Mark Skylar-Scott and his team of Stanford bioengineers aim to use advanced 3D printing techniques to turn a paste of living cells into hearts and other organs.
Few human organs are more alluring to an engineer than the human heart. Its chambers pump in perfect unison; its materials are pliable but contract when needed; Its shape and movement are perfectly tuned to efficiently push fluid throughout the body. It’s a structural marvel – but when something goes wrong within this structure, the inherent complexity makes it a real challenge to fix it. Thousands of young patients with congenital heart defects therefore have to cope with their disease for the rest of their lives.
“Pediatric heart disease is one of the most common forms of congenital birth defects in the United States,” said Mark Skylar-Scott, assistant professor of bioengineering in the engineering and medical schools. “It’s really hard for families. There are ways to extend children’s lives through surgery, but many children suffer from restricted mobility and live uncertain lives. To find a truly healing solution, you must somehow replace damaged or malformed tissue.”
Stanford scientists are working to make human tissue on a therapeutic scale, with a focus on the heart. Photo credit: Kurt Hickman
That’s where Skylar-Scott comes in. He is working on new ways to tackle congenital heart defects by creating artificial heart tissue in the lab.
It takes far more than just culturing cells in a dish, he notes. Most existing techniques deploy heart cells or stem cells on a temporary “scaffold”: a porous, spongy substance that can hold them in place in three dimensions. Although this method allows researchers to grow lab-made tissue, it is only really practical for extremely thin layers of cells.
“If you have a scaffold that’s only a few cells thick, you can put the cells in the right place. But when you try to grow something that’s an inch thick, it becomes really difficult to seed cells in the right places to grow tissue. Keeping them alive, giving them the right nutrients, or vascularizing them becomes a real challenge,” says Skylar-Scott. Human organs are also not monolithic clumps of cells, he adds. Each is made up of complex layers of multiple cell types, resulting in a 3D structure that is incredibly difficult to replicate.
Print organoids
To circumvent this fact, Skylar-Scott and his team are working on a bold new approach to organ engineering. Using advanced 3D printing techniques, they craft thick tissues layer by layer, placing exactly the kind of cells needed in the right places, like a tower rising from a lattice of carefully placed bricks. This type of construction method, he notes, lends itself well to replicating complex tissues like the heart, where 3D shape is critical to its function.
As promising as it may be, cellular 3D printing comes with some profound and thorny challenges. Unlike plastic filaments, which consumer 3D printers can heat and press into myriad shapes, cells are alive. They’re soft, squishy, imperfect, and frustratingly fragile, says Skylar-Scott.
“If you try to place a single cell at a time, printing a liver or a heart can take hundreds or thousands of years. Even if you’re processing 1,000 cells per second, you still have to lay down many billions of cells to get an organ. If you do the math, it doesn’t look so good for a scalable process,” he says.
Instead, Skylar-Scott and his lab are working to speed up the printing process by depositing dense clumps of cells called “organoids.” The group makes these clumps by putting genetically engineered stem cells in a centrifuge, which creates a pasty substance. With this concoction, they can print large numbers of cells at once into a gelatinous 3D structure. “We basically define the large-scale structure of an organ by printing these organoids,” he says.
cell programming
However, attaching the stem cells is only the first step. Once printed, researchers must somehow convince them to differentiate into more specific cell types and form a multi-layered cluster of functioning groups of cells that resemble healthy organ tissue. To achieve this, Skylar-Scott essentially bathes the stem cells in a chemical cocktail.
“Each line of stem cells that we develop is genetically engineered to respond to a specific drug,” he notes. “Once they sense this drug, they differentiate into specific cell types.” Some cells are programmed to become cardiomyocytes, the heart cells that make up the functional core tissue in the heart. Others are instructed to become stromal cells that connect tissues together.
Skylar-Scott tests his printed tissues in a bioreactor, a smartphone-sized container that helps keep the printed cells alive. Inside, his team managed to grow a printed organ-like structure: a tube about 2 inches long and half a centimeter in diameter. Like a vein in the human body, this tiny device could “pump” itself, contracting and expanding to move fluid through itself.
“If we can engineer more tissues like this, we might have a good halfway to building something that can be implanted in the human body,” says Skylar-Scott. “In patients who were born with a single ventricle, for example, there is only one chamber in the heart that can push blood to the body and lungs – which puts a lot of strain on the cardiovascular system and leads to high blood pressure, which organs produce can harm. Something like this could act as a biological pumping device to move blood to and from the heart,” he says.
Enlarge
Skylar-Scott quickly realizes that the printing of a larger structure, such as a functional chamber, grafted onto an existing heart is a long way off. To accomplish that would mean growing a little more than 16 times the size of his lab’s experimental “vein pump.” To make anything even close to that size — or better yet, a whole new organ — his lab would have to increase cell production tremendously.
“Scale-up will be the challenge of our generation,” says Skylar-Scott. However, it will mean more just to build a bigger printer. In many ways, it comes down to the cells themselves.
“Right now it takes a month for enough cells to grow to print something tiny. It’s also extremely expensive – each test costs tens of thousands of dollars,” he says. “We need to find ways to engineer cells that are more robust and cheaper to grow so we can start practicing and perfecting this method.” Once the pipeline for new cells is in place, I think we’re going to see some incredible progress.”
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