scholarly journals Ischaemia reperfusion induces the release of donor derived Passenger Leukocytes (PLs) during normothermic machine perfusion (NMP) of the liver- a new opportunity for ex situ graft leukodepletion?

2021 ◽  
Vol 2 (4) ◽  
Author(s):  
Fungai Dengu
Keyword(s):  
Ex Vivo ◽  
Recipient Cell ◽  
Flow Cytometric Analysis ◽  
Ex Situ ◽  
Machine Perfusion ◽  
Ex Vivo Lung Perfusion ◽  
University Of Oxford ◽  
Mechanical Removal ◽  
Normothermic Machine Perfusion ◽  
Passenger Leukocytes

Fungai Dengu1, Tamsyn Clark1,3, Hussain Abbas1, Etohan Ann Ogbemudia1, Faysal El Gilani1,David Nasralla1, Peter Friend1, James Fildes2 1. Oxford Organ Perfusion Lab, Nuffield Department of Surgical Sciences and Oxford Biomedical ResearchCentre, University of Oxford, Oxford, UK2. The Ex-Vivo Lab, Division of Cell Matrix Biology and Regenerative Medicine, School of BiologicalSciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester AcademicHealth Science Centre, Manchester, UK3. Institute of Biomedical Engineering, University of Oxford, Oxford, UK   Background Passenger Leukocytes (PLs) are implicated in both the direct and semi-direct pathways of allorecognition which is the process that underpins acute allograft rejection1. The majority of liver-derived PLs are short lived and predominantly impact early recipient immune responses2. Removal of PLs has been shown in kidney, lung and vascularised composite allografts to reduce early allograft damage and abrogate ejection3. We aimed to assess the use normothermic machine perfusion (NMP) to investigate PL kinetics and explore PL depletion strategies in donor livers. Methods Porcine livers (N=4) procured in a donation after circulatory death (DCD) model were preserved with sequential static cold storage then NMP. During NMP, livers were subjected to repeated 20 min warm ischaemic hits (IH) followed by 30mins of NMP using a leukocyte depleted autologous RBC based perfusate. Leukocytes were quantified using the Sysmex® cell counter system and samples stored for flow cytometric analysis. Results In total, 3.4x106 PLs are effluxed into the circuit immediately after initiation of NMP, this falls rapidly to 1.35x106 by 30 mins. Following the first IH, a further efflux of occurs with a peak of 3.74x106 occurring. The second IH also induced an efflux of cells (1.61x106) with lymphocytes representing the predominant leukocyte sub-type in each efflux. Discussion During NMP, there is an inducible and reproducible efflux of graft derived PLs into the circuit that is composed of predominantly lymphocytes with unexpectedly low numbers of monocytes. Removal of these PLs from the perfusate during NMP may therefore be feasible using an in-line leukocyte-filter.   References 1. Alsughayyir, J., Motallebzadeh, R. & Pettigrew, G. J. Are donor lymphocytes a barrier to transplantation tolerance? Curr. Opin. Organ Transplant. 23, 90–96 (2018).2. Mastoridis, S. et al. Impact of donor extracellular vesicle release on recipient cell “cross-dressing” following clinical liver and kidney transplantation. Am. J. Transplant. ajt.16123 (2020). doi:10.1111/ajt.161233. Stone, J. P. et al. Mechanical removal of dendritic cell–generating non-classical monocytes via ex vivo lung perfusion. J. Hear. Lung Transplant. 33, 864–869 (2014).

scholarly journals Ex Vivo Mesenchymal Stem Cell Therapy to Regenerate Machine Perfused Organs

2021 ◽  
Vol 22 (10) ◽  
pp. 5233
Author(s):  
Christina Bogensperger ◽  
Julia Hofmann ◽  
Franka Messner ◽  
Thomas Resch ◽  
Andras Meszaros ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Ex Situ ◽  
Machine Perfusion ◽  
Donor Pool ◽  
Mesenchymal Stem Cell Therapy ◽  
Perfusion Process ◽  
Normothermic Machine Perfusion ◽  
Clinical Benefits ◽  
Organ Quality ◽  
End Stage

Transplantation represents the treatment of choice for many end-stage diseases but is limited by the shortage of healthy donor organs. Ex situ normothermic machine perfusion (NMP) has the potential to extend the donor pool by facilitating the use of marginal quality organs such as those from donors after cardiac death (DCD) and extended criteria donors (ECD). NMP provides a platform for organ quality assessment but also offers the opportunity to treat and eventually regenerate organs during the perfusion process prior to transplantation. Due to their anti-inflammatory, immunomodulatory and regenerative capacity, mesenchymal stem cells (MSCs) are considered as an interesting tool in this model system. Only a limited number of studies have reported on the use of MSCs during ex situ machine perfusion so far with a focus on feasibility and safety aspects. At this point, no clinical benefits have been conclusively demonstrated, and studies with controlled transplantation set-ups are urgently warranted to elucidate favorable effects of MSCs in order to improve organs during ex situ machine perfusion.

