scholarly journals Split-Liver Ex Situ Machine Perfusion: A Novel Technique for Studying Organ Preservation and Therapeutic Interventions

2020 ◽  
Vol 9 (1) ◽  
pp. 269 ◽  
Author(s):  
Viola Huang ◽  
Negin Karimian ◽  
Danielle Detelich ◽  
Siavash Raigani ◽  
Sharon Geerts ◽  
...  
Keyword(s):  
Liver Perfusion ◽  
Energy Charge ◽  
Therapeutic Interventions ◽  
Ex Situ ◽  
Preclinical Studies ◽  
Machine Perfusion ◽  
Large Numbers ◽  
Split Liver ◽  
Human Livers ◽  
Lactate Levels

Ex situ machine perfusion is a promising technology to help improve organ viability prior to transplantation. However, preclinical studies using discarded human livers to evaluate therapeutic interventions and optimize perfusion conditions are limited by significant graft heterogeneity. In order to improve the efficacy and reproducibility of future studies, a split-liver perfusion model was developed to allow simultaneous perfusion of left and right lobes, allowing one lobe to serve as a control for the other. Eleven discarded livers were surgically split, and both lobes perfused simultaneously on separate perfusion devices for 3 h at subnormothermic temperatures. Lobar perfusion parameters were also compared with whole livers undergoing perfusion. Similar to whole-liver perfusions, each lobe in the split-liver model exhibited a progressive decrease in arterial resistance and lactate levels throughout perfusion, which were not significantly different between right and left lobes. Split liver lobes also demonstrated comparable energy charge ratios. Ex situ split-liver perfusion is a novel experimental model that allows each graft to act as its own control. This model is particularly well suited for preclinical studies by avoiding the need for large numbers of enrolled livers necessary due to the heterogenous nature of discarded human liver research.

scholarly journals Ex situ Normothermic Split Liver Machine Perfusion: Protocol for Robust Comparative Controls in Liver Function Assessment Suitable for Evaluation of Novel Therapeutic Interventions in the Pre-clinical Setting

2021 ◽  
Vol 8 ◽  
Author(s):  
Joseph A. Attard ◽  
Daniel-Clement Osei-Bordom ◽  
Yuri Boteon ◽  
Lorraine Wallace ◽  
Vincenzo Ronca ◽  
...  
Keyword(s):  
Portal Vein ◽  
Hepatic Artery ◽  
Clinical Setting ◽  
Therapeutic Interventions ◽  
Ex Situ ◽  
Machine Perfusion ◽  
Split Liver ◽  
Liver Machine Perfusion ◽  
Novel Therapeutic ◽  
The Ideal

Background:Ex situ donor liver machine perfusion is a promising tool to assess organ viability prior to transplantation and platform to investigate novel therapeutic interventions. However, the wide variability in donor and graft characteristics between individual donor livers limits the comparability of results. We investigated the hypothesis that the development of a split liver ex situ machine perfusion protocol provides the ideal comparative controls in the investigation of machine perfusion techniques and therapeutic interventions, thus leading to more comparable results.Methods: Four discarded human donor livers were surgically split following identification and separation of right and left inflow and outflow vessels. Each lobe, on separate perfusion machines, was subjected to normothermic perfusion using an artificial hemoglobin-based oxygen carrier solution for 6 h. Metabolic parameters as well as hepatic artery and portal vein perfusion parameters monitored.Results: Trends in hepatic artery and portal vein flows showed a general increase in both lobes throughout each perfusion experiment, even when normalized for tissue weight. Progressive decreases in perfusate lactate and glucose levels exhibited comparable trends in between lobes.Conclusion: Our results demonstrate comparability between right and left lobes when simultaneously subjected to normothermic machine perfusion. In the pre-clinical setting, this model provides the ideal comparative controls in the investigation of therapeutic interventions.

scholarly journals Subnormothermic Machine Perfusion of Steatotic Livers Results in Increased Energy Charge at the Cost of Anti-Oxidant Capacity Compared to Normothermic Perfusion

Metabolites ◽  
2019 ◽  
Vol 9 (11) ◽  
pp. 246 ◽  
Author(s):  
Negin Karimian ◽  
Siavash Raigani ◽  
Viola Huang ◽  
Sonal Nagpal ◽  
Ehab O. A. Hafiz ◽  
...  
Keyword(s):  
Energy Charge ◽  
Redox Status ◽  
High Energy ◽  
Ex Situ ◽  
Machine Perfusion ◽  
Normothermic Perfusion ◽  
Normothermic Machine Perfusion ◽  
Anti Oxidant ◽  
Human Livers ◽  
The Cost

