[Machine perfusion in transplantation surgery]. / Maschinenperfusion in der Transplantationschirurgie.

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.

Cost effectiveness of commercial portable ex vivo lung perfusion at a low-volume US lung transplant center.

BACKGROUND: Portable ex vivo lung perfusion during lung transplantation is a resource-intensive technology. In light of its increasing use, we evaluated the cost-effectiveness of ex vivo lung perfusion at a low-volume lung transplant center in the USA. METHODS: Patients listed for lung transplantation (2015-2021) in the United Network for Organ Sharing database were included. Quality-of-life was approximated by Karnofsky Performance Status scores 1-year post-transplant. Total transplantation encounter and 1-year follow-up costs accrued by our academic center for patients listed from 2018 to 2021 were obtained. Cost-effectiveness was calculated by evaluating the number of patients attaining various Karnofsky scores relative to cost. RESULTS: Of the 13 930 adult patients who underwent lung transplant in the United Network for Organ Sharing database, 13 477 (96.7%) used static cold storage and 453 (3.3%) used ex vivo lung perfusion, compared to 30/58 (51.7%) and 28/58 (48.3%), respectively, at our center. Compared to static cold storage, median total costs at 1 year were higher for ex vivo lung perfusion ($918 000 vs. $516 000; p = 0.007) along with the cost of living 1 year with a Karnofsky functional status of 100 after transplant ($1 290 000 vs. $841 000). In simulated scenarios, each Karnofsky-adjusted life year gained by ex vivo lung perfusion was 1.00-1.72 times more expensive. CONCLUSIONS: Portable ex vivo lung perfusion is not currently cost-effective at a low-volume transplant centers in the USA, being 1.53 times more expensive per Karnofsky-adjusted life year. Improving donor lung and/or recipient biology during ex vivo lung perfusion may improve its utility for routine transplantation.

Graft repair during machine perfusion: a current overview of strategies.

PURPOSE OF REVIEW: With changing donor characteristics (advanced age, obesity), an increase in the use of extended criteria donor (ECD) livers in liver transplantation is seen. Machine perfusion allows graft viability assessment, but still many donor livers are considered nontransplantable. Besides being used as graft viability assessment tool, ex situ machine perfusion offers a platform for therapeutic strategies to ameliorate grafts prior to transplantation. This review describes the current landscape of graft repair during machine perfusion. RECENT FINDINGS: Explored anti-inflammatory therapies, including inflammasome inhibitors, hemoabsorption, and cellular therapies mitigate the inflammatory response and improve hepatic function. Cholangiocyte organoids show promise in repairing the damaged biliary tree. Defatting during normothermic machine perfusion shows a reduction of steatosis and improved hepatobiliary function compared to nontreated livers. Uptake of RNA interference therapies during machine perfusion paves the way for an additional treatment modality. SUMMARY: The possibility to repair injured donor livers during ex situ machine perfusion might increase the utilization of ECD-livers. Application of defatting agents is currently explored in clinical trials, whereas other therapeutics require further research or optimization before entering clinical research.

Machine perfusion organ preservation: Highlights from the American Transplant Congress 2023.

The American Transplant Congress (ATC) 2023, held in San Diego, California, emerged as a pivotal platform showcasing the latest advancements in organ machine perfusion, a key area in solid organ and tissue transplantation. This year's congress, attended by over 4500 participants, including leading experts, emphasized innovations in machine perfusion technologies across various organ types, including liver, kidney, heart, and lung. A total of 85 abstracts on organ machine perfusion were identified. Noteworthy advancements included the use of normothermic machine perfusion in mitigating ex-situ reperfusion injury in liver transplantation, the potential of biomarkers in assessing organ quality, and the impact of machine perfusion on graft survival and ischemic cholangiopathy incidence. Kidney transplantation saw promising developments in novel preservation methods, such as subzero storage and pulsatile perfusion. Heart and lung sessions revealed significant progress in preservation techniques, including metabolic alterations to extend organ preservation time. The conference also highlighted the growing interest in machine perfusion applications in pediatric transplantation, multi-visceral organ recovery, Vascularized Composite Allotransplantation, and discussions on novel technologies for monitoring and optimizing perfusion protocols. Additionally, ATC 2023 included critical discussions on ethical concerns, legal implications, and the evolving definition of death in the era of machine preservation, illustrating the complex landscape of transplantation science. Overall, ATC 2023 showcased significant strides in machine perfusion and continued its tradition of fostering global knowledge exchange, further cementing machine perfusion's role as a transformative force in improving transplant outcomes and expanding the donor pool.

