The Granada laboratory where life is printed
Juan Antonio Marchal, principal investigator of the group of Advanced Therapies: Differentiation, Regeneration and Cancer of the ibs.GRANADA, leads a multidisciplinary team capable of bioprinting organs and tumors from stem cells in 3D structures and chips. A technique called to revolutionize medicine.
With a paper printer we get the recipe. With a 3D printer, plates and cutlery. And with a 3D bioprinter, life. "The future? This is already here!” Juan Antonio Marchal (Algarinejo, 1967), leader of the research group "Advanced Therapies: Differentiation, Regeneration and Cancer" at ibs.GRANADA, speaks with contagious passion about his work. He is a doctor, but his team includes biologists, biochemists, pharmacists, biotechnologists, biomedical engineers, civil engineers, physicists, mathematicians, computer scientists... All united by an ambitious, disturbing and inspiring goal that, until recently, sounded like science fiction. «I always say that here we dedicate ourselves to both sides of the force, like the Jedi of "Star Wars" -explains Marchal, amused-. The light side, with normal stem cells; but also the dark side, with tumor stem cells». What do they do then? Pay attention because it is amazing. And it all happens at the Biomedical Research Center of the Health Technology Park. In Granada.
Imagine that we remove the ink cartridges from a printer and, instead of red, yellow and blue, we load it with a mixture of stem cells and a synthetic material similar to plastic. We press the button and, voilà, the machine creates a human organ out of nothing. Well, it turns out that this simplistic reduction, this kind of “Thermomix” of shamans and alchemies, is very real. Stem cells are the essence of our life. They have the ability to become any type of cell in the body, making them ideal for regenerating or repairing diseased tissues and organs. The possibilities are endless. "We had a great knowledge of stem cells and, with the advent of 3D bioprinting, we began to adapt our projects." This is how Regemat 3D was born, a UGR spin-off company closely linked to Marchal's group.
When there is knee osteoarthritis, what wears out is the cartilage, a kind of protective sheath that, when missing, causes the bone to collide with the bone and cause intense pain. A possible solution would be to place a prosthesis made of some resistant material. But what if tissue could be regenerated? 'We use stem cells to regenerate cartilage. The process, told in this way, may seem very simple. But it is something tremendously complex. Let's see:
Marchal's team uses mesenchymal stem cells, which are literally obtained from what we have left over. “When they do liposuction, they bring us the fat from the abdomen and we reuse it. From there we extract millions of cells with regeneration capacity.” With the "recycling" of these cells they produce a powder that, after a chemical process, turns it into a gel. "And that's how we get our inks for the bioprinter." Natural and biocompatible materials are used in this process, such as alginate (so fashionable in modern cuisine for spherification), gelatin, agarose, hyaluronic acid and collagen.
The UGR has a patent for the biocompatible use of filaflex, a flexible and resistant material that can be integrated into humans. Of course, this genetic concoction needs a support to enter the human body. Here come the 3D structures, geometric figures that are "filled" with stem cells and that must be made of a material compatible with human life, that is, that the body does not expel them. Marchal takes between his fingers a small rose window that seems to be made of plastic and shows it to the air. "Is this plastic? No. It is filaflex. A flexible and resistant material that already existed and is used in insoles or shoe soles, but that was not known to be integrated into humans. We, the UGR, have the patent for biocompatible use”.
Conclution? "It's as if we made a hole in the wall," explains Marchal. To repair it we could put a block and plaster or, also, we could introduce something similar to the composition of the wall. We do this with 3D bioprinting, using biotinks in living 3D structures, similar to the tissue we want to repair, with biocompatible materials that the body accepts. This technique is already used in the world's leading laboratories, printing ears, blood vessels or even mini-hearts. Imagine printing a string of mini-hearts to test drugs. Or, if you have a heart attack, be able to 3D print a patch with stem cells to regenerate the ventriloquist.
Paula Pleguezuelos, with the hydrogel airbrush. Paula Pleguezuelos, with the hydrogel airbrush. / AAmong the group's projects there is a collaboration with the Cellular Therapy Unit of the Virgen de las Nieves Hospital to print skin. «It will be very useful for large burns. Instead of putting layers of skin, we can put full skin, with its three layers. Marchal calls Paula Pleguezuelos, a researcher who finished her thesis last year on an airbrush to regenerate the skin. "What we do is test hydrogels with cells to treat skin pathologies," he says, while showing the airbrush that looks like something out of a "Star Trek" ship. We spread the gel over the wound to create a layer that would help regenerate the skin.”
If stem cells are light, cancer stem cells are darkness. Why would anyone want to bioprint a tumor in 3D? "Now imagine breast cancer," Marchal continues. The patient is biopsied and given a sample. We isolate the cells and print the tumor. We have the real tumor in three dimensions, so we can test there whether a treatment is going to be effective or not, or see if it will have serious side effects on the patient. Do you understand what we can save? ». Cancer stem cells are the generators of cancer itself, resistant to chemotherapy and, therefore, responsible for relapses and metastases. Understanding them is essential to present battle. What if a real tumor, a patient's tumor, could be replicated in a technological device to analyze its possible evolution? Keep up, we're not done.
"Our last step was to print tumors on a chip." A chip, like that of a computer? Yes, a chip. We can bio-print chips to simulate organs and tumors in such a space, "says Marchal, forming the hollow of a chickpea with his fingers. The Junta de Andalucía has named them a project of excellence and has granted them a significant investment from European funds (Feder). “If in such a small chip we are able to generate models of metastasis, antimetastatic drugs could also be tested. There are tremendous possibilities.
"Our last step was to print tumors on a chip" But there is one more step: multi-organ on a chip. "We printed a chip with a breast cancer," continues the doctor. And we connect it to other chips that emulate the organs to which metastasis normally goes: the lung, the liver ... We could see where it is implanted and study the phenomenon. Anyway - Marchal breathes, after the explanation -, do you want to see the machines? ».
Carlos Chocarro, one of the team's researchers and the great master of 3D printing, introduces us to RegenHu, the Ferrari of bioprinters. Valued at 150.000 euros, it is capable of printing with extraordinary precision, controlling all processes from the computer. "With this we are making the three layers of the skin," he points out. On the other side of a perfectly insulated room and in very demanding hygienic conditions, is the researcher Julia López, who works with a bioprinter with ultraviolet light. “Here we make the organs and tumors on a chip. The chips are these - shows a small transparent box-. Here - he points to a kind of ball in the middle - we would place the gel with the cells. And along these lines - two tiny tubes coming out of the ball - we simulate the blood flow ».
Marchal looks at cancer cells under the microscope and then takes a ball with the same shape out of the drawer. "This is a tumor," he says, very seriously, "and I am a doctor. My obsession is that whatever we do here has application to patients as soon as possible. And this - he waves his arms around, pointing to his team - goes faster and faster ».