The use of grafts from donation after circulatory death (DCD) overcomes the inadequate donor organ supply. Our team developed a transportable dual hypothermic oxygenated machine perfusion (DHOPE) device, which initiates DHOPE at a recipient center to reduce static cold storage (SCS) time and the risk of graft failure in DCD liver transplantation.

Six porcine livers per group with 30 min of warm ischemia exposure were preserved via SCS or DHOPE for 6 h and then reperfused for 12 h with whole blood to mimic transplantation. Hepatocellular and biliary function and injury were assessed in perfusate and bile samples. Molecular biomarkers and histology were compared between groups.

Reperfusion portal vein pressure, in a flow-constant manner, and alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and gamma-glutamyltransferase (γ-GGT) release were significantly lower in the DHOPE group than in the SCS group at all time points. Higher bile production paralleled the lower levels of ALP and γ-GGT in the DHOPE group. The DHOPE group secreted more total bilirubin (TBIL) in bile, resulting in decreased TBIL in the perfusate, and livers preserved with DHOPE exhibited better cholangiocellular function. Furthermore, improvements in hypoxia, the inflammatory response, cell-free microRNAs and energy metabolism were observed in the DHOPE group. There were fewer apoptotic cells and TGF-β1-positive cells in the liver parenchyma and extrahepatic bile duct in the DHOPE group than in the SCS group.

This study demonstrates the efficacy of local 4 °C DHOPE to protect porcine liver grafts from 30-min warm ischemia damage.

Liver transplantation is the only curative option for end-stage liver disease. Donor shortages necessitate the use of higher risk donor livers, including fatty livers, which are more susceptible to ischemia-reperfusion injury. Machine perfusion has improved graft utilization and is typically performed at hypothermic (8-12°C) or normothermic (35-37°C) temperatures. Here we studied the impact of mild hyperthermia (40°C) as a therapeutic intervention for fatty livers using in-depth proteomic and lipoprotein profiling of whole organ perfusion and precision-cut liver slices. We observed proteomic changes with metabolic alterations over time, evidenced by a significant increase in lipid export in whole organ perfusions. Furthermore, PCLS showed significant upregulation of metabolic processes and heat shock protein response after 24 h of hyperthermia. Machine perfusion under hyperthermic conditions may be a potential strategy to improve the utilization of fatty liver grafts, ultimately expanding the donor pool and improving transplant outcomes.

Machine perfusion (MP), including hypothermic oxygenated machine perfusion (HOPE), dual HOPE, normothermic machine perfusion (NMP), NMP ischemia-free liver transplantation (NMP-ILT), and controlled oxygenated rewarming (COR), is increasingly being investigated to improve liver graft quality from extended criteria donors and donors after circulatory death and expand the donor pool. This network meta-analysis investigates the comparative efficacy and safety of various liver MP strategies versus traditional static cold storage (SCS). We searched PubMed, Scopus, Web of Science, and Cochrane Controlled Register of Trials for randomized controlled trials comparing liver transplantation outcomes between SCS and MP techniques. The primary outcome was the incidence of early allograft dysfunction. Secondary endpoints included 1-year graft survival, the incidence of graft failure/loss, post-reperfusion syndrome, biliary complications, the need for renal replacement therapy, graft-related patient mortality, and the length of intensive care unit and hospital stay. R-software was used to conduct a network meta-analysis using a frequentist framework (PROSPERO ID: CRD42024549254). We included 12 randomized controlled trials involving 1628 patients undergoing liver transplantation (801 in the liver MP groups and 832 in the SCS group). Compared to SCS, HOPE/dHOPE, but not other MP strategies, was associated with a significantly lower risk of early allograft dysfunction (RR: 0.53, 95% CI [0.37, 0.74], p =0.0002), improved 1-year graft survival rate (RR: 1.07, 95% CI [1.01, 1.14], p =0.02), decreased graft failure/loss (RR: 0.38, 95% CI [0.16, 0.90], p =0.03), and reduced the risk of biliary complications (RR: 0.52, 95% CI [0.43, 0.75], p < 0.0001). Compared to SCS, NMP (RR: 0.49, 95% CI [0.24, 0.96]) and NMP-ILT (RR: 0.15, 95% CI [0.04, 0.57]), both significantly reduced the risk of postperfusion syndrome. There is no difference between SCS and MP groups in the risk of renal replacement therapy, graft-related patient mortality, and intensive care unit and hospital stay length. Our meta-analysis showed that HOPE/dual-HOPE is a promising alternative to SCS for donor liver preservation. These new techniques can help expand the donor pool with similar or even better post-liver transplantation outcomes.

Relatively high mean absorbed doses to the non-tumorous liver tissue (NTLT) are generally well tolerated in transarterial radioembolisation (TARE), potentially due to a heterogeneous dose distribution. This study investigates the macroscopic and microscopic distribution of fractionally administered TARE holmium microspheres in NTLT using an experimental setup of ex vivo perfused human donor livers under magnetic resonance imaging (MRI), and validates these findings through a comparison with MRI data from TARE-treated patients.

MRI-based dose maps of the TARE-treated ex vivo livers and patients revealed a heterogeneous dose distribution pattern throughout the NTLT (heterogeneity index (HI) range 2.96-10.11). Microscopic analysis confirmed this, as a wide variation in the percentage of tissue within 2.1 mm of microspheres (5.4%-84.3%) was observed. Microspheres administered in consecutive fractions decreased the heterogeneity, which was observed macroscopically by a decreased HI, and microscopically by the formation of new microsphere clusters. However, this HI decrease appeared finite, and new clusters formed near existing clusters, maintaining the overall distribution pattern.

