aDepartment of Biochemical Engineering, Frontier Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (MOE), School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350, China
bState Key Laboratory of Synthetic Biology, Tianjin 300072, China
cSchool of Engineering and Technology, University of Washington Tacoma, Tacoma, WA 98402, USA
dHaihe Laboratory of Sustainable Chemical Transfonnations, Tianjin 300192, China
Recent advances in organ transplantation, regenerative medicine, and drug discovery have emphasized the critical importance of effective preservation techniques for organs. Despite these advances, current preservation techniques have significant limitations in maintaining the viability and functional efficacy of organs over the long term. As a result, there is a pressing need to develop reliable and efficient preservation strategies for organs. Currently, the clinical standard for organ preservation involves the use of static cold storage and organ machine perfusion, but these methods can only preserve organs for a couple of days or even a few hours. Notably, the development of cryobiology has yielded promising alternatives. In this review, we aim to provide a comprehensive overview of the progression of organ preservation methods, while emphasizing the limitations of traditional approaches. Moreover, we evaluate advanced preservation techniques for organs, including kidneys, livers, hearts, lungs, and intestines. Furthermore, we share a progress perspective on the future of organ preservation, with the ultimate goal of achieving viable long-term preservation to address the pressing issue of organ shortage.
Organ transplantation is a highly effective treatment that addresses the critical need for organ replacement in individuals with end-stage organ failure [1]. However, the shortage of available donor organs continues to pose a significant challenge. Currently, organ preservation in clinical settings is limited in duration, leading to logistical difficulties in transportation, assessment, allocation, and transplantation. This obstacle impedes advancements in the rapidly developing fields of transplant and regenerative medicine.
The main methods for extending the preservation of organs in clinical practice are static cold storage (SCS) and machine perfusion (MP) [2], [3]. SCS can maintain the function of organs such as the kidney, liver, and pancreas for 12–24 h, while MP, which inhibits organ ischemia-reperfusion injury (IRI), can extend preservation time to several days [4], [5], [6]. Nonetheless, long-term, high-quality organ preservation has not been achieved using either of these approaches.
In recent years, advances in cryopreservation techniques have shown promising potential for the long-term storage of biological samples, including cells, tissues, and organs [7], [8]. Theoretically, temperatures below –140 °C induce a state of “suspended animation” or “dormancy” within organs by halting physiological and metabolic activities, thereby enabling the long-term preservation of biological samples [9]. However, during the processes of cryopreservation and thawing, irreversible damage to organs can occur due to mechanical, osmotic, and thermal stress, posing challenges to preserving the original physiological structure. To address these challenges, researchers have focused on exploring innovation strategies for the long-term preservation of organs, such as the development of novel preservation strategies, cryoprotective agents (CPAs), and rapid thawing methods [4], [10], [11], [12], [13], [14]. These approaches hold promise to overcome current technological limitations in organ cryopreservation.
In this review, we present a comprehensive summary of the demand for organ preservation and provide an in-depth review of the strategies and methods currently used in the field. We highlight the inadequacy of traditional clinical approaches to organ preservation, such as SCS and MP, and argue that cryopreservation is the better available solution to address this growing demand. To this end, we survey the latest advances in cryopreservation techniques and evaluate the efficacy of these approaches in preserving kidneys, livers, hearts, lungs, and intestines. Finally, we provide a perspective on the future of organ preservation, with the ultimate goal of achieving the long-term preservation of organs to resolve the problem of organ shortage.
2. Demand for organ preservation
Organ transplantation is one of the most effective treatments for end-stage organ failure. By addressing the need for organ replacement, this therapy saves a multitude of lives globally each year, while improving individuals’ quality of life [1]. The associated public health benefits of organ transplantation are on par with those attributed to cancer cures. However, the persistent shortage of transplantable organs worldwide has been identified as a significant public health challenge [15]. According to the World Health Organization, it is estimated that only 10% of the global demand for organ transplantation is being met, presenting a formidable crisis that must be resolved through biomedical engineering [16], [17]. The advent of the coronavirus disease 2019 (COVID-19) pandemic significantly exacerbated the pre-existing imbalance between the supply and demand of human organs [18], [19]; while a global total of 150 000 successful organ transplantations were performed in 2019, there was a noticeable decline of 18% in 2020 [20], [21]. A modest recovery occurred in 2022, with a global total of 157 526 successful transplantations. In the United States, approximately 110 000 patients were waiting for organ transplants in 2022, while only slightly over 40 000 organs were donated (Figs. 1(a) and (b)). Tragically, an average of 20 patients lose their lives each day while waiting for organ transplantation [22], [23]. To make matters worse, the limitations of organ preservation exacerbate these challenges. As evidenced by the 2020 statistics on organ recovery and discard rates, a significant percentage of donated organs are ultimately wasted due to limited preservation time and the challenges associated with long-distance transportation [22]. For kidney, liver, heart, lung, and intestine, 24%, 29%, 58%, 72%, and 98% of donor organs are respectively wasted [24], [25], [26].
At present, organ preservation in clinical practice is typically measured in hours [27], which poses significant challenges in transportation duration, assessment, and allocation, as well as in efficiently matching patients in a timely manner during preservation [1]. Moreover, following donor organ removal, rapid transportation to the intended destination is necessary to prepare for transplant surgery, regardless of the time of day [28]. This places a considerable financial burden on healthcare providers. Additionally, continuous inflammation and oxidative stress-induced degradation of donor organs make their preservation more challenging and lead to countless organs being discarded [1]. Significant metabolic activity continues after organ removal, resulting in adenosine triphosphate (ATP) depletion and metabolite buildup, while organs are exposed to inflammation and oxidative stress, leading to subsequent IRI and delayed recovery of graft function—the main cause of transplant failure [29], [30], [31].
Therefore, developing preservation methods for long-term, high-quality organ preservation is crucial in addressing the challenges posed by the high discard rates and inadequate supply of preserved organs, and increasing successful transplantation rates for patients in need.
3. History of organ CPAs
Decades of scientific research have contributed to the preliminary success in the field of organ preservation. The earliest known preservation solution for haploid spermatids was glycerol, which was successfully used to preserve poultry spermatozoa in 1949 [32]. Lovelock and Bishop [33] later discovered the effects of dimethyl sulfoxide (DMSO) on bull spermatozoa. However, DMSO can cause genetic alterations when the concentration exceeds 2 wt%, as well as inducing epigenetic changes in mouse zygotes [34]. The preservation of organs presents remarkable challenges owing to their complex structure and composition, as well as the sensitivity of their intercellular junctions to small organic molecules. Therefore, traditional organic CPAs alone are inadequate in overcoming these obstacles. To address these challenges, various organ preservation solutions have been developed, as summarized in Table 1[35], [36], [37], [38], [39], [40].
In 1966, Keeler et al. [41] demonstrated the use of saline to perfuse rat kidneys, identifying the relationship between tissue damage and the loss of K+ and Mg2+ ions. This was a pivotal milestone in the history of preservation solutions. Building on these findings, Collins et al. [35] developed the first commercially available preservation solution (Collins solution) in 1969. This solution successfully preserved dog kidneys for up to 30 h and is now widely utilized for preserving organs such as heart, liver, kidney, and lung [42]. However, Collins solution has limitations, including a restricted preservation time and the potential for delayed organ function following transplantation. In 1976, the Euro-Collins (EC) solution, based on Collins solution, was introduced as a low-temperature perfusion solution for preserving kidneys [36], [43]. Over the course of the next 15 years, the clinical use of EC preservation solution remained widespread until the advent of the highly regarded University of Wisconsin (UW) solution [37], [44], [45].
Developed in 1986, the UW solution has been recognized as the gold standard in organ preservation [37]. This solution, which contains non-permeable substances, lactobionic acid and raffinose, has the ability to prevent tissue edema and effectively preserve major intra-abdominal organs. With a proven track record for successful clinical application, UW solution has emerged as a vital solution for organ preservation [46], [47]. In 2020, Que et al. [48] developed supercooling preservation at −8 °C using UW solution, prolonging the preservation time for 144 h and improving the post-transplant outcomes in a mouse heart transplantation model. This preservation technique made organ survival after 96 h of preservation possible.