scholarly journals Ex-Vivo Pharmacological Defatting of the Liver: A Review

2021 ◽  
Vol 10 (6) ◽  
pp. 1253
Author(s):  
Claire Goumard ◽  
Célia Turco ◽  
Mehdi Sakka ◽  
Lynda Aoudjehane ◽  
Philippe Lesnik ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Ex Situ ◽  
Special Focus ◽  
Organ Shortage ◽  
Machine Perfusion ◽  
Pharmacological Agents ◽  
Promising Tool ◽  
Normothermic Machine Perfusion ◽  
C Metabolism ◽  
Liver Machine Perfusion

The ongoing organ shortage has forced transplant teams to develop alternate sources of liver grafts. In this setting, ex-situ machine perfusion has rapidly developed as a promising tool to assess viability and improve the function of organs from extended criteria donors, including fatty liver grafts. In particular, normothermic machine perfusion represents a powerful tool to test a liver in full 37 °C metabolism and add pharmacological corrections whenever needed. In this context, many pharmacological agents and therapeutics have been tested to induce liver defatting on normothermic machine perfusion with promising results even on human organs. This systematic review makes a comprehensive synthesis on existing pharmacological therapies for liver defatting, with special focus on normothermic liver machine perfusion as an experimental ex-vivo translational model.

scholarly journals PRESERVAÇÃO DE FÍGADOS HUMANOS COM PERFUSÃO EX-VIVO: UMA VISÃO DO ESTADO DA ARTE

2017 ◽  
Vol 20 (1) ◽  
pp. 20-24
Author(s):  
Samuel Roque Alves ◽  
Lucas Medeiros Lopes ◽  
Ivelise Regina Canito Brasil
Keyword(s):  
Cold Storage ◽  
Ex Vivo ◽  
Ex Situ ◽  
Machine Perfusion ◽  
University Of Wisconsin ◽  
Hypothermic Machine Perfusion ◽  
Normothermic Machine Perfusion

SCS (Static Cold Storage) é a técnica mais utilizada para preservação de órgãos. A HMP (Hypothermic Machine Perfusion) foi inicialmente proposta por Belzer, nos anos 1960. A NMP (Normothermic machine perfusion) evita isquemia fria, mantém a função hepática, monitora a função do enxerto em tempo real pelo fluxo de produção de bile. O presente trabalho visa sumarizar estudos de preservação hepática ex-situ e os resultados com diferentes combinações de parâmetros, dando enfoque aos trabalhos com fígados humanos. Realizamos revisão da literatura, selecionamos 73 artigos, sendo 15 revisões de literatura e 58 estudos experimentais. Destes, oito foram realizados em humanos, 12 em porcos e 39 em ratos. Dos oito estudos com fígados humanos, cinco utilizaram HMP, dois utilizaram SNMP e um utilizou NMP. Todos mostraram melhora da função do enxerto e marcadores bioquímicos de lesão. Quanto às soluções utilizadas, a maioria usou a solução UW (University of Wisconsin), enquanto um trabalho utilizou solução de concentrado de hemácias. O tempo de perfusão variou de 30 minutos a 24 horas. A utilização de órgãos critério-expandidos surge como alternativa para pacientes esperando transplante. As máquinas de perfusão estão cada vez mais presentes no contexto do transplante de órgãos sólidos e serão essenciais para redução das filas de espera, fornecendo maior número de enxertos viáveis para transplante. O desenvolvimento de máquinas viáveis e práticas para perfusão de fígados humanos já está se tornando realidade e representa o futuro do transplante de fígado; espera-se que mais modelos e protocolos sejam testados nos próximos anos e passem a ter utilização clínica rotineira.

Hyperspectral imaging for ex-vivo organ characterization during normothermic machine perfusion

2018 ◽  
Vol 17 (2) ◽  
pp. e767 ◽  
Author(s):  
W. Markgraf ◽  
M.W.W. Janssen ◽  
J. Lilienthal ◽  
P. Feistel ◽  
C. Thiele ◽  
...  
Keyword(s):  
Hyperspectral Imaging ◽  
Ex Vivo ◽  
Machine Perfusion ◽  
Normothermic Machine Perfusion

scholarly journals Biliary Bicarbonate, pH, and Glucose Are Suitable Biomarkers of Biliary Viability During Ex Situ Normothermic Machine Perfusion of Human Donor Livers

2019 ◽  
Vol 103 (7) ◽  
pp. 1405-1413 ◽  
Author(s):  
Alix P.M. Matton ◽  
Yvonne de Vries ◽  
Laura C. Burlage ◽  
Rianne van Rijn ◽  
Masato Fujiyoshi ◽  
...  
Keyword(s):  
Ex Situ ◽  
Machine Perfusion ◽  
Human Donor ◽  
Normothermic Machine Perfusion

