Working at the intersection of tissue engineering, stem cell biology, and optical imaging, scientists at the University of Washington created an effective way to grow heart tissue in vitro.
After a heart attack, the heart muscle is often severely damaged due to the lack of blood flow—which can lead to poorer quality of life and increased risk of heart failure. Scientists have tried for years to find a way to regenerate the muscle tissue but failed to create functional blood vessels.
Researchers from the University of Washington (UW) Institute for Stem Cell and Regenerative Medicine, have now demonstrated a new way to build blood vessels with perfusion outside the body that can successfully be grafted to the heart muscle in an animal model, improving blood flow by twenty-fold.
Charles Murry, director of the Center for Cardiovascular Biology at UW, said past attempts to regenerate heart muscle has been thwarted by a lack of working vasculature to help promote blood flow. While some approaches had successfully regenerated capillaries—the fine branching blood vessels that allow blood to flow across the tissue—the constructed networks didn’t have the pressure required to conduct healthy blood flow.
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“There is a really intimate relationship between blood flow and the heart’s mechanical function and we now understand there’s no way to build significant new functional muscle without having the vasculature to sustain it,” he said. “Older approaches gave us a network, but they were about as efficient in conducting blood flow as a sponge. We needed a hierarchical, systematic branching network, which is what the arterial system brings in, to get there.”
To develop such a network, Ying Zheng, an associate professor of bioengineering, looked to semiconductors for inspiration—what principles of microfluidics might offer better conductance of blood flow? She used photolithography to pattern an arterial circuit in a collagen matrix that would better promote perfusion.
“Vasculature survives and remodels because it’s so dynamic under blood flow. The cells are changing, the structure is changing, and then the surrounding tissue is changing,” she said. “This matrix created an architecture of patterned microchannels that helped to keep that really dynamic flow environment.”
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When researchers placed human stem cell-derived endothelial cells into the patterned microchannels inside the collagen matrix, called a construct, they found the cells readily grew under flow, building a highly vascularized tissue.
When the group grafted the construct on to the hearts of rats who had suffered heart damage after a heart attack, they discovered it easily integrated with existing tissue. In addition, the patch offered significantly higher blood flow to promote tissue survival, with a perfusion rate more than 20 times higher than any previous graft designs.
Zheng said the team was surprised by just how much blood flow this design permitted—and credits their success for taking the time to build this complex flow architecture outside the body first.
“This design made the vasculature adapt to flow and remodel increasing vascularity,” she said. “This led to better integration with the heart tissue and that improved perfusion rate. It shows that this approach could be adapted for cardiovascular tissue re-engineering in the future.”
Next, Zheng and Murry would like to test this graft in larger animals. But there are many challenges involved with scaling up this design for larger hearts.
“The ventricle thickness for rats is on the order of two to three millimeters,” Zheng said. “The current construct can reach about one millimeter, which allows us to repair the tissue to some extent. But for larger animals, we will need a much thicker tissue—and that would involve designing a very complex vascular architecture.”
Beyond creating constructs for larger animals, the team is also hoping to better understand the long-term effects of implanting this engineered tissue.
“How much improvement in vivo can we offer?” Zheng asked. “We need to work out more of the in vitro work first, trying to develop functional tissue that we can implant into animals so we can study cardiovascular diseases as well as the function of more fundamental cardiovascular physiology.”
But while there is plenty of work ahead, Murry said, the study has shown that blood flow is critical to cardiovascular tissue re-engineering efforts—and that this approach offers the arterial-like branching required to get there.
“This construct made for much happier-looking cardiac muscle grafts,” he said. “And while we need further research to understand more about how to successfully regenerate heart muscle tissue, this is definitely an important step in the right direction.”
Kayt Sukel is an independent writer who focuses on technology.
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