ABOVE: The heart valve replacement developed by Tranquillo and colleagues
SYEDAIN, ET AL., TRANQUILLO LAB, UNIVERSITY OF MINNESOTA
A new type of artificial heart valve transplanted into lambs maintained function and grew with the animals for up to a year, scientists reported March 17 in Science Translational Medicine.
“For pediatric patients in need of valve replacements, a tissue-engineered valve that will grow with the patient and can potentially be populated by the patient’s own cells is the holy grail,” says Daniel Levi, a pediatric cardiologist at UCLA Health who was not involved in the study. But, he cautions, “We often see very promising results in the lab and in animals that can’t be replicated in humans.”
There are two main options for patients who need heart valve replacements: a purely mechanical valve, which increases the risk of blood clots, and a bioprosthetic option made from animal tissues. Neither will last long in a growing child. The mechanical valve is a fixed size, and the bioprosthetic valve can’t grow after being treated to prevent the child’s immune system from rejecting it, meaning the patient will soon outgrow the valve and require another surgery to replace it.
“There is no valve that has growth capacity,” says Robert Tranquillo, a biomedical engineer at the University of Minnesota and lead author of the new study. “This has been a mission for us for 20 years, to try and figure out a material that can grow and evolve.”
To develop a lasting replacement, the scientists spent eight weeks growing skin cells from a donor lamb in a tube-shaped gel in a bioreactor. After eight weeks, the team washed the cells away, leaving hollow collagen structures with growth factors. Next, the researchers sewed three tubes together and trimmed them to create flaps that open and close like heart valves do. Once implanted, the animals’ own cells populated the device, avoiding the need to apply the growth-stopping anti-rejection treatment.
The experiment had two phases. First, the team implanted the valves into the pulmonary arteries of four lambs. While ideally the valves would grow in length with the animals, an increase in diameter could diminish the valve’s function by allowing regurgitation—blood leaking the wrong way back through the valve—and indeed that happened. Only one valve lasted the full 52 weeks of the study. The scientists had to remove the other three at 4 weeks, 12 weeks, and 28 weeks as their diameters expanded and regurgitation grew severe.
In hopes of increasing the lifespan of the valves, the team added a fourth tube that surrounded the other three like a sleeve, which they say protected the interior valves from some of the mechanical strain that damaged the first sets. Of the three lambs that received these double-layered valves, two were able keep their valves for the full 52 weeks. The third had to be removed at 44 weeks as its function began to deteriorate. Ultrasound images showed that the valves also grew in length by 17–34 percent as the lambs matured.
“Two of the three lambs survived the entire 52-week implantation period, which means that the lamb grew to be an adult sheep, and doubled its weight at least,” says Tranquillo. There was a small amount of regurgitation, but he says that in the two lambs that kept the valves for 52 weeks, it was “mild leakage, which is clinically almost unimportant.”
As controls, the researchers also implanted two more lambs with devices currently on the market: a chemically treated valve from a cow and a chemically treated valve from a pig. The lamb with the bovine valve died at 11 weeks due to calcification of the valve and a blood clot, while the porcine-derived device was removed at 20 weeks as its function diminished. “Despite the small number of valves tested, the direct comparison with an existing therapy in this study was important to show the potential benefits of living valvular implants over existing prostheses for young patients,” writes Carlijn Bouten, a biomedical engineer at Eindhoven University of Technology in the Netherlands who was not involved in the study, in an email to The Scientist.
For now, Tranquillo is working with a company that is developing the same material to function as a vascular graft in adults, while simultaneously developing strategies to improve its function as a valve for children in the future. The team has another study planned in lambs, and then if all goes well, aims to bring the valve into clinical trials.
Like Levi, Christopher Breuer, a pediatric surgeon specializing in tissue engineering at Nationwide Children’s Hospital in Ohio who was not involved in the study, cautions that animal trials are often difficult to replicate in humans. Still, he calls the study “a real and important step forward in the development of the technology . . . that will hopefully bring us a step closer to being able to create heart valves with growth capacity for use in children.”
R. Tranquillo, et al., “Pediatric tri-tube valved conduits made from fibroblast-produced extracellular matrix evaluated over 52 weeks in growing lambs,” Sci Transl Med, doi:10.1126/scitranslmed.abb7225, 2021.
