat livers: Preservation by hypothermic machine perfusion,” Transplantation, vol. 76, no. 10, pp. 1432–1436, 2003. View at Google Scholar
  76. S. Manekeller and T. Minor, “Possibility of conditioning predamaged grafts after cold storage: influences of oxygen and nutritive stimulation,” Transpl Int, vol. 10, no. 8, pp. 667–74, 2006. View at Google Scholar
  77. O. de Rougemont, S. Breitenstein, B. Leskosek et al., “One hour hypothermic oxygenated perfusion (HOPE) protects nonviable liver allografts donated after cardiac death,” Ann Surg, vol. 250, no. 5, pp. 674–83, 2009. View at Google Scholar
  78. P. Dutkowski, R. Graf, and P. A. Clavien, “Rescue of the cold preserved rat liver by hypothermic oxygenated machine perfusion,” Am J Transplant, vol. 6, no. 5 Pt 1, pp. 903–12, 2006. View at Google Scholar
  79. W. Isselhard and T. Minor, “Gaseous oxygen for protection and conditioning of organs during ischemia,” Zentralbl Chir, vol. 124, no. 4, pp. 252–9, 1999. View at Google Scholar
  80. T. Minor, H. Klauke, B. Vollmar, W. Isselhard, and M. D. Menger, “Biophysical aspects of liver aeration by vascular persufflation with gaseous oxygen,” Transplantation, vol. 63, no. 12, pp. 1843–6, 1997. View at Google Scholar
  81. J. Stegemann, A. Hirner, U. Rauen, and T. Minor, “Gaseous oxygen persufflation or oxygenated machine perfusion with Custodiol-N for long-term perservation of ischemic rat livers?” Cryobiology, vol. 58, no. 1, pp. 45–51, 2008. View at Google Scholar
  82. T. Minor and W. Isselhard, “Synthesis of high energy phosphates during cold ischemic rat liver preservation with gaseous oxygen insufflation,” Transplantation, vol. 61, no. 1, pp. 20–2, 1996. View at Google Scholar
  83. A. Lanir, R. L. Jenkins, C. Caldwell, R. G. Lee, U. Khettry, and M. E. Clouse, “Hepatic transplantation survival: Correlation with adenine nucleotide level in donor liver,” Hepatology, vol. 8, no. 3, pp. 471–5, 1988. View at Google Scholar
  84. T. Minor and M. Kötting, “Gaseous oxygen for hypothermic preservation of predamaged liver grafts: fuel to cellular homeostasis or radical tissue alteration?” Cryobiology, vol. 40, no. 2, pp. 182–6, 2000. View at Google Scholar
  85. J. Treckmann, T. Minor, S. Saad et al., “Retrograde oxygen persufflation preservation of human livers: A pilot study,” Liver Transpl, vol. 14, no. 3, pp. 358–64, 2008. View at Google Scholar
  86. P. A. Clavien, P. R. Harvey, and S. M. Strasberg, “Preservation and reperfusion injuries in liver allografts: an overview and synthesis of current studies,” Transplantation, vol. 53, pp. 957–78, 1992. View at Google Scholar
  87. J. Briceño, T. Marchal, J. Padillo, G. Solórzano, and C. Pera, “Influence of marginal donors on liver preservation injury,” Transplantation, vol. 74, no. 4, pp. 522–6, 2002. View at Google Scholar
  88. C. Fondevila, R. W. Busuttil, and J. W. Kupiec-Weglinski, “Hepatic ischemia reperfusion injury: a fresh look,” Exp Mol Pathol, vol. 74, pp. 86–93, 2003. View at Google Scholar
  89. P. Dutkowski, S. Schönfeld, T. Heinrich et al., “Reduced oxidative stress during acellular reperfusion of the rat liver after hypothermic oscillating perfusion,” Transplantation, vol. 68, no. 1, pp. 44–50, 1999. View at Google Scholar
  90. H. Xu, C. Y. Lee, M. G. Clemens, and J. X. Zhang, “Prolonged hypothermic machine perfusion preserves hepatocellular function but potentiates endothelial cell dysfunction in rat livers,” Transplantation, vol. 77, no. 11, pp. 1676–82, 2004. View at Google Scholar
  91. K. Vekemans, Q. Liu, J. Pirenne, and D. Monbaliu, “Artificial circulation of the liver: Machine perfusion as a preservation method in liver transplantation,” The Anatomical Record, vol. 291, pp. 735–40, 2008. View at Google Scholar
