Built from scratch, lungs are a big leap in bioengineering

Laura Niklason, M.D., Ph.D., has spent the past 15 years in the lab developing ways to build new arteries using tissue engineering techniques, but as an anesthesiologist who works in the intensive care unit, she always had another idea rolling around in the back of her head.

Niklason, professor of anesthesiology and biomedical engineering, was troubled that a large number of her patients suffered damage to the lungs, organs that simply don’t fix themselves very well after injury or serious illness. Hundreds of thousands of Americans die from lung disease each year, and the only effective treatment for severe cases is transplantation. Unfortunately, this expensive procedure is associated with high mortality and is also limited by an extreme shortage of donor organs. An alternative solution is to create synthetic lungs, but past attempts to do so have failed because the lungs, with networks of branching airways and vasculature, are so spatially complex, says Niklason.

“She and her research team took a leap forward recently, when they engineered the first lungs that are capable of exchanging oxygen and carbon dioxide, an achievement that was reported in the journal Science this past July.

The key to the Niklason group’s success was finding a suitable scaffold for supporting lung tissue, and they did so by adapting a tissue engineering technique that has been applied to the heart, liver, and kidney. By using detergent solutions to wash cells out of lung tissue from rats, the researchers removed all cellular components that could cause an immune reaction after transplantation.

What remained was a hollowed-out matrix with the right three-dimensional shape, mechanical properties, and vasculature. Unexpectedly, molecular cues that could guide cells to appropriate regions had been preserved in the matrix as well; when the scientists placed various neonatal lung cells inside the scaffold, the cells positioned themselves in the correct locations.

“I was surprised by how much information is in the matrix,” Niklason says. “I expected the different cell types to go helter-skelter, but by and large, the cells landed in their correct anatomic locations. This tells me that the matrix has ‘zip codes,’ or information about who should go where.”

The next challenge was to develop a bioreactor—a system to mimic the environment in which lungs develop in the fetus, such as the flow of liquid through the growing vasculature. To provide ventilation, the researchers used a syringe pump to withdraw air, which caused the lungs to inhale liquid from the windpipe.

In the reverse process, the pump returned air to the bioreactor, causing the lungs to exhale liquid. Inside the bioreactor, the lungs even produced proteins that allowed the organs to inflate normally.

By imitating natural conditions, the researchers improved the clearance of secretions in the airway, enhanced cell survival, and fostered the growth of the major cell types found in the lung. After culturing the tissue inside the bioreactor for about a week, the researchers implanted it into rats and observed that the lungs exchanged gas for a few hours—a major accomplishment.

The team saw similar results with human cells, suggesting that the same approach, perhaps using stem cells, could help to treat diseases in humans.

Niklason cautions that “it will take us another 10 or 20 years of work to develop reliable and robust means of differentiating primitive stem cells into the lung cell types we’re looking for and keeping them stable over time.”

But the wait will be worthwhile, Niklason says. “The potential advantage in the long run is that we could take a biopsy from a patient who needs a lung replacement, generate stem cells from that biopsy, and from those cells regenerate a whole lung that we could implant without it being rejected,” she says. “It could really be a new era for organ transplantation.”