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International Journal of Molecular... Sep 2020Acute respiratory distress syndrome (ARDS) is associated with high morbidity and mortality, and current management has a dramatic impact on healthcare resource... (Review)
Review
Acute respiratory distress syndrome (ARDS) is associated with high morbidity and mortality, and current management has a dramatic impact on healthcare resource utilization. While our understanding of this disease has improved, the majority of treatment strategies remain supportive in nature and are associated with continued poor outcomes. There is a dramatic need for the development and breakthrough of new methods for the treatment of ARDS. Isolated machine lung perfusion is a promising surgical platform that has been associated with the rehabilitation of injured lungs and the induction of molecular and cellular changes in the lung, including upregulation of anti-inflammatory and regenerative pathways. Initially implemented in an ex vivo fashion to evaluate marginal donor lungs prior to transplantation, recent investigations of isolated lung perfusion have shifted in vivo and are focused on the management of ARDS. This review presents current tenants of ARDS management and isolated lung perfusion, with a focus on how ex vivo lung perfusion (EVLP) has paved the way for current investigations utilizing in vivo lung perfusion (IVLP) in the treatment of severe ARDS.
Topics: Animals; History, 19th Century; History, 20th Century; History, 21st Century; Humans; Inflammation; Lung Injury; Perfusion; Respiratory Distress Syndrome; Tissue Donors
PubMed: 32957547
DOI: 10.3390/ijms21186820 -
Transplantation Sep 2020Machine perfusion (MP) is at the forefront of innovation in modern liver transplantation. Several approaches, mainly varying the temperature at which the graft is... (Review)
Review
Machine perfusion (MP) is at the forefront of innovation in modern liver transplantation. Several approaches, mainly varying the temperature at which the graft is perfused, have shown benefit in preclinical models and nonrandomized clinical trials. Given the recent randomized controlled trial by Nasralla et al demonstrating the efficacy of normothermic MP over static cold storage, MP is likely here to stay for the foreseeable future. We are only beginning to explore the possibilities of this technology, including the prediction of graft function and modification of suboptimal livers. This has the potential to both increase the donor pool and improve the quality of grafts provided to recipients. Beyond transplantation, there may be a role for MP in extracorporeal liver support, cancer research and therapeutics, and pharmaceutical testing. In this review, we provide the rationale and explore the relevant preclinical studies that support the use of ex situ liver perfusion for these extended applications.
Topics: Animals; Humans; Liver; Liver Transplantation; Models, Animal; Neoplasms; Organ Preservation; Perfusion; Toxicology
PubMed: 32433236
DOI: 10.1097/TP.0000000000003320 -
Kidney International Apr 2023Although hypothermic machine perfusion (HMP) is associated with improved kidney graft viability and function, the underlying biological mechanisms are unknown....
Although hypothermic machine perfusion (HMP) is associated with improved kidney graft viability and function, the underlying biological mechanisms are unknown. Untargeted metabolomic profiling may identify potential metabolites and pathways that can help assess allograft viability and contribute to organ preservation. Therefore, in this multicenter study, we measured all detectable metabolites in perfusate collected at the beginning and end of deceased-donor kidney perfusion and evaluated their associations with graft failure. In our cohort of 190 kidney transplants, 33 (17%) had death-censored graft failure over a median follow-up of 5.0 years (IQR 3.0-6.1 years). We identified 553 known metabolites in perfusate and characterized their experimental and biological consistency through duplicate samples and unsupervised clustering. After perfusion-time adjustment and false discovery correction, six metabolites in post-HMP perfusate were significantly associated with death-censored graft failure, including alpha-ketoglutarate, 3-carboxy-4-methyl-5-propyl-2-furanpropanoate, 1-carboxyethylphenylalanine, and three glycerol-phosphatidylcholines. All six metabolites were associated with an increased risk of graft failure (Hazard Ratio per median absolute deviation range 1.04-1.45). Four of six metabolites also demonstrated significant interaction with donation after cardiac death with notably greater risk in the donation after cardiac death group (Hazard Ratios up to 1.69). Discarded kidneys did not have significantly different levels of any death-censored graft failure-associated metabolites. On interrogation of pathway analysis, production of reactive oxygen species and increased metabolism of fatty acids were upregulated in kidneys that subsequently developed death-censored graft failure. Thus, further understanding the role of these metabolites may inform the HMP process and help improve the objective evaluation of allograft offers, thereby reducing the discard of potentially viable organs.
Topics: Humans; Kidney; Kidney Transplantation; Perfusion; Tissue Donors; Death; Allografts; Graft Survival
PubMed: 36549364
DOI: 10.1016/j.kint.2022.11.020 -
Biopharmaceutics & Drug Disposition Feb 2023Efficiently removing blood from the brain vasculature is critical to evaluate accurately the brain penetration and biodistribution of drug candidates, especially for...
Efficiently removing blood from the brain vasculature is critical to evaluate accurately the brain penetration and biodistribution of drug candidates, especially for biologics as their blood concentrations are substantially higher than the brain concentrations. Transcardial perfusion has been used widely to remove residual blood in the brain; however, the perfusion conditions (such as the perfusion rate and time) reported in the literature are quite varied, and the performance of these methods on blood removal has not been investigated thoroughly. In this study, the effectiveness of the perfusion conditions was assessed by measuring brain hemoglobin levels. Sodium nitrite (NaNO ) as an additive in the perfusate was evaluated at different concentrations. Blood removal was significantly improved with 2% NaNO over a 20 min perfusion in mouse without disrupting the integrity of the blood-brain barrier (BBB). In mice, the optimized perfusion method significantly lowered the measured brain-to-plasma ratio (K ) for monoclonal antibodies due to the removal of blood contamination and small molecules with a moderate-to-high BBB permeability and with a high brain-unbound-fraction (f ) presumably due to flux out of the brain during perfusion. Perfusion with or without NaNO clearly removed the residual blood in rat brain but with no difference observed in K between the perfusion groups with or without 2% NaNO . In conclusion, a perfusion method was successfully developed to evaluate the brain penetration of small molecules and biologics in rodents for the first time. The transcardial perfusion with 2% NaNO effectively removed the residual blood in the brain and significantly improved the assessment of brain penetration of biologics. For small molecules, however, transcardial perfusion may not be performed, as small molecule compounds could be washed away from the brain by the perfusion procedure.
