The world was astounded last month at the demonstration of a printed heart in the laboratory of Prof. Tal Dvir from Tel Aviv University, but this is not the only laboratory in Israel achieving astonishing breakthroughs in tissue engineering. Actually, Israel is one of the world’s most advanced countries in this sector. One of the reasons that the country has taken the lead is Israeli law, which has allowed trials with fetal stem cells since the 1990s, when many countries still banned them.
Prof. Shulamit Levenberg, dean of the Faculty of Biomedical Engineering at the Technion – Israel Institute of Technology and head of the recently founded 3-D Bio-Printing Center for Cell and Biomaterials Printing, is one of the world’s leading scientists in this field. She has won many prizes, and was selected by “Scientific American” as one of the world’s 50 leading scientists.
In 2005, Levenberg wrote the first article documenting the creation of muscle tissue from fetal stem cells, which were successfully implanted in mice. In 2007, she was a partner with Prof. Lior Gepstein in creating cardiac tissue from human stem cells. The cells made up a structure that appears like a sponge, except for one unique feature – the sponge expanded and contracted at a constant pace with no external intervention – inanimate and living, natural and artificial.
Several months ago, Technion reported a new achievement in Levenberg’s laboratory: the fusing of a severed spinal column in rats, which restored their movement capabilities and feeling in their legs. This achievement can give hope to people who have suffered spinal column injuries that they will some day be able to walk again. The fusion was achieved by implanting engineered tissue from human stem cells taken from the gums.
“I have hope that we can really help people walk again,” Levenberg says. “I heard Yariv Bash, the entrepreneur of Beresheet, who was paralyzed in an accident, ask, ‘Why can people bring a spaceship to the moon, but can’t repair two centimeters in the spinal column,’ and I said to myself, ‘We’re starting. We’re in the right direction.’ The rats are walking, although there’s a long way to go before we get to people, of course.”
“Globes”: How did you repair a spinal column in rats?
Levenberg: “We use several methods. The method that has already been published is to create 3D scaffolding on which we plant stem cells, and we implant this right into the injured area. This engineered tissue, which is composed of dissolving scaffolding with stems cells from the gums on it, sends signals to the spinal column’s existing nerve cells telling them to grow and advance into the injured area. Nerve cells that have been completely severed usually don’t grow again and do not become connected, but the stem cells secreted material that encouraged them to do this. We saw reconnection that enabled the animals to begin walking, which has never been seen before. 40% of the animals resumed normal walking. In rats, like people, there is no spontaneous regeneration after this kind of injury.”
Why is it impossible to sew a torn spinal column?
“The spinal column is a nervous system that stretches from the brain and is connected to the motor system of all of the muscles. Today, we don’t know the organizing principle for it; they have to be connected independently. Blood vessels can be connected, muscles can be sown, but this cannot be done with the spinal column; it won’t work if it doesn’t happen by itself.”
When will we see this development in human clinical trials?
“It will take time, but we’re also developing less invasive methods that can possibly be applied more quickly to human beings.”
A few years ago, “Globes” interviewed an Italian scientist who wanted to conduct a trial of transplanting one person’s head in another person. Do you think that a head transplant will be possible in the future?
“A head is an organ. It’s tissue. In principle, there’s nothing preventing tissue from being connected, but the main limitation is the brain – how to make connect the central nervous system to the rest of the body. This isn’t clear.”
What are the chances that we’ll be able to develop tissue from scratch that will itself be alive? If it is possible to build organs, why is it impossible to produce new life?
“There’s no need for it, and we’re also very far away from this.”
Blood vessels know in which direction to grow
Levenberg says that in the 1990s, when she began studying, she wanted to study medical engineering, but there was no such BA program, so she began studying biology at the Weizmann Institute. “I went as far as a doctorate in cell biology,” she says. She met Prof. Judah Folkman when he lectured at the Weizmann Institute on development of an anti-cancer drug based on blocking blood vessel activity. That meeting and a newspaper story about the new field of organ engineering fired her desire to understand how human tissue is organized.
“Folkman researched how tissue creates a network of blood vessels for itself that gives it a amount of blood flow precisely adjusted to the size of the tissue and optimally spread around all of the tissue. This mechanism really excited me. I told myself, ‘I’d like to understand how this is done, so that I can imitate it.’ Sometimes one sentence spoken by one person influence the direction of another person’s life. That’s how I started dealing with tissue engineering, with an emphasis on blood vessels. I left biology for medical engineering, which is multidisciplinary.”
Levenberg specialized in the field and joined the laboratory of Prof. Robert Langer (“Magical Bob,” a newspaper interview with whom was recently published) at MIT. Together, they developed the first engineered muscle containing blood vessels.
The field of tissue engineering has undergone several development stages. “It was first necessary to make cells reproduce and be differentiated, so that they would produce complex tissue from a specific type of cell, but that was only the beginning, because those were only uniform cell surfaces,” Levenberg explains. “The next step was addressing the 3D tissue structure. Today, we’re trying to build tissue the way it really is – from different types of cells and with a precise architecture, like a real organ.”
