'Supercooling' may extend life of transplant organs

Behind the Headlines

Monday June 30 2014

Currently, organs can only survive for a few hours once removed from the body

The technique proved successful in supercooling livers from rats

BBC News reports on a new method to keep donated organs fresher for longer: “supercooling”.

US researchers are developing a new technique for the longer term preservation of human organs before transplantation.

Current methods of organ preservation can keep an organ viable for transplant up to around 12 hours once it has been removed from the body. This new technique has potentially extended this time up to three days.

The researchers tested the technique using rat livers. They froze the livers to subzero temperatures of 0C to -6C, while at the same time, passing nutritional preserving fluids to help keep the organ viable.

When rats were transplanted with a liver that had been preserved in this way for 72 hours, they all survived to three months, showing no signs of liver failure.

The number of people needing organ transplant always outnumbers the number of suitable donors available. So a technique that could preserve organs for longer could potentially allow them to be transported across greater distances to suitable recipients.

Hopefully this technique could work in humans, though due to the size and complexity of human organs, this may turn out not to be the case.

 

The Supercool Wood Frog

The bioengineering techniques used in this research are inspired by the North American wood frog. The frog has an ability to hibernate in freezing conditions that would kill most other animals.

 

It does this through a process known as cryoprotection. The frog’s body floods its blood stream with substances such as glucose and urea, which stop essential cells in the frog’s body from dying during the freezing process.

Where did the story come from?

The study was carried out by researchers from Harvard Medical School, Boston; Rutgers University, Piscataway, New Jersey; and University Medical Center, Utrecht, the Netherlands. Funding was provided by the US National Institutes of Health, and the Shriners Hospitals for Children.

The study was published in the peer-reviewed medical journal Nature Medicine.

The BBC's reporting on the study is of a good quality and includes useful discussion from the researchers as well as independent experts about the new development.

Dr Rosemarie Hunziker, from the US National Institute of Biomedical Imaging and Bioengineering, is quoted as saying “It is exciting to see such an achievement in small animals by recombining and optimising existing technology. The longer we are able to store donated organs, the better the chance the patient will find the best match possible, and doctors and patients can be fully prepared for surgery. This is a critically important step in advancing the practice of organ storage for transplantation.”

 

What kind of research was this?

This was laboratory research which tested a new “supercooling” technique to preserve the life of donated organs. The current study tested the technique using rat livers.

The researchers explain the increasing number of people waiting for organ transplants, but the serious shortage of donor organs. When organs are removed from a living body their cells immediately begin to die, meaning they need to be transplanted into the donor as soon as possible to give the best chances of a successful transplant.

The researchers report how current preservation solutions and cooling methods for humans allow organs to remain viable for up to 12 hours.

Methods that could increase the preservation time to days could potentially allow for sharing of donor organs across much greater geographical distances to reach suitably matched recipients.

This could greatly help the problem of the shortage of donor organs. For example, it could be possible to transport an organ with a rare tissue type from Australia to the UK.

So far the researchers say that cryopreservation has been successful for various cell types and some sample tissues. However, its success for the long-term storage of vascularized solid organs (organs, like the liver, with a complex vascular blood system) has been difficult up to now due to freezing and the subsequent rewarming having damaging effects on the intricate anatomy of the organs.

The “supercooling” technique tested here involves freezing to subzero temperatures of 0C to -6C. So far, though previous studies have demonstrated freezing organs to subzero temperatures, they have yet to demonstrate that this can result in the long-term survival of the organ following transplantation. The current research expanded on this by supercooling to subzero temperatures, but additionally using a machine to perfuse the organ with a nutritional preserving solution to support the organ while frozen.

 

What did the research involve?

The researchers used livers from male rats. The organs were surgically removed and then perfusion and supercooling was carried out using a technique called subnormothermic machine perfusion (SNMP).

This makes use of a machine that carefully cools the tissue to below body temperature, and at the same time circulates a preserving solution through the tissue.

