Jon Kelvey Freelance Writer GEN

Researchers Successfully Grow and Implant Engineered Lungs in Pigs

Lung transplants, for conditions such as chronic obstructive pulmonary disease (COPD) or pulmonary fibrosis, are currently limited by the number of available organs for transplant, as well as long-term survival prospects. While there are about 18,000 kidneys transplanted each year in the U.S., there are only about 2,000 lung transplants, and mortality at five years is around 50 percent, with infections and organ rejection particular hazards for patients.

In a new paper in Science Translational Medicine, Joan Nichols, Ph.D., and Joaquin Cortiella, M.D., from The University of Texas Medical Branch at Galveston, and their colleagues describe a whole-lung engineering process that might one day address all of the current problems with lung transplants. They removed one lung each from six pigs, used cells from those lungs to grow new organs in a bioreactor on a decellularized scaffold obtained from the lungs of other donor pigs, and then successfully implanted the engineered lungs into four of the original pigs. The longest survived pig was still healthy when euthanized at two months post-transplant.

“The animal tolerated this tissue well, didn’t have any respiratory problems, and no signs of rejection,” Dr. Nichols says. “Nobody knew that before now. If I took cells from you and grew them for a month outside of you, was your body going to say, ‘oh, welcome home, we missed you?’ Or would your body say, ‘wait a minute, you’re not exactly the same anymore?’”

This is a first in an animal as large as a pig.

“I think Joan Nichols and Joaquin Cortiella are to be congratulated, because they have managed to do this at a large scale,” says Laura Niklason, M.D., Ph.D., the Nicholas Greene Professor of Anesthesiology and Biomedical Engineering at Yale School of Medicine, whose own lab also studies whole lung engineering. “This is an important step forward,” she adds.

There are about 2,000 lung transplants in the U.S. each year, and mortality at five years is around 50 Percent. [Mario Villafuerte/Stringer/Getty Images]

One Drawback

The one drawback to the study, Dr. Niklason says, was that it was not able to show whether or not the engineered lungs were capable of oxygenating venous blood. That’s because Drs. Nichols and Cortiella did not connect the pulmonary artery that brings deoxygenated blood into the lungs.

That was, however, a conscious decision on their part, Dr. Nichols says. “We purposefully did not connect the pulmonary circulation because we knew our lung wasn’t ready to accept those pressures, but we let the lung vascularize naturally,” she says. “A step at a time.”

One of the problems in previous bioengineered lung transplant studies, Dr. Cortiella says, is “people have not waited enough time for the cells to mature, the vasculature to mature, so you wind up with pulmonary edema.”

“Frankly, that has been the bugaboo in lung engineering,” Dr. Niklason adds. “The lung will fill with fluid or blood if the air sacs don’t have a tight barrier, a tight seal.”

The complexity of the lung, with its millions of vascular branchings and delicate alveolar respiratory tree, would seem to make it a poor candidate for whole organ engineering, but Dr. Niklason, who has been working in the field for more than a decade, says working with the lung has certain advantages over other organs.

“What makes a lung different is the fact that your lung is really a series of cellular monolayers. So, if you think of your wind pipe, your trachea, you can trace in an unbroken line, all the way down, many generations of branching, all the way down to your air sac, and then you can come back up again and it’s one big monolayer,” Dr. Niklason says. “We’re pretty good at culturing monolayers of cells. We know how to expand them, and we know how to expose them to enough culture medium to keep them alive.”

That said, more work remains to be done in ensuring the complex community of cell types that make up a lung are properly coordinating with each other, according to Dr. Niklason. “It’s an ecosystem where all the different cell types talk to each other,” she says. “Getting that problem nailed down over the next 5–10 years is, I think, the next big piece.”

The next immediate step for Drs. Nichols and Cortiella, beyond securing funding and the necessary equipment, is a study where pigs are allowed to survive for much longer than two months. With more time for the vasculature to mature, the lungs could be connected to the pulmonary artery so that the organs can actually exchange gas, and, hopefully, show that the animals can survive on the engineered lung alone.

“That’s the proof and we’re very close,” notes Dr. Nichols. “Probably in two years’ time, if we get funding, we’ll be able to answer that question.”

While it’s an admittedly a bold prediction, she says it could be 5–10 years until an engineered human lung is used in a first compassionate-use case, perhaps for diaphragmatic hernia, where the diaphragm fails to develop in utero, allowing the intestines to crowd the chest cavity and preventing the development of the lungs. It is typically fatal for those infants.

“Eventually we would like to get to the point where we bioprint our scaffold and our cells in a lung that is shaped to fit an individual person,” Dr. Nichols says. “We could do a CT scan of your lung, feed that into a bioprinter and print a lung that is exactly the right size [and] shape for you.”

Dr. Niklason, who previously spent 18 years taking a bioengineered artery from bench to clinic, is somewhat more conservative in her estimates of when engineered lungs will be ready for people.

“I tell everybody that it’s still 20 years ‘till we’re in Humans,” Dr. Niklason says, “and I actually believe that.” Still, she adds, there is no denying the accelerating progress in the field, catalyzed in part by a growing understanding of stem cell biology that simply didn’t exist a decade ago.

“This is a good time to be working on this problem, because the substratum of information that we need in order to make progress is happening in the field sort of as we speak,” she says. “If people had been trying to do this 20 years ago, I think it would have been a bridge too far.”

Previous articleVaping Exposes Users to Reactive Carbonyls, Causes DNA Damage
Next articleIdentification of Sprouty 1 and Sprouty 2 Provide Basis for New Immunotherapies