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Review Article

Organ preservation: from the past to the future

Abstract

Organ transplantation is the most effective therapy for patients with end-stage disease. Preservation solutions and techniques are crucial for donor organ quality, which is directly related to morbidity and survival after transplantation. Currently, static cold storage (SCS) is the standard method for organ preservation. However, preservation time with SCS is limited as prolonged cold storage increases the risk of early graft dysfunction that contributes to chronic complications. Furthermore, the growing demand for the use of marginal donor organs requires methods for organ assessment and repair. Machine perfusion has resurfaced and dominates current research on organ preservation. It is credited to its dynamic nature and physiological-like environment. The development of more sophisticated machine perfusion techniques and better perfusates may lead to organ repair/reconditioning. This review describes the history of organ preservation, summarizes the progresses that has been made to date, and discusses future directions for organ preservation.

Introduction

Organ transplantation is the only effective therapy for patients with end-stage disease in many cases. A number of factors have contributed to the success of organ transplantation, including organ preservation, surgery, immunosuppressive medication, and post-transplantation care. A supply of high-quality donor organs is crucial to transplantation procedures; organ preservation has been described as “the supply line for organ transplantation”1. It allows time for preparation of the recipient, organization of staff and facilities, allocation and transportation of the organ, and laboratory tests2,3.

Static cold storage (SCS) offers a simple and effective way to preserve and transport organs and is the most commonly used method4. However, a number of limitations are associated with SCS, including tissue damage induced by prolonged hypothermic preservation, difficulty in assessing donor organ function and viability, inevitability of ischemia-reperfusion injury (IRI), and limited opportunity for organ repair. Recently, the growing use of marginal organs from extended criteria donors has led to an emergence of ex vivo lung perfusion (EVLP) to assess donor lung function5,6. In addition to being an excellent graft assessment tool, EVLP has also shown potential for enabling graft repair, reconditioning, and immunomodulation7, which inspired similar research and clinical applications in other organ systems8,9,10. The desire to extend preservation times has motivated research on optimal preservation solutions, temperatures, techniques, and therapeutic additives for organ repair and reconditioning11,12,13,14. By reviewing the history of organ perfusion and preservation, we noted that before the introduction of SCS in 1960s15, machine perfusion with plasma or blood-based solutions was the clinical method for preserving isolated organs16,17. Reevaluating the advantages and limitations of early organ perfusion/preservation may help with the development of new techniques/solutions that enable prolonged safe preservation and the repair of extended criteria donor organs to address the organ shortage issue. Theories, preservation techniques, preservation solutions, and clinical practices are discussed.

Past: a story of organ perfusion and preservation

Primitive concepts underwent a number of modifications over decades of scientific exploration to arrive at current practices in organ perfusion and preservation. It is essential to understand this history to be able to evaluate the future direction of this field of research.

Organ perfusion as a primitive preservation technique

Organ preservation developed from the primitive concept of extracorporeal circulation, which first emerged in 1812 in the monography of Cesar Julien Jean Le Gallois. He speculated that “if the place of the heart could be supplied by injection—and if, for the regular continuance of this injection, there could be furnished a quantity of arterial blood, whether natural or artificially formed, supposing such a formation possible—then life might be indefinitely maintained in any portion”18. In 1849, German scientist Carl Eduard Loebell described in his Dissertation Inaugurals the first perfusion experiments on isolated pig kidneys. He observed that the bright red arterial blood perfused through porcine kidneys became dark and viscous upon its course through the renal veins19. In 1885, Max von Frey and Max Gruber constructed the first closed artificial circulation system, which shares many similarities to today's organ perfusion systems20. In 1895, Jacobj created a double circulation apparatus, which used an isolated lung as an oxygenator and permitted organ perfusion for several hours19. These early studies led to the development of extracorporeal membrane oxygenation (ECMO) and the subsequent development of perfusion systems for organ preservation19,20,21,22,23,24.

