The evolution of liver graft preservation strategies in liver transplantation
Editorial Commentary

The evolution of liver graft preservation strategies in liver transplantation

Wei Gao1,2#, Jiu-Lin Song1,2,3#, Shan Huang4#, Zhong-Yuan Cai5,6, Zhen-Yu Duan5,6, Xi Xu1,2, Chen Jin1,2, Tao Lv1,2, Gang Xu1,2, Jia-Yin Yang1,2

1Liver Transplant Center, Organ Transplant Center, Department of General Surgery, West China Hospital of Sichuan University, Chengdu, China; 2Laboratory of Liver Transplantation, Institute of Organ Transplantation, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital of Sichuan University, Chengdu, China; 3Department of Pediatric Surgery, West China Hospital of Sichuan University, Chengdu, China; 4Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China; 5Department of Radiology, Huaxi MR Research Center (HMRRC), Institution of Radiology and Medical Imaging, Liver Transplant Center, Organ Transplant Center, Department of General Surgery, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China; 6Psychoradiology Key Laboratory of Sichuan Province, and Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu, China

#These authors contributed equally to this work.

Correspondence to: Gang Xu, MD; Prof. Jia-Yin Yang, MD, PhD. Liver Transplant Center, Organ Transplant Center, Department of General Surgery, West China Hospital of Sichuan University, No. 37 Guoxue Xiang, Wuhou District, Chengdu 610000, China; Laboratory of Liver Transplantation, Institute of Organ Transplantation, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital of Sichuan University, Chengdu 610041, China. Email: gangxu@wchscu.edu.cn; doctoryjy@scu.edu.cn.

Keywords: Organ preservation; machine perfusion (MP); static cold storage (SCS); deep supercooling; vitrification technology

Submitted May 04, 2026. Accepted for publication May 14, 2026. Published online May 26, 2026.

doi: 10.21037/hbsn-2026-0393

Organ preservation is a critical step of organ transplantation and profoundly affects the availability of donor organs and the success rate of transplantation surgery. Static cold storage (SCS) currently serves as the standard method for human organ preservation. In brief, the donor organ is perfused with cold preservation solution and subsequently stored on ice. Low temperature reduces cellular metabolic activity, thereby alleviating ischemia-reperfusion injury (IRI) (1). The core principle of this method is to slow down the metabolic rate by lowering the temperature, thereby reducing cellular energy demand and extending the safe ex vivo preservation duration of donor organs (2). Compared with other preservation methods, SCS is simpler and easier to operate, but it has many disadvantages. Although SCS reduces metabolic demand, it tends to induce mitochondrial dysfunction, which is particularly detrimental to marginal donor organs (3). Furthermore, long-term cryopreservation may damage tissues and reduce the survival rate of donor organs; the time for SCS to effectively preserve organs is also limited, usually less than 24 hours (4). Taking liver as an example, the transplanted liver is generally stored in a static cold solution at 2–5 ℃, and most organ transplant centers will strive to control the cold ischemia time within 12 hours. Once this time is exceeded, the vitality of the liver will decrease proportionally (5). This substantially restricts the transportation of donor livers and elevates the risk of IRI. Therefore, exploring novel strategies for prolonged organ preservation can not only alleviate the shortage of donor organs, but also enable thorough quality evaluation, ex vivo intervention, and even repair and reconditioning of grafts, thereby improving organ utilization and transplantation prognosis. With the progress of research, many new preservation methods have emerged, aiming to prolong the preservation time, reduce postoperative complications, and increase the number of organs available for transplantation. It mainly includes deep cryogenic supercooling (DSC), vitrification preservation technology and machine perfusion. Each technology has different advantages according to different application scenarios.

Deep supercooling is a new type of hypothermic preservation technology, which can preserve biological samples below-10 degrees Celsius without ice crystal formation. Deep cryogenic technology can achieve organ preservation under ice-free conditions without adding permeable cryoprotectants. Compared with the traditional 4 ℃ SCS, the advantage of deep cryogenic technology is that it can significantly prolong the preservation time (6). In 2026, Li et al. first applied DSC technology to preserve rat kidneys at −10 ℃ without ice, and systematically compared it with SCS. The results showed that the recovery of renal function, energy metabolism and ischemic injury after 24-hour DSC preservation were better than SCS. More importantly, the effect of 96-hour DSC storage was comparable to that of 24-hour SCS, extending the effective preservation window by approximately fourfold. Therefore, this study suggests that DSC technology is easy to operate, significantly prolongs the preservation time and improves the quality of grafts, and has the potential to be clinically transformed to expand the use of donor kidneys (7). Although this technology prolongs the shelf life compared with SCS, it is still limited to the stage of animal research. In order to achieve clinical application, a large number of studies are needed to prove its safety and stability.