  92. J. C. Caldwell-Kenkel, R. G. Thurman, and J. J. Lemasters, “Selective loss of nonparenchymal cell viability after cold ischemic storage of rat livers,” Transplantation, vol. 45, no. 5, pp. 834–7, 1988. View at Google Scholar
  93. C. Y. Lee, J. Zhang, H. deSilva, R. Coger, and M. Clemens, “Heterogeneous flow patterns during hypothermic machine perfusion preservation of livers,” Transplantation, vol. 70, no. 12, pp. 1797–1802, 1802. View at Google Scholar
  94. R. W. Jamieson and P. J. Friend, “Organ reperfusion and preservation,” Frontiers in Bioscience, vol. 13, pp. 221–35, 2008. View at Google Scholar
  95. M. H. Maathuis, H. G. Leuvenink, and R. J. Ploeg, “Perspectives in organ preservation,” Transplantation, vol. 83, no. 10, pp. 1289–1297, 2007. View at Google Scholar
  96. S. P. Reddy, J. Butler, and P. J. Friend, “Normothermic perfusion: A mini review,” Transplantation, vol. 87, no. 5, pp. 631–2, 2008. View at Google Scholar
  97. C. J. Imber, S. D. St Peter, I. Lopez de Cenarruzabeitia et al., “Advantages of normothermic perfusion over cold storage in liver preservation,” Transplantation, vol. 73, no. 5, pp. 701–9, 2002. View at Google Scholar
  98. H. Tolboom, R. E. Pouw, M. L. Izamis et al., “Recovery of Warm Ischemic Rat Liver Grafts by Normothermic Extracorporeal Perfusion,” Transplantation, vol. 87, no. 2, pp. 170–177, 2009. View at Google Scholar
  99. M. R. Schön, O. Kollmar, S. Wolf et al., “Liver transplantation after organ preservation with normothermic extracorporeal perfusion,” Ann Surg, vol. 233, no. 1, pp. 114–123, 2001. View at Google Scholar
  100. A. Otero, M. Gómez-Gutiérrez, F. Suárez et al., “Liver transplantation from Maastricht category 2 non-heart-beating donors,” Transplantation, vol. 76, no. 7, pp. 1068–73, 2003. View at Google Scholar
  101. J. Alvarez, M. R. del Barrio, J. Arias et al., “Five years of experience with non-heart beating donors coming from the streets,” Transpl Proc, vol. 34, pp. 2589–2590, 2002. View at Google Scholar
  102. C. Fondevila, A. J. Hessheimer, A. Ruiz et al., “Liver transplant using donors after unexpected cardiac death: Novel preservation protocol and acceptance criteria,” Am J Transplant, vol. 7, pp. 1849–55, 2007. View at Google Scholar
  103. S. Jiménez-Galanes, M. J. Meneu-Diaz, A. M. Elola-Olaso et al., “Liver transplantation using uncontrolled non-heart-beating donors under normothermic extracorporeal membrane oxygenation,” Liver Transpl, vol. 15, pp. 1110–18, 2009. View at Google Scholar
  104. J. Quintela, B. Gala, I. Baamonde et al., “Long-term results for liver transplantation from non-heart-beating donors maintained with chest and abdominal compression-decompression,” Transpl Proc, vol. 37, no. 9, pp. 3857–8, 2005. View at Google Scholar
  105. P. Dutkowski, K. Furrer, Y. Tian, R. Graf, and P. A. Clavien, “Novel short-term hypothermic oxygenated perfusion (HOPE) system prevents injury in rat liver graft from non-heart beating donor,” Annals of Surgery, vol. 244, no. 6, 2006. View at Google Scholar
  106. H. Tolboom, J. M. Milwid, M. L. Izamis, K. Uygun, F. Berthiaume, and M. L. Yarmush, “Sequential cold storage and normothermic perfusion of the ischemic rat liver,” Transplantation Proc, vol. 40, no. 5, pp. 1306–1309, 2008. View at Google Scholar
  107. A. Ar'Rajab, B. Ahrén, and A. Nilsson, “Temperature dependent phospholipid degradation in the rat liver during preservation for transplantation,” Transplantation, vol. 57, no. 8, pp. 1153–60, 1994. View at Google Scholar
  108. P. Biberthaler, B. Luchting, S. Massberg et al., “The influence of organ temperature on hepatic ischemia-reperfusion injury,” Transplantation, vol. 72, no. 9, pp. 1486–1490, 2001. View at Google Scholar