From blood to chemically defined perfusion solution

Historically, blood was used as perfusate in early apparatuses. Primitive perfusion apparatuses required a large supply of blood to operate, whereby the volume of an animal's own blood was insufficient. People tried to substitute an animal's own blood with blood from a different animal species. The use of cross-species blood was toxic to the graft and led to its rapid decline25. Scientists then diluted the animal's own blood with normal saline or Ringer's solution. These methods led to the development of severe edema in organs, especially in the lung25. These early studies led to the realization of xenoimmunity and the development of transfusion solutions.

In 193726, Alexis Carrel perfused isolated cat thyroids in the Lindbergh apparatus with Tyrode's solution comprised of glucose, ions, and 40%–50% homologous serum. He found that the organs were viable for 3–21 days. However, cultivation over 6 days showed a tendency towards hyperplasia. In 196827, Hou et al cultured normal human placentas in a chemically defined culture medium. Placentas were kept viable for at least 14 days, but the stroma underwent great modification within 3 days. These studies demonstrated that organs or tissues were capable of surviving outside of the body for several days under normothermic conditions in culture medium. However, maintaining the normal histological morphology of cultured organs raised challenges, which slowed down organ culture research for several decades.

Temperature: from normothermic to hypothermic

Originally, organs were perfused at room temperature. In 1876, Bunge and Schmiedeberg added a water bath to the circuit to maintain perfusion blood at physiological temperatures19. Later, scientists began to speculate that the use of lower temperatures might attenuate organ damage during perfusion by abating cellular metabolism. In the 1960s, a number of experiments were performed with cooled diluted serum or heparinized blood, and kidney perfusion was extended from hours to days28,29. However, the use of cold blood also caused many problems, such as vascular spasm in kidney grafts30.

From dynamic to static modality

In the 1960s, kidneys were successfully preserved for 3–5 days by continuous perfusion with cooled, oxygenated blood or plasma28,29. However, this method required complex and costly equipment, which limited its availability and made the transportation of organs extremely difficult. In 1969, Collins GM was able to successfully preserve canine kidneys for 12 h by immersing them in iced saline solution, and he later further prolonged cold storage time to 30 h with Collins solution15,31. This simple method for organ preservation was more cost-efficient and convenient for organ transportation than its predecessors. The birth of SCS replaced dynamic perfusion methods and became the standard method of organ preservation.

Present: current practice and research on organ preservation

Preservation techniques (temperature, apparatus, perfusion setting, etc) and perfusion solutions are the major fields of research in organ preservation.

Static cold storage and preservation solutions

Since the 1960s, SCS has gradually become the gold standard method for organ preservation. SCS involves flushing the procured organ with preservation solution at 0–4 °C, then immersing it into preservation solution at the same temperature until transplantation. The hypothermic environment is responsible for decreasing cellular metabolism, and the preservation solution reduces cellular metabolism and provides cytoprotection.

Collins solution was the first preservation solution to enter the commercial market in 196915. It was used to preserve the kidney, heart, liver, and lung grafts. In 1980, Collins solution was modified via impermeant composition and improved chemical stability. The new solution was named a Euro-Collins solution, and it provided better protection during prolonged cold ischemia and was widely used2,32. The University of Wisconsin (UW) solution was introduced in the mid-1980s33 and continues to be used today for abdominal organ preservation34. These solutions are so-called intracellular fluid (ICF)-type solutions characterized by low Na+ and high K+ concentrations. ICF-type solutions were intended to prevent cellular edema by maintaining intracellular ion concentrations upon cold-induced dysfunction of Na+/K+ pumps35.

Adding amino acids to the preservation solution and using a histidine buffer system led to the development of histidine-tryptophan-ketoglutarate (HTK) solution, which is characterized by low K+ and low Na+ concentrations. It was originally developed for cardiac preservation, but it also achieved comparable patient survival for abdominal organ transplants36,37. Custodiol-N is a modified HTK solution with additional amino acids and chemicals. It is currently undergoing clinical trials; experimental studies showed promising reductions of hypoxic and cold-induced cell injury38,39. Celsior solution was originally made available in the 1990s as a heart preservation solution and was later also used for both thoracic and abdominal organ preservations40. Like HTK solution, Celsior solution also uses a histidine buffer and a low K+ concentration. However, its Na+ concentration is much higher. It shows equivalent performance to UW solution at a cheaper cost41,42.

