Only the bravest sailed to the edge of the map. Merchants, military, even pirates stayed in the center, away from unknown waters. The center of medicine is much like the center of the ocean, it’s the “safe” place to stay where things are “normal” even if they’re also tragic. For example, as far back as the 1990’s, 10 percent of those waiting for liver transplants on the Mayo Clinic Rochester’s list died before a transplant could be found.¹ The statistics have not improved since, and that’s the medical state-of-the-art.
However, a crew of brave souls would occasionally sail beyond the map. If they did not return, speculation would run rampant. Had they sailed off the edge of the world? Were they eaten by sea monsters? Or … did they discover a land so wonderful that they chose not to return?
A team of engineers, physicians, and biochemists, in cooperation with the Wyss Zurich Translational Center, have recently sailed beyond the edge of the medical map. The gap between liver supply and demand has led to the transplantation of more and more “marginal” organs, with predictably marginal results. However, a few months ago, the Wyss Zurich team reported a stunning breakthrough.
Inside the body, organs are maintained by thousands of intertwined biological factors. Creating a device that can sustain an organ mechanically, outside the body, is a technological feat akin to a moon mission. Traditionally, donated livers are stored in a cold solution and rushed to the recipient, but this still causes ischemic harm (from lack of blood flow). The Wyss Zurich team has developed an ex situ (out of body) perfusion device, Liver4Life, which maintains the liver in a near-normal state, extending shelf life and reducing or halting the various forms of ex situ deterioration, “namely hemolysis, hemodynamic stability, glucose control, pathologic glycogen deposition in the liver, perfusate quality and dilution and, eventually, pressure necrosis after several days under machine perfusion.”²
After years of liver regeneration research, the team was able to define the parameters that the machine would have to create and manage. Initial trials suggested that liver tissue composition and function could be maintained normally for up to ten days on ex vivo perfusion, but a healthy, transplantable liver is one of the most precious commodities in medicine…
So the Wyss Zurich team—never a group for half-measures—asked for a liver that was surgically unsuitable—an organ so badly compromised that it was rejected for transplant even into those who were dying. Not only would Wyss Zurich’s Liver4Life have to preserve this severely damaged organ, but rehabilitate it to transplant-worthy health (a leap of Neil Armstrong proportions).
May 19th of 2021, their request was granted. The 29-year-old female donor suffered from a host of liver-related problems, including intra-abdominal abscesses and recurrent sepsis by multiple resistant bacterial strains, and a 4-centimeter tumor of indeterminate origin. The voyage of a transplant liver is fraught with risk when it sails on placid seas, but this one set sail into a monsoon.
The liver was removed, cold-flushed per normal procedure, and then connected to the Liver4Life for ex situ perfusion. The Liver4Life’s perfusate is a blood derivative, but specially reformulated (free of white blood cells, and containing various previously researched additives).
The intricate design of the Liver4Life allowed precise control over innumerable variables (temperature, portal vein flow rate, hepatic artery flow rate, etc) but much of this management depended on accurate flow measurement. No matter whether the device was measuring perfusate volume into or out of the liver, flow measurements were paramount in organ recovery.
The liver showed immediate signs of improvement: lactate dropped, bile production rose, transaminase steadily declined, and overall liver function rose from 33 percent to 54 percent in the first day alone. Furthermore, a tumor biopsy indicated no malignancy. The long research cycle had allowed the Wyss Zurich team to establish exhaustive criteria for transplant viability, including response to various vasoactive drugs, bile production, tissue histology, and a decline in various injury indicators, and the research suggested that three days of ex vivo perfusion was optimal for functional recovery (and clearing of the resistant bacteria), so the transplant surgery was set for day four.
A 62-year-old male was found who suffered from hepatic vein hypertension, repeated hepatic carcinoma and severe cirrhosis. He had a near-zero chance of receiving a traditional liver transplant before death, so for him, this became a life-saving opportunity.
In total, after 68 hours of ex situ perfusion, the liver was transplanted in less than an hour. Reperfusion syndrome (hemodynamic instability) is expected with injured-liver transplants, but none was noted in this case. Bile ducts appeared normal, and a biopsy, taken an hour after transplant, showed no tissue death or reperfusion injury. As would be expected with any transplantation, a few issues appeared and were attended to in the days following surgery. A bile duct leak was repaired, and the patient entered acute kidney failure, which was resolved before the patient was discharged. (The kidney issues may have been related to the strength and dose level of the antimicrobials that were necessary to clear the resistant bacteria).²
At six weeks post-op, a biopsy revealed complete lack of injury or rejection, so the steroid course was tapered to zero and other antirejection drugs were reduced to minimal levels. There was no sign of notable inflammation, and no tissue death or fatty buildup.
In medicine, no news is good news, and the six-month and eleven-month follow-ups revealed the same trend of excellent function and astonishing lack of rejection. Ischemic cholangiopathy (injury to a bile duct caused by insufficient blood flow) commonly results from transplant, but it too was conspicuously absent.
In summary, the transplant liver began as a severely injured organ, and after treatment by the Wyss Zurich team, it became a top-tier success. The Liver4Life not only kept the liver alive for three days ex situ, but passed it to the recipient in better health than when it left the donor.
To respectfully disagree with Hamlet, scientific progress is the last “undiscovered country.” Terra incognita fascinates and tantalizes. That’s what organizations like the Wyss Zurich team do: they shine light on the dark continents. They paint the ever-expanding map of human discovery.
We applaud the Wyss Zurich team for their determination, and we congratulate them on this well-deserved success. The cliché “A rising tide raises all ships” is truer nowhere than in medicine. The work of the Wyss Zurich team inspires the rest of us to seek out undiscovered shores, because there’s no telling what we might find, or who we might save.
Thanks for reading,
Transonic Systems Inc.
The Measure of Better Results
References
1. http://pubmed.ncbi.nlm.nih.gov/16440361/. “Deaths on the liver transplant waiting list: an analysis of competing risks” Kim W, Therneau T, Benson J, et al. Access Date: June 6, 2022.
2. Clavien PA, Dutkowski P, Mueller M, et al. “Transplantation of a human liver following 3 days of ex situ normothermic preservation.” Nature Biotechnology, https://doi.org/10.1038/s41587-022-01354-7 May 31, 2022.