TARE induces a heterogeneous dose distribution pattern in human NTLT. This heterogeneous dose distribution pattern persists across additional microsphere fractions, leaving parts of the NTLT unexposed to lethal doses of ionising radiation. Combined with the regenerative capacity of the liver, this may explain why relatively high mean absorbed doses to the NTLT are generally well tolerated in TARE.

For validation purposes, clinical data from patients who participated in a previous study (ClinicalTrials.gov, identifier NCT04269499, registered on February 13, 2020) was analysed in the current study.

The shortage of suitable donor organs has resulted in the use of suboptimal, high-risk, extended-criteria donor (ECD) livers, which are at an increased risk of failure after transplantation. Compared with traditional static cold storage, dynamic preservation by ex situ machine perfusion reduces the risks associated with the transplantation of ECD organs. Ex situ machine perfusion strategies differ in timing (that is, speed of procurement and transport), perfusion duration and perfusion temperature. For 'back-to-base' protocols, the donor liver is statically cold stored during transportation to the recipient hospital (the 'base') and then perfused, instead of transporting the liver using a portable perfusion system. While dual hypothermic (8-12 °C) oxygenated machine perfusion (DHOPE) allows safe prolongation of preservation duration and reduces ischemia-reperfusion injury-related complications, including post-transplant cholangiopathy, normothermic machine perfusion (NMP) at 35-37 °C facilitates ex situ viability testing of both liver parenchyma and bile ducts. Here, we describe a clinical protocol for 'back-to-base' combined DHOPE and NMP, linked by a period of controlled oxygenated rewarming (COR), which we call the DHOPE-COR-NMP protocol. This protocol enables restoration of mitochondrial function after static ischemic preservation and minimizes both ischemia-reperfusion and temperature-shift-induced injury during the start of NMP. The NMP phase allows viability assessment before final donor liver acceptance for transplantation. Sequential DHOPE and COR-NMP may reduce the risks associated with transplantation of ECD livers and facilitate enhanced utilization, thereby helping to alleviate the organ shortage.

Hypothermic oxygenated machine perfusion (HOPE) has become an integral technique to enhance donor graft function in liver transplantation (LiTx). This study compares early posttransplant outcomes of mono-HOPE (portal vein perfusion only) versus dual- HOPE (both portal vein and hepatic artery perfusion). A retrospective analysis was conducted on 183 LiTx recipients, with 90 receiving mono-HOPE and 93 receiving dual-HOPE grafts. Propensity Score Matching (PSM) was applied, resulting in a matched cohort of 146 patients. Primary outcomes included one-year patient and graft survival, and non-anastomotic biliary strictures (NAS). Secondary outcomes included hospital length of stay (HLS). One-year patient survival was 81.7% in the mono-HOPE and 81.7% in the dual-HOPE group, and overall survival did not differ (p = 0.990). One-year death-censored graft survival was similarly comparable (91.2% vs. 93.3%, p = 0.893). NAS were observed in 10.96% in the mono-HOPE and 8.22% in the dual-HOPE group (p = 0.574). The median HLS was 29 days for both groups. Results suggest that dual-HOPE did not significantly improve patient or graft survival, nor did it reduce NAS or HLS compared to mono-HOPE. Assuming that larger cohorts and long-term follow-up data confirm this, additional cannulation of the hepatic artery during machine perfusion in hypothermic conditions may not be beneficial.

Ex situ machine perfusion of the donor liver, such as dual hypothermic oxygenated machine perfusion (DHOPE), is increasingly used in liver transplantation. Although DHOPE reduces ischemia/reperfusion-related complications after liver transplantation, data on cost-effectiveness are lacking. Our objective was to evaluate the cost-effectiveness of DHOPE in donation after circulatory death (DCD) liver transplantation.

We performed an economic evaluation of DHOPE versus static cold storage (SCS) based on a multicenter randomized controlled trial in DCD liver transplantation (DHOPE-DCD trial; ClinicalTrials.gov number, NCT02584283). All patients enrolled in the 3 participating centers in the Netherlands were included. Costs related to the transplant procedure, hospital stay, readmissions, and outpatients treatments up to 1 y posttransplant were calculated. The cost for machine perfusion was calculated using 3 scenarios: (1) costs for machine perfusion, (2) machine perfusion costs plus costs for personnel, and (3) scenario 2 plus depreciation expenses for a dedicated organ perfusion room.

Of 119 patients, 60 received a liver after DHOPE and 59 received a liver after SCS alone. The mean total cost per patient up to 1 y posttransplant was €126 221 for the SCS group and €110 794 for the DHOPE group. The most significant reduction occurred in intensive care costs (28.4%), followed by nonsurgical interventions (24.3%). In cost scenario 1, DHOPE was cost-effective after 1 procedure. In scenarios 2 and 3, cost-effectiveness was achieved after 25 and 30 procedures per year, respectively.

Compared with conventional SCS, machine perfusion using DHOPE is cost-effective in DCD liver transplantation, reducing the total medical costs up to 1 y posttransplant.

In recent years, there has been resurgence in donation after circulatory death (DCD). Despite that, the number of organs transplanted from these donors remains low due to concerns about their function and a lack of an objective assessment at the time of donation. This overview examines the current DCD practices and the classification modifications to accommodate regional perspectives. Several risk factors underscore the reluctance to accept DCD organs, and we discuss the modern strategies to mitigate them. The advent of machine perfusion technology has revolutionized the field of DCD transplantation, leading to improved outcomes and better organ usage. With many strategies at our disposal, there is an urgent need for comparative trials to determine the optimal use of perfusion technologies for each donated organ type. Additional progress in defining therapeutic strategies to repair the damage sustained during the dying process should further improve DCD organ utilization and outcomes. However, there remains wide variability in access to DCD donation and transplantation, and organizational efforts should be doubled up with consensus on key ethical issues that still surround DCD donation in the era of machine perfusion.

