"Barriers are more regulatory than technological"

Prof. Tal Dvir Photo: Eyal Izhar

Having 3D printed a heart, Tel Aviv University's Prof. Tal Dvir says in principle, he can regenerate any organ in the body.

Earlier this week researchers from Tel Aviv University made a 3D print out of a heart for the first time using human tissue. They precisely replicated in a 3D structure the range of cells required for the heart's action: young stem cells with contraction capabilities, cells constituting scaffolding that give the heart its structure, and blood vessel cells that circulate blood to the heart.

The printed cells are young cells. The heart will now be grown in a supporting environment, so that it will develop into a living and functioning heart. The plan is to transplant the heart into animals in the coming year, in the hope that in the future, it will be possible to also print human hearts as an available, cheaper and more effective replacement for heart transplants from people. This groundbreaking development was conducted by doctoral student Nadav Noor and Dr. Assaf Shapira from the laboratory of Prof. Tal Dvir of head of the Institute for Regenerative Medicine at Tel Aviv University's School of Molecular Cell Biology and Biotechnology.

In 2017, Dvir told "Globes" about the work in his unique laboratory, where a variety of methods for regenerating damaged organs was being researched: biological methods based on stem cells, engineering and electronic methods of building artificial organs, and combinations of these methods.

The following are Dvir's comments from 2017.

"Replacement body parts? The barrier is more regulatory than technological"

Ever since stem cell research accelerated 20 year ago, people have been talking about engineering of replacement body parts. Up until now, however, regenerative medicine for regenerating organs has not made it into mainstream medicine. Nevertheless, Prof. Dvir is enthusiastic about the vision of regenerating all types of tissue, and regards medicine of this type as a broader interdisciplinary field than stem cells, ranging from the use of biological materials to printing organs.

According to Dvir, there is no technological barrier keeping us from printing organs for transplanting that cannot be overcome, based cells donated from patients themselves. Actually, he says, "The barrier is more regulatory than technological."

The developments in Dvir's laboratory and its counterparts elsewhere in the world are likely to completely eliminate the need for organ donations. He says that human trials are imminent. "22 people waiting for donated organs die every day in the US alone, and the world is much larger. There aren't enough donors," he says, and emphasizes that alternative solutions are needed.

The tissue will monitor itself

In Dvir's vision, all types of tissue will be regenerated in his laboratory: liver, bone, cartilage, spinal column, and entire organs, such as the heart, pancreas, and lungs. Dvir says that the day is not far off when new tissue can be developed that will monitor and repair itself, in addition to its ordinary activity, for example by releasing drugs, or providing electrical stimulation. Young, fresh bionic tissue will be implanted in people to replace diseased, damaged, and old tissue.

Meanwhile, Dvir is focusing mainly on the heart and on regeneration following heart attacks. "We are regenerating the heart through a variety of approaches: biological, engineering, electronic, and combined methods. Building bionic organs is no longer science fiction," Dvir says, and mentions that heart disease still kills more people in the developed world that all types of cancer combined, and heart attacks also account for a large proportion of these deaths. "When a heart attack is identified, they run to open the blocked artery, but the damage caused to the heart while the blood vessels were blocked and the heart did not get oxygen remains, and gets worse," Dvir says. "The heart suffers a scar. As a result, 50% of people suffering a first major heart attack will die within five years."

Body tissues differ in their ability to regenerate themselves. The heart is not endowed with these capabilities. The scar tissue that is left is unable to contract and expand at the rate dictated by the rest of the heart. The blood is not pushed out, and the result is heart failure. An effort was previously made to solve this by developing mechanical scaffolding for the heart, and the product was given to Israeli company Bioline for commercialization, and later to US company Ikaria, which was also sold in the process, but the product failed in a clinical trial. "The product was a mechanical scaffold, but it did not fill the scar tissue with contracting cells," says Dvir, who did his doctorate with Prof. Smadar Cohen from Ben Gurion University of the Negev, who developed the product.

"We're creating a patch that replaces the scarred area. First of all, we take cells from several sources, and the best source for heart cells is stem cells. This not necessarily the formula for all body tissue. If you want to regenerate skin or muscle, you can reproduce adult cells. In order to regenerate cartilage, you can also take adult bone marrow cells from the patient, but when slightly more complex organs are involved, such as the heart or brain, stem cells are needed, because these cells do not reproduce themselves in their adult form. Our bodies have no such stem cells, but we can create them with the help of a little genetic engineering. In this way, we can create tissue based on the patients' own cells, even if the patient is an adult and all of his or her initial stem cells have already been differentiated.