There continues to be significant debate regarding the most effective mode of ex situ machine perfusion of livers for transplantation. Subnormothermic (SNMP) and normothermic machine perfusion (NMP) are two methods with different benefits. We examined the metabolomic profiles of discarded steatotic human livers during three hours of subnormothermic or normothermic machine perfusion. Steatotic livers regenerate higher stores of ATP during SNMP than NMP. However, there is a significant depletion of available glutathione during SNMP, likely due to an inability to overcome the high energy threshold needed to synthesize glutathione. This highlights the increased oxidative stress apparent in steatotic livers. Rescue of discarded steatotic livers with machine perfusion may require the optimization of redox status through repletion or supplementation of reducing agents.

scholarly journals Ex Situ Dual Hypothermic Oxygenated Machine Perfusion for Human Split Liver Transplantation

2021 ◽  
Vol 7 (3) ◽  
pp. e666
Author(s):  
Adam M. Thorne ◽  
Veerle Lantinga ◽  
Silke Bodewes ◽  
Ruben H. J. de Kleine ◽  
Maarten W. Nijkamp ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
Ex Situ ◽  
Machine Perfusion ◽  
Split Liver Transplantation ◽  
Split Liver

scholarly journals Machine Perfusion: Cold versus Warm, versus Neither. Update on Clinical Trials

2020 ◽  
Vol 40 (03) ◽  
pp. 264-281 ◽  
Author(s):  
E. Bonaccorsi-Riani ◽  
I.M.A. Brüggenwirth ◽  
J.E. Buchwald ◽  
S. Iesari ◽  
P.N. Martins
Keyword(s):  
Liver Transplantation ◽  
Clinical Trials ◽  
Ex Situ ◽  
Machine Perfusion ◽  
Correct Trial ◽  
Gold Standard Method ◽  
Liver Preservation ◽  
Mature Phase ◽  
Normothermic Machine Perfusion ◽  
Human Livers

AbstractMachine perfusion (MP) preservation is potentially one of the most significant improvements in the field of liver transplantation in the last 20 years, and it has been considered a promising strategy for improved preservation and ex situ evaluation of extended criteria donor (ECD) organs. However, MP preservation adds significant cost and logistical considerations to liver transplantation. MP protocols are mainly classified according to the perfusion temperature with hypothermic machine perfusion (HMP) and normothermic machine perfusion (NMP) being the two categories most studied so far. After extensive preclinical work, MP entered the clinical setting, and there are now several studies that demonstrated feasibility and safety. However, because of the limited quality of clinical trials, there is no compelling evidence of superiority in preservation quality, and liver MP is still considered experimental in most countries. MP preservation is moving to a more mature phase, where ongoing and future studies will bring new evidence in order to confirm their superiority in terms of clinical outcomes, organ utilization, and cost-effectiveness. Here, we present an overview of all preclinical MP studies using discarded human livers and liver MP clinical trials, and discuss their results. We describe the different perfusion protocols, pitfalls in MP study design, and provide future perspectives. Recent trials in liver MP have revealed unique challenges beyond those seen in most clinical studies. Randomized trials, correct trial design, and interpretation of data are essential to generate the data necessary to prove if MP will be the new gold standard method of liver preservation.

scholarly journals Production of Physiologically Relevant Quantities of Hemostatic Proteins During Ex Situ Normothermic Machine Perfusion of Human Livers

2018 ◽  
Vol 24 (9) ◽  
pp. 1298-1302 ◽  
Author(s):  
Shanice A. Karangwa ◽  
Jelle Adelmeijer ◽  
Alix P. M. Matton ◽  
Vincent E. de Meijer ◽  
Ton Lisman ◽  
...  
Keyword(s):  
Ex Situ ◽  
Machine Perfusion ◽  
Normothermic Machine Perfusion ◽  
Human Livers

scholarly journals A novel model for ex situ reperfusion of the human liver following subnormothermic machine perfusion

TECHNOLOGY ◽  
2017 ◽  
Vol 05 (04) ◽  
pp. 196-200 ◽  
Author(s):  
James H. Avruch ◽  
Bote G. Bruinsma ◽  
Pepijn D. Weeder ◽  
Gautham V. Sridharan ◽  
Robert J. Porte ◽  
...  
Keyword(s):  
Human Liver ◽  
Ex Situ ◽  
Machine Perfusion ◽  
Human Donor ◽  
Liver Preservation ◽  
Atp Levels ◽  
Preservation Method ◽  
Human Livers ◽  
Novel Model ◽  
Bile Production

