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Transplantation Reviews (Orlando, Fla.) Jul 2020Ex vivo machine perfusion (EVMP) is reported to can successfully be applied for donor heart preservation. To respond to the organ shortage, some centres also accept... (Review)
Review
BACKGROUND
Ex vivo machine perfusion (EVMP) is reported to can successfully be applied for donor heart preservation. To respond to the organ shortage, some centres also accept hearts from marginal donors such as non-heart beating donors (NHBD) or hearts donated after cardiac death (DCD) for heart transplantation (HTx). Clinical as well as preclinical science on EVMP of DCD hearts seems to be promising but the ideal perfusion practice itself appears unclear.
OBJECTIVES
In accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA), this systematic review scopes all EVMP techniques for human and animal DCD heart preservation and addresses three specific questions, which refer to (a) the perfusion solutions, (b) the perfusion parameters and respective target values and (c) if possible, a direct comparison between cold static storage (CSS) and EVMP.
RESULTS
Search results predominantly consisted of animal studies. Either perfusion with a crystalloid or blood-based solution, each with cardioplegic or non-cardioplegic properties was used. Some perfusates were supplemented with specific pharmacological medication to block pathophysiological pathways, which are involved in ischemia/reperfusion injury or edema formation. Besides normothermic EVMP with oxygenated blood, a wide range of temperature was applied in all approaches, with the lowest temperature at 4 °C. Pressure controlled anterograde Langendorff perfusion was applied mostly. If investigated, crystalloid machine perfusion was presented superior to CSS.
CONCLUSIONS
Only blood based EVMP was introduced into clinical practice. More research, clinical as well as preclinical, is needed to develop the ideal EVMP technique, in terms of blood or crystalloid perfusion.
Topics: Animals; Blood Circulation; Death; Heart; Heart Transplantation; Humans; Organ Preservation; Perfusion; Tissue Donors; Tissue and Organ Procurement
PubMed: 32498975
DOI: 10.1016/j.trre.2020.100551 -
Journal of Vascular and Interventional... Jan 2023This study hypothesized that an ex vivo renal perfusion model can create smaller microwave ablation (MWA) measurements during perfused states compared with nonperfused...
This study hypothesized that an ex vivo renal perfusion model can create smaller microwave ablation (MWA) measurements during perfused states compared with nonperfused states across multiple device settings. Nine bovine kidneys, a fluoroscopic compatible perfusion model, and a commercially-available clinical MWA system were used to perform 72 ablations (36 perfused and 36 nonperfused) at 9 different device settings. Comparing perfused and nonperfused ablations at each device setting, significant differences in volume existed for 6 of 9 settings (P < .05). Collapsed across time settings, the ablation volumes by power were the following (perfused and nonperfused, P value): 60 W, 2.3 cm ± 1.0 and 7.2 cm ± 2.7, P < .001; 100 W, 5.4 cm ± 2.1 and 11.5 cm ± 5.6, P < .01; and 140 W, 11.2 cm ± 3.7 and 18.7 cm ± 6.3, P < .01. Applied power correlated with ablation volume: perfused, 0.021 cm/W and R = 0.462, P = .004, and nonperfused, 0.029 cm/W and R = 0.565, P < .001. These results support that an ex vivo perfused organ system can evaluate MWA systems and demonstrate heat sink perfusion effects of decreased ablation size.
Topics: Humans; Animals; Cattle; Liver; Microwaves; Radiofrequency Ablation; Perfusion; Catheter Ablation; Kidney; Ablation Techniques
PubMed: 36244634
DOI: 10.1016/j.jvir.2022.10.013 -
Transplantation Mar 2024Dynamic preservation methods such as normothermic, subnormothermic, and hypothermic machine perfusion circuits have emerged as viable alternatives to conventional static... (Review)
Review
Dynamic preservation methods such as normothermic, subnormothermic, and hypothermic machine perfusion circuits have emerged as viable alternatives to conventional static cold storage. These organ perfusion technologies serve as preservation methods and enable organ assessment, reconditioning, and repair before transplantation. Gene therapy is a novel strategy with the potential to transform the field of graft optimization and treatment. Thereby specific pathways involved in the transplantation process can be targeted and modified. This review aims to provide an overview of gene delivery methods during ex vivo machine perfusion of kidney and liver grafts. Recent literature on state-of-the-art gene therapy approaches during ex situ organ preservation, especially with respect to ischemia-reperfusion injury, as well as acute and chronic graft rejection have been analyzed. Additionally, potential challenges that could affect further refinement of this therapeutic modality are outlined.