In 1980s, histidine–tryptophan–ketoglutarate (HTK) solution was developed by Bretschneider’s group for cardiac preservation [49], [50]. This low-potassium and reduced-viscosity formulation contains the amino acid buffer histidine, which has antiarrhythmic properties and buffers the extracellular space; α-ketoglutarate, which can store ATP during early post-ischemic reperfusion; and mannitol, which can prevent the swelling of ischemic damaged cells and scavenge free radical [38], [51]. Compared with UW solution, HTK solution exhibits lower viscosity and higher fluidity, which facilitates enhanced diffusion within intercellular spaces [52]. This characteristic advantageously promotes rapid organ cooling during transplantation. Currently, HTK solution is predominantly utilized for organ preservation during kidney and liver transplantation. Among the various preservation solutions, UW and HTK solutions are the two most widely utilized, particularly in the United States, accounting for over 95% of all organ preservation cases [52].
The modified, less-toxic histidine–tryptophan–ketoglutarate-N (HTK-N) solution was developed for the purpose of optimizing cardioplegia and organ preservation [39], [53]. HTK-N incorporates additional amino acids, such as glycine, alanine, arginine, and aspartate, and is iron-chelator supplemented, with the aim of inhibiting the formation of hypoxia-induced plasma membrane pores and mitigating cold-induced cell injury [54]. A pivotal study conducted by Saemann et al. [39] demonstrated the notable benefits of HTK-N in improving the preservation of contractile function in donor hearts through the inhibition of IRI. Moreover, a current prospective randomized double-blind multicenter phase-III trial involving patients provided compelling evidence of the safety and promising efficacy of HTK-N in significantly mitigating IRI in the context of coronary bypass surgery [55]. These advancements underscore the noteworthy potential of HTK-N solution as an optimized and well-tolerated approach for effectively inhibiting IRI.
Another preservation solution that is similar to UW solution, Institute Georges Lopez (IGL-1) solution, has also been developed. Instead of the hydroxyethyl in UW solution, polyethylene glycol (PEG) plays a crucial role in IGL-1 [56], [57] with its remarkable ability to create high osmotic pressure, accompanied by its favorable trait of minimal interaction with biological chemicals [58]. This unique combination makes PEG an ideal choice for creating an effective and biocompatible environment in IGL-1. Moreover, studies have demonstrated that PEG exhibits the ability to decrease the infiltration of inflammatory T-cells, including cluster of differentiation (CD)4+ and CD8+ cells, following perfusion [59], [60]. PEG also exhibits promise in reducing reactive oxygen species-induced damage, as evidenced by diminished lipid peroxidation observed in both isolated hepatocytes and an isolated kidney perfusion model [61]. These findings highlight the potential of PEG for attenuating inflammatory responses and protecting against oxidative stress in various organ perfusion scenarios [60], [62].
Celsior solution, introduced in 1994, is another low-viscosity preservation solution used for heart preservation. Composed predominantly of reduced glutathione, mannitol, lactobionate, and histidine, Celsior solution offers a multifaceted approach to mitigate the detrimental effects associated with organ preservation [40]. The mannitol and lactobionate in Celsior solution address cell swelling, while the reduced glutathione and histidine contribute to protecting against oxygen-derived free radical injury. Additionally, the substantial magnesium content in Celsior solution effectively counteracts calcium overload—a crucial contributor to cellular damage. Beyond its initial application in heart preservation, comparative studies have demonstrated the efficacy of Celsior solution in safeguarding various organs. In 2003, a study by Janssen et al. [63] revealed the superior hepatocyte protection conferred by Celsior solution compared with HTK and UW solutions. Garcia-Gil et al. [64] showcased the comparable proficiency of Celsior solution and UW solution in shielding pancreatic grafts against oxidative injury. An investigation involving 187 kidney transplants also demonstrated that Celsior solution (84%) exhibited no statistical significance relative to UW solution (75%) in kidney preservation [65]. Moreover, Celsior solution displayed a similar lower risk of delayed graft function (DGF) when compared with HTK and UW solutions [44]. Thus, the composition and unique attributes of Celsior solution facilitate optimal preservation conditions and provide organ protection that is comparable or superior to those of HTK and UW solutions.
4. Hypothermic preservation of organs
Prior to organ transplantation, a period of complete ischemia and hypoxia is required, which can disrupt the physiological processes that maintain the ion and osmotic balance between the intracellular and extracellular environment [66]. To maintain this balance, ATP-dependent transmembrane enzyme complexes consume significant amounts of energy to rebalance ions and maintain electrochemical stability [29]. Insufficient oxygen supply disables the ion-driven ATPases, leading to cell membrane depolarization and the uncontrolled influx of calcium through voltage-gated calcium channels [67]. This rapid increase in intracellular calcium activates calcium-dependent phospholipases and proteases, accelerating cell membrane depolarization and resulting in uncontrolled cellular swelling and eventual cell death [68]. To mitigate the negative effects of hypoxia, the approach of inducing slowed biological metabolism through hypothermic preservation is a favorable choice. This approach significantly reduces energy consumption by ion-balancing adenosine triphosphatases (ATPases), preserves transmembrane electrochemical gradients, and temporarily halts the activation of apoptotic biochemical pathways [69]. The advancement of SCS and MP technologies has effectively enhanced the preservation of organ functionality and viability. SCS and MP is illustrated in Fig. 2[70], [71], [72].
SCS has gradually come to be considered a gold standard for hypothermic organ preservation due to its simplicity and cost-effectiveness. Organs are typically flushed with a specialized organ preservation solution and subsequently stored on ice under hypothermic conditions (~4 °C) (Fig. 2(a)) [70], [73], [74]. The simplicity and cost-effectiveness of SCS have contributed to its wide application in various organ systems.
The primary objective of SCS is to reduce cellular metabolism and minimize ischemic injury by lowering the utilization of ATP and oxygen consumption during hypothermic storage [75], [76]. In Japan, for instance, SCS is the exclusive technique utilized for kidney preservation [77]. It involves preserving kidneys at 4 °C for 12–24 h using a protective solution, such as UW solution. Similarly, the acceptable preservation time for donor lungs using this method is typically limited to 6–8 h [78], while the current duration for SCS of heart is limited to 4–6 h [73]. In 2019, a study investigated the application of SCS for preserving murine hearts [79], demonstrating that the addition of a mitochondria-targeting hydrogen sulfide donor to UW solution significantly enhanced its anti-apoptotic, antioxidative, and anti-inflammatory properties. In 2021, Guenthart et al. [80] performed a clinical trial on the static hypothermic preservation of an allograft heart, successfully achieving a storage period of 283 min and an ischemic time of 330 min.
SCS extends the preservation time of transplantable organs, making it a widely adopted approach due to its simplicity and affordability. However, there are still limitations and challenges associated with SCS. Under hypothermic conditions, significant physiological metabolic activities persist, leading to ATP depletion and metabolite accumulation, and resulting in subsequent IRI and DGF recovery [29], [30].
5. MP of organs
Organ preservation originates from the idea of extracorporeal circulation, first proposed by Cesar Le Gallois in 1813, which suggests that life could be sustained in any body region through the controlled administration of injections and arterial blood [81]. This concept has influenced the development of modern organ preservation techniques. In the 1860s, Claude Bernard proposed the basic principles of mechanical perfusion, which laid the foundation for organ perfusion preservation [82], [83]. In 1963, Marchioro et al. [84] achieved a breakthrough by performing extracorporeal perfusion of canine organs after femoro-femoral natural blood flow cessation. The organs were preserved in autologous blood at 12–15 °C [85]. Kidney function was successfully maintained for 6 h, while liver function was preserved for 2 h.
Scientists began to speculate that lower temperatures could mitigate organ damage during preservation by reducing cellular metabolism. During the 1960s, numerous experiments were conducted to investigate the effects of cooled diluted serum or heparinized blood on kidney preservation [86], [87]. These studies demonstrated a significant increase in preservation time, extending from a mere few hours to several days, when utilizing hypothermic machine perfusion (HMP) [5]. Schematic diagrams and current techniques of HMP are shown in Figs. 2(b) and (d)[70], [71]. By 1967, the combination of continuous perfusion and hypothermic storage elevated organ preservation to a new level. Belzer et al. [88] successfully preserved canine kidneys for 72 h by means of pulsatile perfusion with oxygenated plasma at 8–12 °C, marking a significant milestone. HMP enables sustained electron transport capacity in organ mitochondria, providing energy for maintaining systemic homeostasis [71], [89]. Compared with SCS, it can improve microcirculation status and enhance organ survival rate. In 2016, continuous HMP was implemented as the standard care method for all types of deceased donor kidneys in the Netherlands [90]. However, HMP also presents various issues, such as vascular spasm in kidney grafts [5]. Therefore, further research is still needed to address these issues.