  109. P. Olschewski, P. Gass, V. Ariyakhagorn et al., “The influence of storage temperature during machine perfusion on preservation quality of marginal donor livers,” Cryobiology, vol. 60, no. 3, pp. 337–43, 2010. View at Google Scholar
  110. H. Tolboom, M. L. Izamis, N. Sharma et al., “Subnormothermic machine perfusion for recovery and preservation of ischemic rat liver grafts,” Journal of Surgical Research, 2011, PMID 21550058. View at Google Scholar
  111. H. Tolboom, R. E. Pouw, M. L. Izamis et al., “Recovery of Warm Ischemic Rat Liver Grafts by Normothermic Extracorporeal Perfusion,” Transplantation, vol. 87, pp. 170–177, 2009. View at Google Scholar
  112. A. Nui, T. Katsuramaki, H. Kikuchi et al., “The functional integrity of a normothermic perfusion system using artificial blood in pig liver,” J Surg Res, vol. 131, pp. 189–98, 2006. View at Google Scholar
  113. B. Sánchez-Perez, J. Santoyo, J. L. Fernández-Aguilar et al., “Preoperative factors and models predicting mortality in liver tranplantation,” Transplant Proc, vol. 37, no. 3, 2005. View at Google Scholar
  114. J. Busquets, X. Xiol, J. Figueras et al., “The impact of donor age on liver transplantation: influence of donor age on early liver function and on subsequent patient and graft survival,” Transplantation, vol. 71, no. 12, p. 1765, 2001. View at Google Scholar
  115. Ch. Zapletal, D. Faust, C. Wullstein et al., “Does the liver ever age? Results of liver transplantation with donors above 80 years of age,” Transpl Proc, vol. 37, no. 2, 2005. View at Google Scholar
  116. J. Pirenne, D. Monbaliu, F. Van Gelder et al., “Liver transplantation using livers from septuagenarian and octogenarian donors: an underused strategy to reduce mortality on the waiting list,” Transpl Proc, vol. 37, no. 2, 2005. View at Google Scholar
  117. J. H. Hoofnagle, M. Lombardero, R. K. Zetterman et al., “Donor age and outcome of liver transplantation,” Hepatology, vol. 24, no. 1, 1996. View at Google Scholar
  118. H. Vilca Melendez, M. Rela, G. Murphy, and N. Heaton, “Assessment of graft function before liver transplantation: quest for the lost ark?” Transplantation, vol. 70, no. 4, pp. 560–5, 2000. View at Google Scholar
  119. J. Ozer, M. Ratner, M. Shaw, W. Bailey, and S. Schomaker, “The current state of serum biomarkers of hepatotoxicity,” Toxicology, vol. 245, pp. 194–205, 2008. View at Google Scholar
  120. D. Monbaliu, L. Libbrecht, R. De Vos et al., “The extent of vacuolation in non-heart beating porcine donor liver grafts prior to transplantation predicts their viability,” Liver Transpl, vol. 14, pp. 1256–1265, 2008. View at Google Scholar
  121. T. Wu, “Predicting the viability of liver allografts procured from non-heart-beating donors: The role of histopathology,” Liver Transpl, vol. 14, pp. 1240–42, 2008. View at Google Scholar
  122. S. Perk, M. L. Izamis, H. Tolboom et al., “A metabolic index of ischemic injury for perfusion-recovery of cadaveric rat livers,” PLoS ONE, vol. 6, no. 12, p. e28518, 2011. View at Google Scholar
  123. K. Uygun, H. Tolboom, M. L. Izamis et al., “Diluted blood reperfusion as a model for transplantation of ischemic rat livers: ALT is a direct indicator of viability,” Transpl Proc, vol. 42, no. 7, pp. 2463–7, 2010. View at Google Scholar
  124. J. Devlin, J. B. Dunne, R. A. Sherwood et al., “Relationship between early liver graft viability and enzyme activities in effluent preservation solution,” Transplantation, vol. 60, no. 7, pp. 627–31, 1995. View at Google Scholar
  125. E. G. Pacheco, O. D. Silva Jr., A. K. Sankarankutty, and M. A. Ribeiro Jr., “Analysis of the liver effluent as a marker of preservation injury and early graft performance,” Transplant Proc, vol. 42, no. 2, pp. 435–9.
