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Interview

Gabriel Liguori: A bioartificial heart on the horizon

The creator of bioengineering startup TissueLabs discusses how he has sought to overcome the challenges involved in the construction of human tissues and organs with 3D printers

Liguori: clinical trials with bioartificial hearts are expected to begin within 10 to 15 years

Tácia Liguori

The year 2020 and the immense challenges caused by the global coronavirus pandemic was also time of success for Gabriel Liguori, a 31-year-old São Paulo doctor, researcher, and entrepreneur. His work at TissueLabs, a startup he created with computer engineer Emerson Moretto in 2019, was a success and achieved international recognition.

Last December, Liguori was named one of the most innovative young people in Latin America by MIT Technology Review, published by the Massachusetts Institute of Technology, in the United States. He was included on the list in the “Visionaries” category, which  honors young people 35 or younger for their innovative ideas.

Liguori’s company, which received support from FAPESP, specializes in the development of artificial organs and tissues built from stem cells and biomaterials. In 2020, TissueLabs more than tripled in size and, according to the researcher, has already become the nation’s leader in the field of 3D bioprinting, competing with about half a dozen other domestic and foreign companies. In this interview Liguori explains to Pesquisa FAPESP  why, envisioning the possibility of starting clinical trials with bioartificial hearts within 10 to 15 years, he decided to make the move from academia to the private sector to achieve this goal, and tells us how a congenital health problem ended up defining his professional future.

Did being put on MIT’s list of young innovators surprise you?
In a way, yes. The process is a bit more involved than MIT simply sending you an email telling you that you’ve been chosen. First, they identified my profile—I have no idea how—and then got in touch through LinkedIn, asking for information about the company and my work. I replied, still unsure if the inclusion of my name on the list was already certain or if they were still in the middle of the selection process. A few months later, I received an email saying that I had been selected as one of the 35 most innovative entrepreneurs in Latin America, in the category of visionaries—of young people who have ambitious future projects. The first contact was a surprise; after that, I was already expecting an answer, positive or negative.

The recognition was awarded for your ambitious goal to create an artificial heart using three-dimensional printing of stem cells. How is the project going?
Yes, in fact, this is my focus and was the reason I received the award. Manufacturing artificial organs—in particular a heart for transplantation—is the long-term goal of our company, TissueLabs. It is difficult, however, to work exclusively on scientific development for long periods without needing to hold funding rounds on a regular basis. And since it’s a 10 to 15 year project, we need to generate a source of income for the company to be sustainable. So, we’ve created a business model—which we call a dual business model. At the same time that we’re doing research with the goal of manufacturing organs and tissues for clinical application a few years from now, much of what we develop along the way is put on the market in the form of products. In order to manufacture the first artificial heart, we need to develop technologies in several areas that precede the manufacture of the heart itself.

For example?
When we talk about 3D bioprinting, we’re referring to a 3D bioprinter that
uses a biomaterial to build three-dimensional tissues. We needed a printer and materials that were in line with what we believed would be ideal for manufacturing these organs and tissues. With support from FAPESP’s Research for Innovation in Small Businesses program [RISB, or PIPE in the Portuguese acronym], we developed hydrogels on an industrial scale—biomaterials for the manufacture of organs and tissues—something we had already done on a pilot scale. Today we produce hydrogels on the scale of liters, which is a large quantity. In 2020, we also received an angel investment of R$1.5 million, which allowed us to expand our horizons. With that, we put our second product on the market , the 3D bioprinter called TissueStart. In addition to selling TissueStart to interested researchers, we use it internally on our own projects.

I was always interested in cardiovascular surgery. I was born with a congenital cardiopathy and was operated on when I was two years old

How far are you from finishing the artificial heart?
A long way. It’s important that be said in order to avoid false expectations. Sometimes, the headlines give the impression that we’re going to put them on the market and implant a heart by next year. It’s just not like that. This is a project that will require a lot of time. We’ve talked about needing at least a decade or more until we begin clinical trials. So, it’s not something that will be in the headlines anytime soon. It’s a challenge that we’re quite well prepared for. We have the technologies, the knowledge and partnerships, and a very focused, high-quality team. Of course, it will still require a lot of development.

