With mechanical stretching, MIT engineers can control how artificial arteries sprout new capillaries. Image Credit: Courtesy of the researchers
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Scientific Frontline: Extended "At a Glance" Summary: Mechanically Patterned Artificial Blood Vessels
The Core Concept: MIT engineers have developed a method to precisely control the growth and patterning of artificial blood vessels by applying targeted mechanical forces to a "blood vessel on a chip."
Key Distinction/Mechanism: Unlike conventional tissue engineering, which relies on imprecise chemical growth factors, this approach uses a magnetic, nutrient-rich gel to physically stretch human endothelial cells. The direction and magnitude of the mechanical stretch strictly dictate the number, length, and spatial orientation of the newly sprouted capillaries.
Major Frameworks/Components:
- Blood Vessel on a Chip: A microfluidic device containing a central channel lined with live human endothelial cells embedded in a hydrogel.
- Magnetic Actuation: The integration of suspended and embedded magnets to administer precise, directional, and variable mechanical "exercise" to the tissue.
- PIEZO1 Ion Channels: Mechanosensitive protein channels in the cell membrane that act as gatekeepers; mechanical stimulation forces these channels open to trigger the genetic pathways for blood vessel growth.
Branch of Science: Bioengineering, Tissue Engineering, Mechanical Engineering, and Molecular Biology.
Future Application: This protocol paves the way for the scalable fabrication of fully vascularized artificial organs and engineered tissues, which could be implanted into patients to restore biological function following severe disease or traumatic injury.
Why It Matters: Because any engineered tissue requires an intricate vascular network to deliver nutrients and oxygen, the inability to reliably pattern fine capillaries has been a major bottleneck in regenerative medicine; this mechanical approach successfully overcomes that fundamental barrier.
A video constructed from a 3D high-resolution microscopy image of the engineered tissue demonstrates a fly-through of a central artery and new capillaries sprouting in response to mechanical stimulation.
Tissue engineers are developing methods to grow living organs and tissues from cells with the aim of replacing 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, some of which are finer than a human hair.
Without a vascular network to deliver nutrients, artificial tissues—no matter how lifelike—cannot function.
Massachusetts Institute of Technology (MIT) engineers have now discovered they can engineer and control the growth of blood vessels through mechanical stretching.
The team developed a human "blood vessel on a chip" composed of a central artery, made from human endothelial cells, embedded in a gel containing a small magnet. The researchers studied how the main artery responded as they jostled the gel back and forth using an external magnet to move the embedded magnet.
They found that the simple mechanical action of repeatedly jostling the artery stimulated it to sprout smaller capillaries. By changing the direction in which the artery was jostled or stretched, the researchers could redirect the growing vessels. Furthermore, stretching the artery to various degrees influenced the quantity of new vessels that sprouted.
Their results, published in the Proceedings of the National Academy of Sciences, offer scientists a new method for engineering artificial blood vessels and programming their growth patterns.
“Healthy tissues depend on organized blood vessel networks, but state-of-the-art protocols do not enable fabricating such networks within engineered tissues,” says Ritu Raman, associate professor of mechanical engineering at MIT and the study’s co-lead author. “The ability to program blood vessel growth with physical cues may enable reproducible and scalable fabrication of engineered tissues that can be implanted in the body to restore function after debilitating disease or injury.”
The study’s MIT coauthors include Sina Kheiri, Jessica Shah, Shashaank Venkatesh, and Roger Kamm, along with Peiyuan Chai and Ryan Flynn at Harvard University.
Moving Is Good
Blood vessels are difficult to cultivate and control using conventional fabrication techniques. Although 3D printers can produce vessels at the scale of major arteries and veins, the technology lacks the precision required to print intricate networks of much finer, thread-like capillaries. Scientists have achieved some success in growing blood vessels from individual cells by cultivating them in petri dishes filled with nutrients and growth factors; however, controlling how and where they grow remains a challenge.
“You can try to pattern chemical cues, like growth factors, to direct where vessels grow, but you cannot do this very precisely,” Raman says. “We thus need other types of patternable cues that can help us build tissues with organized vessels.”
