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An integrated perfusion machine preserves injured human livers for 1 week

Nature Biotechnology volume 38, pages 189–198 (2020)Cite this article

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Matters Arising to this article was published on 26 October 2020

Matters Arising to this article was published on 26 October 2020

Abstract

The ability to preserve metabolically active livers ex vivo for 1 week or more could allow repair of poor-quality livers that would otherwise be declined for transplantation. Current approaches for normothermic perfusion can preserve human livers for only 24 h. Here we report a liver perfusion machine that integrates multiple core physiological functions, including automated management of glucose levels and oxygenation, waste-product removal and hematocrit control. We developed the machine in a stepwise fashion using pig livers. Study of multiple ex vivo parameters and early phase reperfusion in vivo demonstrated the viability of pig livers perfused for 1 week without the need for additional blood products or perfusate exchange. We tested the approach on ten injured human livers that had been declined for transplantation by all European centers. After a 7-d perfusion, six of the human livers showed preserved function as indicated by bile production, synthesis of coagulation factors, maintained cellular energy (ATP) and intact liver structure.

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Fig. 1: Long-term liver perfusion machine specifications.
Fig. 2: Step-by-step integration of the components for long-term perfusion using pig livers.
Fig. 3: Injury markers in perfusate and tissue during ex vivo human liver perfusion (n = 10 livers).
Fig. 4: Liver function during human liver perfusion (n = 10 livers).
Fig. 5: Multistep approach for viability assessment of preinjured human livers during long-term perfusion.

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Data in the manuscript will be made available upon reasonable request to the corresponding author.

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Acknowledgements

We would like thank all the collaborators from the University Hospital Zurich for their expertise and substantial contributions in the development of the long-term perfusion technology: M. Halbe, R. Lenherr, B. Krueger, S. Segerer, N. Mueller, R. A. Schuepbach, S. Klinzing, B. Stieger, J.-D. Studt, K. Koch, M. Huellner, M. A. Schneider, M. Lipiski, M. Sauer, M. Canic, R. Schüpbach and M. Schlaepfer. We also thank F. Immer, B. Burg, D. Goslings, V. Figueiredo, B. Humar, M. Duskabilova, M. Tibbitt, E. Gygax, L. Mancina, A. Fleischli, C. Studer, V. T. Nguyen, S. Huber and A. Gupta. Special thanks go to Swisstransplant, the Swiss Donor Care Association and all of the organ donors and their families for their generous support, which enables research with human organs. The study was funded by a grant from Wyss Zurich, Helmut Horten Foundation, PROMEDICA Foundation and the Liver and Gastrointestinal foundation (LGID). We gratefully acknowledge this financial support. A.W. was supported by the Swiss National Science Foundation (320030_182764/1).

Author information

Author notes

  1. These authors contributed equally: Dilmurodjon Eshmuminov, Dustin Becker.

  2. These authors jointly supervised this work: Philipp Rudolf von Rohr, Pierre-Alain Clavien.

Authors and Affiliations

  1. Department of Surgery and Transplantation, Swiss Hepato-Pancreato-Biliary (HPB) Center, University Hospital Zurich, Zurich, Switzerland

    Dilmurodjon Eshmuminov, Lucia Bautista Borrego, Catherine Hagedorn, Xavier Muller, Matteo Mueller, Rolf Graf, Philipp Dutkowski & Pierre-Alain Clavien

  2. Wyss Zurich, ETH Zurich and University of Zurich, Zurich, Switzerland

    Dilmurodjon Eshmuminov, Dustin Becker, Lucia Bautista Borrego, Max Hefti, Martin J. Schuler, Catherine Hagedorn, Xavier Muller, Matteo Mueller, Christopher Onder, Rolf Graf, Philipp Dutkowski, Philipp Rudolf von Rohr & Pierre-Alain Clavien

  3. Transport Processes and Reactions Laboratory, Department of Mechanical and Process Engineering, ETH Zurich, Zurich, Switzerland

    Dustin Becker, Max Hefti, Martin J. Schuler & Philipp Rudolf von Rohr

  4. Institute for Dynamic Systems and Control, Department of Mechanical and Process Engineering, ETH Zurich, Zurich, Switzerland

    Christopher Onder

  5. Department of Pathology and Molecular Pathology, and Institute of Molecular Cancer Research (IMCR), University Zurich and University Hospital Zurich, Zurich, Switzerland

    Achim Weber

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Contributions

D.E., D.B., L.B.B., M.H., M.J.S., X.M., M.M., P.D., P.R.v.R. and P.-A.C. designed the perfusion machine and established the perfusion protocol, performed the perfusion experiments, generated and interpreted the data and wrote the manuscript. C.H. generated the data. C.O. designed the perfusion machine. R.G. established the perfusion protocol and interpreted the data. A.W. generated data and edited the manuscript.