Do any other companies already produce bioartifical organs?
Today, there isn’t one company in the world that produces bioartificial organs for use in humans. Sometimes, we hear about mechanical ventricles or artificial kidneys for dialysis, for example, but bioartificial organs manufactured in the laboratory aren’t yet a reality. There hasn’t been even one clinical study, in humans, in this area. The projects are at most being done on an experimental scale, still in animal testing.

What’s your career path been like up to this point?
I’m a doctor by training. I graduated from USP [University of São Paulo] and, as soon as I finished college, I decided to continue on in the research field. After getting my doctorate in Holland, where I stayed for two years, I returned to Brazil and had the opportunity to work at InCor [The Heart Institute], as a researcher. We created a tissue engineering laboratory there and, some time later, I realized that this project needed to go to the private sector because we had big ambitions that demanded amounts of resources that neither academia nor the government itself, through funding agencies like FAPESP, are able to provide. Having that clarity was one of the reasons that compelled me to move to entrepreneurship. I founded TissueLabs in 2019 with my partner, Emerson Moretto, who’s an engineer. We had already worked together at the university and it was a  great experience. FAPESP helped us to take the first steps. That same year, we received support from the RISB program, which gave us the security to move on. We put in some of our own resources, but of course we didn’t have the capital to develop super-expensive research activities. When the FAPESP funding ended in November 2019 we had to walk on our own legs. We brought to market the first products related to tissue engineering [hydrogels and the TissueStart bioprinter].

How did you become interested in this field of research?
During my undergraduate studies I was always very interested in cardiovascular surgery. I have a personal history with this because I was born with a congenital heart disease. At the age of two I was operated on at InCor, and since then I’ve continued to be a patient at the institution. Since I entered the School of Medicine at USP, which runs InCor, I’ve been involved in the area of cardiac surgery, especially pediatric surgery. I did my undergraduate research in this area, participated in congresses, and published books. My idea was to be a research surgeon, which is almost a figure of medical mythology, because very few surgeons are able to dedicate themselves to research. When I went to work on my doctorate I had no intention of actually abandoning medical practice; the idea was to do it temporarily, then return and combine the two. When I selected my specialty, I opted for regenerative medicine, which tissue engineering is a part of.

What exactly is tissue engineering?
It’s a new area of medicine, which isn’t yet practical in clinical practice in any relevant way, but which will become so in the coming years. It uses cells, mainly stem cells, for organ regeneration. This can be done with either cell therapy or with tissue engineering—which means manufacturing a new organ for implantation. I saw that this area had potential, especially for pediatric cardiac surgery. Today, when a child has a heart disease, we try to fix the heart by putting in a tube here, doing a repair there, or another fix over there. One can say it works well; I even have tubes and patches of this sort. But, over time, some of these children may have problems and need a transplant. We managed to give the patient quality of life, but we didn’t actually cure them. At least, not all of them. When I returned from getting my doctorate, I was already so involved and enchanted with this field that it felt natural to give up the idea of pursuing a career as a surgeon and focus exclusively on research.

Léo Ramos Chaves The TissueStart bioprinter was designed to manufacture complex three-dimensional human tissuesLéo Ramos Chaves

What does TissueLabs do?
TissueLabs is a very young company; we just passed the two-year mark at the end of January. The company has a research front and a product development and marketing front. On one hand, we’re researching technologies that allow organs to be developed in the laboratory. On the other hand, we use these developments to launch products to the market, such as our 3D bioprinter TissueStart. It was designed to manufacture complex three-dimensional human tissues, formed by more than one type of cell. This is the case with the myocardium [heart muscle], which combines muscle and endothelial cells. Another item in the company’s portfolio is the MatriXpec hydrogels, the raw material that goes into the bioprinter to manufacture the tissues. The hydrogels contain hundreds of specific extracellular matrix proteins derived from native tissue and are available for 15 different tissue types. Our third product, MatriCoat, is a solution containing extracellular matrix proteins. When the researcher places this solution in culture plates or flasks, the proteins contained in it bind to the surfaces of these containers. As a result, they transform non-representative synthetic materials [the culture plates and flasks] into an environment that’s a little more like the human body, making the experiment to be conducted there a little more representative of a real environment. And finally, we also offer the MatriWell platform for culturing epithelial cells. With an initial focus on the lungs, it was created at the beginning of the pandemic and distributed free of charge to a few researchers. We’re receiving the first results now. Recently, we obtained support from the Brazilian Funding Authority for Studies and Projects [FINEP] to expand this project so that more scientists, in Brazil and around the world, can use the platform. We want to make the same technologies that we use internally available to other researchers, both in academia and industry. We say that if we’re unable to make the first artificial heart, but someone else does it using our products, we’ll be just as happy.