Normothermic machine perfusion (NMP) refers to the extracorporeal MP of organs while simulating a normal body temperature of approximately 38 °C. In particular, the perfusate of NMP has the capability to transport oxygen (Fig. 2(c)) [70]. A randomized clinical trial conducted in Europe on NMP for liver transplantation demonstrated superior transplant survival rates compared with the SCS group (Fig. 2(e)) [72]. The trial revealed that the NMP group exhibited lower peak levels of serum aspartate aminotransferase (AST), indicating reduced cold ischemic injury and improved organ viability. However, in a rigorous phase-II clinical trial, it was observed that livers preserved with NMP still experienced post-transplant issues such as non-anastomotic biliary strictures, requiring subsequent surgical interventions [91]. A recent review article emphasized the additional benefits of NMP for livers across all donor types in terms of reduced length of hospital stay and decreased risk of primary graft non-function [92]. Multiple portable perfusion machines have been developed for the purpose of organ preservation and transportation, specifically for organs such as hearts, lungs, and kidneys [93], [94], [95]. These machines enable real-time data acquisition, continuous monitoring, and evaluation of graft function throughout the transportation process [96].
6. Supercooling preservation of organs
Supercooling is a preservation technique that maintains the temperature below the freezing point without ice. In general, water can be divided into three stages of supercooling and freezing, as shown in Fig. 3(a)[97]. In the precooling stage, water can remain in a liquid state even when its temperature drops below its freezing point due to the energy required for ice formation [97]. This state is called supercooling. Once the temperature drops low enough and enough energy is present, ice crystals will begin to form and water will freeze. Once all the water has transformed into ice, the temperature of the ice drops quickly as energy is released. Many organisms in nature—including fishes, insects, and reptiles—possess the remarkable ability to maintain their body temperature below freezing for extended periods [98]. This ability is attributed to the synthesis of abundant carbohydrates, which stabilize the cell membranes [99]. In addition, the synthesis of ice-blocking substances, known as ice recrystallization inhibitors, prevents the formation of ice crystal [100]. In recent years, supercooling preservation has gained significant attention among researchers.
In 1996, Scotte et al. [101] successfully preserved rat livers at −4 °C by adding 2,3-butanediol to UW solution. They found that liver preservation below 0 °C was feasible but required evaluation using transplantation models. Further studies confirmed the benefits of supercooling organs. Compared with SCS at 4 °C, the supercooling preservation of rat lungs at −4 °C significantly reduced IRI [102]. In 2015, Bruinsma et al. [103] combined ex vivo perfusion and supercooling, enabling the successful transplantation of rat livers with an extended supercooling time of up to 4 days. However, achieving supercooling for larger volumes posed challenges due to the instability of the supercooled state. In 2019, de Vries et al. [4] optimized perfusion methods, enabling the preservation of large-volume organs, including human livers (Figs. 3(b) and (c)). The strategy relies on several crucial components: minimizing the gas–liquid interface through aqueous-phase sealing, lowering the melting point by adding UW solution, employing uniform loading, and optimizing the perfusion method.
Recently, Rubinsky et al. [104] pioneered an isochoric preservation approach for bio-specimens, wherein biological samples are stored within rigid containers to maintain a constant volume. During the supercooling process, the formation of low-density ice crystals elevates the system pressure, resulting in significant thermodynamic constraints along the liquid phase curve [105]. The increased pressure imposes considerable energy dissipation, impeding the final growth of ice crystals and decreasing the likelihood of nucleation in supercooled aqueous systems [106], [107], [108]. The isochoric preservation approach has shown promising results in extending the stability of bio-specimens without the use of CPAs that can potentially damage them. In 2021, Powell-Palm et al. [109] successfully generated cardiac microtissues derived from three-dimensional human induced pluripotent stem cells (hiPSCs) that exhibited autonomous contractions. Notably, this achievement was accomplished through isochoric hypothermic preservation, entirely eliminating the requirement for CPAs. In addition, Năstase et al. [110], [111] performed a series of experiments that successfully demonstrated the application of isochoric preservation to extend the stability of pig livers under non-freezing conditions for 48 h, without employing CPAs. This innovative preservation technique offers promising prospects for advanced organ transplantation procedures by enhancing post-preservation functionality and extending the lifespans of donor organs. However, conclusive evidence validating the successful transplantation of these preserved organs remains to be established.
7. Partial freezing preservation of organs
Supercooling preservation relies on temperatures slightly below 0 °C (approximately −4 to −6 °C). However, achieving deeper metabolic slowdown requires even lower temperatures. Recently, a strategy employing partial freezing preservation was developed to promote thermodynamic stability while simultaneously mitigating ice damage and excessive dehydration by maintaining a sufficient unfrozen portion [112]. Drawing inspiration from freeze-tolerant organisms, Da Silveira Cavalcante et al. [113] conducted a study examining the cardiac activity and circulatory indicators of zebrafish hearts pre- and post-freezing at −10 °C. Experiments were also conducted on rodent livers and hearts, which were stored at −15 °C for up to 5 days. Expanding upon these investigations, in 2022, the application of ice nucleators in conjunction with CPAs facilitated the partial cryopreservation of human livers at temperatures ranging between −10 and −15 °C, thereby extending the preservation timeframe to 5 days [114].
8. Long-term cryopreservation of organs
The long-term preservation of organs has a significant impact on organ assessment, allocation, and transplantation [1]. Firstly, extending the preservation time for organs can contribute to shifting emergency operations to planned operations [115]. This not only reduces organ transplant costs but also improves the matching based on human leukocyte antigen compatibility [116]. Besides, environmental factors—including the geographical distance between donors and recipients—often result in organ discards [22]. Prolonging organ preservation time effectively assuages this predicament, obviating the need for premature organ disposal and thereby ameliorating organ scarcity.
Organ cryopreservation is considered the holy grail of cryopreservation. Theoretically, the physiological metabolism and activity of organs or tissues could be suspended at the temperature of liquid nitrogen (−196 °C) [117], [118]. Some strategies have been highly successful in the preservation of cells and tissues, leading to the promise of organ cryopreservation, such as classical cryopreservation (i.e., slow freezing) and vitrification cryopreservation (Fig. 4(a)) [119]. The thermodynamic paths of classical and vitrification cryopreservation are shown in Fig. 4(b)[8]. In the following sections, we focus on elucidating several key factors involved in achieving the long-term cryopreservation of organs.
8.1. Vitrification
Cryopreservation by vitrification is regarded as the most promising approach for long-term organ preservation, as it completely avoids the damage of ice formation. In the 1930s, researchers reported the vitrification of biological materials—such as frog spermatozoa, moss, drosophila melanogaster embryos, and other materials—by means of fast freezing [120], [121], [122], [123], [124], [125]. Vitrification at extremely fast cooling rates is effective for small volumes. Fahy et al. [126] adopted a different approach, focusing on the development of vitrification solutions that replace a portion of the water in organs with solutes that undergo vitrification more easily. The vitrification solution forms strong hydration interactions with water molecules which increases the aqueous solution’s viscosity and reduces ice crystal formation, providing cell protection during rapid cooling or rewarming [127]. This enables vitrification to be achieved at lower cooling rates. Research on vitrification has been widely conducted [128]. In 2000, the vitrification of arterial blood vessels was achieved [129]. Vitrification is the preferred method for the cryopreservation of oocytes and embryos in clinical settings [130] and currently appears to be the most promising approach for successful organ cryopreservation [119], [131], [132].
To achieve vitrification, high concentrations of a permeating CPA (e.g., DMSO, glycerol, ethylene glycol (EG), propylene glycol) and non-permeating CPA (saccharides, polymers, etc.) are required [133]. In 2021, Faltus et al. [134] studied the vitrification abilities of EG, DMSO, glycerol, sucrose, and poly(vinyl alcohol), providing theoretical support for the design of vitrification CPAs. The use of ice-free vitrification circumvents the issue of ice crystal growth during the freezing process. However, the high concentration of CPAs used in vitrification solutions can lead to toxicity issues in cells (Fig. 4(c)) [8]. Moreover, the nucleation of ice crystals during warming and devitrification can cause fatal damage to cryopreserved samples [135]. The formation and growth of ice crystals, along with associated mechanical injuries, are the primary causes of functional and structural damage to cryopreserved biological samples [136]. The main challenges of vitrification include CPA toxicity, rapid cooling and rewarming rates, and CPA removal (to avoid both osmotic stress and ice recrystallization injury) [137].