Topics: Perfusion; Kidney; Organ Preservation; Kidney Transplantation; Extracorporeal Circulation
PubMed: 37482634
DOI: 10.1097/TP.0000000000004738 -
Liver Transplantation : Official... Dec 2017The efficacy of cold in situ perfusion and static storage of the liver is a possible determinant of transplantation outcomes. The aim of this study was to determine... (Meta-Analysis)
Meta-Analysis Review
The efficacy of cold in situ perfusion and static storage of the liver is a possible determinant of transplantation outcomes. The aim of this study was to determine whether there is evidence to substantiate a preference for a particular perfusion route (aortic or dual) or perfusion/preservation solution in donation after brain death (DBD) liver transplantation. The Embase, MEDLINE, and Cochrane databases were used (1980-2017). Random effects modeling was used to estimate effects on transplantation outcomes based on (1) aortic or dual in situ perfusion and (2) the use of University of Wisconsin (UW), histidine tryptophan ketoglutarate (HTK), Celsior, and/or Institut Georges Lopez-1 (IGL-1) solutions for perfusion/preservation. A total of 22 articles were included (2294 liver transplants). The quality of evidence ranged from very low to moderate Grading of Recommendations, Assessment, Development and Evaluations score. Meta-analyses were conducted for 14 eligible studies. Although there was no difference in the primary nonfunction (PNF) rate, a higher peak alanine aminotransferase (ALT) was recorded in dual compared with aortic-only UW-perfused livers (standardized mean difference, 0.24; 95% confidence interval, 0.01-0.47); a back-table portal venous flush was undertaken in the majority of aortic-only perfused livers. There were no relevant differences in peak enzymes, PNF, thrombotic graft loss, biliary complications, or 1-year graft survival in comparisons between dual-perfused livers using UW, HTK, Celsior, or IGL-1. In conclusion, there is no significant evidence that aortic-only perfusion of the DBD liver compromises transplantation outcomes, and it may be favored because of its simplicity. However, there is currently insufficient evidence to advocate for the use of any particular perfusion/preservation fluid over the others. Liver Transplantation 23 1615-1627 2017 AASLD.
Topics: Allografts; Cold Ischemia; Graft Survival; Humans; Liver; Liver Transplantation; Organ Preservation; Organ Preservation Solutions; Perfusion; Practice Guidelines as Topic; Tissue and Organ Procurement; Treatment Outcome
PubMed: 28734125
DOI: 10.1002/lt.24829 -
Frontiers in Immunology 2022The frequent use of marginal livers forces transplant centres to explore novel technologies to improve organ quality and outcomes after implantation. Organ perfusion... (Review)
Review
The frequent use of marginal livers forces transplant centres to explore novel technologies to improve organ quality and outcomes after implantation. Organ perfusion techniques are therefore frequently discussed with an ever-increasing number of experimental and clinical studies. Two main approaches, hypothermic and normothermic perfusion, are the leading strategies to be introduced in clinical practice in many western countries today. Despite this success, the number of studies, which provide robust data on the underlying mechanisms of protection conveyed through this technology remains scarce, particularly in context of different stages of ischemia-reperfusion-injury (IRI). Prior to a successful clinical implementation of machine perfusion, the concept of IRI and potential key molecules, which should be addressed to reduce IRI-associated inflammation, requires a better exploration. During ischemia, Krebs cycle metabolites, including succinate play a crucial role with their direct impact on the production of reactive oxygen species (ROS) at mitochondrial complex I upon reperfusion. Such features are even more pronounced under normothermic conditions and lead to even higher levels of downstream inflammation. The direct consequence appears with an activation of the innate immune system. The number of articles, which focus on the impact of machine perfusion with and without the use of specific perfusate additives to modulate the inflammatory cascade after transplantation is very small. This review describes first, the subcellular processes found in mitochondria, which instigate the IRI cascade together with proinflammatory downstream effects and their link to the innate immune system. Next, the impact of currently established machine perfusion strategies is described with a focus on protective mechanisms known for the different perfusion approaches. Finally, the role of such dynamic preservation techniques to deliver specific agents, which appear currently of interest to modulate this posttransplant inflammation, is discussed together with future aspects in this field.