Levenberg’s laboratory now emphasizes the integration of blood vessels in complex tissue. “We found that when we build tissue with the blood vessels already inside it, it integrates better in the body and connects better with existing blood vessels. In the most recent article, we showed that the blood flow in these tissues is better, and fewer blood clots are formed,” she says.
The blood vessels included in tissue will also change directionality. “If we stretch the tissue, something in the mechanical power applied to the blood vessels makes their cells point in the same direction, and the blood vessel tubes themselves point in the direction of the stretching. It’s exciting to see the cells respond to signaling that is mechanical, not chemical or electrical. If we stretch them in another direction a few days later, this entire tube will simply turn and start growing at a 90 degree angle from the direction of the earlier growth.”
In which organs do the blood vessels have to be directional?
“In muscle tissue, the blood vessels are straightened in the muscle fiber directionality, and that’s also true of the heart muscle and the spinal column.”
Levenberg stresses that there are also many challenges in this aspect. “As we progress to larger animals, for example in the transition from rats to human beings, the tissues become larger, and larger blood vessels, a wider variety of blood vessels, and a more complex hierarchy of blood cells of various sizes are needed. 3D printing can make it possible to produce such tissue as soon as we understand its exact composition.”
Even now, after many years of research, Levenberg regards the ability of tissue to independently organize itself into its complex structure in one body as one of nature’s most impressive phenomena. “We don’t know exactly what mechanism dictates the organizing. We do know that there are diseases in which the organizing mechanism is damaged. For example, you see it in certain skin diseases. We see less tissue regeneration among older people, and also incorrect growth of blood vessels. If the blood vessels don’t function well, the tissue can’t function, either. If we knew exactly what gives cells the organizing signal, it might be possible to intervene in some of these cell aging processes.”
Pancreas cells instead of an insulin injection
One of the hot areas in tissue engineering is creation of an artificial pancreas. Today, diabetes patients are themselves an “artificial pancreas.” They take upon themselves the function of the cell that secretes insulin: feeling the level of blood sugar in the bloodstream, deciding how much insulin is needed for balance, and injecting it. This process is very difficult for the human brain. For a pancreas cell, the process is simple. Creating an alternative pancreas is likely to greatly improve the situation.
Creating an artificial pancreas does not necessarily require removal of the entire pancreas and transplanting another one in its place. It is enough to transplant pancreas cells of a certain type that are capable of feeling sugar and secreting insulin from under the skin, where they are connected to the bloodstream. How can these cells be kept alive? In the current methods, they are damaged by the immune system or by a lack of oxygen.
In Levenberg’s laboratory, with funding from the European Union, researchers are working on 3D printing of pancreas tissue. “Our cells come from the pancreas itself, together with new cells. If the tissue is transplanted in an environment containing many blood cells, and if our tissue is well connected to the existing blood vessels, it can function well,” Levenberg says.
Until now, pancreas cell implants were not connected quickly enough to the body’s blood supply, and many of the desirable cells therefore died before the tissue began functioning. “We believe that if we implant them together with the nutritious environment, more cells will survive,” Levenberg says.
Is there some religious barrier to intervening in the human body? You are really intervening in creation.
“On the contrary. I think we are obligated to study and understand the world, and this will bring us closer to the creator through an understanding of the complexity of the world that he created. We have an obligation to improve the world, develop it, and preserve it. This is a very important element in Judaism, so there’s no contradiction; there’s a connection.”
A taste from an engineered organ
In addition to engineering organs for medicine and transplants, Levenberg’s ideas are also being used to develop cultured meat tissue for food. “For me, this is a positive side effect of our research into building organs. The idea came from my doctoral student, for whom it was important from a young age. He began the laboratory’s work in this area.
“We created tissue containing the muscle cells and other cells from muscle tissue that looks exactly like tissue – like steak, in contrast to the cloned hamburger that now exists, which contains one type of tissue, without creating the tissue structure of muscle. The tissue may be so similar to steak that a person eating it will be unable to tell the difference.”
Eating cultured steak instead of living tissue is not only more moral, but also healthier. Potentially, “This product, which is grown in a laboratory, is clean, free of diseases, and without antibiotics. You can use less oil in preparing it,” Levenberg says. This development is being commercialized by a company named Aleph Farm, which is part of food-tech incubator “The Kitchen.”
Organ printing: 0.001-millimeter precision
A month ago, Technion announced the founding of 3-D Bio-Printing Center for Cell and Biomaterials Printing, headed by Levenberg, in the Faculty of Biomedical Engineering. The center is open to all of the institution’s researchers.
The center has a 3D printer, which Dvir and his students used to print the living heart. 3D printers for printing animal tissues are fed images from a scanner. The printers can not only print organs with great precision; they can also potentially adjust them perfectly to a specific patient’s body.
Because of the level of precision needed, the printer has to be equipped with very accurate engines moving at changing speeds accurate to 0.001 millimeters, plus a camera that improves the accuracy of the printer needle. The ink heads in the printer have to be capable of releasing a variety of materials at different temperatures and different viscosity levels, and these printers therefore include a number of heads, each of which is responsible for different types of material. The printing is done either directly to a Petri dish, or the cells are printed on 3D scaffolding.
Published by Globes, Israel business news – en.globes.co.il – on May 15, 2019
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