Transplantation of High-risk Donor Livers After Ex Situ Resuscitation and Assessment Using Combined Hypo- and Normothermic Machine Perfusion

2019 ◽  
Vol 270 (5) ◽  
pp. 906-914 ◽  
Author(s):  
Otto B. van Leeuwen ◽  
Yvonne de Vries ◽  
Masato Fujiyoshi ◽  
Maarten W. N. Nijsten ◽  
Rinse Ubbink ◽  
...  
Keyword(s):  
High Risk ◽  
Ex Situ ◽  
Machine Perfusion ◽  
Normothermic Machine Perfusion

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 Clinical transplantation using negative pressure ventilation ex situ lung perfusion with extended criteria donor lungs

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Max T. Buchko ◽  
Nasim Boroumand ◽  
Jeffrey C. Cheng ◽  
Alim Hirji ◽  
Kieran Halloran ◽  
...  
Keyword(s):  
Negative Pressure ◽  
Ex Vivo ◽  
Lung Perfusion ◽  
Ex Situ ◽  
Positive Pressure ◽  
Ex Vivo Lung Perfusion ◽  
Extended Criteria Donor ◽  
Negative Pressure Ventilation ◽  
Discharge From Hospital ◽  
End Stage

AbstractLung transplantation remains the best treatment option for end-stage lung disease; however, is limited by a shortage of donor grafts. Ex situ lung perfusion, also known as ex vivo lung perfusion, has been shown to allow for the safe evaluation and reconditioning of extended criteria donor lungs, increasing donor utilization. Negative pressure ventilation ex situ lung perfusion has been shown, preclinically, to result in less ventilator-induced lung injury than positive pressure ventilation. Here we demonstrate that, in a single-arm interventional study (ClinicalTrials.gov number NCT03293043) of 12 extended criteria donor human lungs, negative pressure ventilation ex situ lung perfusion allows for preservation and evaluation of donor lungs with all grafts and patients surviving to 30 days and recovered to discharge from hospital. This trial also demonstrates that ex situ lung perfusion is safe and feasible with no patients demonstrating primary graft dysfunction scores grade 3 at 72 h or requiring post-operative extracorporeal membrane oxygenation.

scholarly journals Ex situ Perfusion of Pancreas for Whole-Organ Transplantation: Is it Safe and Feasible? A Systematic Review

2019 ◽  
Vol 14 (1) ◽  
pp. 120-134 ◽  
Author(s):  
Thomas Prudhomme ◽  
Delphine Kervella ◽  
Stéphanie Le Bas-Bernardet ◽  
Diego Cantarovich ◽  
Georges Karam ◽  
...  
Keyword(s):  
Organ Transplantation ◽  
Pancreas Transplantation ◽  
Ex Vivo ◽  
English Literature ◽  
Ischemia Reperfusion ◽  
Graft Loss ◽  
Ex Situ ◽  
Machine Perfusion ◽  
Pancreas Perfusion ◽  
Ischemic Reperfusion

Introduction: Pancreas transplantation is currently one of the best treatments proposed in highly selected patients with unstable and brittle type 1 diabetes. The objective of pancreas transplantation is to restore normoglycemia and avoid the occurrence of complications associated with diabetes. Graft pancreatitis and thrombosis, arising from ischemia reperfusion injuries, are major causes of graft loss in the postoperative period. Ex situ perfusion, in hypothermic or normothermic settings, allowed to improve ischemic reperfusion injury in other organ transplantations (kidney, liver, or lung). The development of pancreatic graft perfusion techniques would limit these ischemic reperfusion injuries. Objective: Evaluation of the safety and feasibility of ex situ perfusion of pancreas for whole-organ transplantation. Methods: English literature about pancreas perfusion was analyzed using electronic database Medline via PubMed (1950-2018). Exclusion criteria were studies that did not specify the technical aspects of machine perfusion and studies focused only on pancreas perfusion for islet isolation. Results: Hypothermic machine perfusion for pancreas preservation has been evaluated in nine studies and normothermic machine perfusion in ten studies. We evaluated machine perfusion model, types of experimental model, anatomy, perfusion parameters, flushing and perfusion solution, length of perfusion, and comparison between static cold storage and perfusion. Conclusions: This review compared ex vivo machine perfusion of experimental pancreas for whole-organ transplantation. Pancreas perfusion is feasible and could be a helpful tool to evaluate pancreas prior to transplantation. Pancreas perfusion (in hypothermic or normothermic settings) could reduce ischemic reperfusion injuries, and maybe could avoid pancreas thrombosis and reduce morbidity of pancreas transplantation.

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