  126. I. Marzi, Z. Zhong, J. J. Lemasters, and R. G. Thurman, “Evidence that graft survival is not related to parenchymal cell viability in rat liver transplantation,” Transplantation, vol. 48, pp. 463–8, 1989. View at Google Scholar
  127. U. Rauen, J. Erhard, P. Kühnhenrich et al., “Nonparenchymal cell and hepatocellular injury to human liver grafts assessed by enzyme-release into the perfusate,” Langenbecks Arch Chir, vol. 379, no. 4, pp. 241–7, 1994. View at Google Scholar
  128. JC. García-Valdecasas, J. Tabet, R. Valero et al., “Evaluation of ischemic injury during liver procurement from non-heart-beating donors,” European Surgical Research, vol. 31, pp. 447–456, 1999. View at Google Scholar
  129. D. S. Pratt and M. M. Kaplan, “Evaluation of abnormal liver-enzyme results in asymptomatic patients,” N Engl J Med, vol. 342, pp. 1266–1271, 2000. View at Google Scholar
  130. L. L. Almada, A. L. Scandizzi, E. E. Guibert, G. Furno, and J. V. Rodriguez, “Biliary inorganic phosphate as a tool for assessing cold preservation-reperfusion injury: a study in the isolated perfused rat liver model,” Liver Transpl, vol. 9, no. 2, pp. 160–9, 2003. View at Google Scholar
  131. S. Op den Dries, M. E. Sutton, T. Lisman, and R. J. Porte, “Protection of bile ducts in liver transplantation: looking beyond ischemia,” Tranplantation, vol. 92, no. 4, pp. 373–9, 2011. View at Google Scholar
  132. M. Hertl and A. B. Cosimi, “Living donor liver transplantation: how can we better protect the donors?” Transplantation, vol. 83, no. 3, pp. 263–264, 2007. View at Google Scholar
  133. M. Hertl, M. C. Hertl, P. Kunkel et al., “Tauroursodeoxycholate ameliorates reperfusion injury after pig liver transplantation,” Transpl Int, vol. 12, no. 6, pp. 454–62, 1999. View at Google Scholar
  134. M. Hertl, M. C. Hertl, D. Kluth, and C. E. Broelsch, “Hydrophilic bile salts protect bile duct epithelium during cold preservation: a scanning electron microscopy study,” Liver Transpl, vol. 6, no. 2, pp. 207–12, 2000. View at Google Scholar
  135. M. Hertl, P. R. Harvey, P. E. Swanson et al., “Evidence of preservation injury to bile ducts by bile salts in the pig and its prevention by infusions of hydrophilic bile salts,” Hepatology, vol. 21, no. 4, pp. 1130–7, 1995. View at Google Scholar
  136. T. A. Berendsen, M. L. Izamis, H. Xu et al., “Hepatocyte viability and adenosine triphosphate content decrease linearly over time during conventional cold storage of rat liver grafts,” Transpl Proc, vol. 43, no. 5, pp. 1484–8, 2011. View at Google Scholar
  137. M. Net, R. Valero, R. Almenara et al., “Hepatic xanthine levels as viability preictor of livers procured from non-heart-beating donor pigs,” Transplantation, vol. 71, no. 9, pp. 1232–7, 2001. View at Google Scholar
  138. W. Kamiike, M. Burdelski, G. Steinhoff, B. Ringe, W. Lauchart, and R. Pichlmayr, “Adenine nucleotide metabolism and its relation to organ viability in human liver transplantation,” Transplantation, vol. 45, pp. 138–43, 1988. View at Google Scholar
  139. N. Tygstrup, “Determination of the hepatic elimination capacity (Lm) of galactose by a single injection,” Scand J Clin Lab Invest, vol. 18, Suppl 92, p. 118, 1966. View at Google Scholar