Vitrification technology refers to the process in which a liquid substance bypasses crystallization and directly transforms into an amorphous solid (glassy state) without crystallization during rapid cooling or continuous heating. Its essence is that in the finite temperature zone near the glass transition temperature, the degree of freedom of molecular rotation and translation is significantly limited, and the system deviates from the thermodynamic equilibrium to form a stable ice-free state. Since this process can effectively inhibit the nucleation and growth of ice crystals, it is regarded as a critical strategy for the long-term cryopreservation of cells, tissues and organs (8,9). Recent studies have achieved a milestone breakthrough in the rat kidney model. After long-term vitrification (100 days) and nano-rewarming, the kidney not only restores key functions such as urine generation, oxygen consumption and creatinine clearance during ex vivo perfusion, but also gradually restores renal function and maintains long-term animal survival after transplantation to bilateral nephrectomy rats (10). In addition, in the study of rat whole liver, the researchers used vascular perfusion technology to uniformly introduce nanoparticles into the liver, and successfully achieved ice-free vitrification preservation and rapid rewarming of the organ. The rewarmed liver can maintain a relatively complete tissue structure, vascular endothelial integrity, and retain some metabolic and secretory functions. This indicates that the liver still has high biological integrity after vitrification and nano-rewarming treatment, which can be used as a research direction in the future (11). Although vitrification and nanowarming hold great promise for long-term organ preservation, their clinical translation is still hindered by several critical challenges: high concentrations of cryoprotectants are prone to causing cellular damage and are difficult to penetrate the entire organ uniformly; nanowarming tends to induce temperature inhomogeneity and thermal stress in large-sized organs; and long-term safety remains a major concern. Therefore, to achieve clinical application, vitrification also requires a lot of research to screen out less toxic preservation solutions and rewarming nanoparticles.

Machine perfusion (MP) technology entered clinical practice in 2010. After years of research, the most commonly used clinical strategies currently include single/double-path hypothermic (2–10 ℃) oxygenated machine perfusion (D/HOPE), subnormothermic perfusion (15–30 ℃), normothermic machine perfusion (NMP, 35–37 ℃), and controlled rewarming perfusion (COR, 5–35 ℃) (4,12-15) (Table 1). Regarding the safety of MP, a retrospective cohort study of liver transplant recipients from March 2016 to June 2023 in a single center showed that compared with SCS, HOPE had no significant differences in infection risk, microbiological positive rate, donor-derived infection rate, and patient/graft survival rate within 10 days after liver transplantation. It has the potential to expand the donor pool without affecting the prognosis of recipients (16). In view of the effectiveness of MP, ex vivo machine can evaluate organ function, reduce IRI, reduce the incidence of ischemic biliary disease (IC), and prolong cold ischemia tolerance time (17). A systematic review (7 trials, 1024 liver transplantations) showed that compared with SCS, HOPE can improve graft survival, reduce serious adverse events, and reduce ischemic biliary complications of donation after death (DCD) donors (high/moderate conclusive evidence). Although NMP did not show the above benefits, it reduced the organ loss rate by 50% (18). While MP [especially HOPE and normothermic regional perfusion (NRP)] has the potential to reduce acute rejection in DCD liver transplantation, the existing evidence is still limited. The conclusion should be extrapolated cautiously, and its effects and underlying mechanisms deserve further in-depth study (19). Multiple studies have shown that the function of the graft can be evaluated by detecting lactic acid, bile and protein in the perfusion fluid. A prospective cohort study demonstrated that the concentration of syndecan-1 (Sdc-1) in the perfusion solution at 60 minutes after the initiation of HOPE could effectively predict early allograft dysfunction (EAD) after liver transplantation, with an area under the curve (AUC) of 0.73; the cut-off value of 808 ng/mL corresponded to an EAD incidence of 66.7%. Therefore, it is expected to be a supplementary biomarker for graft viability assessment during HOPE (20).