The risk of hyperkalemia-induced pulmonary vasoconstriction led to the development of extracellular fluid (ECF)-type solutions, which have lower K+ and higher Na+ concentrations43. In the 1980s, an ECF-type solution called EP4 (or EP-TU) was introduced, which sustained a canine lung preservation model for as long as 96 h44. A low-potassium dextran glucose (LPDG) solution was developed and currently used as the gold standard for lung preservation43,45,46. ET-K solution was developed by optimizing the properties of sugar and electrolyte contents and by adding a protective component for pulmonary endothelium, which showed excellent postoperative lung graft performance47. ET-K and EP-TU solutions have been applied in clinical lung transplantation in Japan48,49. Table 1 summarizes information regarding the composition of popular cold preservation solutions.

Table 1 Composition of popular cold preservation solutions.

Ex vivo machine perfusion

IR-induced injury increases the risk of early graft dysfunction and reduces long-term survival after transplantation50 (Figure 1). Meanwhile, the shortage of donor organs has led to the use of extended criteria donor (ECD) organs. Proper donor organ functional assessment and ex vivo repair/reconditioning of organs prior to transplantation has become necessary. Machine perfusion is a method involving organ perfusion with a controlled flow of perfusate. It facilitates the maintenance of organ microvasculature tone, provision of oxygen and nutrients in support of tissue metabolism, and removal of toxic metabolic waste.

Figure 1
figure1

Biological processes induced during ischemia-reperfusion that may lead to primary graft dysfunction.

PowerPoint slide

The cellular rate of respiration is proportional to the surrounding temperature51. For example, SCS at 0–4 °C reduces the metabolic rate of the organ to approximately 5% of its physiological level52,53. Different temperatures have been investigated for ex vivo machine perfusion, including normothermic machine perfusion (NMP) at 35–38 °C, subnormothermic machine perfusion (SNMP) at 20–34 °C, controlled oxygenated rewarming (COR) at 8–20 °C, and hypothermic machine perfusion (HMP) at 0–8 °C (Figure 2) (Table 2).

Figure 2
figure2

Metabolic rate reduces with a decrease in temperature in humans. (SCS=static cold storage, HMP=hypothermic machine perfusion, COR=controlled oxygenated rewarming, SNMP=subnormothermic machine perfusion, and NMP=normothermic machine perfusion).

PowerPoint slide

Table 2 Comparison of various methods used for preservation of organs.

Hypothermic machine perfusion

HMP (0–8 °C) is based on the concept that oxidative energy production by mitochondrial electron transport is sustained at hypothermic temperatures. HMP continuously provides metabolic substrates for the generation of ATP, which enables the graft to restore tissue energy. The first clinically available HMP device was developed by Folkert Belzer in 1960s28 and used to perform the first HMP-preserved human kidney transplant in 196816. Belzer et al achieved perfusion of the kidney with hypothermic, diluted plasma or blood for 3 days28. Humphries et al were able to extend kidney perfusion to 5 days29.

The 1990s saw the resurgence in interest in HMP for kidney preservation as both the demand for organs and reliance on ECD donors grew54. New HMP technology showed decreased rates of delayed graft function and improved outcomes in the case of marginal donors relative to SCS. By 2015, approximately 25% to 35% of all transplanted kidneys in the United States were preserved with HMP54.

Challenges arise in the use of HMP for liver preservation since the liver receives blood from both the portal vein and hepatic artery2. However, the first clinical trial of HMP-preserved liver grafts showed shorter hospital stays and reduced vascular and biliary complications as benefits55. Few studies on HMP in heart and lung transplants have been reported. Nakajima et al reported that short-term HMP (1–2 h) can improve lung tissue energy levels and ameliorate IRI by decreasing the production of reactive oxygen species in rat lungs56,57. Michel et al showed that HMP preserved the cellular structure of donor hearts better than SCS during prolonged ischemic times in pigs58. Additional research in the field of cardiac and lung HMP is required.