  140. M. L. Izamis, N. S. Sharma, B. Uygun et al., “In situ metabolic flux analysis to quantify the liver metabolic response to experimental burn injury,” Biotechnol Bioeng, vol. 108, no. 4, pp. 839–52, 2010. View at Google Scholar
  141. M. Oellerich, M. Burdelski, B. Ringe et al., “Lignocaine metabolite formation as a measure of pre-transplant liver function,” Lancet, vol. 1, no. 8639, 1989. View at Google Scholar
  142. M. Oellerich, M. Burdelski, B. Ringe et al., “Functional state of the donor liver and early outcome of transplantation,” Transpl Proc, vol. 23, no. 1 Pt 2, 1991. View at Google Scholar
  143. R. B. Zotz, J. von Schönfeld, J. Erhard et al., “Value of an extended monoethylglycinexylidide formation test and other dynamic liver function tests in liver transplant donors,” Tranplantation, vol. 63, no. 4, 1997. View at Google Scholar
  144. W. Kamiike, M. Nakahara, K. Nakao et al., “Correlation Between Cellular Atp Level And Bile Excretion In The Rat-Liver,” Transplantation, vol. 39, no. 1, pp. 50–55, 1985. View at Google Scholar
  145. P. L. Abt, N. M. Desai, M. D. Crawford et al., “Survival following liver transplantation from non-heart-beating donors,” Annals of Surgery, vol. 239, no. 1, pp. 87–92, 2004. View at Google Scholar
  146. S. J. Karp, S. Johnson, A. Evenson et al., “Minimising cold ischemic time is essential in cardiac death donor-associated liver transplantation,” HPB (Oxford), vol. 13, no. 6, pp. 411–6, 2011. View at Google Scholar
  147. K. Vajdová, R. Graf, and P. A. Clavien, “ATP-supplies in the cold-preserved liver: A long neglected factor of organ viability,” Hepatology, vol. 36, no. 6, pp. 1543–52, 2002. View at Google Scholar
  148. V. Costa, J. Brophy, and M. McGregor, Pulsatile machine perfusion compared to cold storage in kidney preservation. 44, Montreal: Technology Assessment Unit of the McGill University Health Centre (MUHC), 2007.
  149. M. Bond, M. Pitt, J. Akoh, T. Moxham, M. Hoyle, and R. Anderson, “The effectiveness and cost-effectiveness of methods of storing donated kidneys from deceased donors: a systematic review and economic model,” Health Technol Assess, vol. 13, no. 38, pp. 1–156, 2009. View at Google Scholar
  150. J. Wight, J. Chilcott, M. Holmes, and N. Brewer, “The clinical and cost-effectiveness of pulsatile machine perfusion versus cold storage of kidneys for transplantation retrieved from heart-beating and non-heart-beating donors,” Health Technol Assess, vol. 7, 2003. View at Google Scholar
  151. C. Guyomard, C. Chesne, B. Meunier et al., “Primary culture of adult rat hepatocytes after 48-hour preservation of the liver with cold UW solution,” Hepatology, vol. 12, pp. 1329–1336, 1990. View at Google Scholar
  152. R. D. Hughes, R. R. Mitry, A. Dhawan et al., “Isolation of hepatocytes from livers from non-heart-beating donors for cell transplantation,” Liver Transpl, vol. 12, no. 5, pp. 713–7, 2006. View at Google Scholar
  153. B. E. Uygun, A. Soto-Gutierrez, H. Yagi et al., “Organ reengineering through development of a transplantable recellularized liver graft using decellularized liver matrix,” Nat Med, vol. 16, no. 7, pp. 814–20, 2010. View at Google Scholar