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.

scholarly journals Ischemia-Reperfusion Injuries Assessment during Pancreas Preservation

2021 ◽  
Vol 22 (10) ◽  
pp. 5172
Author(s):  
Thomas Prudhomme ◽  
John F. Mulvey ◽  
Liam A. J. Young ◽  
Benoit Mesnard ◽  
Maria Letizia Lo Faro ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Graft Function ◽  
Impedance Analysis ◽  
Experimental Models ◽  
Caspase Activation ◽  
Pancreas Perfusion ◽  
Number Of Factors ◽  
Pancreas Preservation ◽  
Metabolite Concentrations

Maintaining organ viability between donation and transplantation is of critical importance for optimal graft function and survival. To date in pancreas transplantation, static cold storage (SCS) is the most widely practiced method of organ preservation. The first experiments in ex vivo perfusion of the pancreas were performed at the beginning of the 20th century. These perfusions led to organ oedema, hemorrhage, and venous congestion after revascularization. Despite these early hurdles, a number of factors now favor the use of perfusion during preservation: the encouraging results of HMP in kidney transplantation, the development of new perfusion solutions, and the development of organ perfusion machines for the lung, heart, kidneys and liver. This has led to a resurgence of research in machine perfusion for whole organ pancreas preservation. This review highlights the ischemia-reperfusion injuries assessment during ex vivo pancreas perfusion, both for assessment in pre-clinical experimental models as well for future use in the clinic. We evaluated perfusion dynamics, oedema assessment, especially by impedance analysis and MRI, whole organ oxygen consumption, tissue oxygen tension, metabolite concentrations in tissue and perfusate, mitochondrial respiration, cell death, especially by histology, total cell free DNA, caspase activation, and exocrine and endocrine assessment.

scholarly journals Review: Ischemia Reperfusion Injury—A Translational Perspective in Organ Transplantation

2020 ◽  
Vol 21 (22) ◽  
pp. 8549
Author(s):  
André Renaldo Fernández ◽  
Rodrigo Sánchez-Tarjuelo ◽  
Paolo Cravedi ◽  
Jordi Ochando ◽  
Marcos López-Hoyos
Keyword(s):  
Reperfusion Injury ◽  
Organ Transplantation ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Graft Loss ◽  
Surgical Techniques ◽  
Immunosuppressive Drugs ◽  
Donation Process ◽  
End Stage ◽  
Significant Injury

Thanks to the development of new, more potent and selective immunosuppressive drugs together with advances in surgical techniques, organ transplantation has emerged from an experimental surgery over fifty years ago to being the treatment of choice for many end-stage organ diseases, with over 139,000 organ transplants performed worldwide in 2019. Inherent to the transplantation procedure is the fact that the donor organ is subjected to blood flow cessation and ischemia during harvesting, which is followed by preservation and reperfusion of the organ once transplanted into the recipient. Consequently, ischemia/reperfusion induces a significant injury to the graft with activation of the immune response in the recipient and deleterious effect on the graft. The purpose of this review is to discuss and shed new light on the pathways involved in ischemia/reperfusion injury (IRI) that act at different stages during the donation process, surgery, and immediate post-transplant period. Here, we present strategies that combine various treatments targeted at different mechanistic pathways during several time points to prevent graft loss secondary to the inflammation caused by IRI.

scholarly journals Restoring Mitochondrial Function While Avoiding Redox Stress: The Key to Preventing Ischemia/Reperfusion Injury in Machine Perfused Liver Grafts?

2020 ◽  
Vol 21 (9) ◽  
pp. 3132 ◽  
Author(s):  
Julia Hofmann ◽  
Giorgi Otarashvili ◽  
Andras Meszaros ◽  
Susanne Ebner ◽  
Annemarie Weissenbacher ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Graft Function ◽  
Ros Production ◽  
Machine Perfusion ◽  
Redox Stress ◽  
Molecular Events ◽  
Regulate Cell Death

Mitochondria sense changes resulting from the ischemia and subsequent reperfusion of an organ and mitochondrial reactive oxygen species (ROS) production initiates a series of events, which over time result in the development of full-fledged ischemia-reperfusion injury (IRI), severely affecting graft function and survival after transplantation. ROS activate the innate immune system, regulate cell death, impair mitochondrial and cellular performance and hence organ function. Arresting the development of IRI before the onset of ROS production is currently not feasible and clinicians are faced with limiting the consequences. Ex vivo machine perfusion has opened the possibility to ameliorate or antagonize the development of IRI and may be particularly beneficial for extended criteria donor organs. The molecular events occurring during machine perfusion remain incompletely understood. Accumulation of succinate and depletion of adenosine triphosphate (ATP) have been considered key mechanisms in the initiation; however, a plethora of molecular events contribute to the final tissue damage. Here we discuss how understanding mitochondrial dysfunction linked to IRI may help to develop novel strategies for the prevention of ROS-initiated damage in the evolving era of machine perfusion.