Table 1

Comparison of different machine perfusion methods

Machine perfusion method Temperature range Preservation time limits Advantages Disadvantages
HMP 2–10 ℃ (4) Heart, lung: ~6 h liver, intestine, pancreas: 8–12 h kidney: up to 36 h (4) Reduction of ATP depletion, reduction of cellular metabolism, remove toxic metabolites possibility to obtain perfusate sample for constant graft monitoring (12,13) Some cytoskeletal changes, increased ROS production after reoxygenation, loss of cellular phospholipids, high viscosity of perfusate at low temperatures increases shear stress (12,13)
SNMP 15–30 ℃ (4) Up to 24 h in liver; potentially up to day (4) Mitochondrial injury minimization, provide a balance between hypothermic and normothermic perfusion (12,13) Do not fully protect the graft from reperfusion injury, impairment of the physiological functions of the organ, real-time assessment of liver function is inferior to NMP (12,13)
NMP 35–37 ℃ 68 h reported in liver4 but upper limits ill-defined (4) Similar nutrition and oxygen level as in vivo condition, possibility to control graft function, reduce ischemia-reperfusion injury, possibility of using the NMP as a resuscitation platform for graft (12,13) High level of ATP depletion, high metabolism level, risk of infection, Complex equipment and high costs make transportation difficult (12,13)
COR 5–35 ℃ Transitional mode rather than preservation mode (14) Prevent thermal shock and rewarming injury, minimize graft damage caused by temperature fluctuations High operational and application complexity (15)

ATP, adenosine triphosphate; COR, controlled oxygenated rewarming; HMP, hypothermic machine perfusion; NMP, normothermic machine perfusion; ROS, reactive oxygen species; SNMP, subnormothermic machine perfusion.

As MP technology has become increasingly mature, its safety and effectiveness have been gradually verified in clinical studies, which is likely to replace SCS. In order to further explore the current research trend and future development direction of MP, we conducted a literature analysis on MP technology, with the detailed results shown in Figure 1.

Figure 1 Bibliometric analysis of (A) publication trends, (B) keyword citation burst strength, (C) cooperation relationships among authors of the top 1,000 articles, and (D) keyword co-occurrence.

Despite its operational simplicity, SCS falls short of meeting the escalating demand for marginal donors in the modern transplantation era, owing to its limited preservation window and profound IRI. Deep supercooling and vitrification technologies can achieve a longer preservation window, but they are still in the initial animal experiment stage. With the maturity of MP, it may gradually replace SCS. MP not only has multiple modes to choose from, but also can transform organ preservation into an active and therapeutic intervention process, especially prolonging organ preservation time and repairing marginal donors. It is expected to expand the donor pool and alleviate organ shortage in the future. However, before MP can fully replace SCS, attention should be paid to its cost of use, unified guidelines, and more clinical evidence. Despite the large number of clinical studies currently available, large-scale multi-center randomized trials remain scarce. In addition, MP has high initial costs, but its potential to reduce postoperative complications may enable it to achieve cost parity or even cost savings (17).

In the future, research on organ preservation will no longer be merely confined to prolonging preservation duration. Instead, greater emphasis will be placed on optimizing and individually integrating preservation protocols with novel immunomodulatory strategies, so as to maximize graft utilization and patient survival rates. In addition, the field of organ preservation is moving from static preservation to dynamic preservation technology. Its goal is not only preservation, but also real-time evaluation and graft modification, expanding the donor pool as much as possible to alleviate organ shortage.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, HepatoBiliary Surgery and Nutrition. The article did not undergo external peer review.

Funding: The work was supported by the National Natural Science Foundation of China (No. 82300663).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2026-0393/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