"Once we have cells, we have to create tissue. Cells need a matrix to grow on, which has to be built like the issue we want to regenerate. We build this matrix in a laboratory, and try to imitate the original as much as possible. We're building all sorts of 3D structures, planting the cells on them, and adding material that encourages the cells to become organized the right way as tissue. In order to get cells to communicate with each other, we add gold nanoparticles, for example, which can transmit an electrical signal. We do everything we can to make the tissue functional," Dvir explains. In completely natural body tissue, of course, there are no gold nanoparticles, but Dvir is not guided by a wish to create tissue that is identical to tissue in nature; above all, he wants tissue that works and can replace the damaged organ in its body function.

Dvir says that all tissue also needs something else in order to become functional. "If it's cartilage tissue, it has to be flexible and contain many proteins. If its bone, it has to be rigid, not flexible. The electrical signals needed are different. We're examining all the tissue in the body, and testing which signals it gets during fetal development, which we integrate in the tissue that we're building."

"Globes": Have you already transplanted such tissue?

Dvir: "We're now conducting trails on pigs, and have gotten very fine results so far. We really want to put the product into human trials, and we're talking with several companies about taking it forward, because the first one to bring to market such a patch for repairing scarred heart tissue will help both millions of people and his or herself. Maybe we'll start a company ourselves that can commercialize all of the inventions from our laboratory, not just around one organ, and not just the more natural material, but also our bio-materials."

Dvir says that the product does not require open heart surgery in order to transplant it. Like Prof. Cohen and Bioline's product, it is injected in a gel configuration and solidifies at body temperature. "This way, it can be brought to anywhere in the body with a catheter," he says.

The next natural step for Dvir is to transplant an entire heart. "In order to create an entire tissue like heart tissue, various elements have to be integrated in it, such as blood vessels, so we also print blood vessels."

Do you have to print them in the form of blood vessels?

"We have to integrate all sorts of cells that create blood vessels, and they natural assume the form of blood vessels, but it takes time. 3D printing can help us print heart tissue with blood vessels already inside."

And when you print them like that, can they already function as blood vessels for all intents and purposes?

"If you give them the right signals, then the answer is yes. There is also a challenge in printing a heart from the patient's cells, in the form of a heart, so that it will exactly fit the patient's body, or in the case of a patch, printing it to replace exactly the scar there."

"Printing a heart is not science fiction"

Would you say that the question of what makes a collection of cells become an organ operating as a single unit is still a mystery?

"No. The knowledge is being accumulated. The patch that we build from a collection of individual cells and transplant on the damaged organ is already unified with the heart very well, and relatively quickly. An electrical signal moves very well from the healthy area to the engineered area."

Does artificial tissue have any disadvantages or gaps in comparison with the patient's natural tissue?

"It is different in that the cells in it are younger, but this is an advantage. I'd say that our tissue now is not inferior to natural tissue. As for an entire heart, we're already able to print it, so that all of the rises, ventricles, and valves are inside, and we're working on integrating the blood vessels, and believe that it will happen. I would no longer call it science fiction, despite the challenges, because we see an organ in the laboratory, and it contracts really well."

What are the challenges to making every hospital into an organ printing farm and giving every patients the organ that he or she needs?

"There are still technological barriers, and there are also regulatory barriers. We were in talks with a 3D printing company, and we wanted to jointly develop a printer that would be suitable for printing organs. When they realized that it couldn't happen in three years, they said that it was too big for them right now. Nevertheless, the route can be shorter than for drugs, if we want to offer just a scaffold, instead of replacing the entire heart."

What other organs have already been nurtured and transplanted?

"Prof. Anthony Atala from the Wake Forest Institute for Regenerative Medicine, a huge center that deals exclusively with regenerative medicine, is already in clinical trials for organs such as the bladder. He transplanted the first bladders almost 10 years ago, and people are living with this. These bladders are not from the patient's own cells, like the heart tissue that we're developing, so it's likely that these patients are being treated with drugs for repressing the immune system, like every patient undergoing a transplant."

What about brain regeneration and spinal fusion for paralyzed patients?