Background: Hypothermic oxygenated machine perfusion has emerged as a strategy to alleviate ischemic-reperfusion injury in liver grafts. Nevertheless, there is limited data on the effectiveness of hypothermic liver perfusion in evaluating organ quality. This study aimed to introduce a readily accessible real-time predictive biomarker measured in machine perfusate for post-transplant liver graft function. Methods: The study evaluated perfusate analytes over a 90-day postoperative period in 26 patients randomly assigned to receive a liver graft following dual hypothermic machine perfusion in a prospective randomized controlled trial. Machine perfusion was consistently conducted end-ischemically for at least 120 min, with real-time perfusate assessment at 30-min intervals. Graft functionality was assessed using established metrics, including Early Allograft Dysfunction (EAD). Results: Perfusate lactate concentration after 120 min of machine perfusion demonstrated significant predictive value for EAD (AUC ROC: 0.841, p = 0.009). Additionally, it correlated with post-transplant peak transaminase levels and extended hospital stays. Subgroup analysis revealed significantly higher lactate accumulation in livers with post-transplant EAD. Conclusions: Liver graft quality can be effectively assessed during hypothermic machine perfusion using simple perfusate lactate measurements. The reliability and accessibility of this evaluation support its potential integration into diverse transplant centers.

The clinical standard for pancreas preservation for transplantation is static cold storage (SCS). Oxygenation during preservation has been shown to be advantageous in clinical studies. This study evaluates the efficiency of different oxygenation modalities during hypothermic pancreas preservation.

Thirty-two porcine pancreases were procured in a controlled donation after circulatory death model and were divided to be preserved in 8 groups: (1) SCS, (2) hypothermic machine perfusion (HMP), (3) hypothermic oxygenated machine perfusion (HOPE) with 21% oxygen, (4) HOPE and 100%, (5) SCS and oxygen carrier, M101, (6) HMP and M101, (7) HOPE 21% and M101, and (8) HOPE 100% and M101. All the groups underwent 24 h of hypothermic preservation, followed by 2 h of normothermic reperfusion. Oxygen partial pressures were assessed using parenchymal probes. Perfusion parameters, perfusate samples, and tissue biopsies were analyzed.

This study showed that HMP was linked to higher tissue oxygen partial pressures, lower succinate levels, and better reperfusion parameters. Furthermore, the addition of M101 to either SCS or HMP was associated with lower succinate and creatinine phosphokinase accumulation, suggesting a protective effect against ischemia.

Our research has demonstrated the efficacy of machine perfusion in hypothermic conditions in providing oxygen to the pancreas during preservation and conditioning the pancreatic microvasculature for reperfusion during transplantation. Furthermore, the addition of M101 suggests a protective effect on the graft from ischemia.

Background: Hypothermic oxygenated machine perfusion (HOPE) has emerged as a critical innovation in liver transplantation (LTx), offering significant protection against ischemia-reperfusion injury (IRI). This study focuses on quantifying and characterizing immune cells flushed out during HOPE to explore its effects on graft function and post-transplant outcomes. Materials and Methods: Fifty liver grafts underwent end-ischemic HOPE. Perfusate samples were collected at three time points: at the start of perfusion, after 10 min, and at the end of perfusion. The samples were analyzed to quantify and characterize immune cells, assessing the effectiveness of HOPE in reducing cellular debris and its impact on graft quality. Results: The primary perfusate contained significant concentrations of immune cells, mainly segmented neutrophils, lymphocytes, and monocytes. After 10 min of perfusion, outflow cell concentration decreased by over 95%, and by the end of perfusion, a more than 99% reduction was observed. Conclusions: HOPE effectively reduces immune cell concentrations in liver grafts, suggesting a mechanism for improved graft function and reduced post-transplant complications. These findings support the continued use and optimization of HOPE in LTx.

Outcomes after pediatric liver transplantation are generally excellent, but the limited avavailability of suitable, size-matched liver allografts remains a significant barrier. Machine perfusion technology has emerged as a promising approach to expand the donor pool, enabling the use of less ideal whole liver grafts, such as livers donated after circulatory death, and enhancing the execution of split liver transplantation.

This review examines the application of machine perfusion in pediatric liver transplantation, focusing on two primary techniques: hypothermic oxygentaed perfusion and normothermic machine perfusion. These methods optimize storage, resuscitation, and assessment of liver grafts before transplantation, potentially expanding the range of usable donor organs.

The use of machine perfusion allows for the consideration of suboptimal donor livers and facilitates split liver transplantation, both of which could increase organ availability for pediatric patients. Implementation of machine perfusion could also help reduce waiting list mortality by enabling the safe use of a broader spectrum of donor organs.

Adoption of machine perfusion in pediatric liver transplantation will require collaborative, multidisciplinary efforts across transplant centers. By fostering cooperative learning and sharing resources. the integration of machine perfusion into clinical practice has the potential to reduce mortality among children awaiting liver transplantation.

Liver transplantation is used for treating end-stage liver disease, fulminant hepatitis, and oncological malignancies and organ shortage is a major limiting factor worldwide. The use of grafts based on extended donor criteria have become internationally accepted. Oxygenated machine perfusion technologies are the most recent advances in organ transplantation; however, it is only applied after a period of cold ischemia. Due to its high cost, we aimed to use a novel device, OxyFlush®, based on oxygenation of the preservation solution, applied during liver procurement targeting the maintenance of ATP during static cold storage (SCS).

Twenty patients were randomly assigned to the OxyFlush or control group based on a 1:1 ratio. In the OxyFlush group, the perfusion solution was oxygenated with OxyFlush® device while the control group received a non-oxygenated solution. Liver and the common bile duct (CBD) biopsies were obtained at three different time points. The first was at the beginning of the procedure, the second during organ preparation, and the third after total liver reperfusion. Biopsies were analyzed, and adenosine triphosphate (ATP) levels and histological scores of the liver parenchyma and CBD were assessed. Postoperative laboratory tests were performed.