Full-left/Full-right Liver Splitting With Middle Hepatic Vein and Caval Partition During Dual Hypothermic Oxygenated Machine Perfusion.

BACKGROUND: Split liver transplantation is a valuable means of mitigating organ scarcity but requires significant surgical and logistical effort. Ex vivo splitting is associated with prolonged cold ischemia, with potentially negative effects on organ viability. Machine perfusion can mitigate the effects of ischemia-reperfusion injury by restoring cellular energy and improving outcomes. METHODS: We describe a novel technique of full-left/full-right liver splitting, with splitting and reconstruction of the vena cava and middle hepatic vein, with dual arterial and portal hypothermic oxygenated machine perfusion. The accompanying video depicts the main surgical passages, notably the splitting of the vena cava and middle hepatic vein, the parenchymal transection, and the venous reconstruction. RESULTS: The left graft was allocated to a pediatric patient having methylmalonic aciduria, whereas the right graft was allocated to an adult patient affected by hepatocellular carcinoma and cirrhosis. CONCLUSIONS: This technique allows ex situ splitting, counterbalancing prolonged ischemia with the positive effects of hypothermic oxygenated machine perfusion on graft viability. The venous outflow is preserved, safeguarding both grafts from venous congestion; all reconstructions can be performed ex situ, minimizing warm ischemia. Moreover, there is no need for highly skilled surgeons to reach the donor hospital, thereby simplifying logistical aspects.

27 MHz constant field dielectric warming of kidneys cryopreserved by vitrification.

Organs cryopreserved by vitrification are exposed to the lowest possible concentration of cryoprotectants for the least time necessary to successfully avoid ice formation. Faster cooling and warming rates enable lower concentrations and perfusion times, reducing toxicity. Since warming rates necessary to avoid ice formation during recovery from vitrification are typically faster than cooling rates necessary for vitrification, warming speed is a major determining factor for successful vitrification. Dielectric warming uses an oscillating electric field to directly heat water and cryoprotectant molecules inside organs to achieve warming that's faster and more uniform than can be achieved by heat conduction from the organ surface. This work studied 27 MHz dielectric warming of rabbit kidneys perfused with M22 vitrification solution. The 27 MHz frequency was chosen because its long wavelength and penetration depth are suitable for human organs, because it had an anticipated favorable temperature of maximum dielectric absorption in M22, and because it's an allocated frequency for industrial and amateur use with inexpensive amplifiers available. Previously vitrified kidneys were warmed from -100 °C by placement in a 27 MHz electric field formed between parallel capacitor plates in a resonant circuit. Power was varied during warming to maintain constant electric field amplitude between the plates. Maximum power absorption occurred near -70 °C, with a peak warming rate near 150 °C/min in 50 mL total volume with approximately 500 W power. After some optimization, it was possible to warm ∼13 g vitrified kidneys with unprecedentedly little injury from medullary ice formation and a favorable serum creatinine trend after transplant. Distinct behaviors of power absorption and system tuning observed as a function of temperature during warming are promising for non-invasive thermometry and future automated control of the warming process at even faster rates with user-defined temperature dependence.

Preclinical validation of a customized circuit for ex situ uninterrupted cold-to-warm prolonged perfusion of the liver.