Recent advances have brought new possibilities for addressing the bottleneck issues in vitrification. The use of isochoric preservation has been explored to reduce the required concentration of CPAs [138], [139]. Liquid perfusion, which involves increasing the CPA concentration as the organ’s temperature decreases, has been investigated as a means to minimize toxicity [140]. Excitingly, the use of magnetic nanoparticles has shown promise for the rapid and uniform rewarming of vitrified tissues in an alternating magnetic field [12], [141]. These nanoparticles can be infused into organs prior to vitrification, preventing ice crystal formation and organ rupture during the rewarming process.
8.2. Vascular perfusion
In general, the penetration of CPAs into solid organs cannot be achieved solely through local exposure and diffusion. Perfusion of CPA into the vascular network is a potentially effective method [142]. This technique dynamically increases the concentration of CPA in the organ and allows for the active cellular uptake of CPA due to the metabolic activity of the organ during perfusion [66]. Experimental evidence of favorable outcomes has been obtained, such as the extended ex vivo preservation time of human livers under HMP [4]. Recent studies have utilized perfusion techniques such as magnetic nanoparticle infusion to enhance the cryopreservation rewarming efficiency in organs such as hearts and kidneys [119], [132].
The composition of the carrier solution used for CPA perfusion is crucial. It is necessary to consider the toxicity of the CPAs; moreover, CPAs affect the osmotic pressure of tissue cells as they enter (and leave) cells, resulting in cell volume changes similar to those in single-cell suspensions [66]. These changes may alter the perfusion resistance and organ weight during CPA infusion, potentially damaging the blood vessels even in the absence of freezing. Such changes can be partially mitigated by selecting specific perfusion agents, adding osmotic buffer solutions, and performing perfusion at lower temperatures (e.g., HMP). Karow et al. [143] discussed the permeability kinetics of DMSO at different temperatures for reducing osmotic damage and designing a cryopreservation protocol.
8.3. Toxicity
The utilization of high-concentration CPAs facilitates ice-free vitrification cryopreservation but also presents challenges associated with CPA toxicity. In-depth comprehension of the mechanisms underlying CPA toxicity and the exploration of strategies to mitigate the effects of toxicity are critical for successful organ preservation.
Cells and tissues display varying sensitivities to certain constituents of CPAs, resulting in specific CPA toxicities. For example, the toxicity of EG is related to the organ metabolism pathway rather than the cryopreservation procedure [144]. EG is metabolized in liver via the enzyme aldehyde dehydrogenase, resulting in the formation of glycolaldehyde [145], [146]. Subsequently, glycolaldehyde is further metabolized by aldehyde dehydrogenase to produce glycolic acid [147]. This metabolic process can lead to the development of metabolic acidosis. In addition, glycolic acid can be enzymatically converted to oxalic acid. In the presence of calcium ions, oxalic acid can form calcium oxalate crystals, which may cause gastrointestinal irritation, pulmonary edema, and widespread systemic inflammation of the lung [148], [149].
The use of glycerol has been a significant breakthrough in sperm cryopreservation [32]. However, it is associated with side effects such as damage to sperm morphology, mitochondria, and viability [150]. Moreover, when glycerol is metabolized by caspases in the kidneys, it depletes the levels of reduced glutathione [151], [152]. This depletion, in turn, triggers oxidative stress, inflammation, and cell apoptosis. In experimental studies conducted on rodents, this cascade of events ultimately leads to renal failure [153].
Among permeating CPAs, DMSO is deemed an optimal CPA for cells. However, at concentrations exceeding 30% in rat studies at 30 °C, DMSO has been found to cause irreversible alterations in myocardial ultrastructure [154]. Exposing guinea pig heart muscles to 10% DMSO for 30 min at room temperature led to a sustained increase in the potential associated with myocardial cell contraction [155]. This effect may stem from irreversible binding between DMSO molecules and proteins, leading to the disruption of protein conformation and blockade of membrane channel proteins [156], [157], [158]. DMSO also impacts cell membrane properties [159]. The exposure of cells to low concentrations of DMSO (2.5%–7.5%) at 77 °C was found to decrease the cell membrane thickness [160]. At moderate concentrations (10%–20%), DMSO induces the transient formation of water pores. However, at higher concentrations (25%–30%), it can cause membrane disruption. DMSO can also affect mitochondrial respiration and intracellular calcium levels [161]. Fibroblasts exposed to 1% DMSO demonstrated a rapid increase in intracellular calcium, leading to cell apoptosis [162], [163].
In order to mitigate the toxicity of conventional CPAs, a cohort of researchers are spearheading the development of alternative cryopreservation techniques. Sui et al. [164] demonstrated the efficacy of a composite consisting of the biocompatible zwitterionic betaine and membrane-stabilizing agents, which yielded a post-thaw cell viability rate exceeding 80% in red blood cells, thereby circumventing the need for exogenous CPAs. Their approach involves the strategic modulation of osmotic pressure to obviate the requirement for such toxic agents altogether. The group also explored the potential of zwitterionic polymers in cryopreservation, achieving a cell viability rate of 90% in cryopreserved chondrocytes, Gejiu lung carcinoma-82 (GLC-82) cells, and HeLa cells (Fig. 4(d)) [165], [166]. Similarly, Zhu et al. [167] implemented zirconium-based metal–organic framework nanoparticles for cryopreservation, excluding toxic organic solvents, and achieved a red blood cell survival rate in excess of 40%. Nonetheless, it should be noted that the applicability of these groundbreaking cryopreservation techniques in macroscopic tissue and organ cryopreservation domains requires further scrutiny and development.
8.4. Addition and removal of vitrification solutions
Vitrification requires high concentrations of CPAs to prevent the formation of ice crystals, which can result in both cytotoxicity and substantial osmotic stress damage. In order to minimize such injuries, CPAs have traditionally been loaded and unloaded via laborious and time-consuming multi-step procedures [168]. Various microfluidic devices are being studied to enhance and streamline the process of loading and unloading CPAs at the cellular level. By harnessing the principles of laminar flow and precise molecular diffusion in microchannels, these microfluidic devices optimize the speed of CPA loading (or unloading) and minimize the cytotoxic effects associated with extended exposure to CPAs [169], [170]. This approach can also reduce cellular volume changes and the speed of CPA washout to mitigate osmotic stress. In 2022, Zhan et al. [10] devised a microfluidic platform tailored for the high-throughput, high-viability vitrification cryopreservation of islets. By employing a programmatic approach to the design of CPA loading and unloading protocols, they effectively minimized osmotic damage during these critical processes. The successful implementation of this technique holds significant promise for the advancement of islet preservation techniques.
8.5. Cooling
Successful vitrification relies on fast cooling and warming rates (Figs. 5(a) and (b)) [119]. When the cooling rate reaches a critical threshold, water molecules lose their ability to move freely and their kinetic energy decreases, resulting in the inability to form regular ice crystals and leading to vitrification [171], [172]. The critical cooling rate (CCR) mainly depends on the formulation and concentration of CPAs. Lower concentrations of CPAs require higher CCRs to prevent ice crystal formation. For example, three commonly used CPAs, DP6 (6 mol∙L−1), VS55 (8.4 mol∙L−1), and M22 (9.3 mol∙L−1), have respective CCRs of 40, 2.5, and 0.1 °C∙min−1[173], [174], [175], [176].
The advancement of the Johnson–Mehl–Avrami (JMA) kinetics theory provides a framework to evaluate the ability of vitrification [177], [178], [179], [180]. This approach estimates the minimum cooling rate required to prevent ice crystal formation and growth in the glassy state by evaluating the crystallization rate. Uhlmann et al. [181], [182] proposed a model of using a time–temperature–transformation (TTT) curve to determine the CCR. However, this model is based on isothermal transformations and may not accurately reflect actual cooling processes. To address non-isothermal crystallization transformations, MacFarlane [183] considered a numerical integration method to construct a continuous-cooling-transformation (CCT) curve, providing a direct estimation of the CCR. That said, obtaining physical parameters such as nucleation rate and crystal growth rate during cooling and crystallization processes with low-temperature protective agents can be challenging, which makes the construction of TTT and CCT curves to produce useful experimental results difficult.