Corresponding author

Correspondence to Pierre-Alain Clavien.

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Competing interests

ETH (Swiss Federal Institute of Technology in Zurich) and the University of Zurich (D.E., D.B., L.B.B., M.H., M.J.S., X.M., P.D., R. G., P.R.v.R. and P.-A.C.) have applied for a patent on this new perfusion technology (PCT/EP2019/051252).

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Integrated supplementary information

Supplementary Fig. 1 Machine specifications.

a, A representative graphic showing the continuous reduction of the caval pressure until the fluctuation point (pressure <0 mmHg) is reached. After detection of the fluctuation point, the vena cava (VC) target pressure is raised by 1 mmHg. For further details please refer to the Methods. b, Representative illustration of the pO2 control, where the system automatically adapts FiO2 of the gas supply to keep a targeted pO2 in the hepatic artery (HA). c, Representative illustration of the control system adjusting the wash-out rate of CO2 from the perfusate and thereby, controlling the pH. d, Representative illustration of the automated glucagon infusion. The glucagon supply is integrated as a safety feature to prevent severe hypoglycemia. Glucagon is injected, if the desired glucose level is undershot after spontaneous glucose level recovery was not sufficient. e, Illustration of periodic liver movement with pressurized air. f, Illustration of the current mobile laboratory prototype with internal gas and power supply. Liver4Life refers to the name of our research group. g, Detailed schematics of the perfusion loop. The functions of the integrated components were described in the Methods of the manuscript.

Supplementary Fig. 2 Glucose metabolism in pig livers.

The activation of insulin signaling pathway during perfusion for the “hyperglycemic” (n=4 pig livers), “normoglycemic” (n=4 pig livers) and “automated control” (n=4 pig livers) groups. a-b, Insulin induces phosphorylation of Akt and an activation of its signaling pathway. a, P-Akt Western blot analysis and b, quantification. c-d, Glycogen synthase activation depending on insulin application in each study group. P-Akt induces phosphorylation and inactivation of GSK3b, leading to the activation of glycogen synthase. c, P-GSK3b Western blot analysis and d, quantification. e, Glucose level during perfusion for every study group. (hyperglycemic, normoglycemic, automated control). Data reported as mean ± s.d.

Supplementary Fig. 3 Pig liver performance during 7 days ex vivo perfusion (n=8 pig livers).

n=8 pig livers for measurements in perfusate and n=5 pig livers for measurements in tissue. Livers with the intention to transplant (n=3 pig livers) were not biopsied on a daily basis during perfusion to prevent bleeding after transplantation. a, b, Oxygen consumption and pH: Perfused pig livers consumed a substantial amounts of oxygen (a) and maintained mean pH >7.2 (b). c, Lactate clearance: Compared to the perfusion of human livers with a high lactate at start caused by the packed blood products, the pig blood was collected freshly with a minimal storage time. Thus, lactate was less than 2 mmol/l at perfusion start. d, e, f, Synthetic functions: Perfused livers produced blood urea nitrogen (BUN) (d) and maintained albumin within physiologic levels (e). ATP synthesis in tissue shown as a parameter of maintenance of cell energy (f). g, Flow and pressure in the hepatic artery (HA). h, Flow and pressure in the portal vein (PV). i, Continuous bile flow was present in all of the eight pig livers. j, k Total bilirubin level in bile (j) and blood (k). l, m, n, o, Injury markers: The initially increased injury marker AST declined during perfusion (l). 8-Hydroxydesoxyguanosin (8OHdG)(n=5) presented as an injury marker for DNA (m) and Cytochrome C representing an injury marker for mitochondria (n), (n=5). o, One week course of Gamma-glutamyl transferase. Data reported as mean ± s.d.

Supplementary Fig. 4 Pig liver performance during 7 days ex vivo perfusion (n=8 livers).

n=8 pig livers for measurements in perfusate and n=5 pig livers for measurements in tissue. Livers with the intention to transplant (n=3 pig livers) were not biopsied on a daily basis during perfusion to prevent bleeding after transplantation. p, Cholestasis marker alkaline phosphatase (ALP) remained low in the perfusate during 7 days. q, Inflammation marker IL-6 in tissue illustrated as fold change at mRNA level. r, Intercellular adhesion molecule 1 (ICAM-1) as a marker of endothelial cell activation shown as fold change at mRNA level in tissue. s, Representative macroscopic view on day 7 of perfusion with the contact areas presented (1) and shortly after termination of perfusion (2). Dark areas correspond to biopsy spots during perfusion. t, u, v, w, Representative histology slides on day 7: Preserved liver integrity shown on H&E staining (t) with preserved glycogen seen on PAS staining (u) (slides shown in 5x and 20x magnification). v, Endothelial cells were not activated as shown with von Willebrand immunohistochemistry staining (20x magnification). Caspase 3 staining showing the absence of relevant cell apoptosis on day 7. Data reported as mean ± s.d.

