Few human organs are more enticing to engineers than the human heart. The chamber pumping is perfectly consistent; Its materials are flexible, but contracts are made on demand; Its shape and movement are perfectly adjusted to effectively squeeze fluid through the body. It’s a structural marvel – but when things go wrong in that structure, the inherent complexity makes it a real challenge to fix. As a result, thousands of young patients with congenital heart disease must deal with their disease for life.
“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 School of Engineering and Medicine. It’s really hard on families. There are ways to prolong the lives of children who have surgery, but many live uncertain lives with movement restrictions. To get a true healing solution, you need to somehow replace damaged or malformed tissue.
Scientists at Stanford University are working to produce human tissue on a therapeutic scale, with a focus on the heart. Image credit: Kurt Hickman
That’s where Skylar-Scott comes in. He is working on new ways to treat congenital heart disease by building engineered heart tissue in the lab.
It takes more than just growing cells in petri dishes, he points out. Most existing techniques seed heart cells or stem cells with temporary “scaffolders” : porous spongy materials that hold them in place in three dimensions. While this method allows researchers to grow lab-made tissue, it’s only really useful for extremely thin layers of cells.
“If your scaffold is only a few cells thick, you can put the cells in the right place. But if you’re trying to grow something a centimeter thick, it becomes very difficult to plant cells in the right places to grow tissue. “Keeping them alive, getting them the right nutrition or getting the vasculature becomes a real challenge, “Skylar-Scott says. He added that human organs are not single balls of cells either. Each cell is made up of complex layers of multiple cell types, making 3D structures difficult to replicate.
To solve this problem, Skylar-Scott and his team are looking for a bold new Angle on organ growth. Using advanced 3D printing technology, they created thick tissue one layer at a time, placing the exact types of cells needed in the right places, such as towers rising from a carefully placed grid of bricks. He points out that this construction method is ideal for replicating complex tissues such as the heart, where the 3D form is important to its function.
As promising as it may be, 3D printing using cells presents some deep and thorny challenges. Unlike consumer-grade 3D printers, which can heat and extrude plastic filaments into myriad shapes, cells are alive. They’re soft, soft, imperfect and frustratingly fragile, Skylar-Scott says.
3D bio-printer prints samples
3D bio-printer prints samples. Photo credit: Andrew Brodhead
“If you try to place one cell at a time, printing a liver or a heart could take hundreds or thousands of years. Even if you do 1,000 cells per second, you still have to put down billions of cells to get an organ. “If you do the math, it’s not so good for a scalable process,” he says.
Instead, Skylar-Scott and his lab are trying to speed up the printing process by placing dense clumps of cells called organoids. The team created the clumps by putting genetically modified stem cells into a centrifuge that produced a mushy substance. Using this mixture, they were able to print large numbers of cells simultaneously into gelatinous 3D structures.” “We basically print these organoids to define the large-scale structure of an organ,” he says.
Putting the stem cells in place, however, is only the first step. Once they were printed, researchers had to somehow persuade them to differentiate into more specific cell types, forming a multilayer population of working cells similar to healthy organ tissue. To do this, Skylar-Scott essentially dunks stem cells in a chemical cocktail.
“Every stem cell line we are developing has been genetically engineered to respond to specific drugs,” he noted. Once they sense the drug, they differentiate into specific cell types. Some cells are programmed as cardiomyocytes, the heart cells that form the functional tissue at the heart’s core. Others were instructed to become stromal cells, which glue tissues together.
Skylar-scott is testing his printing tissue in a bioreactor, a container about the size of a smartphone that helps keep the printing cells alive. Inside, his team was able to grow a printed organ-like structure: a tube about two inches long and half a centimeter in diameter. Much like veins in the human body, the tiny devices “pump” themselves, contracting and expanding to pass fluid through them.
“If we can develop more of these tissues, we might have a good halfway point to build something that can be implanted into people, “Skylar-Scott says. For example, in patients born with only one ventricle, there is only one chamber in the heart that pushes blood into the body and lungs — putting a lot of pressure on the cardiovascular system and leading to high blood pressure, which can cause organ damage. “Something like this can act as a biological pumping device to help get blood in and out of the heart,” he says.
Skylar-scott was quick to note that printing a larger structure, such as a functional chamber, to graft onto an existing heart was still a way off. Creating the technology meant growing something 16 times bigger than his lab’s experimental venous pump. To produce anything close to that size — or, better yet, an entirely new organ — his lab would need to dramatically increase cell production.
“Scaling up is going to be the challenge of our generation, “Skylar-Scott said. However, this means more than just building a bigger printer. In many ways, it comes down to the cell itself.
“Right now, it takes a month to grow enough cells to print something small. “It’s also very expensive – each test represents tens of thousands of dollars,” he says. We need to find ways to design cells to make them more powerful and cheaper to grow, so we can start practicing and perfecting that approach. Once the pipeline of new cells is in place, I think we’ll start to see some incredible progress.