Based on the dynamics of crystal growth, a semi-empirical crystallization kinetics model was proposed [184], [185]. Under certain assumptions, this model derives analytical expressions for the variation of ice crystal formation with cooling rate and other parameters. In the Boutron model, the amount of ice crystal formed during the cooling process follows an S-shaped relationship (Fig. 5(c)) [186], [187].
where $x$ represents the ratio of crystallized ice during the cooling process (0 ≤ x ≤ 1), $V$ stands for the cooling rate, and $k_{4}$ is a constant fitting parameter obtained through the least squares approximation technique. The amount of ice crystal formation in the system is a dimensionless function, determined by the ratio of the enthalpy of freezing to the enthalpy of water [187]. When $x$ = 0.2, the amount of ice crystal formation can be considered negligible [188]. Therefore, the corresponding cooling rate at this point is considered to be the CCR.
8.6. Rewarming
The phenomenon of rapid cooling during vitrification leads to the formation of unstable amorphous structures that can undergo devitrification upon rewarming (Fig. 5(d)) [187], [189]. Therefore, the critical heating rate is typically one to two orders magnitude higher than the CCR [190], [191]. The critical warming rate (CWR) can be defined as the heating rate at which devitrification is negligible or nearly nonexistent. Boutron and Mehl [190] defined the CWR as the rate during the warming process that causes less than $q$ = 0.5 freezing (q is the quantity of ice formed). As the heating rate increases, the disparity between devitrification temperature (Td) and melting temperature (Tm) gradually diminishes (Fig. 5(e)) [187]. As an illustration, the CWR for DP6 is 189 °C∙min−1[187]. The rewarming temperature should be kept slightly above the melting point (Tm) to prevent potential tissue damage from excessive heat exposure [10], [192].
To improve the rewarming rate of vitrification-based cryopreservation, techniques such as nano-warming and radiofrequency (RF), electromagnetic heating, and high-intensity focused ultrasound (HIFU) have been proposed and investigated [193]. These approaches aim to achieve faster and more uniform heating of large samples during the recovery process from the vitrified state, offering potential improvements in the field of cryopreservation.
8.6.1. Nano-warming and RF
In recent years, the application of nanomaterials has opened up new avenues in the field of cryopreservation. Nanomaterials have revolutionized the field of rewarming by enabling advanced techniques such as magnetic heating and photothermal heating, which ensure the swift and uniform rewarming of biological samples [194]. Thanks to the unique properties of nanomaterials, advanced rewarming techniques surpass traditional heat-conduction-based methods. These innovative approaches tap into the distinctive characteristics of nanomaterials to avoid sole reliance on heat transfer from the tissue surface to its interior, resulting in superior performance.
Nanoscale materials, including carbon black (India ink), gold nanorods, and liquid metal nanoparticles, exhibit high extinction coefficients that facilitate the conversion of near-infrared light into heat [195], [196], [197]. This enables rewarming heating rates of up to 107 °C∙min−1, making such materials particularly well-suited for the ultra-fast rewarming of small-volume biological samples [198]. However, their limited laser penetrability currently hinders their application in rewarming larger biological samples.
As an alternative approach, magnetic nanoparticles such as iron oxide nanoparticles possess magnetocaloric properties, which significantly enhance the heating rate and eliminate temperature nonuniformity when subjected to a magnetic field (Figs. 6(a) and (b)) [12], [132]. This approach minimizes thermal stress and shows great promise for overcoming the limitations of traditional cryopreservation techniques (Fig. 6(c)) [132]. In a notable study in 2017, Manuchehrabadi et al. [12] achieved vitrification-based cryopreservation in a system with a volume of up to 80 mL using mesoporous silica-coated iron oxide nanoparticles stimulated by RF. Subsequently, the researchers applied this heating technique to successfully cryopreserve kidneys and hearts, demonstrating its potential for cryopreserving larger and more complex organs [119], [132], [141], [199], [200]. In 2023, the team accomplished a significant milestone by achieving the long-term vitrification-based cryopreservation of rat kidneys, which were then successfully transplanted [192].
These advancements highlight the significant contributions of nanomaterials in the pursuit of enhanced rewarming techniques for cryopreservation, paving the way for improvements in preserving biological samples and organs for various applications.
8.6.2. Electromagnetic rewarming
Although the nano-warming method facilitates the cryopreservation of large organs, the potential cytotoxicity induced by the penetration of magnetic nanoparticles into certain cells should be taken into consideration. In response, a novel method known as single-mode electromagnetic resonance (SMER) has been developed, which is primarily based on Maxwell’s theory of dielectric heating [201]. This method leverages the omnipresent dipolar water molecules in biological systems to generate heat through friction when non-conductive samples are subjected to a high-frequency electromagnetic field [202]. The sample is placed within a resonant cavity with feeding oscillating electromagnetic waves. The primary advantage of this approach is its ability to achieve rapid and uniform heating within a short period of time [13], [203]. This groundbreaking technique has demonstrated the capability to rapidly rewarm large-volume cells and arterial vessels, so it holds promising potential for the vitrification cryopreservation of substantial organs [204], [205].
8.6.3. High-intensity focused ultrasound
The HIFU technique has recently gained considerable interest for its potential in rewarming cryopreserved samples [206], [207]. Based on the piezoelectric effect, HIFU can convert electrical stimulation into mechanical vibrations, generating precisely focused pressure waves to achieve controlled and localized heating. Ultrasound has a long history of being utilized for heating normothermic tissues, and HIFU has undergone clinical trials and been approved for medical use [208], [209]. In 2023, Alcalá et al. [210] applied the HIFU technique to rewarm Caenorhabditis elegans nematodes cryopreserved at −80 °C. This approach effectively addresses the challenge of recrystallization by leveraging the inherent attenuation properties of ultrasound, thereby minimizing the risk of thermal runaway [211], [212]. In contrast to electromagnetic rewarming, which is constrained by the proximity of the coil positioning, HIFU offers enhanced flexibility and precision. Furthermore, in 2024, Encabo et al. [213] accomplished the recovery of mouse hearts cryopreserved at −6 °C through the HIFU rewarming technique. These promising findings signify the potential of HIFU as a viable solution to mitigate recrystallization-related concerns in the cryopreservation domain. However, comprehensive evaluation is imperative to assess the applicability of HIFU for deep cryopreservation rewarming and its viability for larger organ systems.
9. Assessments in organ preservation
In organ preservation, assessments play a pivotal role in ensuring the quality and suitability of organs. The evaluation of the effectiveness of the vitrification process serves as a critical approach for maintaining organ quality and suitability, directly impacting the extent of cryogenic injury incurred and the preservation of organ function. Through comprehensive assessments encompassing organ morphology, physiology, and functionality, it becomes possible to determine the feasibility of organs and assess the success of subsequent transplant surgeries, as well as the survival rate of patients. The development of assessment techniques contributes to further enhancing quality control in organ preservation, bringing new hope to a larger population in need of organ transplantation.
9.1. Loading/unloading of CPAs
In the assessment of CPA loading and unloading in organs, the combined use of mass transfer models and CPA toxicity models is commonly employed. Numerous mass transfer models have been developed, including the Krogh model [214], multidimensional models [215], and network thermodynamics models [216]. The evaluation of CPA toxicity and the optimization of loading/unloading protocols can be achieved through the application of solution effect models [217], [218], [219], CPA interaction models [220], and toxicity cost function models [184]. In 2023, Han et al. [186] made a significant contribution by deriving the Boyle–van’t Hoff equation for organs and determining the non-permeating volume fraction through perfusion experiments. The researchers employed the Krogh model and the toxicity cost function model to measure and optimize CPA loading/unloading strategies. Within a Krogh cylinder, the transport kinetics of water and CPAs across the capillary membrane were described using the Kedem–Katchalsky equations.
represents the total volumetric flow rate, including water and CPAs; $J_{cpa}$ specifically denotes the flow rate of CPAs; $S$ represents the surface area available for transport; and $L_{p}$ indicates the membrane’s hydraulic conductivity. $P$ represents the hydraulic pressure exerted on the membrane, and $R_{g}$ is the universal gas constant. $T$ represents the system’s temperature, and $C$ signifies the concentration of a substance. $ω$ represents the membrane’s permeability to the CPA, and σ is the reflection coefficient, both relating to the membrane’s characteristics. The subscripts “t” and “f” indicate the concentration in tissue and in the fluid flowing in the capillary, respectively. The subscripts “cpa” and “is” represent the total concentration of CPAs and the concentration of impermeable solutes (e.g., sugars, sugar alcohols, and polymers), respectively.
