Tissue engineers are exploring ways to grow living organs and tissues from cells to replace diseased and damaged counterparts in the body. Scientists have successfully grown artificial muscles, livers, kidneys, skin, and other tissues. However, there has been no reliable method to engineer precisely patterned networks of blood vessels, which can be finer than a human hair. Now, MIT engineers have discovered that they can control blood vessel growth by mechanically stretching them. They created a "blood vessel on a chip," featuring a central artery made from human endothelial cells embedded in a gel containing a small magnet. The researchers investigated how the artery responded to jostling the gel using an external magnet to move the embedded magnet. They found that this mechanical action stimulated the artery to sprout smaller capillaries. By altering the direction of the artery's movement or stretch, they could redirect the growth of new vessels. Additionally, varying the degree of stretching influenced the quantity of new vessels sprouting.
The results, published in the Proceedings of the National Academy of Sciences, provide a new approach to engineer artificial blood vessels and program their growth patterns. "Healthy tissues depend on organized blood vessel networks, but current protocols do not enable the fabrication of such networks in engineered tissues," says Ritu Raman, associate professor of mechanical engineering at MIT. "The ability to program blood vessel growth with physical cues may enable reproducible and scalable fabrication of engineered tissues that can be implanted to restore function after debilitating disease or injury."
Growing and controlling blood vessels is challenging with conventional fabrication techniques. While 3D printers can produce major arteries and veins, the technology lacks precision for intricate networks of fine capillaries. Some success has been achieved by cultivating individual cells in Petri dishes filled with nutrients and growth factors, but controlling their growth remains difficult. Raman and her students aimed to see if they could grow and control new blood vessels using a protocol they previously developed for artificial muscles and nerves.
In their new work, they built a "blood-vessel-on-a-chip," smaller than a postage stamp, filled with a nutrient-rich gel containing a small magnet. A thin tube was inserted to create a hollow channel, and live endothelial cells were coated on the channel. Once the cells conformed to the channel's shape, they began sprouting new, capillary-like vessels. The device was placed under a motorized stage with small magnets, and the researchers moved the magnets back and forth in various directions to observe how blood vessels sprouted from the central artery.
The main takeaway is that stretching the blood vessel enhances the number of new capillaries that grow. If the main artery were left undisturbed, it would grow some new vessels randomly, but when jostled, significantly more vessels sprouted. When the gel was stretched by 5% of its total width, many new vessels emerged, while stretching by 15% produced fewer but longer vessels. Changing the direction of stretching also influenced the new vessels' growth, which followed the pattern of mechanical stimulation.
The researchers delved into why blood vessels grow in response to mechanical forces, focusing on gene editing and the role of the Piezo1 gene. After discussing their findings with Nobel laureate Ardem Patapoutian, they hypothesized that mechanical exercise of the artery stimulated Piezo1 ion channels, triggering new blood vessel growth. To test this, they edited the Piezo1 gene and found that fewer new blood vessels sprouted, confirming the gene's role in mechanical stimulation.
Now that the team has a method to grow and control blood vessel growth, they plan to apply it to create organized networks for supplying artificial organs and tissues. "We are investigating how precisely patterning blood vessel growth can help improve muscle function," co-author Jessica Shah states. This work was supported by the U.S. Army Research Office Early Career Program and PECASE Grant.
Blogger's Review: This research highlights the critical role of mechanical forces in bioengineering, particularly in blood vessel generation. By precisely controlling vessel growth, there is potential for significant advancements in tissue engineering and regenerative medicine, enhancing the functionality and adaptability of artificial organs.