Breathe in, breathe out — it may seem simple, but lungs are devilishly complicated structures, boasting more than 40 different cell types and an intricate network of tiny blood vessels and air sacs.
It's no wonder, then, that engineering lungs in the lab, either for transplantation or study, has been extremely challenging.
Now two research groups have made major strides in attacking the problem. One has successfully engineered a lung that can sustain a living rat and the other has created a lung-mimicking device for toxicology studies that acts more like a real lung than any earlier efforts, the groups reported Thursday in the journal Science.
One report brings closer the day when artificial lungs might be grown for human transplants; the other offers a method for testing the effects of toxic chemicals on lungs that is cheaper and more humane than animal tests and more reliable than ones done in test tubes, scientists said.
In work colleagues described as daring, a team led by Dr. Laura Niklason at Yale University grew rat lungs almost from scratch.
Because lungs are so complicated, the group used a scaffold-based approach — they took lungs from adult rats and dissolved away all the cells, leaving behind a fibrous lung "skeleton."
They seeded these scaffolds with lung cells from newborn rats and — through careful coaxing that included incubation in a "lung bioreactor" that mimicked the fetal lung environment — produced what appeared to be functional lungs.
They then implanted the lungs into four live rats and showed that the engineered lungs were 95% as efficient as natural ones.
The same methodology had been used to successfully create beating rat and pig hearts in 2008 — although in those cases, the organs were never transplanted into living animals.
"It's exciting to see that it's not just about [the] heart; it works in other organs and tissues too," said Doris Taylor of the University of Minnesota, who conducted the pioneering heart work. "It really reinforces the belief that these scaffolds are smart. They know how to tell cells what to do, where to go and how to behave."
There are still kinks in the process: A few hours after rats received the lungs, tiny blood clots began to form, probably because of bare spots on the scaffold. "It's pointed out to us what worked, but it's also pointed out to us what needs to be made better," Niklason said.
And though the work represents a significant leap, Niklason predicts it will be 20 or 25 years before the technology can be used to build lungs for human transplants. Aside from solving the clotting issue, she also is waiting for stem cell technology to provide the precursor cells needed to grow engineered human lungs.
"I clearly don't think we've solved the whole problem, but I sort of feel like we're laying train tracks into the mountains," Niklason said. "We haven't gotten to the other side of the mountain range yet, but when we do, I hope there's a big bus of stem cells waiting for us."
The other Science paper described the design of a very different lung, for a very different purpose. Dr. Don Ingber and his team at Harvard University created a "lung on a chip" — a tiny device that is remarkably effective at replicating the behavior of actual lung tissue.
Their immediate goal was to investigate the respiratory effects of tiny substances called nanoparticles as an alternative to animal and cell culture testing, with hopes of additional applications down the line.
Nanomaterials are used in an increasingly wide range of products, including food packaging, textiles and sunscreen. Although concerns have been raised about their safety, their health effects have been studied very little.
"It's kind of scary that we don't know how these particles affect our body," said the study's lead author, Dan Huh, a postdoctoral fellow in Ingber's lab.
The device falls into the field of "biomimetics" — using biological design principles to inspire new technology. The crucial element of lung tissue is the interface between the air sacs and blood vessels, so the team re-created this surface using a membrane covered with human lung cells.
The membrane was sandwiched between two pieces of a rubber-like material, creating channels on both sides that could be filled with liquid to expose the cells to different environments and chemicals.
The chip acted like proper lung tissue when exposed to blood flow and invading bacteria, fighting off the bug and transporting it to the other side of the membrane. It also mimicked another important biological phenomenon: the stretching that occurs when lungs expand to take in air. This property is missing in traditional toxicology studies using lung cells in dishes.
In preliminary tests, the human lung mimic and a mouse lung showed similar responses to several types of nanoparticles, suggesting the bionic lung would provide reliable results.
"This is fantastic," said Luke Lee, a bioengineer at UC Berkeley. "I think it's the best biomimetic paper I've ever seen."
"This really shows that you can engineer artificial systems outside the body that will be predictive of the things going on inside your body," said Shuichi Takayama, a biomedical engineer at the University of Michigan.
The next challenge is miniaturization. The membrane used in the chip is 10 microns thick — seven times thinner than a human hair — but the membrane in an actual lung is 10 times thinner than that. The fabrication technology can't yet produce materials on such a tiny scale, Huh said.
The researchers are also working on integrating their lung with other organ mimics, particularly a heart, with the goal of improved drug testing.
"Eventually, if we could combine multiple miniature models of organs, we might be able to completely replace the animal models," Huh said.