The toxicity cost function ($J_{tox}$) model is a commonly used approach to assess CPA toxicity, as it incorporates the functional relationship between CPA toxicity and the variables of CPA concentration, exposure time, and temperature [184].
$\left\{\begin{array}{l} k=\beta \cdot C_{\mathrm{cpa}, \mathrm{t}}^{\alpha} \\ \frac{\mathrm{d} N}{\mathrm{~d} t}=-k \cdot N \\ J_{\mathrm{tox}}=\int_{0}^{t_{\mathrm{f}}} k \mathrm{~d} t=\int_{0}^{t_{\mathrm{f}}} \beta \cdot C_{\mathrm{cpa}, \mathrm{t}}^{\alpha} \mathrm{d} t \\ \frac{N}{N_{0}}=\exp \left(-J_{\mathrm{tox}}\right) \end{array}\right.$
where k is the toxicity rate. The constants α and β are specific to the CPA formulation and its interaction with the biological system at a given temperature. $C_{cpa}$ refers to the concentration of the CPAs inside the tissue, and $N_{o}$ represents the initial viability of the tissue. N is the number of viable cells and $t_{f}$ is the duration of CPA exposure.
9.2. Vitrification or crystallization in organs
The formation of a vitrified state occurs when a liquid substance undergoes a rapid cooling process, crossing the crystalline structure phase transition and transforming into an amorphous glass-like state. Achieving the vitrified state requires a high cooling rate, but the preservation of an unstable structure during rapid freezing can lead to devitrification during the rewarming process. The CWR to avoid devitrification/recrystallization is generally several orders of magnitude higher than the CCR for vitrification [134], [189]. Assessment of the vitrification level can be visually performed using imaging devices: A clear and transparent appearance indicates a vitrified state, while the devitrification process appears opaque and turbid due to ice crystal growth (Fig. 4(a)) [12], [119], [132]. The thermodynamic characteristics can be evaluated through heat flow changes during the temperature cycling process, using a differential scanning calorimetry (DSC) device. When the cooling rate is slower than the CCR, a crystallization peak indicating ice crystal formation is observed [187], [221]. As the cooling rate increases, the size of the crystallization peak gradually decreases until it disappears. Similarly, when the rewarming rate does not reach the CWR, a devitrification peak and ice recrystallization peak are observed (Fig. 5(d)). As the rewarming rate increases, these peaks gradually decrease until they disappear, indicating a successful rewarming process without recrystallization.
9.3. Viability and functionalities of organs
As the risks associated with organ donors continue to rise, the majority of organs fall into the “marginal” category. This makes it crucial to assess and predict the quality of organ function. Evaluating the vitality and functionality of organs after cryopreservation is crucial for a proper assessment of the quality of the cryopreserved organs. Current research is focused on developing innovative methods and techniques for this evaluation, through both in vivo and in vitro studies. These advancements aim to ensure precise assessment and selection of organs, ultimately improving the quality of organ preservation and increasing the success rate of transplantation. These efforts drive further advancements in the field of organ transplantation.
9.3.1. In vitro assessment
The vitality, structural integrity, and functionality of an organ after preservation are the main parameters used to evaluate an organ in vitro. In biology, vitality encompasses a range of cellular functions specialized in the survival, growth, and development of individual cells or organisms [222]. Cellular functionality is considered crucial for the state of vitality, including cell morphology, an intact membrane barrier with functional integrity, energy production for maintaining vital functions and enzymatic activity, DNA transcription and RNA translation processes, the maintenance of viable pH gradients, and cellular respiration and reproduction. An evaluation of cellular vitality is indicative of the organ activity. In 2021, Sharma et al. [119] tested the vitality of cryopreserved rat kidneys and found them to exhibit higher activity than the conventional freezing group. In 2023, Lau et al. [223] investigated the efficacy of ex situ NMP on the preservation of human livers. Their research focused on evaluating the liver’s lactate clearance capacity, bile production capability, and storage capacity of factor V synthesis and ATP. The results provided compelling evidence indicating that this advanced preservation technique effectively prolonged the preservation duration of livers, enabling them to be maintained for an impressive period of up to 7 days.
Determining the structural integrity of organs is an important aspect of assessing preservation techniques, as it aids in evaluating organ damage. In 2022, Gao et al. [132] performed hematoxylin and eosin (H&E) staining on cryopreserved hearts and observed well-preserved structural features, such as intact branching striated muscle fibers. The functionality of certain organs is also closely related to their structure, and evaluating organs’ biomechanical performance is critical. In 2017, Manuchehrabadi et al. [12] cryopreserved pig blood vessels using vitrification; the post-cryopreservation H&E staining data demonstrated normal nuclear morphology and intact structure, with a tensile modulus similar to that of the fresh group. It should be noted that different organs possess unique functions, which we will specifically discuss in subsequent sections.
9.3.2. In vivo assessment
Organ transplantation serves as a significant means for the in vivo assessment of cryopreserved organs, allowing for a more precise evaluation of organ viability and functionality within a living organism. This approach is vital for determining the success and quality of organ preservation and transplantation procedures. Through scientific advancements and methods, the assessment of cryopreserved organs within a living body offers invaluable insights for improving transplantation outcomes and enhancing patient care. In liver transplantation, for example, livers are preserved at room temperature, and post-transplant liver injury can be assessed by measuring the release of liver enzymes such as AST [72]. In 2014, Berendsen et al. [224] developed an advanced liver storage technique that combines supercooling with MP. Post-preservation assessments showed normalization of histological, hematological, and morphological parameters, including transaminase levels, albumin, bilirubin, alkaline phosphatase, and blood urea. Furthermore, a randomized trial in 2018 evaluated NMP for liver transplantation [72]. This study found that NMP resulted in a 50% reduction in graft injury, compared with traditional SCS, as indicated by decreased hepatocellular enzyme release.
For kidney transplantation, commercial organ preservation solutions such as UW and HTK solutions are used to preserve kidneys before transplantation. Kidney function can be evaluated through continuous measurement of serum creatinine and blood urea nitrogen, as well as the presence of primary non-function and DGF [3]. Moreover, Wilson et al. [225] developed a sequencing and bioinformatics strategy that enables the deconvolution of recipient-specific and donor-specific gene expression in cryopreserved lung tissue biopsies.
10. Preservation of various major organs
Given the distinct cellular composition and unique structure–function attributes of various organs, their responses and vulnerabilities during the preservation process necessitate tailored preservation methods and strategies. The preservation temperature (cold storage, supercooling preservation, and cryopreservation) is a critical factor, as lower temperatures can impede biological activities and physiological metabolism by diminishing molecular thermal motion. However, careful attention must be given to mitigate the risk of cold-induced injury. Furthermore, the judicious selection and appropriate dosing of protective agents are essential to attenuate cold-induced damage while minimizing potential toxicity. The next section discusses the optimization and refining of the existing preservation methods employed for various major organs.
10.1. Kidney
With the advancements and refinements of organ preservation solutions such as Collins solution, UW solution, and HTK solution, SCS has emerged as the predominant clinical standard for preserving organs [226], [227], [228]. SCS allows kidneys to be stored for an extended period of 24–36 h before transplantation [229], [230], [231]. By reducing the temperature, SCS effectively slows down cellular metabolism, providing a temporary state of preservation [232]. However, prolonged SCS can have several drawbacks, including prolonged warm ischemia time, tissue hypoxia, acidosis, reduced viability and even necrosis of renal tubule cells, and disruption of cellular homeostasis [233]. Furthermore, the limited time window of SCS presents challenges in terms of a shortened matching time between donors and recipients and inadequate surgical preparation [1], [229]. These factors collectively contribute to decreased organ viability and increased patient mortality rates [234]. Consequently, traditional organ preservation methods are being reevaluated, and alternative approaches are being explored.
