Engineers at the Massachusetts Institute of Technology (MIT) have developed an innovative methodology that enables the control of blood vessel development through the application of mechanical stimuli. This progress addresses one of the biggest obstacles in tissue engineering: the creation of structured vascular systems essential for nourishing synthetic organs and tissues.
Researchers aim to cultivate living tissues and organs from cells with the goal of replacing diseased or damaged parts of the human body. Although they have already succeeded in producing various artificial tissues, such as muscle, liver, kidney, and skin, a reliable method for forming vascular networks with exact patterns, including ultrafine capillaries, was missing. Without this supply network, artificial tissues cannot receive sufficient nutrients to function correctly.
The MIT team demonstrated that it is feasible to plan and guide this growth using mechanical stretching. The findings were published in the journal Proceedings of the National Academy of Sciences. To conduct the experiment, scientists set up a 'blood vessel-on-a-chip' model, which consisted of a central artery made of human endothelial cells. This structure was inserted into a nutrient gel containing a small magnet.
By moving an external magnet to displace the internal magnet in the gel, forcing the artery to oscillate laterally, researchers observed the main vessel's reaction to the physical stimulus. The tests revealed that the repetitive movement of the artery induced the appearance of new capillaries. Additionally, by modifying the direction of the stretching, it was possible to direct the growth of these vessels, and varying the intensity of the stretch allowed for modulating the amount of new capillaries formed.
The authors consider this technique a new approach to designing artificial blood vessels and programming their developmental patterns. Ritu Raman, an associate professor of mechanical engineering at MIT and lead co-author, emphasizes that 'healthy tissues depend on organized networks of blood vessels, but the most advanced protocols do not allow for manufacturing such networks within artificial tissues.' She adds that the ability to program vascular growth with physical stimuli could make the reproducible and scalable manufacturing of implantable tissues possible to restore function after severe injuries or diseases.
The researchers emphasize that blood vessels remain among the most difficult structures to replicate using traditional methods. While 3D printers can generate large arteries and veins, they lack the precision needed to construct complex networks of very fine capillaries. Another approach, cell culture in Petri dishes, faces the challenge of precisely controlling where these structures will emerge. Raman explains that although chemical signals, such as growth factors, can be used to guide growth, the precision is limited, thus requiring other standardized stimuli.
The current research evolved from a previous protocol used to culture artificial muscles and nerves, where the mechanical movement of the gel influenced cell growth. In the new experiment, the chip, smaller than a postage stamp, was filled with nutrient gel and a magnet. A hollow channel was created in the gel and lined with live endothelial cells. After the cells assumed the shape of the channel, new capillary vessels began to sprout. The device was placed under a motorized platform with suspended magnets, whose directions and intensities were varied to monitor the vascular response.
Raman concludes that stretching the vessel from side to side increases the number of new capillaries. When the vessel remained still, few vessels appeared randomly; with repetitive movement, the quantity increased drastically. Tests also showed that stretching the gel by 5% of its width generated many new vessels, while stretching to 15% reduced the quantity but increased the length of the formed vessels. Furthermore, the new vessels followed the direction of the stretch when it was altered.
The scientists investigated the reason for the vascular response to mechanical stimulation by focusing on the PIEZO1 gene. Inspired by a lecture from molecular biologist Ardem Patapoutian, who won the 2021 Nobel Prize in Physiology or Medicine for discovering pressure-sensitive ion channels (PIEZO1 and PIEZO2), the researchers hypothesized that mechanical exercise would activate these channels, promoting the formation of new vessels.
To verify this theory, they employed genetic editing to reduce the activity of the PIEZO1 gene in endothelial cells. The result confirmed the hypothesis: cells with the suppressed PIEZO1 gene produced significantly fewer blood vessels under the same mechanical stimulus, indicating that vascular growth depends on the activation of these ion channels.
With the confirmation of control over the quantity and direction of vascular growth, the team plans to apply this protocol to build organized vascular networks capable of supplying artificial tissues and organs. Jessica Shah, a co-author, stated that they are investigating how precise guidance of this growth can optimize muscle function. The study received partial financial support from the Early Career Program and the PECASE Grant from the Army Research Office of the United States Department of Defense, as well as a DURIP Program Grant from the same department.
Researchers at the University of Minnesota announced a remarkable achievement in the field of synthetic biology: the creation of artificial cells named SpudCell. These synthetic structures were developed with the ability to perform vital functions, such as nourishing, proliferating, and replicating, although they are not considered life in the traditional sense.
SpudCells are systems designed to mimic fundamental processes of a real biological cell. Although they do not constitute complete organisms, they demonstrate notable characteristics, including growth, division, and competition for resources. The system is significantly simplified compared to natural cells; while the human genome has approximately 20 thousand genes and the bacterium Escherichia coli exceeds 4 thousand, SpudCells operate with only 36 genes.
The components used in this experiment include 36 genes responsible for primary functions, such as DNA copying, in addition to proteins and molecules that enable crucial chemical reactions. Lipid vesicles were also employed, acting as artificial membranes, and externally supplied ribosomes for protein synthesis.
Kate Adamala, a synthetic biologist at the University of Minnesota, led this project. Her team combined various chemical substances to form structures capable of executing typical living cell reactions. For this purpose, genes from viruses and the bacterium Escherichia coli were incorporated. In a controlled laboratory environment, the system began to self-organize.
A fundamental aspect of this work is that it is not a digital simulation, but rather a direct interaction between matter and matter. The cells emerge after mixing the ingredients and subsequently manage to separate thanks to proteins that promote the folding of their membranes.
Despite the progress, the creators emphasize that SpudCells should not be classified as full living organisms. Kate Adamala stresses this caution by stating that 'life is not binary,' indicating that there is no strict boundary between what is alive and what is not.
The scientific community reacted positively to the finding. John Glass, from the J. Craig Venter Institute, expressed admiration for the integrated functionality of so many elements in a single system. Drew Endy, from Stanford University, characterized the experiment as something constructed, yet exhibiting cellular behavior.
The possibilities arising from this study are vast, potentially aiding in understanding the minimum requirements for the existence of life and paving the way for future applications, such as pharmaceutical production or carbon capture. Theoretically, future versions of these cells could synthesize complex compounds currently difficult to obtain in the laboratory.
To foster this advancement, the researchers established the Biotic initiative, which aims to unite scientists and facilitate access to the materials necessary for creating new SpudCells. However, there is a delicate consideration: more sophisticated systems may generate fears about their misuse, motivating the maintenance of development in an open and collaborative format. Drew Endy made an analogy with the first flight of the Wright brothers: a modest, but transformative beginning.
Currently, SpudCells still depend on external supplies and their survival is limited to a few generations, but the advance is already recognized as a significant milestone in synthetic biology.
