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 Novel delivery of cellular therapy to reduce ischaemia reperfusion injury in kidney transplantation

2019 ◽  
Author(s):  
Emily R Thompson ◽  
Lucy Bates ◽  
Ibrahim K Ibrahim ◽  
Avinash Sewpaul ◽  
Ben Stenberg ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Reperfusion Injury ◽  
Cellular Therapy ◽  
Ex Vivo ◽  
Left Kidney ◽  
Kidney Injury ◽  
Machine Perfusion ◽  
Ischaemia Reperfusion Injury ◽  
Ischaemia Reperfusion ◽  
Normothermic Machine Perfusion

AbstractEx-vivo normothermic machine perfusion (NMP) of donor kidneys prior to transplantation provides a platform for direct delivery of cellular therapeutics to optimise organ quality prior to transplantation. Multipotent Adult Progenitor Cells (MAPC®) possess potent immunomodulatory properties which could prove beneficial in minimising subsequent ischaemia reperfusion injury. We investigated the potential reconditioning capability of MAPC cells in kidney NMP.MethodsPairs (5) of human kidneys from the same donor were simultaneously perfused for 7 hours. The right or left kidney was randomly allocated to receive MAPC treatment. Serial samples of perfusate, urine and tissue biopsies were taken for comparison with the control paired kidney.ResultsMAPC-treated kidneys demonstrated improved urine output (p<0.01), decreased expression of the kidney injury biomarker NGAL (p<0.01), improved microvascular perfusion on contrast enhanced ultrasound (cortex p<0.05, medulla p<0.01), downregulation of IL-1β (p<0.05) and upregulation of IL-10 (p<0.05) and Indolamine-2, 3-dioxygenase (p<0.05). A mouse model of intraperitoneal chemotaxis demonstrated decreased neutrophil recruitment when stimulated with perfusate from MAPC-treated kidneys (p<0.01). Immunofluorescence revealed pre-labelled MAPC cells home to the perivascular space in the kidneys during NMP. MAPC therapy was not associated with detrimental physiological or embolic events.ConclusionWe report the first successful delivery of cellular therapy to a kidney during NMP. Kidneys treated with MAPC cells demonstrate improvement in clinically relevant functional parameters and injury biomarkers. This novel method of cell therapy delivery provides an exciting opportunity to recondition organs prior to clinical transplantation.One Sentence SummaryEx-vivo reconditioning of human kidneys using Multipotent Adult Progenitor Cell therapy delivered during normothermic machine perfusion.

scholarly journals O25: TARGETING THE RENAL TUBULAR EPITHELIUM WITH ANTI-MIRNA THERAPY: A POTENTIAL MECHANISM FOR MINIMISING ISCHAEMIA REPERFUSION INJURY

2021 ◽  
Vol 108 (Supplement_1) ◽  
Author(s):  
E Irwin ◽  
E Thompson ◽  
S Tingle ◽  
P Ezuma ◽  
L Matthews ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Cell Types ◽  
Specific Response ◽  
Machine Perfusion ◽  
Ischaemia Reperfusion Injury ◽  
Western Blots ◽  
Mrna Targets ◽  
Renal Tubular Epithelium ◽  
Ischaemia Reperfusion ◽  
Normothermic Machine Perfusion

Abstract Introduction Ischaemia reperfusion injury (IRI) is an unavoidable, significant consequence of renal transplantation. MicroRNAs are small, non-coding RNA molecules that regulate multiple downstream mRNA targets. MiRNA-21-5p and miRNA-24-3p have been previously implicated in IRI. Antisense oligonucleotides (ASOs) block specific microRNAs, with previous work by our group demonstrating their delivery to kidneys using normothermic machine perfusion. Imaging these kidneys revealed ASO localisation around proximal tubule epithelial cells (PTECs). This project aimed to characterise ASO blockade against miRNA-21-5p and miRNA-24-3p in PTECs. Method HKC8 cells, a human PTEC cell line, were used throughout these experiments. Cells were placed in a hypoxic incubator for 24hrs, followed by 6hrs of reoxygenation to mimic IRI. HKC8s were transfected with ASOs using lipofectamine. RT-qPCR and Western Blots were used to evaluate expression of antioxidant targets, SOD2 and HMOX1. Result MiRNA-21-5p and miRNA-24-3p levels were high throughout hypoxia and reoxygenation. Single blockade with anti-miRNA-21-5p resulted in a significant increase in its downstream target SOD2 (P&lt;0.05). Anti-miRNA-24-3p treatment resulted in no change in either of its downstream targets, HMOX1 or SOD2. This was reflected in the failure of dual blockade to produce a synergistic effect on the shared target, SOD2. Conclusion Anti-miRNA-21-5p results in a significant increase of SOD2, which is well characterised as protective during IRI. Anti-miRNA-24-3p appears to have no effect on PTECs, contrary to previous work in endothelial cells, perhaps suggesting a cell specific response of microRNAs. Normothermic machine perfusion could be used to deliver dual ASOs; allowing simultaneous targeting of different kidney cell types. Take-home message The delivery of anti-miRNA-21-5p therapy pre-transplant, using normothermic machine perfusion, has the potential to reduce ischaemia reperfusion injury and improve kidney transplant outcomes.

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 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.

Rewarming Machine Perfusion System for Liver Transplantation

2013 ◽  
Vol 7 (4) ◽  
Author(s):  
Hiromichi Obara ◽  
Naoto Matsuno ◽  
Takanobu Shigeta ◽  
Shin Enosawa ◽  
Toshihiko Hirano ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
Organ Donor ◽  
Liver Graft ◽  
Donation After Cardiac Death ◽  
Organ Shortage ◽  
Machine Perfusion ◽  
Porcine Liver ◽  
Donor Pool ◽  
Liver Preservation ◽  
End Stage

The liver is one of the most essential organs, and transplantation is an established treatment for patients with end-stage disease who have lost their liver function. However, organ shortage is a critical problem in transplantation; thus, the development of an innovative preservation system to adopt critical grafts obtained from extended criteria donors or donation after cardiac death donors as viable organs for transplantation is necessary. We recently developed a novel rewarming machine perfusion preservation system for liver transplantation, and herein discuss this system, which allows the perfusion temperature to be controlled during the transition from hypothermic to subnormothermic conditions. This system has two functions: (1) the preservation and recovery of organ function and (2) screening the organ for viability. To achieve these functions, this system has three features: (1) temperature control of the preservation perfusate and liver graft, (2) dual-controlled perfusion of the portal vein and hepatic artery, and (3) real-time monitoring of the perfusion conditions, including the flow rate, perfusion pressure and temperature. This system was useful for liver preservation and for evaluating the graft viability and recovery of functions during machine perfusion before transplantation. This novel rewarming machine preservation system was tested in an experimental model using porcine liver grafts. We report that this system has certain advantages in liver preservation, and believe that this system will positively contribute to the expansion of the organ donor pool.

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 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.

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