The machine first perfused the organ at room temperature (21C) with a nutritional preserving solution containing various substances (such as antibiotics, steroids, proteins and anti-clotting chemicals). There were various stages of recirculation and oxygenation. After one hour of perfusion, the temperature of the perfusing solution was gradually lowered by 1C every minute until the temperature of 4C was reached. At this point the liver was again briefly flushed through with preserving solution and then transferred to a sterile bag filled with the same solution and moved to a freezer, which gradually cooled at a controlled rate until the temperature of −6C was reached.

The liver was kept at this temperature for up to 96 hours (four days). The organ was then gradually rewarmed. The temperature was raised to 4C, and then the organ was again perfused using the SNMP machine for a further three hours. During this time they took various organ measurements, including analysing the organ’s weight, liver enzymes, dissolved oxygen and carbon dioxide, and bile flow.

The liver was then transplanted into a recipient rat, and the rat’s blood samples were analysed for one month. They then continued to observe the clinical condition of the rat for up to three months, particularly looking at clinical signs of liver cirrhosis and overall survival.

They compared the results with those when rats were transplanted with livers that were kept for the same duration using current preservation techniques.

 

What were the basic results?

All the rats transplanted with supercooled livers that had been preserved for 72 hours survived to three months, and showed no signs of liver failure. Comparatively when rats were transplanted with livers that were kept for three days under standard preservation techniques, all of those rats died from liver failure within the first two days.

Using standard preservation techniques the same survival results were only seen if the rat livers were preserved for no more than 24 hours – therefore the supercooling technique tripled the storage time.

Increasing supercooling duration to 96 hours however, resulted in only 58% rat survival, which the researchers say is comparable to the 50% survival following 48 hours of standard preservation.

Control rats transplanted with livers that had been frozen to the same subzero temperatures but which were not subjected to the full sequence and duration of perfusion with the nutritional solution also did not survive.

 

How did the researchers interpret the results?

The researchers say that as far as they are aware “supercooling is the first preservation technique capable of rendering livers transplantable after four days of storage”.

 

Conclusion

When organs are removed from a living body their cells immediately begin to die, meaning they need to be transplanted into the donor as soon as possible to give the best chances of a successful transplant. The number of people needing organ transplant always outnumbers the number of suitable matched donors available. So having a technique that could preserve organs for longer and potentially allow them to be transported across greater distances to suitable recipients could, as the researchers say, be a great breakthrough.

This is especially important as it can often be difficult to find a suitably matched donor (to prevent the body from rejecting the donation, the tissue type has to be as similar as possible), but if the geographical availability of donors were increased, then this could increase the likelihood of finding a matched donor. 

This research demonstrated the technique of preserving with a nutritional solution and then supercooling to subzero temperatures of 0C to -6C. When rats were transplanted with a liver that had been preserved in this way for 72 hours, all of them survived to three months, showing no signs of liver failure. This triples the preservation time from 24 hours, which is the maximum that can be successfully achieved using standard techniques in rats.

The 100% rat survival was limited to 72 hours of storage. When the storage time was extended by one day, rat survival almost halved to 58%. However, as the researchers say, with continued study of different additives for the preserving solution, or variations in protocol, additional improvements could be achieved from future experiments.

The researchers also importantly highlight that this is only a proof-of-concept study in small animals. As they say, the robustness and preservation properties of human liver cells differ from those of rodents.

Though their research with the rat livers was successful, with no signs of liver failure when stored for three days, they need to see whether the same results can be achieved with larger animals, before they can test with human livers.

They also need to perform longer follow up to see if survival and liver function are maintained for longer than three months

The current study also used healthy livers surgically removed from living, healthy rats.

The researchers also need to consider removing organs from dead bodies, so the organ has already been subjected to being starved of oxygen.

They also need to see if the technique can be extended to other organs, besides the liver.

Overall, this is promising early research, which paves the way for much further study.

Analysis by Bazian. Edited by NHS Choices. Follow Behind the Headlines on Twitter. Join the Healthy Evidence forum.

Analysis by Bazian

Edited by NHS Choices

Links to the headlines

Organ transplants: 'Supercooling' keeps organs fresh. BBC News, June 29 2014

Links to the science

Berendsen TA, Bruinsma BG, Puts CF, et al. Supercooling enables long-term transplantation survival following 4 days of liver preservation. Nature Medicine. Published online June 29 2014

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