OxyFlush® was able to maintain ATP levels during SCS and improved the damage caused by the lack of oxygen in the CBD. However, OxyFlush® did not affect laboratory test results and histological findings of the parenchyma.

We present a novel low-cost device that is feasible and could represent a valuable tool in organ preservation during SCS.

Hypothermic Oxygenated machine PErfusion (HOPE) can reduce ischemic reperfusion injury and improve outcomes for liver transplant recipients. However, the effect of HOPE on high-risk extended criteria donor (ECD) and donation after circulatory death determination (DCDD) grafts is incomplete, despite the expectation that this cohort benefit maximally from HOPE. Accordingly, this paper aims to characterize the effect of HOPE on ECD and DCDD grafts.

This study includes all papers comparing HOPE to static cold storage for high-risk ECD and DCDD grafts. Systematic searches of Medline, Embase, and Scopus were completed using the terms "HOPE" OR "hypothermic oxygenated machine perfusion" AND "liver transplantation". Data were extracted and analyzed using IBM SPSS to perform the meta-analysis.

A total of 2286 records were identified, with 10 meeting the inclusion criteria. Overall, the quality of evidence is heterogenous with many papers relying on retrospective controls. However, pooled analysis demonstrates HOPE to significantly reduce the rate of early allograft dysfunction, 12-month graft failure, re-transplantation, total biliary complications, and non-anastomotic strictures for high-risk grafts.

There is good evidence that HOPE improves outcomes following liver transplantation across a number of biochemical and clinical endpoints for high-risk grafts. Of note, the reduction in biliary complications and re-transplantation is particularly significant given the morbidity associated with these endpoints. However, further, high-quality prospective trials with contemporary controls and clinically relevant primary endpoints are needed to better define the impact of HOPE for this cohort of grafts.

Despite a significant increase in utilization over the past decade, the number of donation after circulatory death (DCD) organs that are procured and transplanted in the United States (US) remains well below its potential. There is still room for expansion, as utilizing DCD organs to the fullest extent is currently the most viable solution to the persistent mismatch between supply and demand in transplantation. We convened a multidisciplinary transplantation summit to examine various aspects of DCD, with faculty members from around the world with clinical and academic interest in DCD donation and transplantation, including abdominal and cardiothoracic surgeons, organ procurement organization directors, hepatologists, and gastroenterologists. The conference focused on identifying barriers to DCD organ utilization and strategies to overcome these barriers. We divide the barriers to DCD utilization into three mains categories: (I) policy and process variation; (II) logistical and transportation challenges; and (III) higher risk perceptions related to DCD outcomes. For each barrier, we proposed a variety of solutions, providing an overview of the status of DCD donation in the US and suggestions on how to increase the use of DCD. There is a specific focus on ex situ machine perfusion, normothermic regional perfusion, and other opportunities to expand DCD utilization without negatively impacting recipient outcomes.

Liver transplantation is the preferred treatment for end-stage liver disease. Emerging evidence suggests a potential role for liver transplantation in treating liver tumors such as colorectal liver metastases and cholangiocarcinoma. However, due to a limited donor pool, the use of marginal grafts from donation after circulatory death (DCD) donors is increasing to meet demand. Machine perfusion is crucial in this context for improving graft acceptance rates and reducing ischemia-reperfusion injury. Few studies have evaluated the role of machine perfusion in the context of transplant oncology. Perfusion machines can be utilized in situ (normothermic regional perfusion-NRP) or ex situ (hypothermic and normothermic machine perfusion), either in combination or as a complement to conventional in situ cold flush and static cold storage. The objective of this analysis is to provide an up-to-date overview of perfusion machines and their function in donation after circulatory death with particular attention to their current and likely potential effects on transplant oncology. A literature review comparing standard cold storage to machine perfusion methods showed that, so far, there is no evidence that these devices can reduce the tumor recurrence rate. However, some evidence suggests that these innovative perfusion techniques can improve graft function, reduce ischemia-reperfusion injury, and, based on this mechanism, may lead to future improvements in cancer recurrence.

The use of machine perfusion in solid organ transplantation has developed tremendously worldwide in recent years. Although the number of randomized controlled trials in the field of organ preservation is still limited, machine perfusion has been shown to be superior to static cold storage of donor organs. Various devices for clinical use with hypothermia or normothermia are already available for most organs. Whether and which perfusion strategy is superior to the others is the subject of current clinical research. This also applies to the further evaluation of possible synergistic effects in the sequential use of the various protocols. The common goal of all dynamic perfusion technologies is to optimize organ preservation between removal and transplantation. By testing the quality of marginal donor organs prior to transplantation, it should also be possible to use these organs without exposing the patient to increased risk. This can lead to a significant expansion of the donor pool. This is particularly important in Germany, where there is an ongoing shortage of organs and restrictive legislation regarding the expansion of the donor pool. Furthermore, the perfusion technology offers the possibility to serve as a platform for other ex situ and in situ therapies on isolated organs. In addition to the conditioning of pre-damaged organs for transplantation, this could lead to further applications in the context of targeted organ therapies and also to improved transplant logistics in the future.