CONTEXT: Clinical adoption of ex situ liver perfusion is growing. While hypothermic perfusion protects against ischemia-reperfusion injury in marginal grafts, normothermic perfusion enables organ viability assessment and therefore selection of borderline grafts. The combination of hypothermic and normothermic perfusion, known as "cold-to-warm," may be the optimal sequence for organ preservation, but is difficult to achieve with most commercial perfusion systems. We developed an adaptable customized circuit allowing uninterrupted "cold-to-warm" perfusion and conducted preclinical studies on healthy porcine livers and discarded human livers to demonstrate the circuit's efficacy. METHODS: In collaboration with bioengineers, we developed a customized circuit that adapts to extracorporeal circulation consoles used in cardiovascular surgery and includes a proprietary reservoir enabling easy perfusate change without interrupting perfusion. This preclinical study was conducted on porcine and human livers. Perfusion parameters (pressures, flows, oxygenation) and organ viability were monitored. RESULTS: The customized circuit was adapted to a LivaNova S5® console, and the perfusions were flow-driven with real-time pressure monitoring. Ten porcine liver and 12 discarded human liver perfusions were performed during 14 to 18 h and 7 to 25 h, respectively. No hyperpressure was observed (porcine and human portal pressure 2-6 and 2-8 mm Hg; arterial pressure 10-65 and 20-65 mm Hg, respectively). No severe histological tissue injury was observed (Suzuki score ≤ 3 at the end of perfusion). Seven (70%) porcine livers and five (42%) human livers met the UK viability criteria. CONCLUSION: The customized circuit and system design enables smooth uninterrupted "cold-to-warm" perfusion not present in current commercial perfusion systems.

Incorporating a hemodialysis filter into a commercial normothermic perfusion system to facilitate long-term preservation of human split-livers.

BACKGROUND: Normothermic machine perfusion (NMP) allows for the assessment and resuscitation of ex-vivo human livers prior to transplantation. Commercially available NMP systems are closed circuits that accumulate metabolic waste and cytokines over time, potentially limiting organ preservation times. Dialysis has been proposed as a method to remove waste and excess fluid from such systems. This study aimed to demonstrate the utility of integrating dialysis into a commercially available system by quantifying solute removal. METHODS: A dialysis filter was attached in parallel to a commercially available liver perfusion system. Three livers declined for transplantation were split before undergoing long-term NMP with blood using the modified system. During perfusion, dialysate flow rates were set in the range of 100-600 mL/h for short periods of time. At each flow rate, perfusate and spent dialysate samples were collected and analyzed for solute clearance. RESULTS: The addition of dialysis to a commercial NMP system removed water-soluble waste and helped regulate electrolyte concentrations. Interleukin-6 was successfully removed from the perfusate. Solute clearance was proportional to dialysate flow rate. A guide for our perfusion setup was created for the appropriate selection of dialysis flow rates and duration based on real-time perfusate composition. CONCLUSIONS: Dialysis circuits can efficiently remove waste and regulate perfusate composition, and can be easily incorporated to improve the performance of commercially available systems. Quantification of the effect of dialysis on perfusate composition enables refined dialysis control to optimize electrolyte profiles and avoid the over- or under-correction of key solutes.

The establishment of diseased human whole organ model by normothermic machine perfusion technique: Principle of concept.

BACKGROUND: The global incidence of liver diseases is rising, yet there remains a dearth of precise research models to mimic these diseases. The use of normothermic machine perfusion (NMP) to study diseased livers recovered from liver transplantation (LT) recipients presents a promising avenue. Accordingly, we have developed a machine perfusion system tailored specifically for the human whole diseased livers and present our experience from the NMP of diseased livers. METHODS: Six diseased livers recovered from LT recipients with different diagnoses were collected. The diseased livers were connected to the machine perfusion system that circulated tailored perfusate, providing oxygen and nutrients. The pressure and flow of the system were recorded, and blood gas analysis and laboratory tests of perfusate and bile were examined to analyze the function of the diseased livers. Liver tissues before and after NMP were collected for histological analysis. RESULTS: Experiments showed that the system maintained the diseased livers in a physiological state, ensuring stable hemodynamics and a suitable partial pressure of oxygen and carbon dioxide. The results of blood gas analysis and laboratory tests demonstrated a restoration and sustenance of metabolism with minimal damage. Notably, a majority of the diseased livers exhibited bile production continuously, signifying their vivid functional integrity. The pathological characteristics remained stable before and after NMP. CONCLUSION: We successfully established the machine perfusion system tailored specifically for diseased human whole livers. Through the application of this system, we have developed a novel in vitro model that faithfully recapitulates the main features of human liver disease. This model holds immense promise as an advanced disease modeling platform, offering profound insights into liver diseases and potential implications for research and therapeutic development.