Normothermic machine perfusion

NMP (35–38 °C) is a method of perfusing organs under physiologic conditions to maintain metabolic activity and viability. NMP maintains donor organs at body temperature while providing oxygen and essential substrates. Historically, NMP was developed to assess organ function prior to transplantation59,60,61 and to preserve donor organs during distant procurement62,63. In 2001, Steen et al reintroduced the EVLP technique to evaluate lungs from donation after cardiac death (DCD)64. In 2007, they performed the first human transplantation of a rejected donor lung after assessment with EVLP65. Early studies were only able to achieve perfusion times of less than 6 h in large animal models66,67. In 2008, Cypel et al in Toronto modified the EVLP technique with low tidal volume ventilation, reduced perfusion rate and acellular perfusate, and extended perfusion time for up to 12 h in swine lungs with stable lung function68. The Toronto group conducted the first clinical trial successfully and reported excellent outcomes in 201169. They further reported extended clinical outcome data70,71, and the marginal donor lungs treated with EVLP showed comparable or even better results than regular lung transplants72.

The success of EVLP inspired many research groups worldwide to further investigate the role of NMP in other organ systems. Nicholson et al described that a short period (1 or 2 h) of NMP could restore function and replenish ATP after warm and cold ischemia in porcine kidneys8,73,74. The first clinical study on preserving kidney grafts with NMP was reported in 201175. A follow-up clinical study showed that the delayed graft function rate was significantly lower in the NMP group than in the SCS group in ECD kidney transplantation76. The first clinical trial on NMP in liver transplantation was reported in 2016; 16 donations after brain death livers and 4 DCD livers were transplanted after NMP. The results showed that 30-day graft survival was similar between the NMP and SCS groups, and the median peak aspartate aminotransferase level was significantly lower in the NMP group than in the SCS group77. Clinical studies have shown promising results with NMP in resuscitating marginal and declined donor livers9,78. In addition, NMP has been shown to be superior to SCS in preserving DCD hearts in dogs79. In pigs, DCD hearts reconditioned with NMP showed comparable function to brain death donor hearts80. Over a 2-year period in a clinical trial involving 159 cases of orthotopic heart transplantation, NMP showed higher recipient survival and lower incidences of primary graft dysfunction (PGD) and acute rejection than SCS10.

Several companies have now marketed a commercial portable machine to facilitate ex vivo machine perfusion, such as Organ Care System (TransMedics, USA) for the heart, lung, or liver and Organ Assist® device (Organ Assist, The Netherlands) for the lung, liver, or kidney. These devices can be used during organ transportation, which offers a platform for normothermic organ preservation immediately after procurement, monitoring and assessing graft function continuously11,81. These mobile devices have demonstrated encouraging results in clinical studies, which opens new avenues for organ preservation and transportation82,83,84.

Subnormothermic machine perfusion

Subnormothermic machine perfusion (SNMP, 20–34 °C) is a midway approach between HMP and NMP85. Although better preservation times were accomplished with NMP than with HMP, it was speculated that the cytoprotective benefits of reduced cellular metabolism under hypothermic temperatures could further improve organ preservation. Meanwhile, sufficient metabolism would be maintained for viability assessment and organ repair/reconditioning86. Although studies have shown that livers or kidneys perfused with SNMP are superior to grafts preserved under SCS87,88, a recent study showed that porcine kidneys preserved under SNMP were associated with higher indices of renal and tubular injury upon reperfusion than those preserved under NMP89. Therefore, whether SNMP should be developed in addition to NMP should be further determined.