Topics: Humans; Immunity; Inflammation; Liver Transplantation; Organ Preservation; Perfusion
PubMed: 35874758
DOI: 10.3389/fimmu.2022.855263 -
Transplant International : Official... 2022Currently, static cold storage (SCS) of hearts from donations after brainstem death remains the standard clinically. However, machine perfusion (MP) is considered an... (Review)
Review
Currently, static cold storage (SCS) of hearts from donations after brainstem death remains the standard clinically. However, machine perfusion (MP) is considered an approach for donor organ management to extend the donor pool and/or increase the utilization rate. This review summarizes and critically assesses the available clinical data on MP in heart transplantation. We searched Medline (PubMed), Cochrane, Embase, and clinicaltrials.gov, along with reference lists of the included publications and identified 40 publications, including 18 articles, 17 conference abstracts, and five ongoing clinical trials. Two types of MP were used: hypothermic MP (HMP) and normothermic MP (NMP). Three studies evaluated HMP, and 32 evaluated NMP. Independent of the system, MP resulted in clinical outcomes comparable to traditional SCS. However, NMP seemed especially beneficial for high-risk cases and donation after circulatory death (DCD) hearts. Based on currently available data, MP is non-inferior to standard SCS. Additionally, single-centre studies suggest that NMP could preserve the hearts from donors outside standard acceptability criteria and DCD hearts with comparable results to SCS. Finally, HMP is theoretically safer and simpler to use than NMP. If a machine malfunction or user error occurs, NMP, which perfuses a beating heart, would have a narrower margin of safety. However, further well-designed studies need to be conducted to draw clear conclusions.
Topics: Heart; Heart Transplantation; Humans; Organ Preservation; Perfusion; Tissue Donors
PubMed: 35401041
DOI: 10.3389/ti.2022.10258 -
Cancer Letters May 2019Cancer research uses in vitro studies for controllable analysis of tumor behavior and preclinical testing of therapeutics. Shortcomings of basic cell culture systems in... (Review)
Review
Cancer research uses in vitro studies for controllable analysis of tumor behavior and preclinical testing of therapeutics. Shortcomings of basic cell culture systems in recreating in vivo interactions have driven the development of more efficient and biomimetic in vitro environments for cancer research. Assimilation of certain developments in tissue engineering will accelerate and improve the design of these environments. With the continual improvement of the tumor engineering field, the next step is towards macroscopic systems such as scaffold-supported, flow-perfused macroscale tumor bioreactors. Surface modifications of synthetic scaffolds allow for targeted cell adhesion and improved ECM development. Flow perfusion has emerged as means to expose cancerous tissues to critical biomechanical forces for tumor progression while simultaneously improving nutrient and waste transport. Macroscale perfusable systems allow for non-destructive real-time monitoring using biosensors capable of improving understanding of in vitro tumor development at reduced cost and waste. The combination of macroscale perfusable systems, surface-modified synthetic scaffolds, and non-destructive real-time monitoring will provide advanced platforms for in vitro modeling of tumor development, with broad applications in basic tumor research and preclinical drug development.
Topics: Bioreactors; Humans; Models, Biological; Neoplasms; Perfusion; Tissue Engineering; Tissue Scaffolds
PubMed: 30763717
DOI: 10.1016/j.canlet.2019.01.043 -
Perfusion May 2020
Topics: Biological Evolution; Humans; Perfusion
PubMed: 32397887
DOI: 10.1177/0267659120910035 -
The British Journal of Surgery May 2021Attempts to improve limb preservation for transplantation using ex vivo perfusion have yielded promising results. However, metabolic acidosis, aberrant perfusate...
BACKGROUND
Attempts to improve limb preservation for transplantation using ex vivo perfusion have yielded promising results. However, metabolic acidosis, aberrant perfusate biochemistry and significant perfusion-induced oedema are reported universally. Optimizing perfusion protocols is therefore essential for maintaining tissue health.