The dynamics of cytokine release during 24 hours continuous normothermic machine perfusion liver preservation: An explorative porcine study.

BACKGROUND: Normothermic machine perfusion (NMP) has been proposed to preserve liver grafts in a less pro-inflammatory environment. However, the effect of NMP on liver inflammation remains unclear. Therefore, we aimed at characterizing the inflammatory response during continuous NMP with a comprehensive investigation of cytokine release during perfusion. METHODS: Ten porcine livers underwent either 24 h NMP or whole blood-based NMP (WB-NMP) immediately after procurement. WB-NMP was used as a positive control to mimic early post-reperfusion inflammation. High mobility group box-1 (HMGB1), interleukin 1-beta (IL-1beta), tumor necrosis factor-alpha (TNFalpha), interleukin 6 (IL-6), 8 (IL-8), and 10 (IL-10), transforming growth factor-beta (TGFbeta), aspartate transferase (AST), and hyaluronic acid were measured in the perfusate. The area under the curve (AUC) of their perfusate concentration was compared between groups. Median (IQR) is given. RESULTS: The AUC of HMGB1 and IL-1beta was similar between groups. Compared to WB-NMP, NMP inhibited the release of TNFalpha [NMP: 20275 (18402-32 152), WB-NMP: 242100 (203511-244 238); p = 0.01], IL-6 [NMP: 1206 (338.9-1686), WB-NMP: 8444 (7359-10 087); p = 0.03], and IL-8 [NMP: 1635 (106.90-2130), WB-NMP: 3951 (3090-4116); p = 0.008]. The release of TGFbeta remained unchanged but IL-10 release was lower in NMP [1612 (1313-1916), WB-NMP: 5591 (4312-6421); p = 0.01]. The ratios TGFbeta:TNFalpha and IL-10:TNFalpha were significantly higher in the NMP than in the WB-NMP group. Importantly, the AUC of AST was significantly lower during NMP [1960 (1950-2893)] than WB-NMP [6812 (6370-7916); p = 0.02]. CONCLUSIONS: Continuous NMP leads to the release of detectable levels of cytokines with a slow, linear increase over time and a shift toward anti-inflammatory signaling.

Transplantation of declined livers after normothermic perfusion.

BACKGROUND: The persistent shortage of liver allografts contributes to significant waitlist mortality despite efforts to increase organ donation. Normothermic machine perfusion holds the potential to enhance graft preservation, extend viability, and allow liver function evaluation in organs previously discarded because considered too high-risk for transplant. METHODS: Discarded livers from other transplant centers were transplanted after assessment and reconditioning with our institutionally developed normothermic machine perfusion device. We report here our preliminary data. RESULTS: Twenty-one human livers declined for transplantation were enrolled for assessment with normothermic machine perfusion. Six livers (28.5%) were ultimately discarded after normothermic machine perfusion because of insufficient lactate clearance (>4.1 mmol/L after 4 hours), limited bile production (<0.5 mI/h), or moderate macrosteatosis, whereas 15 (71.5%) were considered suitable for transplantation. Normothermic machine perfusion duration was from 3 hours, 49 minutes to 10 hours, 29 minutes without technical problems or adverse events. No intraoperative or major early postoperative complications occurred in all transplanted recipients. No primary nonfunction occurred after transplantation. Seven livers had early allograft dysfunction with fast recovery, and 1 patient developed ischemic cholangiopathy after 4 months treated with biliary stents. All other patients had good liver function with a follow-up time of 8 weeks to 14 months. CONCLUSION: In total, 71.5% of discarded livers subjected to ex vivo normothermic machine perfusion were successfully transplanted after organ perfusion and assessment using an institutionally built device. This study challenges the current viability criteria reported in the literature and calls for a standardization of viability markers collection, an essential condition for the advancement of the field.