"We can already create brain tissue in the laboratory, the effect of which we're testing on animals with Parkinson's Disease. The door to creating brain tissue was opened when the technique was invented for restoring a patient's cells to their state when they were fetal stem cells. It is known that in Parkinson's Disease, certain brain cells in a specific area of the brain die, so using regenerative medicine methods to treat this disease is relatively less complicated. We inject cells wrapped in our special gel, which is also produced from the patient him or herself (so far, only animals), and this helps the cells stay alive until they are absorbed in the right place.

"As for motor neurons, I don't know whether this is really the most challenging area. We are already transplanting our gel in animals whose spinal column was cut. There's no need for blood vessels, and the transplant is in a very specific location. We can already see that the state of the rat improves. (shows a video clip) Here it's dragging its leg, and here it's dragging it a lot less."

Is there another group in the world that has managed to do this?

"When we publish the full results, we'll be among the first."

What have you succeeded in doing that others did not manage to do?

"The ability to generate stem cells from the patient the main advance. It has been 10 years since this technology was discovered and approved for use. Another special thing is the gel, which enables cells to work together, but within material that is familiar to the body, which prevents rejection.

"When isolated stem cells are injected into the spinal column, 95% of them die, because they don't manage to connect with each other. Researchers first tried to solve this by injecting a higher dosage of cells, but that isn't so good, because there are so many cells in a given area that are in the process of dying. Regeneration is more effective when we use the gel. The cells themselves get support until they are integrated in the area."

What about the possibility of creating an entire brain?

"We're not close to creating an entire brain. The biological-technical challenge here is enormous, because no one knows how the brain really works."

What is really the barrier now to eternal life?

"Eternal life? I don't know whether people want eternal life. In any case, we're not there."

The Internet of Tissues

In addition to the tissue designed to replace existing tissue in the body, bionic tissue is also being built in Dvir's lab designed to be even better than the body's tissue. "We're combining electronics, sensors, and new materials in issues, and not just because it's cool to combine disciplines. We started doing it so that we'd be able to get constant feedback about the functioning of the hearth tissue we built. We created a system of many small sensors that can tell us at any given time about the cells' activity: whether they're contracting, whether they're doing it in synchronization, and whether there are problems. The research was revolutionary and was published in the Nature periodical, but we didn't stop there.

"We wanted to also have the option of intervention in a case in which the cells do not contract the way that they ought to, if there's an inflammation. Today, we have tissue capable of providing electrical stimulation when needed (as a replacement for a pacemaker), causing tissue to release anti-inflammatory factors, or signaling cells to supply more oxygen. The goal is to reach a situation in which we'll be able to prevent in advance another heart attack in a patient in which the tissue has been transplanted."

It is like the Internet of Things, only for tissues

"Right. Every transplant patient can install a mobile phone app in which he or she gets a constant report on the functioning of his or her tissue, and can intervene when necessary. These systems will probably also be hacked. Check Point will get more work. This vision is in the future. The patch will be able to regulate itself, even without intervention. At the same time, we're planning now a printing of an entire heart completely networked with electronics."

Before you build an entire heart able to cure itself, isn't there a more urgent need now for simple tissue like a retina? Kidneys?

"We're working on retinas with researchers from Ichilov Hospital, and also on the sight nerve. There are laboratories working on cartilage, bone, and blood vessels. Atala is making advances in kidneys. The lung is an organ I want to deal with, but my laboratory is limited in both room and budget."

"Researchers from various fields are already now working with me in the laboratory: chemistry, engineering, and biology. We're cooperating with both hospital doctors and doctors working here in the laboratory," Dvir says. "The goal is for the center to cooperate regularly with doctors raising various problems and looking for various technological solutions. A while ago, an ENT doctor came to me and asked about the possibility of replacing the trachea for people being operated on, or who had tumors in their trachea. It's now possible that this doctor will stop working in a clinic and start working here in the laboratory. We want a lot of cooperative efforts of this type. The institute also plans to recruit Israeli and other researchers now working at leading overseas universities."

Dvir's gratitude to Sagol, is not limited to his role as a donor. "Sami is a man with a vision who reads so much and knows so much about diverse fields. It's a pleasure to interact with him," Dvir says. "After we met at the university, he learned this field, and realized that he wanted to move it ahead. Without him, we couldn't even think about such a center, because it requires big money."

Published by Globes, Israel business news - en.globes.co.il - on April 17, 2019

© Copyright of Globes Publisher Itonut (1983) Ltd. 2019

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Prof. Tal Dvir Photo: Eyal Izhar
Prof. Tal Dvir Photo: Eyal Izhar
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