Controlled oxygenated rewarming

Following cold ischemic preservation, the abrupt change in temperature from hypothermia to normothermia upon reperfusion may effectuate dysfunction of the mitochondria and pro-apoptotic signal transduction, which contributes to reperfusion-induced organ injury90. Hypothermic preservation is meant to protect the ischemic organ by reducing metabolism. However, ischemic redox dyshomeostasis leads to impairment of the mitochondrial membrane potential through mitochondrial transition pore opening. Mitochondrial damage can be further enhanced upon reperfusion91. COR (8–20 °C) is an alternative organ perfusion method involving a slow, gradual rise in the perfusate temperature. The period of COR is aimed to minimize injury to the graft and improve hepatocellular function upon reperfusion, offering gentle restitution of mitochondrial function91. Clinical studies have shown that COR is safely transferable to clinical practice in liver transplantation91. By the end of 2016, COR had been effectively applied in 15 human liver transplantations92. Minor and colleagues demonstrated that COR following SCS had better kidney function with mitigated activity of mitochondrial permeability transition pore opening, caspase 9 activation, and apoptosis in porcine kidneys90. It should be noted that during EVLP, lung perfusate was gradually warmed up during the first 30 min68. COR could be integrated into NMP.

Organ perfusate: from chemically defined solutions to blood/blood substitute

Perfusate composition is of central importance in maintaining stable organ function ex vivo. Blood-based perfusates were commonly used for organ perfusion before cell culture media were developed in the 1950s93,94. Due to its variable nature and associated technical and ethical concerns, the use of blood or blood products was gradually replaced by chemically defined solutions. For example, Steen Solution, a chemically defined solution, has been widely used for EVLP and machine perfusion of other organs; it contains colloid components (human serum albumin and Dextran 40) to maintain oncotic pressure, physiological ion concentrations to regulate osmolality, and buffers to retain normal pH and glucose as an energy resource. However, the supplementation of additional nutrients, including red blood cells and other blood substitutes, to Steen Solution is under investigation to extend perfusion time.

Blood/blood substitutes

Studies have identified that blood-based perfusate is necessary during NMP to transport oxygen and meet metabolic demands, and it provides superior functional preservation in the case of kidney, liver and heart storage95,96,97,98. It is still disputed whether blood or red blood cells should be involved in EVLP. Some studies have highlighted the use of blood over acellular perfusates99, whereas others have observed spontaneous lung injury when using whole blood100. When looking over the studies that have currently achieved the longest perfusion times, it is interesting to see that perfusates used in these studies were either whole blood or blood-based solutions95,101,102,103,104. One study that provided pertinent evidence in support of the essentiality of blood in perfusate is a cross-circulation study. O'Neill et al connected a conventional EVLP circuit to the internal jugular vein of a recipient pig so that metabolic substrates and hormones from the recipient pig were available to the perfused lungs, whereas metabolic waste produced by the perfused lungs was cleared by the recipient; they effectively perfused the lungs with recipient autologous blood for 36 h without notable changes in physiological parameters105.

However, the use of blood-based perfusate is accompanied by a series of concerns, such as immune-mediated responses, hemolysis, thrombus formation, biochemical and humoral variations, and a risk of blood-borne infectious transmission106. Further development of an acellular perfusate is another major direction.

Nutrients

Currently, commonly used perfusates, such as Steen solution and Organ Care System (OCS) perfusate, use glucose as the only energy resource. However, during NMP, organs are perfused at body temperature. Glucose alone is not sufficient for organ metabolism. To prolong NMP for organ repair, the incorporation of more nutrients, such as amino acids, vitamins, lipids and others, should be considered. Amino acids are basic components of proteins and are essential nutrients for cell survival and proliferation. Vitamins can help cells use the provided chemical energy to process proteins, carbohydrates, and fats required for cellular metabolism107. Amino acids and vitamins have been used routinely in cell culture media93,94. Interestingly, cell culture media were used for organ culture to maintain isolated organs for days without serum or blood supplements27. In liver and kidney studies, amino acids and extra glucose have been added into perfusate during NMP, and this approach showed promising results in pigs108,109.

