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 Normothermic Machine Perfusion (NMP) of the Liver as a Platform for Therapeutic Interventions during Ex-Vivo Liver Preservation: A Review

2020 ◽  
Vol 9 (4) ◽  
pp. 1046 ◽  
Author(s):  
Fungai Dengu ◽  
Syed Hussain Abbas ◽  
Georg Ebeling ◽  
David Nasralla
Keyword(s):  
Ex Vivo ◽  
Organ Donor ◽  
Therapeutic Interventions ◽  
Machine Perfusion ◽  
Real Potential ◽  
Ischaemia Reperfusion Injury ◽  
Donor Pool ◽  
Liver Preservation ◽  
Ischaemia Reperfusion ◽  
Normothermic Machine Perfusion

Liver transplantation is increasingly dependent on the use of extended criteria donors (ECD) to increase the organ donor pool and address rising demand. This has necessitated the adoption of innovative technologies and strategies to protect these higher-risk grafts from the deleterious effects of traditional preservation and ischaemia reperfusion injury (IRI). The advent of normothermic machine perfusion (NMP) and rapid growth in the clinical adoption of this technology has accelerated efforts to utilise NMP as a platform for therapeutic intervention to optimise donor livers. In this review we will explore the emerging preclinical data related to ameliorating the effects of IRI, protecting the microcirculation and reducing the immunogenicity of donor organs during NMP. Exploiting the window of opportunity afforded by NMP, whereby the liver can be continuously supported and functionally assessed while therapies are directly delivered during the preservation period, has clear logistical and theoretical advantages over current preservation methods. The clinical translation of many of the therapeutic agents and strategies we will describe is becoming more feasible with widespread adaptation of NMP devices and rapid advances in molecular biology and gene therapy, which have substantially improved the performance of these agents. The delivery of novel therapeutics during NMP represents one of the new frontiers in transplantation research and offers real potential for successfully tackling fundamental challenges in transplantation such as IRI.

scholarly journals Machine Perfusion in Liver Transplantation: A Systematic Review and Meta-Analysis

2021 ◽  
pp. 1-12
Author(s):  
Matas Jakubauskas ◽  
Lina Jakubauskiene ◽  
Bettina Leber ◽  
Kestutis Strupas ◽  
Philipp Stiegler ◽  
...  
Keyword(s):  
Systematic Review ◽  
Liver Transplantation ◽  
Meta Analysis ◽  
Biliary Complication ◽  
Liver Graft ◽  
Machine Perfusion ◽  
Biliary Strictures ◽  
Normothermic Machine Perfusion ◽  
Organ Quality ◽  
End Stage

<b><i>Background:</i></b> Liver transplantation (LTx) is the only treatment option for patients with end-stage liver disease. Novel organ preservation techniques such as hypothermic machine perfusion (HMP) or normothermic machine perfusion (NMP) are under investigation in order to improve organ quality from extended criteria donors and donors after circulatory death. The aim of this study was to systematically review the literature reporting LTx outcomes using NMP or HMP compared to static cold storage (SCS). <b><i>Methods:</i></b> The following data were retrieved: graft primary nonfunction rate, early allograft dysfunction (EAD) rate, biliary complication rate, and 12-month graft and patient survival. A total of 15 studies were included (6 NMP and 9 HMP studies), and meta-analysis was performed only for HMP studies because NMP had considerable differences. <b><i>Results:</i></b> The systematic review showed the potential of NMP to reduce graft injury and lower the liver graft discard rate. The performed quantitative analyses showed that the use of HMP reduces the rate of EAD (odds ratio [OR] 0.51; 95% confidence interval [CI] 0.34–0.76; <i>p</i> = 0.001; <i>I</i><sup>2</sup> = 0%) and non-anastomotic biliary strictures (OR 0.34; 95% CI 0.17–0.67; <i>p</i> = 0.002; <i>I</i><sup>2</sup> = 0%) compared to SCS. <b><i>Conclusion:</i></b> Our systematic review and meta-analysis revealed that the use of HMP reduces the rate of EAD and non-anastomotic biliary strictures compared to SCS.

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.

Ex vivo normothermic perfusion in heart transplantation: a review of the TransMedics® Organ Care System

2021 ◽  
Author(s):  
Rebecca Pinnelas ◽  
Jon A Kobashigawa
Keyword(s):  
Viral Vector ◽  
Ex Vivo ◽  
Donation After Cardiac Death ◽  
Machine Perfusion ◽  
Donor Pool ◽  
Complex Anatomy ◽  
Normothermic Perfusion ◽  
End Stage Heart Failure ◽  
End Stage ◽  
Care System

Cardiac transplantation is the gold standard for treatment for select patients with end-stage heart failure, yet donor supply is limited. Ex vivo machine perfusion is an emerging technology capable of safely preserving organs and expanding the viable donor pool. The TransMedics® Organ Care System™ is an investigational device which mimics physiologic conditions while maintaining the heart in a warm, beating state rather than cold storage. The use of Organ Care System allows increased opportunities for using organs from marginal donors, distant procurement sites, donation after cardiac death, and in recipients with complex anatomy. In the future, bioengineering technologies including use of mesenchymal stem cells, viral vector delivery of gene therapy, and alternate devices may further broaden the field of ex vivo 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 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 machine perfusion: current applications and future directions in liver transplantation