scholarly journals Ischemia-Reperfusion Injury in Marginal Liver Grafts and the Role of Hypothermic Machine Perfusion: Molecular Mechanisms and Clinical Implications

2020 ◽  
Vol 9 (3) ◽  
pp. 846 ◽  
Author(s):  
Zoltan Czigany ◽  
Isabella Lurje ◽  
Moritz Schmelzle ◽  
Wenzel Schöning ◽  
Robert Öllinger ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion Injury ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Graft Function ◽  
Organ Shortage ◽  
Machine Perfusion ◽  
Hypothermic Machine Perfusion ◽  
Critical Organ

Ischemia-reperfusion injury (IRI) constitutes a significant source of morbidity and mortality after orthotopic liver transplantation (OLT). The allograft is metabolically impaired during warm and cold ischemia and is further damaged by a paradox reperfusion injury after revascularization and reoxygenation. Short-term and long-term complications including post-reperfusion syndrome, delayed graft function, and immune activation have been associated with IRI. Due to the current critical organ shortage, extended criteria grafts are increasingly considered for transplantation, however, with an elevated risk to develop significant features of IRI. In recent years, ex vivo machine perfusion (MP) of the donor liver has witnessed significant advancements. Here, we describe the concept of hypothermic (oxygenated) machine perfusion (HMP/HOPE) approaches and highlight which allografts may benefit from this technology. This review also summarizes clinical applications and the main aspects of ongoing randomized controlled trials on hypothermic perfusion. The mechanistic aspects of IRI and hypothermic MP—which include tissue energy replenishment, optimization of mitochondrial function, and the reduction of oxidative and inflammatory damage following reperfusion—will be comprehensively discussed within the context of current preclinical and clinical evidence. Finally, we highlight novel trends and future perspectives in the field of hypothermic MP in the context of recent findings of basic and translational research.

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 Application of Mesenchymal Stem Cells During Machine Perfusion: An Emerging Novel Strategy for Organ Preservation

2021 ◽  
Vol 12 ◽  
Author(s):  
Jiale Li ◽  
Qinbao Peng ◽  
Ronghua Yang ◽  
Kunsheng Li ◽  
Peng Zhu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Organ Transplantation ◽  
Organ Preservation ◽  
Ischemia Reperfusion ◽  
Solid Organ Transplantation ◽  
Therapeutic Effects ◽  
Solid Organ ◽  
Machine Perfusion ◽  
Marginal Grafts

Although solid organ transplantation remains the definitive management for patients with end-stage organ failure, this ultimate treatment has been limited by the number of acceptable donor organs. Therefore, efforts have been made to expand the donor pool by utilizing marginal organs from donation after circulatory death or extended criteria donors. However, marginal organs are susceptible to ischemia-reperfusion injury (IRI) and entail higher requirements for organ preservation. Recently, machine perfusion has emerged as a novel preservation strategy for marginal grafts. This technique continually perfuses the organs to mimic the physiologic condition, allows the evaluation of pretransplant graft function, and more excitingly facilitates organ reconditioning during perfusion with pharmacological, gene, and stem cell therapy. As mesenchymal stem cells (MSCs) have anti-oxidative, immunomodulatory, and regenerative properties, mounting studies have demonstrated the therapeutic effects of MSCs on organ IRI and solid organ transplantation. Therefore, MSCs are promising candidates for organ reconditioning during machine perfusion. This review provides an overview of the application of MSCs combined with machine perfusion for lung, kidney, liver, and heart preservation and reconditioning. Promising preclinical results highlight the potential clinical translation of this innovative strategy to improve the quality of marginal grafts.

scholarly journals O3 Ex vivo normothermic machine perfusion facilitates gymnotic delivery of RNA interference therapeutics in donor kidneys