Machine perfusion organ preservation: Highlights from the American Transplant Congress 2021.

The American Transplant Congress 2021 was a virtual meeting and occurred between June 4 and June 9 through an online platform. We highlighted abstracts discussing machine perfusion preservation, a hot topic that may become the gold standard of organ preservation in the future. A total of 33 abstracts on organ machine preservation (3 for heart, 4 for lungs, 18 for liver, and 8 for kidneys) were presented at the meeting. We selected 23 abstracts that showed advances including new approaches to organ preservation, promising treatments and biomarkers, cellular therapy, and novel research areas. Here, we summarize the new developments concerning machine perfusion in both experimental and clinical studies.

Oxygenated machine perfusion at room temperature as an alternative for static cold storage in porcine donor hearts.

BACKGROUND: There is a continued interest in ex situ heart perfusion as an alternative strategy for donor heart preservation. We hypothesize that oxygenated machine perfusion of donor hearts at a temperature that avoids both normothermia and deep hypothermia offers adequate and safe preservation. METHODS: Cardioplegia-arrested porcine donor hearts were randomly assigned to six hours of preservation using cold storage (CS, n = 5) or machine perfusion using an oxygenated acellular perfusate at 21°C (MP, n = 5). Subsequently, all grafts were evaluated using the Langendorff method for 120 min. Metabolic parameters and histology were analyzed. Systolic function was assessed by contractility and elastance. Diastolic function was assessed by lusitropy and stiffness. RESULTS: For both groups, in vivo baseline and post-Langendorff biopsies were comparable, as were lactate difference and myocardial oxygen consumption. Injury markers gradually increased and were comparable. Significant weight gain was seen in MP (p = 0.008). Diastolic function was not impaired in MP, and lusitropy was superior from 30 min up to 90 min of reperfusion. Contractility was superior in MP during the first hour of evaluation. CONCLUSION: We conclude that the initial functional outcome of MP-preserved hearts was transiently superior compared to CS, with no histological injury post-Langendorff. Our machine perfusion strategy could offer feasible and safe storage of hearts prior to transplantation. Future studies are warranted for further optimization.

The TransMedics Organ Care System for the liver receives FDA pre-market approval.

The Federal Drug Administration grants pre-market approval to TransMedics Organ Care System Liver, a platform designed to prolong donor organ viability via ex vivo perfusion in preparation for transplant.

A proof of concept study on real-time LiMAx CYP1A2 liver function assessment of donor grafts during normothermic machine perfusion.

No single reliable parameter exists to assess liver graft function of extended criteria donors during ex-vivo normothermic machine perfusion (NMP). The liver maximum capacity (LiMAx) test is a clinically validated cytochromal breath test, measuring liver function based on 13CO2 production. As an innovative concept, we aimed to integrate the LiMAx breath test with NMP to assess organ function. Eleven human livers were perfused using NMP. After one hour of stabilization, LiMAx testing was performed. Injury markers (ALT, AST, miR-122, FMN, and Suzuki-score) and lactate clearance were measured and related to LiMAx values. LiMAx values ranged between 111 and 1838 µg/kg/h, and performing consecutive LiMAx tests during longer NMP was feasible. No correlation was found between LiMAx value and miR-122 and FMN levels in the perfusate. However, a significant inverse correlation was found between LiMAx value and histological injury (Suzuki-score, R = - 0.874, P < 0.001), AST (R = - 0.812, P = 0.004) and ALT (R = - 0.687, P = 0.028). Furthermore, a significant correlation was found with lactate clearance (R = 0.683, P = 0.043). We demonstrate, as proof of principle, that liver function during NMP can be quantified using the LiMAx test, illustrating a positive correlation with traditional injury markers. This new breath-test application separates livers with adequate cytochromal liver function from inadequate ones and may support decision-making in the safe utilization of extended criteria donor grafts.