  1. Boffa C, Lo Faro L, van de Leemkolk F, et al. Efficacy and Quality of Flush-Out Prior to Cold Storage of Liver and Kidney in Donation after Circulatory Death. Transplantation 2018;102:S399.
  2. Durán M, Calleja R, Hann A, et al. Machine perfusion and the prevention of ischemic type biliary lesions following liver transplant: What is the evidence? World J Gastroenterol 2023;29:3066-83. [Crossref] [PubMed]
  3. Shamma T, England C, Ortas TS, et al. Cellular and Molecular Changes Induced by Various Preservation Temperatures and Methods of Preservation in Renal Grafts and Other Solid Organ Grafts. Int J Mol Sci 2026;27:1294. [Crossref] [PubMed]
  4. Pruett TL, Wolf SM, McVan CC, et al. Governing new technologies that stop biological time: Preparing for prolonged biopreservation of human organs in transplantation. Am J Transplant 2025;25:269-76. [Crossref] [PubMed]
  5. Clavien PA, Dutkowski P, Mueller M, et al. Transplantation of a human liver following 3 days of ex situ normothermic preservation. Nat Biotechnol 2022;40:1610-6. [Crossref] [PubMed]
  6. Qiu J, Yu B, Ren C, et al. Deep-supercooling preservation of stem cell spheroids for chondral defect repairment. Stem Cell Reports 2024;19:1665-76. [Crossref] [PubMed]
  7. Li Y, Li Z, Peng L, et al. Deep-supercooling Preservation for Rat Kidneys. Transplantation 2026;110:e363-73. [Crossref] [PubMed]
  8. Giwa S, Lewis JK, Alvarez L, et al. The promise of organ and tissue preservation to transform medicine. Nat Biotechnol 2017;35:530-42. [Crossref] [PubMed]
  9. Peyridieu JF, Baudot A, Boutron P, et al. Critical cooling and warming rates to avoid ice crystallization in small pieces of mammalian organs permeated with cryoprotective agents. Cryobiology 1996;33:436-46. [Crossref] [PubMed]
  10. Han Z, Rao JS, Gangwar L, et al. Vitrification and nanowarming enable long-term organ cryopreservation and life-sustaining kidney transplantation in a rat model. Nat Commun 2023;14:3407. [Crossref] [PubMed]
  11. Sharma A, Lee CY, Namsrai BE, et al. Cryopreservation of Whole Rat Livers by Vitrification and Nanowarming. Ann Biomed Eng 2023;51:566-77. [Crossref] [PubMed]
  12. Radajewska A, Krzywonos-Zawadzka A, Bil-Lula I. Recent Methods of Kidney Storage and Therapeutic Possibilities of Transplant Kidney. Biomedicines 2022;10:1013. [Crossref] [PubMed]
  13. Fu B, Wang J, Yu W, et al. Development of machine perfusion strategies for liver support and beyond. J Adv Res 2026;S2090-1232(26)00238-9.
  14. Ogurlu B, Pamplona CC, Van Tricht IM, et al. Prolonged Controlled Oxygenated Rewarming Improves Immediate Tubular Function and Energetic Recovery of Porcine Kidneys During Normothermic Machine Perfusion. Transplantation 2023;107:639-47. [Crossref] [PubMed]
  15. van Leeuwen OB, Lantinga VA, Lascaris B, et al. 'Back-to-base' combined hypothermic and normothermic machine perfusion of human donor livers. Nat Protoc 2025;20:2151-70. [Crossref] [PubMed]
  16. Corcione S, Patrono D, Shbaklo N, et al. Hypothermic oxygenated machine perfusion does not increase the risk of infection after liver transplantation: a retrospective cohort study. Hepatobiliary Surg Nutr 2025;14:562-74. [Crossref] [PubMed]
  17. Finotti M, Wall A, D'Alessandro A, et al. The Dallas Donation after Circulatory Death Transplantation Summit: expanding donation after circulatory death procedures through process improvement, broader utilization, and innovation. Hepatobiliary Surg Nutr 2024;13:824-36. [Crossref] [PubMed]
  18. Tingle SJ, Dobbins JJ, Thompson ER, et al. Machine perfusion in liver transplantation. Cochrane Database Syst Rev 2023;9:CD014685. [Crossref] [PubMed]
  19. Liang A, Zhang L, Jia J, et al. The conclusion of reducing acute rejection after liver transplantation by machine perfusion should be extrapolated with caution. Hepatobiliary Surg Nutr 2023;12:785-9. [Crossref] [PubMed]
  20. Rauter L, Kollmann D, Schiefer J, et al. Endothelial glycocalyx damage marker syndecan-1 during hypothermic oxygenated machine perfusion of donor grafts facilitates prediction of early allograft dysfunction after liver transplantation. Hepatobiliary Surg Nutr 2025;14:233-45. [Crossref] [PubMed]
Cite this article as: Gao W, Song JL, Huang S, Cai ZY, Duan ZY, Xu X, Jin C, Lv T, Xu G, Yang JY. The evolution of liver graft preservation strategies in liver transplantation. Hepatobiliary Surg Nutr 2026;15(3):92. doi: 10.21037/hbsn-2026-0393

Article Options

Download Citation

Share