Machine perfusion-based organ preservation techniques are prudently transitioning into clinical practice. Although experimental data is compelling, the outcomes in the highly variable clinical donation-transplantation setting are unpredictable. Here, we offer an intermediate tool for pre-clinical assessment of human donor livers. We present a model for ex situ reperfusion of discarded human livers and report on its application in three human livers that have undergone subnormothermic (21[Formula: see text]C) machine perfusion as an experimental preservation method. During reperfusion, the livers macroscopically reperfused in the first 15 minutes, and remained visually well-perfused for 3 hours of ex situ reperfusion. Bile production and oxygen consumption were observed throughout ex situ reperfusion. ATP levels increased 4.25-fold during SNMP. Between the end of SNMP and the end of reperfusion ATP levels dropped 45%. ALT levels in blood increased rapidly in the first 30 minutes and ALT release continued to taper off towards the end of perfusion. Release of CRP, TNF-[Formula: see text], IL-1[Formula: see text], and IL-12, IFN-[Formula: see text] was sustained during reperfusion. These findings support the use of this model for the evaluation of novel human liver preservation techniques.

scholarly journals Twenty-four hour ex-vivo normothermic machine perfusion in rat livers

TECHNOLOGY ◽  
2020 ◽  
pp. 1-10
Author(s):  
Omar Haque ◽  
Casie A. Pendexter ◽  
Stephanie E.J. Cronin ◽  
Siavash Raigani ◽  
Reiner J. de Vries ◽  
...  
Keyword(s):  
Rat Liver ◽  
Ex Vivo ◽  
Liver Perfusion ◽  
Therapeutic Interventions ◽  
Liver Graft ◽  
Large Animal ◽  
Machine Perfusion ◽  
Normothermic Machine Perfusion ◽  
Organ Quality ◽  
Rat Livers

Ex-vivo liver perfusion (EVLP) is an ideal platform to study liver disease, therapeutic interventions, and pharmacokinetic properties of drugs without any patient risk. Rat livers are an ideal model for EVLP due to less organ quality variability, ease of hepatectomy, well-defined molecular pathways, and relatively low costs compared to large animal or human perfusions. However, the major limitation with rat liver normothermic machine perfusion (NMP) is maintaining physiologic liver function on an ex-vivo machine perfusion system. To address this need, our research demonstrates 24-hour EVLP in rats under normothermic conditions. Early (6 hour) perfusate transaminase levels and oxygen consumption of the liver graft are shown to be good markers of perfusion success and correlate with viable 24-hour post-perfusion histology. Finally, we address overcoming challenges in long-term rat liver perfusions such as rising intrahepatic pressures and contamination, and offer future directions necessary to build upon our work.

scholarly journals Tryptophan Metabolism via the Kynurenine Pathway: Implications for Graft Optimization during Machine Perfusion

2020 ◽  
Vol 9 (6) ◽  
pp. 1864 ◽  
Author(s):  
Anna Zhang ◽  
Cailah Carroll ◽  
Siavash Raigani ◽  
Negin Karimian ◽  
Viola Huang ◽  
...  
Keyword(s):  
Amino Acid ◽  
Ischemia Reperfusion ◽  
Energy Charge ◽  
Kynurenine Pathway ◽  
Tryptophan Metabolism ◽  
Ex Situ ◽  
Glutathione Metabolism ◽  
Organ Shortage ◽  
Machine Perfusion ◽  
Tissue Concentrations

Access to liver transplantation continues to be hindered by the severe organ shortage. Extended-criteria donor livers could be used to expand the donor pool but are prone to ischemia-reperfusion injury (IRI) and post-transplant graft dysfunction. Ex situ machine perfusion may be used as a platform to rehabilitate discarded or extended-criteria livers prior to transplantation, though there is a lack of data guiding the utilization of different perfusion modalities and therapeutics. Since amino acid derivatives involved in inflammatory and antioxidant pathways are critical in IRI, we analyzed differences in amino acid metabolism in seven discarded non-steatotic human livers during normothermic- (NMP) and subnormothermic-machine perfusion (SNMP) using data from untargeted metabolomic profiling. We found notable differences in tryptophan, histamine, and glutathione metabolism. Greater tryptophan metabolism via the kynurenine pathway during NMP was indicated by significantly higher kynurenine and kynurenate tissue concentrations compared to pre-perfusion levels. Livers undergoing SNMP demonstrated impaired glutathione synthesis indicated by depletion of reduced and oxidized glutathione tissue concentrations. Notably, ATP and energy charge ratios were greater in livers during SNMP compared to NMP. Given these findings, several targeted therapeutic interventions are proposed to mitigate IRI during liver machine perfusion and optimize marginal liver grafts during SNMP and NMP.

The New Horizon of Split‐Liver Transplantation: Ex Situ Liver Splitting During Hypothermic Oxygenated Machine Perfusion

2020 ◽  
Vol 26 (10) ◽  
pp. 1363-1367 ◽  
Author(s):  
Marco Spada ◽  
Roberta Angelico ◽  
Chiara Grimaldi ◽  
Paola Francalanci ◽  
Maria Cristina Saffioti ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
Ex Situ ◽  
Machine Perfusion ◽  
Split Liver Transplantation ◽  
Split Liver
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