Hypothermic Oxygenated Machine Perfusion Reduces Early Allograft Injury and Improves Post-transplant Outcomes in Extended Criteria Donation Liver Transplantation From Donation After Brain Death: Results From a Multicenter Randomized Controlled Trial (HOPE ECD-DBD).

OBJECTIVE: The aim of this study was to evaluate peak serum alanine aminotransferase (ALT) and postoperative clinical outcomes after hypothermic oxygenated machine perfusion (HOPE) versus static cold storage (SCS) in extended criteria donation (ECD) liver transplantation (LT) from donation after brain death (DBD). BACKGROUND: HOPE might improve outcomes in LT, particularly in high-risk settings such as ECD organs after DBD, but this hypothesis has not yet been tested in a randomized controlled clinical trial (RCT). METHODS: Between September 2017 and September 2020, 46 patients undergoing ECD-DBD LT from four centers were randomly assigned to HOPE (n = 23) or SCS (n = 23). Peak-ALT levels within 7 days following LT constituted the primary endpoint. Secondary endpoints included incidence of postoperative complications [Clavien-Dindo classification (CD), Comprehensive Complication Index (CCI)], length of intensive care- (ICU) and hospital-stay, and incidence of early allograft dysfunction (EAD). RESULTS: Demographics were equally distributed between both groups [donor age: 72 (IQR: 59-78) years, recipient age: 62 (IQR: 55-65) years, labMELD: 15 (IQR: 9-25), 38 male and 8 female recipients]. HOPE resulted in a 47% decrease in serum peak ALT [418 (IQR: 221-828) vs 796 (IQR: 477-1195) IU/L, P = 0.030], a significant reduction in 90-day complications [44% vs 74% CD grade ≥3, P = 0.036; 32 (IQR: 12-56) vs 52 (IQR: 35-98) CCI, P = 0.021], and shorter ICU- and hospital-stays [5 (IQR: 4-8) vs 8 (IQR: 5-18) days, P = 0.045; 20 (IQR: 16-27) vs 36 (IQR: 23-62) days, P = 0.002] compared to SCS. A trend toward reduced EAD was observed for HOPE (17% vs 35%; P = 0.314). CONCLUSION: This multicenter RCT demonstrates that HOPE, in comparison to SCS, significantly reduces early allograft injury and improves post-transplant outcomes in ECD-DBD liver transplantation.

Characterizing and Tuning Perfusion Parameters Within an Innovative, Versatile Oxygenating Perfusion System.

The advantages of oxygenated perfusion are continuing to be demonstrated by many groups focused on improving the efficacy of tissue preservation for transplant, bioreactors for studies of basic tissue physiology, and closed-loop resuscitation. This work presents a novel and portable device that supplies oxygenated and pulsatile perfusion, both of which are regulated by a single pump-oxygenator component comprised of silicone tubes that are cyclically inflated/deflated with compressed oxygen. In this study, pump variables (oxygen supply pressure and length of a silicone tube) were evaluated against hydraulic elements that mimicked the vascular resistance of kidneys, livers, and hearts. The perfusion pressures, flow rates, and oxygenation rates produced by the device were characterized for all configurations of pump variables, and the pulse rates were tuned to improve performance. The device supplied perfusion pressures ranging from 3.5 to 109 mmHg, flow rates ranging from 1.4 to 71.8 mL min-1, and oxygenation rates up to 316.6 µmol min-1. From those results, it was determined that the device was capable of achieving perfusion parameters used in previous kidney, liver, and heart preservation studies. Ultimately, this research demonstrated the efficacy of a novel device that is designed to supply oxygenated perfusion across a range of applications.

Utilization of Paragonix SherpaPak for human donor heart preservation.

A heart transplant is the gold standard treatment for end stage heart failure. Preservation of the donor heart during its transfer from the hospital of the donor to that of the recipient has a significant impact on the outcome of the transplant procedure. Icebox storage is a conventional method utilized for this purpose that may not provide uniform cooling of the donor heart and does not allow monitoring of the temperature of the donor heart during preservation. The Paragonix SherpaPak Cardiac Transport System offers uniform cooling by suspending the donor heart in a preservation solution and provides continuous temperature monitoring.