A milestone in cryobiology announced this week is literally heart-warming.
A new nanoparticle technology warmed cryopreserved heart valves and blood vessels without damaging the tissues, found a study published Wednesday in the journal Science Translational Medicine. According to the researchers, this means that cryopreserving human hearts and kidneys in organ banks — and making them available for later use in patients — is finally within sight.
“We are not in any way declaring victory here,” said John Bischof, senior author of the study and a mechanical engineering professor at the University of Minnesota. “We have promising results, but we have not yet done it,” he said, warning of “many hurdles” still ahead.
Still, his co-author Kelvin G.M. Brockbank, CEO of Tissue Testing Technologies LLC and a research professor at Clemson University, is willing to estimate the time frame for moving this research from the laboratory to a doctor’s office.
“Most organs, we’re talking seven to 10 years at least,” said Brockbank, who noted that the “time to market” for this technology will depend on both the science itself, which still needs some work, and the regulatory agencies, which may not intercede for human tissue banking but most likely will when it comes to organ banking.
“I believe the Food and Drug Administration will get involved, but there may be may be opportunities for humanitarian exceptions, at least in the beginning, until we get enough organs and this becomes a commonplace organ banking method,” Brockbank said.
Currently, more than 60% of the hearts and lungs donated for transplantation must be discarded each year because they cannot be kept for longer than 48 hours. If only half of these discarded organs were transplanted, wait lists for these organs could be eliminated within three years, according to recent estimates cited by Bischof, Brockbank and their co-authors.
Organs for transplants
Since the mid-1980s, cryobiologists have been looking at long-term preservation methods for organs, such as vitrification. A necessary part of this method is the use of cryoprotectants — “essentially antifreeze chemicals,” explained Bischof. Cryoprotectants allowed scientists to use ultra-low temperatures — between minus 160 and minus 196 degrees Celsius — to supercool biological tissues, including animal kidneys, and preserve them in a glassy or vitrified state.
Unfortunately, there’s a major problem with cryopreservation: No one has been able to figure out how to bring tissues or organs back from the vitrified state without damaging them during reheating, explained Bischof. During the rewarming process, ice crystals form, resulting in major damage that makes them unusable.
The rewarming process must be sufficiently uniform so that “we don’t crack the organ,” Bischof said. What this requires is “to bring that kidney back faster than the way we brought it down” with warming rates that are much more rapid than cooling rates.
Another problem encountered by cryobiologists has been heat distribution. “We actually tried to use microwave warming, which failed terribly due to hot spots in the tissue,” Brockbank said.
For the new study, Brockbank, Bischof and their colleagues developed their own warming process, one that relied on nanoparticles to create the heat necessary for a thaw.
They began with the most essential component: the nanoparticles themselves. The team used a commercially available product of supermagnetic iron oxide particles, which had great heating ability. However, these nanoparticles tended to glom together in the viscous cryoprotectant solution.
To correct this problem, the researchers modified the particles, coating them with chemicals to provide stability while maintaining their heating ability.
Once the nanoparticles were perfected, they could be placed in the cryoprotective solution, which was put “in and around the tissues of interest” and placed “right around the tissue as necessary,” Bischof explained.
Next, the team perfected the concentration of nanoparticles within the nanowarming system, an inductive heating system capable of generating heat within the tissue itself.
In essence, the nanowarming system consists of “a lot of machine surrounding a very tiny coil,” explained Bischof, where the coil is a couple twists of copper tubing through which electricity blows in order to create a magnetic field.
Within the field, the tiny nanoparticles become magnetic, which creates heat.
Yet, in experiments, whenever the current was increased for larger organs, eddy currents — which move from the center to the edge of the organ — caused uneven warming that damaged the tissues. By learning how to deploy enough particles and balance their concentration, the researchers were able to compensate for this negative effect.
