With waiting lists for organ transplants at an all-time high, there is a serious shortage of donor organs. This is due in part to current preservation methods, which only enable a very short shelf-life. However, emerging new technologies could improve storage duration, enable transportation over longer distances, and improve the odds that the organ remains intact. Dr Korkut Uygun, assistant professor in surgery at Harvard Medical School, explains the implications.
Dr Korkut Uygun, assistant professor in surgery at Harvard Medical School, is a man on a mission.
Intent on improving the storage and transport of cell-based medical products – and changing the face of organ transplantation in the process – he is nothing if not ambitious about the prospects.
“To an extent we are talking about creating a supply of replacement parts for humans,” he says. “One estimate found that around 35% of all deaths in the US could be postponed significantly if we can manage this.”
These may seem like strong words from a man whose research, to date, has mostly involved performing interesting experiments with rat livers. That said, the technologies he is working on have reached a critical juncture. Now at a stage to be used for human organs, they are due to be tested out in early stage clinical trials in 2016. If this goes according to plan, the implications could be very profound indeed.
Currently, the gold standard for organ storage is the University of Wisconsin (UW) organ preservation solution, otherwise known as Viaspan. Developed in the late 1980s, this was the first intracellular-like medium specifically developed for this purpose, providing dramatic improvement in preservation methods.
During donation surgery, the organ is flushed with solution, before being packed in several layers of sterile containers and surrounded by ice. The aim is to keep it just above freezing temperature, slowing its biological deterioration by reducing cellular metabolism. It can then be transferred to the recipient before its tissues break down. This method, however, is far from infallible.
“One disadvantage is limited storage duration: 12 hours, and preferably under nine, for the liver; much less for the heart and lung; a bit longer for the kidney,” says Uygun. “This restricts organ sharing to regions, say the New England states in the US. Also, the organ has to be in near perfect condition to start with or it becomes unusable after static storage, as it suffers injury in the process. This means we can only use a fraction of donated organs.”
The problems associated with organ shortages are well known. While waiting lists are growing steadily longer, the number of donors has failed to keep pace: 28,052 transplants were performed in the US in 2012, eclipsed by the 120,873 people on waiting lists. This means most potential recipients die before they can receive an organ. According to the World Health Organization, transplants currently meet less than 10% of the global demand.
While the figures would doubtless be improved by increasing the numbers of registered donors, the real solutions have been pegged as lying within regenerative medicine. In the not-too-distant future, we can envisage that stem cell technologies will be used to regenerate whole organs, functional human tissues will be created using 3D bioprinting, and artificial organs will be bioengineered for transplant.
Should this come to pass, there will be potential not just to close the donor gap, but also to eliminate the problems of organ rejection and to improve the transplanted organs’ longevity.
As developments of this kind get underway, improving storage is another important piece of the puzzle. Given the limitations of cold static storage, Uygun’s team have been focusing their efforts on another way to keep organs healthy: functional organ preservation via machine perfusion. Commonly used for kidney transplants, machine perfusion involves pumping a cool solution through the organ to delay cell death and fend off organ deterioration.
“The simplest explanation is to think of machine perfusion as an artificial body,” explains Uygun. “The organ is pumped with oxygen and nutrients, which are analogues for the heart, lungs and blood. This means it can function and to a limited extent repair itself as it’s being shipped to the recipient site.”
Currently, his team is trying to develop machine perfusion as a platform technology, rendering it suitable for donor organs that have been marginally injured and are currently deemed unusable. This, he says, amounts to a huge pool of potential transplants, as yet untapped.
“We have our protocol that we are aiming to take to clinical trials in 2016,” he says. “We are also developing statistical methods that can tell you how good the organ is online during perfusion, so if it’s good for transplant we’ll have the green light on and the surgeon will know it’s good.’
“If it’s not functioning as expected, it’ll throw a red light – or maybe a predicted likelihood of success so the team can decide. In the longer run, this will allow feedback so we can automatically fix certain problems. It’s the self-driving car for the organ – think of it that way.”
In recent months, there has been a significant degree of hype around warm perfusion methods (see box out). Uygun’s team, however, has been pioneering a ‘supercooled’ approach that combines machine perfusion and static cold storage. It essentially promises the upsides of cryogenic storage (i.e. more time to transport the organs) without the damage sustained by freezing and subsequently thawing cells.
Described in Nature as a ‘breakthrough’, this work involves incorporating a specially-designed glucose compound that both keeps the cell membranes cool and acts as a barrier against the cold. Having been tested successfully on rats, it will be soon brought to a small safety clinical trial at Massachusetts General, with collaborators in the Division of Transplantation.
“The twist is that the static storage takes place at subzero temperatures without freezing, which is called supercooling in thermodynamics,” says Uygun. “With this, we can triple the storage duration compared to our current standard in a rat model.”
To date, Uygun’s work has looked into donor livers, but, pending a few adjustments, it is likely to be applicable both to other donor organs and even tissue-engineered grafts (Uygun says there is a substantial amount of technology transfer between the two). And while the procedure is not cheap, costs are expected to tumble in the future.
“Cost effectiveness depends on your perspective,” he points out. “If we are talking about saving a patient who’d perish without a transplant, than I think the current costs are manageable. However, compared to static cold storage they are quite expensive and I think we’ll need to go through a few more generations of perfusion protocols to get there.”
According to Nature, this preservation method could make an additional 5,000 organs available each year, as well as enabling organs to be transported far greater distances to reach the most appropriate recipients. Should the technical and cost hurdles be overcome, Uygun’s work holds significant promise for the future of organ preservation, a step change comparable to the introduction of the UW organ preservation solution nearly 30 years ago.
As Uygun remarks of his work, and advanced organ storage more generally: “It’s full of technical challenges, but a promise to dramatically change human life forever.”
FROM THE VERY HOT…
While Uygun’s supercooling methods show great promise, another area that is gaining traction is warm perfusion, which is likely to supersede older technologies as it becomes more cost-effective.
At the forefront of this field is Massachusetts-based company Transmedics, which has developed an Organ Care System comprising a portable platform with a wireless monitor, and a warm perfusion module. It incorporates a solution that delivers the same nutrients and substrates as the organ would receive in vivo. This means hearts can be kept pumping, and lungs can be kept breathing, inside a box.
This system, currently pending approval in the US, has shown impressive results in clinical trials. It has already been used for at least 15 heart transplants in the UK and Australia, MIT Technology Review reports.
TO THE VERY COLD
In the longer term, however, we are likely to see a reversion to the very cold. As cryobiology advances, it may become possible to freeze organs and store them within organ banks, without damaging tissues in the process. This in turn will mean an enhanced ability to match the organ to the recipient, and a greater number of viable organs at a lower cost.
To date, researchers have shown little success at cryopreserving organs; however, they are edging ever closer to realising their (slightly gory) dream. In January 2015, the US Department of Defence announced government grant programs for organ and tissue banking, stating that the challenges could be broken down into six solvable engineering problems.
“The impact of a true organ and tissue banking capability on how we treat our war wounded would be enormous; the impact on broader civilian healthcare would be even larger. If we can make a strong push in advancing this field we may see breakthroughs sooner than we think,” said Lt Col Luis Alvarez, deputy director of the Department of Defence’s Tissue Injury and Regenerative Medicine Program.
This article appears in the 2015 vol 2 edition of Medical Device Developments