Supplementary Fig. 5 Pig liver transplantation after 7 days of ex-vivo perfusion (n=3 pig livers after ex vivo perfusion, n=5 pigs as control after standard cold storage). Representative images and histology were shown only for ex vivo perfused livers.

a, Representative macroscopic view: The portal vein (PV) and hepatic artery (HA) during back-table preparation after ex vivo perfusion (1). Liver after reperfusion (2). b, AST release during the first 3 post-transplant hours (n=3) compared to control transplants without ex vivo perfusion (n=5). c, Representative core needle biopsies at 3 hours of reperfusion showing retained glycogen storages on PAS staining (1) and preserved liver architecture on H&E staining (2). Higher magnification (20x) shows vital hepatocytes but with few apoptotic cells (arrow)). Representative extrahepatic bile duct after reperfusion on H&E staining (5x and 20x magnification) showed a preserved epithelial lining and subepithelial glands on H&E staining (3). Data reported as mean ± s.d.

Supplementary Fig. 6 Performance of human livers during 7 days ex vivo perfusion (n=10 livers).

Human livers 1-6 (blue line, n=6 livers), human livers 7-10 (red line, n=4 livers)). a, b, c, d, Injury marker release into perfusate shown for uric acid (UA) (a), lactate dehydrogenase LDH (b), gamma-glutamyl transferase (GGT) (c) and total bilirubin (d). Increase of GGT and total bilirubin was observed with some delay, similar to the clinical setting. e, Course of Alkaline phosphatase level in perfusate. f, pH maintenance in both groups without significant difference. g, ICAM-1 course shown as fold change at mRNA level in tissue. h, Glycogen amount in tissue measured chemically. i, Blood urea nitrogen (BUN) level in perfusate. j, k, l, Representative histology slides at the end of the experiment. (Slides shown in 5x and 20x magnification): preserved glycogen stores on PAS staining in livers 1-6 (j1). Scattered loss of tissue glycogen in necrotic areas of livers 7-10. (j2). Endothelial cells were not activated as shown with von Willebrand immunohistochemistry staining (livers 1-6 k1, livers 7-10 k2). Caspase 3 staining showing the absence of relevant cell -apoptosis on day 7 (livers 1-6 l1, livers 7-10 l2). Data reported as mean ± s.d. P-value *<0.05, **<0.01, *** <0.001. ns, not significant. For comparison of two groups two-tailed Student’s t-test was used. Exact P values were provided in the Supplementary Table 3 for p values.

Supplementary Fig. 7 Flow and pressure during one week perfusion of human livers (n=10 livers).

Human livers 1-6 (blue line, n=6 livers), human livers 7-10 (red line, n=4 livers). a, b, Pressure and flow in the portal vein (PV). c, d, Pressure and flow in the hepatic artery (HA). Data reported as mean ± s.d. Livers 1-6: solid blue lines for mean value, dotted blue lines for s.d. Livers 7-10: dashed red lines for mean value, dotted red lines for s.d.

Supplementary Fig. 8 Bile duct viability in injured human livers (n=10) and healthy pig livers (n=8) during one week of perfusion.

Human livers 1-6 (red line, n=6 livers), pig livers blue line (n=5 livers). a, Glucose level in bile. b, Bile/perfusate glucose ratio ≤0.7 has been recommended as a reliable viability sign. During perfusion the mean ratio was <0.5. pH of the bile was not reported due to contact of bile with ambient air during collection. c, Lactate content of bile during perfusion. d, Intrahepatic bile ductuli shown with a staining for CK7 without signs of cholestasis in a human liver (10x magnification) in livers 1-6 (n=6 livers). Of note, human livers with cirrhosis or fibrosis showed bile duct metaplasia at perfusion start related to the primary liver disease. e, f Extrahepatic bile ducts from three representative experiments on day 7. The biopsy samples were taken close to the point, where the cannulas had been attached. e 1 and 2, Ki-67 immunohistochemistry staining demonstrated mitotic activity in extrahepatic bile ducts. f 1, 2, 3, Extrahepatic bile ducts disclosed some hemorrhagic changes of the surrounding soft tissue (black arrows) with less than 50% epithelial denudation and preserved submucosal glands on H&E staining. (Slides presented in 5x magnification and 20x magnification). Data reported as mean ± s.d.

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Eshmuminov, D., Becker, D., Bautista Borrego, L. et al. An integrated perfusion machine preserves injured human livers for 1 week. Nat Biotechnol 38, 189–198 (2020). https://doi.org/10.1038/s41587-019-0374-x

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