Hypothermic Oxygenated machine PErfusion (HOPE) has recently emerged as a preservation technique which can reduce ischemic injury and improve clinical outcomes following liver transplantation. First developed with the advent solid organ transplantation techniques, hypothermic machine perfusion largely fell out of favour following the development of preservation solutions which can satisfactorily preserve grafts using the cheap and simple method, static cold storage (SCS). However, with an increasing need to develop techniques to reduce graft injury and better utilise marginal and donation after circulatory death (DCD) grafts, HOPE has emerged as a relatively simple and safe technique to optimise clinical outcomes following liver transplantation. Perfusing the graft with cold, acellular, oxygenated perfusate either via the portal vein (PV) alone, or via both the PV and hepatic artery (HA), HOPE is generally commenced for a period of 1-2 h immediately prior to implantation. The technique has been validated by multiple randomised control trials, and pre-clinical evidence suggests HOPE primarily reduces graft injury by decreasing the accumulation of harmful mitochondrial intermediates, and subsequently, the severity of post-reperfusion injury. HOPE can also facilitate real time graft assessment, most notably via the measurement of flavin mononucleotide (FMN) in the perfusate, allowing transplant teams to make better informed clinical decisions prior to transplantation. HOPE may also provide a platform to administer novel therapeutic agents to ex situ organs without risk of systemic side effects. As such, HOPE is uniquely positioned to revolutionise how liver transplantation is approached and facilitate optimised clinical outcomes for liver transplant recipients.

The shortage of donor liver hinders the development of liver transplantation. This study aimed to clarify the poor outcomes of functionally marginal liver grafts (FMLs) and provide evidence for the improvement of ischemia-free liver transplantation (IFLT) after FML transplantation.

Propensity score matching was used to control for confounding factors. The outcomes of the control group and FML group were compared to demonstrate the negative impact of FMLs on liver transplantation patients. We compared the clinical improvements of the different surgical types. To elucidate the underlying mechanism, we conducted bioinformatic analysis based on transcriptome and single-cell profiles.

FMLs had a significantly greater hazard ratio (HR: 1.969, P=0.018) than did other marginal livers. A worse 90-day survival (Mortality: 12.3% vs. 5.0%, P=0.007) was observed in patients who underwent FML transplantation. Patients who received FMLs had a significant improvement in overall survival after IFLT (Mortality: 10.4% vs 31.3%, P=0.006). Pyroptosis and inflammation were inhibited in patients who underwent IFLT. The infiltration of natural killer cells was lower in liver grafts from these patients. Bulk transcriptome profiles revealed a positive relationship between IL-32 and Caspase 1 (R=0.73, P=0.01) and between IL-32 and Gasdermin D (R=0.84, P=0.0012).

FML is a more important negative prognostic parameter than other marginal liver parameters. IFLT might ameliorate liver injury in FMLs by inhibiting the infiltration of NK cells, consequently leading to the abortion of IL-32, which drives pyroptosis in monocytes and macrophages.

The shortage of donor organs remains an unresolved issue in livertransplantation worldwide. Consequently, strategies for expanding the donor pool are currently being developed. Donors meeting extended criteria undergo thorough evaluation, as livers obtained from marginal donors yield poorer outcomes in recipients, including exacerbated reperfusion injury, acute kidney injury, early graft dysfunction, and primary nonfunctioning graft. However, the implementation of machine perfusion has shown excellent potential in preserving donor livers and improving their characteristics to achieve better outcomes for recipients. In this review, we analyzed the global experience of using machine perfusion in livertransplantation through the history ofthe development ofthis method to the latest trends and possibilities for increasing the number of liver transplants.

The magnitude of potential benefits that hypothermic oxygenated perfusion (HOPE) may provide for liver transplantation (LT) patients compared to static cold storage (SCS) remains uncertain. In this systematic review and meta-analysis, we aimed to investigate the therapeutic effect that HOPE can offer LT recipients relative to SCS by synthesizing available evidence.

A literature search was conducted in Embase, Medline, Web of Science, and the Cochrane database up to 1 June, 2023. The included studies were pooled for meta-analysis to synthesize their findings. Subgroup analysis was performed to investigate potential differences between HOPE and SCS for specific subgroups.

A total of 11 studies comprising 1765 patients were included. Compared with SCS, HOPE was associated with a significant reduction in the incidence of early allograft dysfunction (EAD) (OR: 0.36, 95% CI: 0.26-0.50), as well as a noteworthy decrease in graft loss rate within one year (OR: 0.57, 95% CI: 0.33-0.97) and a lower occurrence of Clavien-Dindo grade IIIa or higher complications (OR: 0.62, 95% CI: 0.43-0.89). Subgroup analysis revealed that HOPE significantly reduced the one-year mortality rate, any biliary complications incidence, and acute rejection of transplanted liver rate in patients who received organs from donation after cardiac death (DCD).

HOPE has demonstrated efficacy in reducing the incidence of EAD after LT and shows some potential in diminishing postoperative complications such as biliary complications and acute rejection. This ultimately leads to improved patient prognosis, particularly among those receiving DCD grafts.

Since the advent of University of Wisconsin preservation solution in the 1980s, clinicians have learned to work within its confines. While affording improved outcomes, considerable limitations still exist and contribute to the large number of livers that go unused each year, often for fear they may never work. The last 10 years have seen the widespread availability of new perfusion modalities which provide an opportunity for assessing organ viability and prolonged organ storage. This review will discuss the role of in situ normothermic regional perfusion for livers donated after circulatory death. It will also describe the different modalities of ex situ perfusion, both normothermic and hypothermic, and discuss how they are thought to work and the opportunities afforded by them.

While 4 randomized controlled clinical trials confirmed the early benefits of hypothermic oxygenated machine perfusion (HOPE), high-level evidence regarding long-term clinical outcomes is lacking. The aim of this follow-up study from the HOPE-ECD-DBD trial was to compare long-term outcomes in patients who underwent liver transplantation using extended criteria donor allografts from donation after brain death (ECD-DBD), randomized to either HOPE or static cold storage (SCS).