2020 ◽  
Author(s):  
Julian Michelotto ◽  
Joseph M. G. V. Gassner ◽  
Simon Moosburner ◽  
Vanessa Muth ◽  
Madhukar S. Patel ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
Ex Vivo ◽  
Machine Perfusion ◽  
Donor Organ ◽  
Donor Pool ◽  
Future Directions ◽  
Link Type ◽  
Expanded Criteria ◽  
End Stage ◽  
Liver Machine Perfusion

Abstract Background Liver transplantation is the only curative treatment option for end-stage liver disease; however, its use remains limited due to a shortage of suitable organs. In recent years, ex vivo liver machine perfusion has been introduced to liver transplantation, as a means to expand the donor organ pool. Purpose To present a systematic review of prospective clinical studies on ex vivo liver machine perfusion, in order to assess current applications and highlight future directions. Methods A systematic literature search of both PubMed and ISI web of science databases as well as the ClinicalTrials.gov registry was performed. Results Twenty-one articles on prospective clinical trials on ex vivo liver machine perfusion were identified. Out of these, eight reported on hypothermic, eleven on normothermic, and two on sequential perfusion. These trials have demonstrated the safety and feasibility of ex vivo liver machine perfusion in both standard and expanded criteria donors. Currently, there are twelve studies enrolled in the clinicaltrials.gov registry, and these focus on use of ex vivo perfusion in extended criteria donors and declined organs. Conclusion Ex vivo liver machine perfusion seems to be a suitable strategy to expand the donor pool for liver transplantation and holds promise as a platform for reconditioning diseased organs.

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.

scholarly journals Zebrafish as a New Tool in Heart Preservation Research

2021 ◽  
Vol 8 (4) ◽  
pp. 39
Author(s):  
Luciana Da Silveira Cavalcante ◽  
Shannon N. Tessier
Keyword(s):  
New Technologies ◽  
Ex Vivo ◽  
Machine Perfusion ◽  
Life Saving ◽  
First Choice ◽  
Heart Preservation ◽  
End Stage Heart Failure ◽  
Ischemia Tolerance ◽  
The 1960S ◽  
End Stage

Heart transplantation became a reality at the end of the 1960s as a life-saving option for patients with end-stage heart failure. Static cold storage (SCS) at 4–6 °C has remained the standard for heart preservation for decades. However, SCS only allows for short-term storage that precludes optimal matching programs, requires emergency surgeries, and results in the unnecessary discard of organs. Among the alternatives seeking to extend ex vivo lifespan and mitigate the shortage of organs are sub-zero or machine perfusion modalities. Sub-zero approaches aim to prolong cold ischemia tolerance by deepening metabolic stasis, while machine perfusion aims to support metabolism through the continuous delivery of oxygen and nutrients. Each of these approaches hold promise; however, complex barriers must be overcome before their potential can be fully realized. We suggest that one barrier facing all experimental efforts to extend ex vivo lifespan are limited research tools. Mammalian models are usually the first choice due to translational aspects, yet experimentation can be restricted by expertise, time, and resources. Instead, there are instances when smaller vertebrate models, like the zebrafish, could fill critical experimental gaps in the field. Taken together, this review provides a summary of the current gold standard for heart preservation as well as new technologies in ex vivo lifespan extension. Furthermore, we describe how existing tools in zebrafish research, including isolated organ, cell specific and functional assays, as well as molecular tools, could complement and elevate heart preservation research.

scholarly journals Generation of vascular chimerism within donor organs

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shahar Cohen ◽  
Shirly Partouche ◽  
Michael Gurevich ◽  
Vladimir Tennak ◽  
Vadym Mezhybovsky ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Patient Specific ◽  
Machine Perfusion ◽  
Organ Perfusion ◽  
Perfusion Process ◽  
Hind Limbs ◽  
Porcine Organs ◽  
Immunological Barrier

AbstractWhole organ perfusion decellularization has been proposed as a promising method to generate non-immunogenic organs from allogeneic and xenogeneic donors. However, the ability to recellularize organ scaffolds with multiple patient-specific cells in a spatially controlled manner remains challenging. Here, we propose that replacing donor endothelial cells alone, while keeping the rest of the organ viable and functional, is more technically feasible, and may offer a significant shortcut in the efforts to engineer transplantable organs. Vascular decellularization was achieved ex vivo, under controlled machine perfusion conditions, in various rat and porcine organs, including the kidneys, liver, lungs, heart, aorta, hind limbs, and pancreas. In addition, vascular decellularization of selected organs was performed in situ, within the donor body, achieving better control over the perfusion process. Human placenta-derived endothelial progenitor cells (EPCs) were used as immunologically-acceptable human cells to repopulate the luminal surface of de-endothelialized aorta (in vitro), kidneys, lungs and hind limbs (ex vivo). This study provides evidence that artificially generating vascular chimerism is feasible and could potentially pave the way for crossing the immunological barrier to xenotransplantation, as well as reducing the immunological burden of allogeneic grafts.

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