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The humble lizards offer a surprising take on the engineering of artificial lungs

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Lizard lungs form quickly through a simple mechanical process that researchers compared to a mesh stress ball, the common toy. As the fluid fills the developing lung, the inner membrane pushes against the smooth muscle tissue. The muscle separates into a honeycomb-shaped mesh, and the membrane swells through the interstices, creating the surface area necessary for gas exchange. Credit: Image Courtesy of Celeste Nelson and Michael Palmer

When it comes to studying the lungs, humans soak up all the air, but it turns out that scientists have a lot to learn from lizards.

A new study by Princeton University shows how the Brown Anole Lizard solves one of nature’s most complex problems – breathing – with ultimate simplicity. While human lungs develop over months and years into baroque, tree-like structures, the anole lung in just a few days develops into coarse lobes covered with bulbous protuberances. These gourd-like structures, although much less refined, allow the lizard to exchange oxygen for waste gases, much like human lungs do. And because they grow rapidly using simple mechanical processes, anole lungs provide new inspiration for engineers designing advanced biotechnology.

“Our group is really interested in understanding lung development for engineering purposes,” said Celeste Nelson, Wilke Family Professor of Bioengineering and Principal Investigator of the study. “If we understand how the lungs are built, then maybe we can take advantage of the mechanisms that mother nature uses to regenerate or modify tissue. “

While the lungs of birds and mammals develop great complexity through endless ramifications and complicated biochemical signaling, the brown anole lung forms its relatively modest complexity through a mechanical process that the authors likened to a bullet. mesh stress reliever – the common toy found in desk drawers and DIY videos. The study, published on December 22, 2021 in the journal Scientists progress, is the first to examine the development of a reptile lung, according to the researchers.

The anole lung begins a few days after its development as a hollow, elongated membrane surrounded by an even layer of smooth muscle. During development, lung cells secrete fluid, and in doing so, the inner membrane slowly inflates and thins like a balloon. The pressure pushes against the smooth muscle, causing it to tighten and separate into bundles of fibers that ultimately form a honeycomb-shaped mesh. Fluid pressure continues to push the expandable membrane outward, inflating through the interstices of the nerve mesh and forming fluid-filled bulbs that cover the lung. These bulges create a lot of surface area where gas exchange occurs. And that’s all. The whole process takes less than two days and is completed within the first week of incubation. After the lizard hatches, air enters through the top of the lung, swirls around the cavities, and then flows back.

For engineers looking to use nature’s shortcuts in the name of human health, this speed and simplicity constitutes a radical new design paradigm. The study also breaks new ground for scientists to study reptile development in much more detail.

When Nelson began studying chicken lungs in the late 2000s, conventional wisdom held that “chicken lungs were the same as mouse lungs were the same as human lungs,” Nelson said. “And that’s not true.”

Eager to destabilize these assumptions, she guided her team to ask fundamental questions about how the lungs of different classes of vertebrates are constructed. “The architecture of the lung of birds is so different from that of the lung of mammals,” Nelson said. For example, instead of a diaphragm, birds have air sacs embedded throughout their body that act like bellows.

To adapt the exquisite complexity of avian lungs to tools that could benefit human health, Nelson believed the science needed to go even further. Nature had solved the problem of gas exchange with two radically different systems. How were they related? And wouldn’t there be other systems as well? This led his team in evolutionary time to search for a common origin. And there sat the reptile, doing what reptiles do so well: hide in plain sight.

When Michael Palmer joined the lab as a graduate student, he took on the challenge of organizing this study – literally – from scratch. The alligators turned out to be too aggressive. Green anoles refused to breed. After years of preliminary work, Palmer took a trip to Florida to capture wild brown anoles in late 2019. He and his colleague hung out in the mud of a suburban park, flipping rocks and leaves to the edge of the woods. They used dental floss traps to capture a dozen individuals and place them each in their own miniature vivarium. They then returned the animals from North Florida to Princeton, where vets and the university’s animal resources staff helped the team establish a permanent anole facility.

It was at this point that Palmer began examining eggs to map the lung development of organisms. Working with Andrej Košmrlj, assistant professor of mechanical and aerospace engineering, as well as graduate student Anvitha Sudhakar, Palmer used his observations to build a computer model of the lung and understand its physics.

“We were curious if there was anything we could learn about the basics of lung development by studying such a simple lung,” said Palmer, who earned his doctorate. in chemical and biological engineering earlier this year. He had seen evidence that smooth muscle played a sculpting role in other systems, but in this study he was able to observe how it worked directly.

“The lizard lung develops using a very physical mechanism,” Palmer said. “A cascade of pressure induced stress and pressure induced buckling.” In less than two days, the organ passes from the flat balloon to the fully formed lung. And the process is simple enough that Palmer can use his computer model to create a working replica in the lab. While the designed system did not match the full complexity of the living system, it came close.

The researchers cast the membrane using a silicone material called Ecoflex, commonly used in the film industry for makeup and special effects. They then coated this silicone with 3D printed muscle cells to create the same types of ripples in the swollen silicone Palmer had found in the living organ. They encountered technical barriers that limited the likelihood of their creation, but in the end it was eerily similar to the living organ.

These humble backyard lizards had inspired a new type of artificial lung and a framework that engineers can refine for unknowable future purposes.

“Different organisms have different organ structures, and it’s beautiful, and we can learn a lot from it,” Nelson said. “If we understand that there is a lot of biodiversity that we cannot see, and that we try to take advantage of it, then we as engineers will have more tools to tackle some of the major challenges. facing society. “

Reference: “Stress ball morphogenesis: How the lizard builds its lung” by Michael A. Palmer, Bryan A. Nerger, Katharine Goodwin, Anvitha Sudhakar, Sandra B. Lemke, Pavithran T. Ravindran, Jared E. Toettcher, Andrej Košmrlj and Celeste Mr. Nelson, December 22, 2021, Scientists progress.
DOI: 10.1126 / sciadv.abk0161

The document was supported in part by funding from the National Institutes of Health, the National Science Foundation, the Eric and Wendy Schmidt Transformative Technology Fund, and the Howard Hughes Medical Institute. Other authors include Bryan A. Nerger, Katharine Goodwin, Sandra B. Lemke, Pavithran T. Ravindran, and Jared E. Toettcher, associate professor of molecular biology.


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