In response to SCS limitations, MP has emerged as a focal point in kidney preservation [235]. This approach, which leverages a continuous oxygen and nutrient supply to reconstitute the renal energetic reserves, effectively reverses the injury occasioned by the cessation of ATP supply during warm ischemia [236], [237], [238]. MP also impedes the induction of further renal damage during the preservation process. In 1973, Sacks et al. [239] utilized a hypertonic electrolyte solution as a CPA for the HMP of dog kidneys, reducing damage caused by warm ischemia. The serum creatinine levels reached normal levels one week after transplantation, extending the preservation time to 72 h. In 2005, Monzen et al. [240] reduced organ metabolism and alleviated tissue ex vivo injury through HMP, achieving a preservation time of 72 h.
Since the turn of the millennium, significant strides have been made in the discipline of organ preservation utilizing vitrification cryopreservation and transplantation [175]. In an initial proof-of-concept study, rabbit kidneys were subjected to M22 vitrification solution perfusion and successfully cryopreserved for a nine-day span prior to transplantation [241]. Follow-up investigations compared the performance characteristics of the vitrification solutions VS41A and VS4, with the latter formulation exhibiting advantageous kidney preservation capabilities (Fig. 7(a)) [242]. In 2021, seminal work by Sharma et al. [119] explored the viability of kidney vitrification in combination with an innovative nano-warming technique, with a meticulous microscopic histological analysis providing a compelling evidence base (Fig. 7(b)). Notably, the team achieved an impressive milestone in 2023 by successfully transplanting rat kidneys that had undergone vitrification cryopreservation and nano-warming after 100 days of cryopreservation [192]. A post-transplantation assessment of hematological and physiological parameters, including serum creatinine, venous potassium, venous pH, and venous lactate, demonstrated the complete restoration of kidney function within the recipients (Figs. 7(c) and (d)) [192]. These pioneering developments hold tremendous promise for the optimization of future organ transplantation practices.
10.2. Liver
The liver, being a vital organ dependent on a continuous oxygen and energy supply, is highly vulnerable to IRI during preservation, leading to significant liver graft discards [243], [244]. When blood flow is interrupted during storage, it leads to damage to the liver cells, known as hepatocytes [245]. This damage is exacerbated when blood flow is restored, resulting in the activation of Kupffer cells (a type of immune cell in the liver), the release of pro-inflammatory cytokines (signaling molecules involved in inflammation), and the induction of oxidative stress [246], [247], [248].
At present, SCS is the predominant method for preserving donor livers, owing to its convenience and cost-effectiveness [1], [249]. However, the preservation time for a healthy donor liver is typically limited to 12–18 h. This constraint arises from the hypoxic conditions experienced by liver cells during preservation, which lead to the depletion of intracellular ATP levels while generating substantial amounts of xanthine [250]. Consequently, hepatocytes and sinusoidal endothelial cells are susceptible to damage, triggering the release of adenosine diphosphate, uridine triphosphate, inflammatory cytokines, and other molecules. These detrimental effects can compromise the viability and functional integrity of the liver graft, negatively impacting its post-transplantation outcomes. Notably, some researchers have reported a relatively high incidence, ranging from 25% to 44%, of early graft dysfunction following liver transplantation by SCS [91], [251], [252], [253]. To address this challenge, the application of MP techniques for liver preservation has garnered substantial attention and investigation in recent years [254].
The NMP technique currently has a limited perfusion duration of approximately 9 h, which hinders the comprehensive evaluation of liver parameters [72]. To address this, Eshmuminov et al. [255] introduced an integrated NMP that prolonged the perfusion time to 24 h, enabling the preservation of human livers for up to one week (Figs. 8(a) and (b)). Subsequently, in 2022, Clavien et al. [256] clinically demonstrated the successful transplantation of livers preserved through non-original perfusion after 3 days (Fig. 8(c)). This breakthrough offers the potential to extend the preservation time window to up to 10 days, facilitating the thorough assessment of organ viability and transforming emergency surgeries into planned procedures. Taking inspiration from freeze-tolerant animals, in 2022, Tessier et al. [114] combined ice-nucleating agents and CPAs to maintain the unfrozen liquid fraction, extending the preservation time of rat livers to 5 days (Fig. 8(d)). Further research is required to investigate the long-term survival capability and safety of transplantation models in large animals such as pigs.
10.3. Heart
Clinical preservation of the heart during transplantation mainly relies on SCS solutions such as UW solution, EC solution, Celsior solution, and HTK solution at present [257]. However, this method poses challenges, as the heart consumes significant amounts of ATP and suffers from acidosis during warm ischemia under these conditions [258], [259], [260], which leads to cell apoptosis, necrosis, and IRI, increasing the risk of primary graft dysfunction [261], [262]. Additionally, the preservation time is limited to only 4–6 h [263]. Prolonged preservation time exacerbates damage to the coronary endothelium, resulting in impaired myocardial cell function and complications after heart transplantation, including heart transplant vasculopathy and graft failure, which are major causes of post-transplant mortality [264]. Therefore, reducing IRI and protecting myocardial cells are the primary goals of heart preservation [265]. Recently, MP has emerged as a promising alternative for donor heart preservation, utilizing an oxygenated and nutrient-rich perfusion solution to effectively attenuate IRI in the heart [266], [267], [268], [269].
Early experiments with MP on isolated dog hearts in 1968 demonstrated a preservation time of 72 h [270]. However, when transplanted, these hearts only survived for 6 h. Subsequent studies by Wicomb et al. [271] showcased the first successful implementation of a human heart MP system. Hearts were preserved for various durations ranging from 6 to 15 h before transplantation. Astonishingly, one patient’s transplanted heart survived for an impressive 16 months. In addition, McLeod et al. [272] provided evidence supporting the preservation of a sheep heart for 72 h through the evaluation of parameters such as heart function and oxygen kinetics by means of NMP (Figs. 9(a) and (b)). In another breakthrough study, researchers utilized UW solution in a novel storage solution (Columbia University (CU) solution), achieving an extended preservation time of 24 h for rat and baboon hearts, with long-term survival observed in transplanted baboons [273]. Further advancements in mechanical perfusion have been made using the Organ Care System (OCS). In 2019, Kaliyev et al. [274] were able to extend the preservation time of human heart grafts to an impressive 16 h through NMP. Moreover, the utilization of the OCS ensures a secure and prolonged preservation and evaluation of marginal grafts (Fig. 9(c)) [272]. These advancements have opened up new possibilities for heart preservation and eventual transplantation [269], [275], [276].
The application of vitrification cryopreservation combined with magnetic-nanoparticle-based rewarming has also shown promise in heart preservation. Researchers—such as Chiu-Lam et al. [141] in 2021—have successfully utilized the CPA VS55 and magnetic nanoparticles to achieve a preservation time of up to one week (Fig. 9(d)). This technique harnesses the potential of vitrification cryopreservation and nanoparticle-mediated rewarming, providing further avenues for improving heart preservation strategies. However, further research is still necessary to fully understand the impact and effectiveness of these preservation techniques in the context of heart transplantation.
10.4. Lung
The conventional method for preserving and transporting donor lungs is SCS, which only allows for a preservation period of 4–8 h in clinical settings [277], [278], [279]. This approach relies on a low-temperature environment to reduce metabolic and physiological activities, thereby minimizing potential damage to the ex vivo lungs [280]. However, this cold preservation technique can lead to cold-induced injury to the lungs. During the process, Na+–K+–ATPase activity decreases, leading to an accumulation of intracellular sodium chloride and calcium [281]. This disturbance in ion balance results in cellular swelling and injury [68], [282]. In addition, the anaerobic metabolism generates lactate, causing a decrease in cellular pH and leading to cellular acidosis [283]. Moreover, the rapid increase in intracellular calcium levels prompts the release of cytochrome C from mitochondria, triggering the activation of calcium-dependent enzymes and proteases [284], [285]. These enzymatic activities disrupt cellular structures and cleave pro-apoptotic enzymes, ultimately contributing to cellular dysfunction and apoptosis [286].