Between September 2017 and September 2020, recipients of liver transplantation from 4 European centers receiving extended criteria donor-donation after brain death allografts were randomly assigned to HOPE or SCS (1:1). Follow-up data were available for all patients. Analyzed endpoints included the incidence of late-onset complications (occurring later than 6 months and graded according to the Clavien-Dindo Classification and the Comprehensive Complication Index) and long-term graft survival and patient survival.

A total of 46 patients were randomized, 23 in both arms. The median follow-up was 48 months (95% CI: 41-55). After excluding early perioperative morbidity, a significant reduction in late-onset morbidity was observed in the HOPE group (median reduction of 23 Comprehensive Complication Index-points [p=0.003] and lower incidence of major complications [Clavien-Dindo ≥3, 43% vs. 85%, p=0.009]). Primary graft loss occurred in 13 patients (HOPE n=3 vs. SCS n=10), resulting in a significantly lower overall graft survival (p=0.029) and adverse 1-, 3-, and 5-year survival probabilities in the SCS group, which did not reach the level of significance (HOPE 0.913, 0.869, 0.869 vs. SCS 0.783, 0.606, 0.519, respectively).

Our exploratory findings indicate that HOPE reduces late-onset morbidity and improves long-term graft survival providing clinical evidence to further support the broad implementation of HOPE in human liver transplantation.

Given the current severe shortage of available livers for transplantation, there is an urgent need to maximize the utilization of donor organs. One of the strategies to increase the number of available livers for transplantation is to improve organ utilization through the use of elderly, overweight, or organs donated after circulatory death. However, the utilization of these "marginal" organs was associated with an increased risk of early allograft dysfunction, primary nonfunction, ischemic biliary complications, or even re-transplantation. Ischemia-reperfusion injury is a key mechanism in the pathogenesis of these complications.

Intestine transplantation (IT) is a critical treatment strategy for irreversible intestinal failure. Among all abdominal solid organ transplants, the intestine was the most vulnerable to ischemia and reperfusion injury (IRI). The static cold storage (SCS) technique is currently the most commonly used graft preservation method, but its hypoxia condition causes metabolic disorders, resulting in the occurrence of IRI, limiting its application in marginal organs. It is especially important to improve preservation techniques in order to minimize damage to marginal donor organs, which draws more attention to machine perfusion (MP). There has been much debate about whether it is necessary to increase oxygen in these conditions to support low levels of metabolism since the use of machine perfusion to preserve organs. There is evidence that oxygenation helps to restore intracellular ATP levels in the intestine after thermal or cold ischemia damage. The goal of this review is to provide an overview of the role of oxygen in maintaining environmental stability in the gut under hypoxic conditions, as well as to investigate the possibilities and mechanisms of oxygen delivery during preservation in intestine transplantation studies and clinical models.

Hypothermic oxygenated machine perfusion (HOPE) is a novel organ-preservation technology designed to optimize organ quality. However, the effects of HOPE on morbidity and mortality after liver transplantation remain unclear. This meta-analysis evaluated the potential benefits of HOPE in liver transplantation.

The Embase, Web of Science, PubMed, Cochrane Library, and Scopus databases were searched for articles published up to 15 June 2023 (updated on 12 August 2023). Mean differences (MDs), risk ratios (RRs), and 95% confidence intervals were calculated.

Eleven studies encompassing five randomized controlled trials and six matched studies were included, with a total of 1000 patients. HOPE did not reduce the incidence of major postoperative complications (RR 0.80), primary non-function (PNF) (RR 0.54), reperfusion syndrome (RR 0.92), hepatic artery thrombosis (RR 0.92), renal replacement therapy (RR 0.98), length of hospital stay (MD, -1.38 days), 1-year recipient death (RR 0.67), or intensive care unit stay (MD, 0.19 days) after liver transplantation. HOPE reduced the incidence of biliary complications (RR 0.74), non-anastomotic biliary strictures (NAS) (RR 0.34), early allograft dysfunction (EAD) (RR 0.54), and acute rejection (RR 0.54). In addition, HOPE improved the retransplantation (RR 0.42) and 1-year graft loss rates (RR 0.38).

Compared with static cold storage (SCS), HOPE can reduce the incidence of biliary complications, NAS, EAD, and acute rejection and retransplantation rate after liver transplantation and improve the 1-year graft loss rate. These findings suggest that HOPE, when compared to SCS, can contribute to minimizing complications and enhancing graft survival in liver transplantation. Further research is needed to investigate long-term outcomes and confirm the promising advantages of HOPE in liver transplantation settings.

Normothermic machine perfusion (NMP) after static cold storage is increasingly used for preservation and assessment of human donor livers prior to transplantation. Biliary viability assessment during NMP reduces the risk of post-transplant biliary complications. However, understanding of molecular changes in the biliary system during NMP remains incomplete. We performed an in-depth, unbiased proteomics analysis of bile collected during sequential hypothermic machine perfusion, rewarming and NMP of 55 human donor livers. Longitudinal analysis during NMP reveals proteins reflective of cellular damage at early stages, followed by upregulation of secretory and immune response processes. Livers with bile chemistry acceptable for transplantation reveal protein patterns implicated in regenerative processes, including cellular proliferation, compared to livers with inadequate bile chemistry. These findings are reinforced by detection of regenerative gene transcripts in liver tissue before machine perfusion. Our comprehensive bile proteomics and liver transcriptomics data sets provide the potential to further evaluate molecular mechanisms during NMP and refine viability assessment criteria.