Topics: Rats; Mice; Animals; Tissue Distribution; Rodentia; Biological Products; Brain; Blood-Brain Barrier; Perfusion
PubMed: 35508078
DOI: 10.1002/bdd.2317 -
PloS One 2021Normothermic machine perfusion (NMP) of donor kidneys provides the opportunity for improved graft preservation and objective pre-transplant ex-vivo organ assessment....
Normothermic machine perfusion (NMP) of donor kidneys provides the opportunity for improved graft preservation and objective pre-transplant ex-vivo organ assessment. Currently, a multitude of perfusion solutions exist for renal NMP. This study aimed to evaluate four different perfusion solutions side-by-side and determine the influence of different perfusate compositions on measured renal perfusion parameters. Porcine kidneys and blood were obtained from a slaughterhouse. Kidneys underwent NMP at 37°C for 7 hours, with 4 different perfusion solutions (n = 5 per group). Group 1 consisted of red blood cells (RBCs) and a perfusion solution based on Williams' Medium E. Group 2 consisted of RBCs, albumin and a balanced electrolyte composition. Group 3 contained RBCs and a medium based on a British clinical NMP solution. Group 4 contained RBCs and a medium used in 24-hour perfusion experiments. NMP flow patterns for solutions 1 and 2 were similar, solutions 3 and 4 showed lower but more stable flow rates. Thiobarbituric acid reactive substances were significantly higher in solution 1 and 4 compared to the other groups. Levels of injury marker N-acetyl-β-D glucosaminidase were significantly lower in solution 2 in comparison with solution 3 and 4. This study illustrates that the perfusate composition during NMP significantly impacts the measured perfusion and injury parameters and thus affects the interpretation of potential viability markers. Further research is required to investigate the individual influences of principal perfusate components to determine the most optimal conditions during NMP and eventually develop universal organ assessment criteria.
Topics: Animals; Kidney; Kidney Transplantation; Organ Preservation; Perfusion; Swine
PubMed: 34003874
DOI: 10.1371/journal.pone.0251595 -
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 -
Fertility and Sterility Dec 2023To describe the feasibility of hypothermic machine perfusion (HMP) in uterus transplantation (UT) to potentially improve the preservation of the uterus and enhance graft...
OBJECTIVE
To describe the feasibility of hypothermic machine perfusion (HMP) in uterus transplantation (UT) to potentially improve the preservation of the uterus and enhance graft preservation in the donation after brainstem death (DBD) context. Uterus transplantation is a new surgical approach to treating absolute uterine infertility; it can be performed after living donation or after DBD. In the DBD context, the uterus is typically the last organ removed after other vital organs, with the exception of the Baylor team, which removes the uterus first. This key aspect imposes an unavoidable mild temperature ischemia for >1 hour on the uterus during the removal of the vital abdominal and chest organs. In renal transplantation, the perfusion machine reduces the risk of delayed graft function; thus, we hypothesized that machine perfusion could result in a reduction of uterus graft dysfunction. The uterus graft dysfunction could be expressed by a low embryo implantation rate, pregnancy loss, or vascular pregnancy diseases such as preeclampsia or fetal growth restriction." To date, static cold storage of the uterus is the only standard method for preservation before transplantation. HMP is an emerging method that could potentially improve the preservation of the uterus to enhance graft preservation in the DBD context.
DESIGN
This video article shows all the technical details of using the HMP for uterine transplantation.
SETTING
University.
ANIMALS
Porcine model.
INTERVENTION
Porcine uterus was retrieved from a DBD domestic animal model and flushed with KPS MP (Bridge To Life Ltd in UK) at 4 °C. After vascular preparation on the back table, the uterus was perfused using KPS MP through a cannula in the aorta using the VitaSmart device (Bridge To Life Ltd in UK) for 18 hours. Then, the uterus was transplanted to the porcine recipient.
MAIN OUTCOME MEASURES
The macroscopic appearance of the uterus at the end of HMP and the assessment of the uterus vascularization after transplantation in the recipient compared with the native uterus.
RESULTS
This video shows the cannulation of the iliac vessels, cooling and removal of the uterus on a porcine model, uterus preservation using HMP during 18 hours, and then UT in a new recipient pig with the reperfusion of the transplanted uterus next to the native, intact uterus of the recipient. The macroscopic appearance of the uterus at the end of HMP appeared viable and was perfectly flushed. The assessment of the uterus vascularization after transplantation in the recipient was similar to that of the native uterus. To our knowledge, we describe here for the first time the UT procedure in DBD context on an animal model and the use of HMP for uterus preservation in UT programs; this could increase the number of uterine grafts available for a greater number of female recipients.
CONCLUSION
Hypothermic machine perfusion could allow the duration of cold ischemia to be prolonged without altering the uterine graft. Nevertheless, this assertion has to be validated in a human context.
Topics: Animals; Female; Cold Temperature; Organ Preservation; Perfusion; Swine; Uterus
PubMed: 37660880
DOI: 10.1016/j.fertnstert.2023.08.020 -
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