Raman and her students investigated whether they could grow and control new blood vessels using a protocol they had previously developed to cultivate artificial muscles and nerves. In their earlier work, the team engineered a small chip filled with a gel infused with nutrients and growth factors. They embedded a small magnet within the gel and carpeted the surface with live muscle or neuron cells. The researchers then manipulated an external magnet to pull the embedded magnet and the cell-covered gel back and forth. This study revealed that mechanical “exercise”—pulling the cells back and forth—directly influenced how the cells grew.
In their current study, the team utilized a similar setup to determine if they could cultivate and control new blood vessels.
The researchers built a "blood-vessel-on-a-chip" smaller than a postage stamp and filled it with a similar nutrient-rich gel containing a small magnet. They inserted a thin tube lengthwise through the gel to create a hollow channel and coated the channel with live endothelial cells, which naturally grow and fuse to form blood vessels in the body. Once the cells assumed the channel’s shape, they began sprouting new, capillary-like vessels into the gel.
Placing the device under a motorized stage fitted with small, suspended magnets, the researchers moved the magnets back and forth in various directions and to varying degrees. They then observed whether and how blood vessels sprouted from the central artery in response.
“The main takeaway is: Stretching the blood vessel back and forth seems to enhance the number of new capillaries that grow,” Raman states.
If the main artery were simply left undisturbed in the gel, it would grow some new vessels in random locations along its length. However, when the artery was jostled, significantly more vessels sprouted. When the team used the magnets to stretch the gel back and forth by 5 percent of its total width, many new vessels grew from the main artery. When stretched by 15 percent, fewer vessels sprouted, but those that did grew longer. Furthermore, when the team altered the direction of stretching, the new vessels adapted in response, changing direction and following the pattern of the mechanical stimulation.
“We are finding that moving is good, which is always the takeaway of everything we do in our lab,” Raman says. “Mechanical forces play an important role in our bodies. That means that if you want to grow more or fewer vessels, or shorter or longer vessels, or vessels in certain directions, we now know how to do that.”
A Gatekeeping Gene
The researchers investigated further to determine why blood vessels grow in response to mechanical forces. To do so, they utilized gene editing to examine the role of one particular gene: PIEZO1.
Raman had recently attended a lecture by molecular biologist Ardem Patapoutian. In 2021, Patapoutian received the Nobel Prize in Physiology or Medicine for discovering ion channels in cell membranes that open and close in response to mechanical pressure. These channels, named PIEZO1 and PIEZO2, act as a cell’s gatekeepers, controlling what enters and exits a cell. Both types of channels, Patapoutian found, are regulated by their respective genes, PIEZO1 and PIEZO2.
Following his talk, Raman shared her group’s experimental results with Patapoutian, demonstrating a connection between blood vessel growth and mechanical stimulation. Patapoutian proposed that the PIEZO1 channel could be the explanation; by mechanically exercising the central artery, Raman may have stimulated ion channels in the artery’s cells to open, triggering the growth of new blood vessels.
To test this hypothesis, Raman's team suppressed the PIEZO1 gene. If this gene were less active and fewer blood vessels grew as a result, it would indicate that blood vessels do indeed grow in response to mechanical stimulation—specifically, through the activation of PIEZO1 ion channels.
The team repeated their experiments, this time utilizing endothelial cells genetically edited to suppress the PIEZO1 gene. As expected, they observed that significantly fewer new blood vessels sprouted, even when mechanically exercising the central artery.
Now that the team has discovered a method to cultivate and control blood vessel growth, they plan to apply the protocol to develop organized networks of vessels to supply artificial organs and tissues. “We are now investigating how precisely patterning blood vessel growth can help improve muscle function,” says coauthor Jessica Shah.
Funding: This work was supported, in part, by the US Department of Defense Army Research Office Early Career Program and PECASE Grant, and a US Department of Defense DURIP Program Grant.
Published in journal: Proceedings of the National Academy of Sciences
Title: 4D force patterning enables spatial control of angiogenesis
Authors: Sina Kheiri, Jessica Shah, Peiyuan Chai, Shashaank A. Venkatesh, Ryan A. Flynn, Roger D. Kamm, and Ritu Raman
Source/Credit: Massachusetts Institute of Technology | Jennifer Chu
Edited by: Scientific Frontline
Reference Number: beng071426_01
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