The advancement of organ perfusion techniques has given rise to the utilization of ex vivo lung perfusion (EVLP) in lung preservation. EVLP, which was initially introduced by Steen et al. [287] in 2001, involves an assessment of lung function through perfusion outside of the body before transplantation. Over time, improvements have been made to optimize EVLP. The EVLP circuit is shown in Fig. 10(a)[288]. In 2008, the Toronto Lung Transplant Program used NMP in EVLP to avoid damage caused by low temperatures and oxygen deprivation [289]. This upgraded system, known as the Toronto system, has demonstrated promising results. Apart from the Toronto system, there are two other widely used EVLP systems: the Lund protocol and the OCS, each with slight technical variations [290], [291]. The Toronto system employs a cell-free Steen solution, while the other systems incorporate red blood cells. Research on the use of cell-based versus cell-free perfusion fluids has generated inconsistent findings. However, overall, both approaches have demonstrated comparable lung protection effects [292], [293], [294]. In terms of perfusion flow, the Lund system matches the transplantation scenario by using 100% of cardiac output. Another significant distinction lies in the status of the left atrium [295]. The Toronto system is the only one that closes the left atrium, but studies have shown that leaving it open yields better outcomes, possibly due to the avoidance of uncontrollable low pressure associated with left atrium closure, which can lead to microvascular collapse and pulmonary edema. The OCS, as the only portable system available, is suitable for procuring lungs from remote areas. It can be transported to the donor site, allowing for evaluation and ongoing perfusion, thus reducing ischemic time. Ischemic time is associated with primary graft dysfunction, and prospective studies have demonstrated that the OCS system reduces the incidence of severe grade-3 primary graft dysfunction within 72 h [296].
Cryopreservation holds promise for significantly extending the storage duration compared with SCS and EVLP [297]. However, the complexity of cryopreservation arises from numerous challenges at the cellular, tissue, and organ levels. While several studies have focused on the cryopreservation of lung cells or tissues due to their unique cellular diversity, research on the cryopreservation of whole lungs remains relatively limited [298], [299], [300], [301]. In a notable study, Okamoto et al. [102] explored the cryopreservation of rat lungs using the ET-Kyoto solution at a temperature of −2 °C for 17 h. Their results indicated that lung function—including tidal volume, arterial oxygen tension, and weight gain—was maintained at a level comparable to that of the fresh control group (Fig. 10(b)) [102]. This study highlights the potential of cryopreserving lungs under supercooling conditions. However, the long-term feasibility of this approach for transplantation purposes still requires evaluation. Ali et al. [302] established the clinical viability of preserving human lungs through EVLP, effectively sustaining metabolic activity and mitochondrial functionality (Figs. 10(c) and (d)). This innovative preservation technique allowed for successful transplantation of these preserved lungs into five patients after a preservation duration of 10–16 h. Vitrification or partial freezing are potential approaches in lung cryopreservation research, but there is currently limited research available on their application to whole lungs. Further investigations are needed to assess their effectiveness and suitability for long-term storage and eventual transplantation.
10.5. Intestine
Intestine preservation techniques are crucial for successful transplantation procedures. SCS is a commonly employed technique to preserve the small intestine, using CPAs such as UW solution and HTK solution [303], [304]. However, the clinical preservation window for the small intestine is relatively limited, ranging from 6 to 8 h [305], [306], [307]. The underlying reason is the fact that the small intestine serves as the body’s largest reservoir of bacteria and endotoxins [308]. The small intestine’s delicate mucosal barrier is particularly prone to damage caused by ischemia-reperfusion, which can lead to a heightened translocation of microorganisms and the release of endotoxins into the bloodstream [247], [309]. These effects can subsequently give rise to challenges such as recipient immune rejection and bacteremia [310], [311].
To mitigate these issues, researchers have explored innovative MP techniques involving the delivery of metabolic substrates and the removal of waste products to minimize damage to the small intestine [312]. Although studies on small intestine preservation techniques are relatively scarce, some promising findings have been reported. For example, in 2003, Zhu et al. [313] demonstrated improved mucosal integrity of the small intestine using UW solution perfusion, indicating the potential benefits of MP. Furthermore, in 2016, Muñoz-Abraham et al. [314] from Yale University presented a groundbreaking study unveiling the novel approach of HMP for preserving human small intestinal units, encompassing both the vascular and luminal compartments. Their results established that this method was more effective in preserving intestinal tissue and produced better histopathological outcomes compared with traditional SCS methods. In recent years, NMP has gained attention as an alternative approach. Ludwig et al. [315] conducted a study using porcine full-length intestines preserved with NMP, which demonstrated enhanced cell proliferation and vitality compared with cold storage. This finding suggests that NMP has the potential to improve the regenerative capacity of allograft transplantation.
It is important to highlight that there are no reports currently available on the cryopreservation of the small intestine. Future research efforts should focus on advancing preservation techniques for the small intestine, considering the organ’s unique challenges and characteristics. By further exploring MP methods, such as NMP, and continuously improving our understanding of small intestine preservation, we can enhance the success rates of small intestine transplantation and improve patient outcomes.
11. Discussions and conclusions
Current preservation methods may not always provide an ideal environment for organs, impacting their swift recovery and restoration of functionalities post-transplantation. Traditional organ preservation methods primarily rely on SCS. However, they are unable to meet the pressing demand for more efficient preservation techniques within a specified timeframe. MP, which provides nutrients and removes metabolic waste, has become increasingly prevalent as a result. Building upon this foundation, various organ preservation methods have been developed, including MP at different temperatures, hypothermic preservation, subzero preservation, and long-term cryopreservation.
Exploring new strategies for organ cryopreservation entails addressing two key challenges: how to mitigate or avoid IRI during the preservation process and how to reduce organ metabolism while preventing cold-induced damage during cold storage. Long-term cryopreservation methods allow organs to enter a state of physiological metabolic pause, similar to halting a “life clock,” at ultra-low temperatures. However, slow freezing processes can lead to ice crystal nucleation and growth, necessitating effective control of ice crystal formation and growth. Emerging cryopreservation methods are being developed, such as ice-free vitrification. It is crucial to achieve an ice-free vitrified state while minimizing the toxicity of CPAs to establish successful vitrification. Furthermore, the rewarming process after cryopreservation requires increased attention due to the potential for ice recrystallization. To advance organ cryopreservation, the development of novel low-concentration vitrification CPAs, coupled with uniform and rapid rewarming strategies, is a promising avenue for future research and application.
Given organs’ relatively large volumes, the need for efficient and uniform rewarming methods is paramount. In the context of vitrification cryopreservation, potential benefits can be derived from techniques such as RF and nano-warming that accelerate the rewarming process while minimizing the required concentration of CPAs. Furthermore, electromagnetic rewarming offers distinct advantages by eliminating the use of cell-toxic nanoparticles and achieving rapid and uniform rewarming. However, a cautious evaluation is needed to determine the impact of this approach on organ function in the post-transplantation period.
In the realm of organ transplantation, assessments play a pivotal role in ensuring the quality and suitability of donated organs, leading to successful transplant procedures and optimal patient outcomes. When assessing the process of vitrification cryopreservation, attention is directed toward determining the successful attainment of an amorphous, crystal-free state in the organs. This encompasses a comprehensive evaluation of the organs’ morphology, physiology, and functionality. By assessing the effectiveness of vitrification cryopreservation, it is possible to discern whether the organs exhibit favorable preservation quality and suitability, which informs the decision on their suitability for subsequent organ transplantation procedures.
Collectively, the preservation of organs presents complex challenges, as it involves maintaining organ vitality and functionality despite a limited blood supply, incomplete waste clearance, and insufficient metabolic substrates. Future advancements in organ preservation will rely on the integration of innovative techniques with MP, with the aim of providing comprehensive solutions for long-term preservation. However, this process remains complex, as the specific mechanisms of cryopreservation-induced damage vary across different types of organs. Therefore, it is crucial to design effective cryopreservation protocols tailored to the unique characteristics and injury mechanisms of each organ. Breakthroughs in this field could revolutionize organ preservation, paving the way for the establishment of organ transplant repositories and making significant contributions to the overall health and well-being of humanity.
Acknowledgments
This work was financially supported by the National Key Research and Development Program of China (2022YFC2100800), the National Natural Science Foundation of China (22478296, 22078238, 52373117, and U23B20121), the Haihe Laboratory of Sustainable Chemical Transformations (24HHWCSS00005), and the Open Funding Project of the National Key Laboratory of Biochemical Engineering.
Compliance with ethics guidelines
Xinmeng Liu, Zhiquan Shu, Liming Zhang, Haoyue Li, Jing Yang, and Lei Zhang declare that they have no conflict of interest or financial conflicts to disclose.
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