What is the main challenge to building artificial organs with 3D printers?
Manufacturing these three-dimensional artificial tissues has one major limitation, which is the maturation of the tissues. Sometimes, we’re able to print a mouse heart using stem cells—the extracellular matrix—but it’s far from being a functional organ. This is because the original tissue, in a native heart, has detail that we haven’t yet been able to reproduce via 3D printing. The first of these is cell density. In today’s 3D printers, we work at around 10 million cells per milliliter. A native heart, in the same space and volume, of 1 cubic centimeter [cm3], has almost 1 billion cells, up to 100 times more than we can reproduce in vitro today.

What are the other challenges?
Cell alignment. Cardiomyocytes, which are the cells that contract the heart, are aligned and have a very particular geometric position. These cells must be connected and aligned in such a way that when they contract they generate a force vector from within the heart to the blood vessels. It’s useless, for example, to have a lot of cells inside your printed heart contracting, but each to one side. If this happens, a so-called fibrillation occurs. The heart beats aimlessly. There is also a third point of difficulty to be overcome: vascularization. If there is no vascularization in the artificial organ, oxygen won’t arrive and the tissue dies. There’s no point in building a little three or four cubic centimeter mouse heart, if it will die as a whole, if only the outermost two millimeters are going to remain alive. Vascularity is a fundamental point, one which we’ve also been studying.

Do you plan to develop other organs?
We have a preference for, and familiarity with, the cardiovascular system, mainly due to the team’s background. Most likely, we will develop blood vessels and heart valves. But we haven’t closed our eyes to other areas.

Does the company also produce organs for testing new drugs, instead of using animal models?
Although it will take us many years to get organs for transplantation on the market, we’ve already managed to use our technology for this other type of application, which is the development of three-dimensional, in-vitro models to replace some animal models in drug development, screening [disease tracking], and in personalized medicine. For example, if a patient has a heart disease, instead of testing various drugs directly on them, we can create a small piece of their individual heart, based on their own cells, and investigate which medications work best before giving them the medicine.

How is your startup positioned in the market?
We are leaders in Brazil in 3D bioprinting, both in the supply of equipment and in biomaterials. More than 20 laboratories in the country use our printer, TissueStart. About 70% to 80% of our clients are academic researchers, most of them Brazilian. But there are also scientists from the United States, Switzerland, Portugal, and Mexico. We have customers in industry, in startups, and large companies. One of them, from outside Brazil, acquired our equipment for developing laboratory meat. I believe there is room for growth. We expect to have more than a hundred laboratories around the country working with our products in the coming years. We want more people to know about TissueLabs, because we offer solutions that give a new perspective to research in the field. Today, 95% of biomedical research in the world is done in two dimensions, in the famous Petri dishes. We know that these results aren’t representative of the human body, of the nature of the organism. So, the proposal is to bring biomedical, in-vitro studies to 3D. In the next ten years there will be a great movement of scientists moving from the two to the three-dimensional.

Projects
1. Characterization of hydrogels mimetic to the extracellular matrix derived from different tissues and their influence on cellular behavior (no. 19/22468-0); Grant Mechanism Research for Innovation in Small Businesses program (RISB/PIPE); Principal Investigator Gabriel Liguori (TissueLabs); Investment R$821,306.56.
2. Optimization and standardization of the manufacture of a hydrogel mimetic to the extracellular matrix for applications in regenerative medicine, tissue engineering, and other in-vitro research (no. 18/15450-5); Grant Mechanism Research for Innovation in Small Businesses program (RISB/PIPE) Principal Investigator Gabriel Liguori (TissueLabs); Investment R$96,292.65.

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