Fetal mouse lungs cultured in a medium without growth factors showed poorly developed airways and a lack of defined acinar structures110, which suggests that growth factors and hormones may also be required for organ rebuilding /regeneration.

To avoid the use of human blood products, interest has increased in acellular oxygen carriers, which have similar oxygen carrying capacity to human hemoglobin111. Initial studies on hemoglobin-based oxygen carriers have shown encouraging results, including enhanced oxygenation and improved allograft function of ex vivo perfused organs in normothermic/subnormothermic conditions106,112, which opens the door for blood substitution in future.

It is reasonable to conclude that an ideal perfusate should offer oxygen carrying capacity, oncotic properties, buffers to maintain physiological pH, metabolic substrates and physiological electrolyte levels, growth factors and hormones. A blood substitute designed to replace human blood in ex vivo machine perfusion will be a promising direction for prolonging the preservation of isolated organs.

Future perspectives: organ repair/reprogramming with ex vivo machine perfusion

Prolonged ex vivo machine perfusion & organ repair/reprogramming

The incredible progress of organ preservation research over the past few decades has led to the booming success of clinical organ transplantation as a treatment for patients with end-stage disease. However, this demand has skyrocketed to a level that cannot be satisfied by the number of available donor organs. The use of ex vivo machine perfusion aspires to warranting the use of marginal donors by minimizing IRI and facilitating the repair/regeneration of suboptimal grafts in order to expand the donor pool and improve overall graft function after transplantation. For this purpose, prolonged ex vivo perfusion time is required (Figure 3).

Figure 3
figure3

The advantage of the potential use of normothermic machine perfusion.

PowerPoint slide

Organ repair

There has been an increasing number of studies focusing on the application of ex vivo machine perfusion for organ repair. EVLP is among the most active areas of study. A series of therapeutic strategies have been studied using EVLP for lung repair. For example, different drugs were delivered through perfusate to mitigate IRI113,114,115, therapeutic gases (NO, CO, H2) were inhaled during EVLP to reduce inflammatory response and lung edema116,117,118, mesenchymal stem cells were used to treat lung injury induced by endotoxins and infection119, and IL-10 gene therapy was developed to prevent IRI120,121. When the types of injury are clear, injury-specific treatments can be used during EVLP. For example, high-dose, broad-spectrum anti-microbial agents were added to perfusate to treat human donor lung infection122,123, lung lavage and surfactant replacement were used to treat acid aspiration-induced pig lung injury124,125,126, and pulmonary thrombolysis was performed to eliminate pulmonary embolism followed by successful lung transplantation127,128.

In kidney, Brasile et al delivered heme analog cobalt protoporphyrin during ex vivo kidney perfusion to reduce inflammatory and free radical injury by upregulating the protective gene hemoxygenase-1 in canines129. They also used growth factors to upregulate cellular processes to resuscitate and repair warm IRI in canines and in rejected human kidneys130. Hosgood et al delivered nitric oxide donors and carbon monoxide-releasing molecules during NMP, which enhanced renal flow and improved renal function in pigs131. Yang et al investigated the effect of adding erythropoietin to perfusate during NMP and found that erythropoietin promoted inflammatory cell apoptosis and drived inflammatory and apoptotic cells into tubular lumens, which led to inflammation clearance, renal protection, and tissue remodeling in a porcine model132.

In liver, studies on therapeutic medications during NMP to reduce IRI showed promising results in pigs and rats133,134,135. Goldaracena et al delivered an antiviral drug to perfusate during normothermic ex vivo liver perfusion and effectively induced Hepatitis C virus resistance after pig liver transplantation136.