2021 ◽  
Vol 108 (Supplement_5) ◽  
Author(s):  
E R Thompson ◽  
A Sewpaul ◽  
R Figuereido ◽  
L Bates ◽  
J R Ferdinand ◽  
...  
Keyword(s):  
Rna Interference ◽  
Ischemia Reperfusion Injury ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Machine Perfusion ◽  
Endosomal Sorting ◽  
Early Endosomes ◽  
Normothermic Machine Perfusion ◽  
Rnai Therapeutics ◽  
The Many

Abstract Introduction Normothermic machine perfusion (NMP) of donor kidneys prior to transplantation provides a platform for delivery of novel therapeutics to optimize organ quality. This includes RNA interference (RNAi) therapeutics e.g. antisense oligonucleotides (ASO) that block detrimental microRNAs. The intracellular kinetics of RNAi therapeutics are crucial for their pharmacological effect, however, it remains poorly understood. NMP provides an ideal platform to investigate this further. Method During NMP, human kidneys (n = 12) were treated for 6 hours with a fluorescently-labelled ASO designed to block microRNA-24-3p activity. Biopsies were taken at 0, 2, 4, and 6 hours. Kidney sections were stained with antibodies against early endosomes (Rab5), late endosomes (Rab7), RNA-induced silencing complexes (GW182) and lysosomes (LAMP2). Confocal microscopy images were obtained and co-localisation quantified using Hugyens™ software following batch deconvolution. The global transcriptomic impact of ASO therapy was also assessed using RNA sequencing. Result Following 2 hours of NMP, ASO was primarily found in tubular epithelial cells. Co-localisation studies revealed ASO uptake via endocytosis and endosomal sorting occurring during NMP. This was followed by cytoplasmic escape and co-localisation of ASO with GW182 proteins. This pattern of co-localisation was not seen in scrambled sequence or cold perfusion controls. RNAseq analysis revealed a decrease in inflammatory pathways and upregulation of microRNA-24-3p targets. Discussion This is the first study to demonstrate NMP facilitates gymnotic ASO delivery directly into the RISC, whereby, it blocks microRNA-mediated mRNA silencing and increases bioavailability of protective targets. This study highlights the capacity of NMP to re-programme gene expression in donor kidneys using RNAi therapeutics. Take-home Message Ex vivo normothermic machine perfusion of donor kidneys provides a unique window of opportunity prior to transplantation when we can deliver therapies to improve the quality of the organ. Novel genetic therapies designed to protect kidneys against ischemia reperfusion injury could potentially increase organ utilisation and improve post-transplant outcomes for the many patients on the kidney transplant waiting list.

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.

scholarly journals Nanoparticle targeting to the endothelium during normothermic machine perfusion of human kidneys

2017 ◽  
Vol 9 (418) ◽  
pp. eaam6764 ◽  
Author(s):  
Gregory T. Tietjen ◽  
Sarah A. Hosgood ◽  
Jenna DiRito ◽  
Jiajia Cui ◽  
Deeksha Deep ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Therapeutic Potential ◽  
Vascular Endothelial Cells ◽  
Ex Vivo ◽  
Polymeric Nanoparticles ◽  
Ischemia Reperfusion ◽  
Machine Perfusion ◽  
Renal Vasculature ◽  
Normothermic Machine Perfusion

Ex vivo normothermic machine perfusion (NMP) is a new clinical strategy to assess and resuscitate organs likely to be declined for transplantation, thereby increasing the number of viable organs available. Short periods of NMP provide a window of opportunity to deliver therapeutics directly to the organ and, in particular, to the vascular endothelial cells (ECs) that constitute the first point of contact with the recipient’s immune system. ECs are the primary targets of both ischemia-reperfusion injury and damage from preformed antidonor antibodies, and reduction of perioperative EC injury could have long-term benefits by reducing the intensity of the host’s alloimmune response. Using NMP to administer therapeutics directly to the graft avoids many of the limitations associated with systemic drug delivery. We have previously shown that polymeric nanoparticles (NPs) can serve as depots for long-term drug release, but ensuring robust NP accumulation within a target cell type (graft ECs in this case) remains a fundamental challenge of nanomedicine. We show that surface conjugation of an anti-CD31 antibody enhances targeting of NPs to graft ECs of human kidneys undergoing NMP. Using a two-color quantitative microscopy approach, we demonstrate that targeting can enhance EC accumulation by about 5- to 10-fold or higher in discrete regions of the renal vasculature. In addition, our studies reveal that NPs can also nonspecifically accumulate within obstructed regions of the vasculature that are poorly perfused. These quantitative preclinical human studies demonstrate the therapeutic potential for targeted nanomedicines delivered during ex vivo NMP.

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.

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