Scaling up to human organs
Ultimately, the research team refined the nanoparticles and how they were dispersed so they could act as tiny heaters, rapidly and uniformly warming tissues at rates 10 to 100 times faster than any previous method. Testing the rewarmed tissues, the team discovered no signs of damage, and the nanoparticles washed away easily.
To scale up nanowarming to accommodate human organs, the team will further refine and optimize each element of the system. They plan to start with rabbit organs, work next with pig organs and finally attempt cryopreservation and rewarming of human organs, including the heart.
“Everybody thinks cryopreservation is simple, but unfortunately that’s not the case,” Brockbank said. As a result of this misperception, the “cryopreservation of organs and tissues has pretty much been an orphan child of transplant biology,” with no “clear-cut places to go for funding.” As he sees it, depending on whether private or public funding becomes available, about a decade seems “a reasonable time frame” for this new nanowarming process to begin changing the existing organ bank process.
“From my perspective, the ability to do tissue banking in the volumes that we report in the paper exists now,” Bischof said. Tissue transplants include corneas, bone grafts, heart valves, veins/arteries and skin.
“In the US, there are an estimated 1.75 million tissue transplants per year, which is almost 4,800 tissue transplants each day, every day of the year,” said Sarah Gray, a spokeswoman for the American Association of Tissue Banks. There is no waiting list for most tissue transplants, except pediatric heart valves, because tissue can be cryopreserved, in some cases up to 10 years, she noted.
Although nanowarming is not urgently needed for tissue banking, the study authors believe the technology could make the process easier.
Meanwhile, “there’s been a groundswell of interest” in using the technology to preserve organs, Bischof said.
‘Revolutionary’ research
“A decade goes by pretty fast,” said Dr. David Klassen, chief medical officer of United Network for Organ Sharing, which serves under federal contract and brings together medical professionals, transplant recipients and donor families. Applying nanowarming to organ banking “would be a huge and revolutionary change than what we do currently,” he said. “It would clearly change allocation, and it would radically alter how things are done in a good way — good for everybody.
“This would solve the organ preservation and distribution issues,” Klassen said. “Sometimes, the time just runs out. It cannot be gotten to the recipient on time.”
When a kidney becomes available from a deceased donor, that kidney must be used almost immediately, within 24 to 48 hours, according to Dr. Anthony J. Bleyer, a nephrologist and professor at Wake Forest School of Medicine.
“The waiting time for a kidney can be about five years for some individuals,” he said. As a result, “thousands and thousands of people” are on the kidney transplant waiting list. Although many patients try to obtain a kidney from a relative or a friend — a living donor — many cannot find someone.
“The ability to obtains kidneys from individuals who are deceased is incredibly important,” Bleyer said. “But as soon as a kidney is harvested, we are racing against the clock.”
“So the ability to cryopreserve a kidney would raise tremendous opportunities,” he said.
As an example, he mentioned inherited kidney diseases in which both kidneys gradually deteriorate at the same rate. “It would be great if we could take one of the kidneys when someone is 10 or 11 years old and cryopreserve it and then wait until the other kidney failed and retransplant that cryopreserved kidney.”
“We can’t even really begin to think about all the possibilities,” Bleyer said. “But I think this is just incredibly outstanding research that is leading us rapidly into the future and holds promise for many people who suffer from chronic diseases of all kinds.
“Scientists and doctors with incredible imagination will probably think of ideas we cannot even fathom today,” he said. “It would raise many unique and important opportunities that we’ve never even considered.”
Unique opportunities may include a concept lifted straight from science fiction.
According to Bischof, “I suppose once you have done a whole organ, there is a certain intellectual connecting of the dots that takes you from the organ to the whole person.” Yet he does not believe that cryonics — freezing and rewarming a whole human body — will be possible anytime soon.
Brockbank noted that the “cryonics movement” will probably “distort the importance” of their new research. Still, he said, “I don’t believe we’ll be seeing success for whole bodies within the next 100 years.”