Organ regeneration

In 2008, Ott et al reported the first whole organ engineering success. They used ex vivo machine perfusion as a platform, decellularized rat hearts by coronary perfusion with detergents in a Langendorff apparatus, then reseeded these constructs by perfusion with cardiac or endothelial cells; eight constructs were maintained for up to 28 days by coronary perfusion with a nutrient-rich medium in a bioreactor that simulated cardiac physiology. This study revolutionized the field of tissue engineering, kindled hope for possibility of whole organ engineering137. They also successfully created bioartificial rat lungs using a slightly modified approach and subsequently transplanted the regenerated left lungs orthotopically. The bioartificial lungs provided gas exchange in vivo for up to 6 h after extubation138. Using the same perfusion system, Ott's group further maintained the bioartificial rat lungs for up to 7 days with good function after implantation139. They later decellularized human and porcine lungs140, which brought the matrix to clinical scale. A similar perfusion method has also been used to create kidney and liver scaffolds in animals and in clinically rejected human organs141. Although there are still many challenges, the use of NMP alongside stem cells for organ engineering has received increasing interest.

Organ immunomodulation

Ex vivo machine perfusion has also provided a potential platform for organ immunomodulation. Miyoshi et al reported that ex vivo perfusion of canine pancreaticoduodenal allografts using class-II-specific monoclonal antibodies delays the onset of acute rejection142. Brasile et al treated canine kidney grafts with a bioengineered interface consisting of a nano-barrier membrane during NMP for 3 h. They found that untreated control dogs experienced a mean onset of rejection on day 6, whereas the mean onset of rejection was significantly delayed until day 30 in dogs in the treatment group143. Martens et al distributed multipotent adult progenitor cells in the airway during EVLP and observed a reduction in pro-inflammatory cytokines and neutrophils in bronchoalveolar lavage fluid, which is related to innate immune system modulation and may play an important role in reducing PGD after transplantation144.

Due to severe donor shortage from humans, xenotransplantation is gaining more attention. Ex vivo perfusion of porcine lungs with fresh human blood is used to study discordant pulmonary xenograft injury145,146. Pre-perfusion of donor organs with recipient serum147 and the delivery of targeted drugs have been attempted to prevent hyperacute rejection148. Ex vivo machine perfusion offers an effective platform to alleviate discordant xenograft rejection by removing the recipient's xenoreactive natural antibodies149. Studies on the recellularization of animal organ scaffolds by human liver stem/progenitor cells with ex vivo machine perfusion techniques are under investigation150,151.

Conclusion

Since the very first speculation on organ preservation made by Cesar Julien Jean Le Gallois over two centuries ago, tremendous progress has been made in this field of research. In the early days, organs were perfused with blood at physiological temperatures. The introduction of SCS in the 1960s revolutionized organ preservation. From then on, it became standard practice to statically preserve organs at hypothermic temperatures. With the recent demand to expand the organ donor pool, the currently accepted status of organ preservation is seeing a retrospective shift from SCS to theories inspired by early techniques, as these techniques provide great potential for improved graft preservation, viability assessment, and most importantly, repair/regeneration. The success of organ preservation with dynamic machine perfusion operating on the basis of blood-based perfusates at close-to-physiological temperatures has prompted further in-depth studies on organ preservation and repair/reconditioning. The need to prolong ex vivo machine perfusion time requires the optimization of current perfusates with the addition of essential components to meet metabolic needs. Prolonged ex vivo machine perfusion opens a door for organ repair and reprogramming, warranting further investigation of novel strategies to improve donor graft quality prior to transplantation.

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Acknowledgements

Lei JING is a PhD candidate of the First Bethune Hospital of Jilin University and is supervised by Dr Li-ping PENG; she is supported by the First Bethune Hospital of Jilin University. This work was supported by research grants from the Canadian Institutes of Health Research (MOP-42546, MOP-119514, and PJT-148847) and an Ontario Research Fund-Research Excellence award.

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Correspondence to Li-ping Peng or Mingyao Liu.

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Jing, L., Yao, L., Zhao, M. et al. Organ preservation: from the past to the future. Acta Pharmacol Sin 39, 845–857 (2018). https://doi.org/10.1038/aps.2017.182

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Keywords

  • organ transplantation
  • organ preservation
  • static cold storage
  • machine perfusion
  • organ assessment
  • organ repair
  • ischemia-reperfusion injury

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