Liver transplantation is the most successful treatment for limited-stage HCC. The waiting time for liver transplantation (LT) can be a critical factor affecting the oncological prognosis and outcome of patients with HCC. Efficient strategies to optimize waiting time are essential to maximize the benefits of LT and to reduce the harm of delay in transplantation. The ever-increasing demand for donor livers emphasizes the need to improve the organization of the waiting list for transplantation and to optimize organ availability for patients with and without HCC. Current progress in innovations to expand the donor pool includes the implementation of living donor LT and the use of grafts from extended donors. By expanding selection criteria, an increased number of patients are eligible for transplantation, which necessitates criteria to prevent futile transplantations. Thus, the selection criteria for LT have evolved to include not only tumor characteristics but biomarkers as well. Enhancing our understanding of HCC tumor biology through the analysis of subtypes and molecular genetics holds significant promise in advancing the personalized approach for patients. In this review, the effect of waiting time duration on outcome in patients with HCC enlisted for LT is discussed.

The increasing use of extended criteria donors (ECD) sets higher requirements for graft preservation. Machine perfusion (MP) improves orthotopic liver transplantation (OLT) outcomes, but its effects on different donor types remains unclear. The authors' aim was to assess the effects of hypothermic machine perfusion (HMP), normothermic machine perfusion (NMP), or normothermic regional perfusion (NRP) versus static cold storage (SCS) on different donor types.

A literature search comparing the efficacy of MP versus SCS in PubMed, Cochrane, and EMBASE database was conducted. A meta-analysis was performed to obtain pooled effects of MP on ECD, donation after circulatory death (DCD), and donor after brainstem death.

Thirty nine studies were included (nine randomized controlled trials and 30 cohort studies). Compared with SCS, HMP significantly reduced the risk of non-anastomotic biliary stricture (NAS) [odds ratio (OR) 0.43, 95% confidence interval (CI) 0.26-0.72], major complications (OR 0.55, 95% CI 0.39-0.78), and early allograft dysfunction (EAD) (OR 0.46, 95% CI 0.32-0.65) and improved 1-year graft survival (OR 2.36, 95% CI 1.55-3.62) in ECD-OLT. HMP also reduced primary non-function (PNF) (OR 0.40, 95% CI 0.18-0.92) and acute rejection (OR 0.62, 95% CI 0.40-0.97). NMP only reduced major complications in ECD-OLT (OR 0.56, 95% CI 0.34-0.94), without favorable effects on other complications and survival. NRP lowered the overall risk of NAS (OR 0.27, 95% CI 0.11-0.68), PNF (OR 0.43, 95% CI 0.22-0.85), and EAD (OR 0.58, 95% CI 0.42-0.80) and meanwhile improved 1-year graft survival (OR 2.40, 95% CI 1.65-3.49) in control DCD-OLT.

HMP might currently be considered for marginal livers as it comprehensively improves ECD-OLT outcomes. NMP assists some outcomes in ECD-OLT, but more evidence regarding NMP-ECD is warranted. NRP significantly improves DCD-OLT outcomes and is recommended where longer non-touch periods exist.

To assess whether end-ischemic hypothermic oxygenated machine perfusion (HOPE) is superior to static cold storage (SCS) in preserving livers procured from donors after brain death (DBD).

There is increasing evidence of the benefits of HOPE in liver transplantation, but predominantly in the setting of high-risk donors.

In this randomized clinical trial, livers procured from DBDs were randomly assigned to either end-ischemic dual HOPE for at least 2 hours or SCS (1:3 allocation ratio). The Model for Early Allograft Function (MEAF) was the primary outcome measure. The secondary outcome measure was 90-day morbidity (ClinicalTrials. gov, NCT04812054).

Of the 104 liver transplantations included in the study, 26 were assigned to HOPE and 78 to SCS. Mean MEAF was 4.94 and 5.49 in the HOPE and SCS groups ( P =0.24), respectively, with the corresponding rates of MEAF >8 of 3.8% (1/26) and 15.4% (12/78; P =0.18). Median Comprehensive Complication Index was 20.9 after transplantations with HOPE and 21.8 after transplantations with SCS ( P =0.19). Transaminase activity, bilirubin concentration, and international normalized ratio were similar in both groups. In the case of donor risk index >1.70, HOPE was associated with significantly lower mean MEAF (4.92 vs 6.31; P =0.037) and lower median Comprehensive Complication Index (4.35 vs 22.6; P =0.050). No significant differences between HOPE and SCS were observed for lower donor risk index values.

Routine use of HOPE in DBD liver transplantations does not seem justified as the clinical benefits are limited to high-risk donors.

Liver transplantation is the only chance of cure for people with end-stage liver disease and some people with advanced liver cancers or acute liver failure. The increasing prevalence of these conditions drives demand and necessitates the increasing use of donated livers which have traditionally been considered suboptimal. Several novel machine perfusion preservation technologies have been developed, which attempt to ameliorate some of the deleterious effects of ischaemia reperfusion injury. Machine perfusion technology aims to improve organ quality, thereby improving outcomes in recipients of suboptimal livers when compared to traditional static cold storage (SCS; ice box).

To evaluate the effects of different methods of machine perfusion (including hypothermic oxygenated machine perfusion (HOPE), normothermic machine perfusion (NMP), controlled oxygenated rewarming, and normothermic regional perfusion) versus each other or versus static cold storage (SCS) in people undergoing liver transplantation.

We used standard, extensive Cochrane search methods. The latest search date was 10 January 2023.

We included randomised clinical trials which compared different methods of machine perfusion, either with each other or with SCS. Studies comparing HOPE via both hepatic artery and portal vein, or via portal vein only, were grouped. The protocol detailed that we also planned to include quasi-randomised studies to assess treatment harms.

We used standard Cochrane methods. Our primary outcomes were 1. overall participant survival, 2. quality of life, and 3. serious adverse events. Secondary outcomes were 4. graft survival, 5. ischaemic biliary complications, 6. primary non-function of the graft, 7. early allograft function, 8. non-serious adverse events, 9. transplant utilisation, and 10. transaminase release during the first week post-transplant. We assessed bias using Cochrane's RoB 2 tool and used GRADE to assess certainty of evidence.