METHODS
A randomized, two-stage open preclinical trial design was used to determine the optimal temperature and mean arterial pressure for machine perfusion. Conditions compared were: normothermic machine perfusion at 70 mmHg (NMP-70); subnormothermic perfusion (28°C) at 70 mmHg; subnormothermic (28°C) perfusion at 50 mmHg; and hypothermic perfusion (10°C) at 30 mmHg. Following this, a head-to-head experiment was undertaken comparing the optimal machine perfusion with static cold storage. Paired bilateral limbs (10 in total) were randomized to either 8 h of static cold storage, or 2 h of static cold storage and 6 h of optimal machine perfusion. Both groups of limbs were then reperfused on a circuit primed with matched blood from unrelated donors for 4 h without immunosuppression.
RESULTS
NMP-70 resulted in less tissue injury and stable perfusion biochemistry. Assessing reperfusion outcomes, static cold storage resulted in acidosis with increased lactate and a worsening electrolyte profile, necessitating bolus infusions of bicarbonate to prevent graft loss. Conversely, NMP-70 was associated with haemodynamic and biochemical stability. Histologically, on reperfusion with allogeneic whole blood, limbs subjected to static cold storage exhibited multifocal ischaemic injury and increased inflammation, which was absent with NMP-70. Static cold storage also resulted in significant oedema compared with NMP-70.
CONCLUSION
Normothermic perfusion resulted in superior graft preservation and less reperfusion injury compared with the current static cold storage protocol.
Topics: Animals; Blood Pressure; Composite Tissue Allografts; Graft Survival; Models, Animal; Perfusion; Random Allocation; Reperfusion Injury; Specimen Handling; Swine; Temperature
PubMed: 34043778
DOI: 10.1002/bjs.11921 -
EBioMedicine Dec 2023Normothermic regional perfusion (NRP) and hypothermic-oxygenated-perfusion (HOPE), were both shown to improve outcomes after liver transplantation from donors after...
BACKGROUND
Normothermic regional perfusion (NRP) and hypothermic-oxygenated-perfusion (HOPE), were both shown to improve outcomes after liver transplantation from donors after circulatory death (DCD). Comparative clinical and mechanistical studies are however lacking.
METHODS
A rodent model of NRP and HOPE, both in the donor, was developed. Following asystolic donor warm ischemia time (DWIT), the abdominal compartment was perfused either with a donor-blood-based-perfusate at 37 °C (NRP) or with oxygenated Belzer-MPS at 10 °C (donor-HOPE) for 2 h. Livers were then procured and underwent 5 h static cold storage (CS), followed by transplantation. Un-perfused and HOPE-treated DCD-livers (after CS) and healthy livers (DBD) with direct implantation after NRP served as controls. Endpoints included the entire spectrum of ischemia-reperfusion-injury.
FINDINGS
Healthy control livers (DBD) showed minimal signs of inflammation during 2 h NRP and achieved 100% posttransplant recipient survival. In contrast, DCD livers with 30 and 60 min DWIT suffered from greater mitochondrial injury and inflammation as measured by increased perfusate Lactate, FMN- and HMGB-1-levels with subsequent Toll-like-receptor activation during NRP. In contrast, donor-HOPE (instead of NRP) led to significantly less mitochondrial-complex-I-injury and inflammation. Results after donor-HOPE were comparable to ex-situ HOPE after CS. Most DCD-liver recipients survived when treated with one HOPE-technique (86%), compared to only 40% after NRP (p = 0.0053). Following a reduction of DWIT (15 min), DCD liver recipients achieved comparable survivals with NRP (80%).
INTERPRETATION
High-risk DCD livers benefit more from HOPE-treatment, either immediately in the donor or after cold storage. Comparative prospective clinical studies are required to translate the results.
FUNDING
Funding was provided by the Swiss National Science Foundation (grant no: 32003B-140776/1, 3200B-153012/1, 320030-189055/1, and 31IC30-166909) and supported by University Careggi (grant no 32003B-140776/1) and the OTT (grant No.: DRGT641/2019, cod.prog. 19CT03) and the Max Planck Society. Work in the A.G. laboratory was partially supported by the NIH R01NS112381 and R21NS125466 grants.
Topics: Animals; Humans; Liver Transplantation; Rodentia; Prospective Studies; Perfusion; Graft Survival; Organ Preservation; Liver; Tissue Donors; Inflammation
PubMed: 37924707
DOI: 10.1016/j.ebiom.2023.104861