We included seven randomised trials (1024 transplant recipients from 1301 randomised/included livers). All trials were parallel two-group trials; four compared HOPE versus SCS, and three compared NMP versus SCS. No trials used normothermic regional perfusion. When compared with SCS, it was uncertain whether overall participant survival was improved with either HOPE (hazard ratio (HR) 0.91, 95% confidence interval (CI) 0.42 to 1.98; P = 0.81, I2 = 0%; 4 trials, 482 recipients; low-certainty evidence due to imprecision because of low number of events) or NMP (HR 1.08, 95% CI 0.31 to 3.80; P = 0.90; 1 trial, 222 recipients; very low-certainty evidence due to imprecision and risk of bias). No trials reported quality of life. When compared with SCS alone, HOPE was associated with improvement in the following clinically relevant outcomes: graft survival (HR 0.45, 95% CI 0.23 to 0.87; P = 0.02, I2 = 0%; 4 trials, 482 recipients; high-certainty evidence), serious adverse events in extended criteria DBD liver transplants (OR 0.45, 95% CI 0.22 to 0.91; P = 0.03, I2 = 0%; 2 trials, 156 participants; moderate-certainty evidence) and clinically significant ischaemic cholangiopathy in recipients of DCD livers (OR 0.31, 95% CI 0.11 to 0.92; P = 0.03; 1 trial, 156 recipients; high-certainty evidence). In contrast, NMP was not associated with improvement in any of these clinically relevant outcomes. NMP was associated with improved utilisation compared with SCS (one trial found a 50% lower rate of organ discard; P = 0.008), but the reasons underlying this effect are unknown. We identified 11 ongoing studies investigating machine perfusion technologies.

In situations where the decision has been made to transplant a liver donated after circulatory death or donated following brain death, end-ischaemic HOPE will provide superior clinically relevant outcomes compared with SCS alone. Specifically, graft survival is improved (high-certainty evidence), serious adverse events are reduced (moderate-certainty evidence), and in donors after circulatory death, clinically relevant ischaemic biliary complications are reduced (high-certainty evidence). There is no good evidence that NMP has the same benefits over SCS in terms of these clinically relevant outcomes. NMP does appear to improve utilisation of grafts that would otherwise be discarded with SCS; however, the reasons for this, and whether this effect is specific to NMP, is not clear. Further studies into NMP viability criteria and utilisation, as well as head-to-head trials with other perfusion technologies are needed. In the setting of donation following circulatory death transplantation, further trials are needed to assess the effect of these ex situ machine perfusion methods against, or in combination with, normothermic regional perfusion.

Owing to inherent limitations of static cold storage, marginal liver grafts from donors after circulatory death and extended criteria donors after brain death are prone to be discarded secondary to the increased risk of severe early allograft dysfunction and ischemic cholangiopathy. Marginal liver grafts resuscitated with hypothermic machine perfusion and normothermic machine perfusion demonstrate lower degree of ischemia-reperfusion injury and have decreased risk of severe early allograft dysfunction and ischemic cholangiopathy. Marginal grafts preserved by ex vivo machine perfusion technology can be used to rescue patients with acute-on-chronic liver failure who are underserved by the current deceased donor liver allocation system.

Hepatic ischemia-reperfusion injury (IRI) in donation after cardiac death (DCD) donors is a major determinant of transplantation success. Endoplasmic reticulum (ER) stress plays a key role in hepatic IRI, with potential involvement of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway and the antiapoptotic protein hematopoietic-lineage substrate-1-associated protein X-1 (HAX1). In this study, we aimed to investigate the effects of hypothermic oxygenated perfusion (HOPE), an organ preservation modality, on ER stress and apoptosis during hepatic IRI in a DCD rat model.

To investigate whether HOPE could improve IRI in DCD livers, levels of different related proteins were examined by western blotting and quantitative real-time polymerase chain reaction. Further expression analyses, immunohistochemical analyses, immunofluorescence staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, and transmission electron microscopy were conducted to analyze the effects of HOPE on ER stress and apoptosis. To clarify the role of the JAK2/STAT3 pathway and HAX1 in this process, AG490 inhibitor, JAX1 plasmid transfection, co-immunoprecipitation (CO-IP), and flow cytometry analyses were conducted.

HOPE reduced liver injury and inflammation while alleviating ER stress and apoptosis in the DCD rat model. Mechanistically, HOPE inhibited unfolded protein responses by activating the JAK2/STAT3 pathway, thus reducing ER stress and apoptosis. Moreover, the activated JAK2/STAT3 pathway upregulated HAX1, promoting the interaction between HAX1 and SERCA2b to maintain ER calcium homeostasis. Upregulated HAX1 also modulated ER stress and apoptosis by inhibiting the inositol-requiring enzyme 1 (IRE1) pathway.

JAK2/STAT3-mediated upregulation of HAX1 during HOPE alleviates hepatic ER stress and apoptosis, indicating the JAK2/STAT3/HAX1 pathway as a potential target for IRI management during DCD liver transplantation.

Organ transplantation remains the only treatment option for patients with end-stage organ failure. The last decade has seen a flurry of activity in improving organ preservation technologies, which promise to increase utilization in a dramatic fashion. They also bring the promise of extending the preservation duration significantly, which opens the doors to sharing organs across local and international boundaries and transforms the field. In this work, we review the recent literature on machine perfusion of livers across various protocols in development and clinical use, in the context of extending the preservation duration. We then review the next generation of technologies that have the potential to further extend the limits and open the door to banking organs, including supercooling, partial freezing, and nanowarming, and outline the opportunities arising in the field for researchers in the short and long term.