A possible weapon against the pandemic: print human tissue

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As the shortage of personal protective equipment persists during the coronavirus pandemic, 3D printing has helped alleviate some of the gaps. But Anthony Atala, the director of the Wake Forest Institute for Regenerative Medicine, and his team are using the process in a more innovative way: creating tiny replicas of human organs, some as small as a pinhead, to test drugs to fight Covid. 19.

The team is building miniature lungs and colonies, two organs particularly affected by the coronavirus, and then e-mailing them for analysis in a biosecurity lab at George Mason University in Fairfax, Virginia. While they initially created some of the so-called organoids by With the help of a pipette, they start printing them to scale for research as the pandemic continues to escalate.

In recent years, Dr. Atala’s institute had already printed these small clusters of cells to assess the efficacy of drugs against bacteria and infectious diseases like the Zika virus, “but we never thought that we would be considering this for a pandemic.” . His team has the ability to print “thousands per hour,” he said from his laboratory in Winston-Salem, NC.

The process of building human tissue in this way is a form of bioprinting. While its use in humans is still years away, researchers are perfecting methods for testing drugs and ultimately creating full-size organs and skin for transplants. Researchers are making progress on skin impression, essential for burn victims; managing diseases such as diabetes where wound healing is difficult and to test cosmetics without harming animals or, of course, humans.

“Even to us it sometimes feels like science fiction,” said Akhilesh Gaharwar, who runs an interdisciplinary laboratory in the biomedical engineering department at Texas A&M University that focuses on bioprinting and other approaches to regenerative medicine.

The importance of bioprinting for pharmaceutical analysis is paramount now, not only for potential Covid-19 treatments, but also for testing treatments for cancer and other diseases. Dr. Atala says that organoids allow researchers to analyze the impact of a drug on an organ “without the noise” of an individual’s metabolism.

He cited Rezulin, a popular diabetes drug withdrawn from the market in 2000 after there was evidence of liver failure. His lab tested an archived version of the drug, and Dr. Atala said that within two weeks, liver toxicity became apparent. How is the difference explained? An organoid replicates an organ in its purest form and offers data points that might not occur in clinical trials, he said, adding that the test is additive, rather than replacing, clinical trials.

Tests on bioprinted skin or other miniature organs can also more easily determine which drugs that work in animals like rats might not work well in people.

“The Three-dimensional models can bypass animal testing and strengthen the path from the laboratory to the clinic, ”said Dr. Gaharwar. This is important for both consumer goods and pharmaceuticals; Since 2013, the European Union, for example, has banned cosmetic companies from testing products on animals.

The basis for a printed organ is known as a scaffold, made from biodegradable materials. To provide nutrition to the organoid, microscopic channels only 50 microns in diameter, about half the size of a human hair, are included in the scaffold. Once completed, the “biolink,” a liquid combination of cells and hydrogel that turns to gelatin, prints on the scaffold “like a layer cake,” said Dr. Atala.

Another important part of the process is building blood vessels as part of the impression. Pankaj Karande, assistant professor of chemical and biological engineering at the Rensselaer Polytechnic Institute, has been experimenting with skin imprinting since 2014 and was recently successful in this step.

Using a cell known as fibroblasts, which helps with growth, along with collagen, as scaffolding, researchers at the institute printed the epidermis and dermis, the first two layers of skin. (The hypodermis is the third layer). “It turns out that skin cells don’t mind being cut,” Dr. Karande said, and they could eventually survive.

But his work hit an obstacle: Without incorporating blood vessels, the skin eventually falls off. In collaboration with Jordan Pober and W. Mark Saltzman of Yale University, they finally managed to build all three layers of human skin, as well as the vasculature or blood vessels, which Dr. Karande said was essential for the survival of the skin after being grafted.

All three began experimenting with the integration of human endothelial cells, which line blood vessels, and human pericytic cells, which surround endothelial cells, in the skin when it was printed. Finally, after much trial and error, they were able to integrate the blood vessels with the skin and found that connections were formed between the new and existing blood vessels.

While the work is preliminary, tested in mice, Dr. Karande said he was hopeful that success in integrated skin and vasculature impression would lay the foundation for successful human grafting eventually.

The research, according to Dr. Karande, is thorough and involves a lot of trial and error. “We have Plan A, which we often know will not work, and then we move on to the list. We can often write about what works in five pages, but we have 5,000 pages of what didn’t work, “he added.

Dr. Gaharwar’s lab is also investigating whether human bone tissue can be imprinted for an eventual transplant. His hope, he says, is that in the future, the patient’s radiographic scans can be translated to the exact shape required for implantation, especially important in craniofacial defect repair where the necessary curvature may be difficult to recreate.

Like Dr. Gaharwar, Dr. Karande says personalization is important. He says his work has already shown that skin can be manufactured to match an individual’s color. And, because the skin is also critical in regulating body temperature, it is also working to design sweat glands in the skin, along with the hair follicles.

“When we graft, we want to be able to recreate the full functionality of the skin,” said Dr. Karande. And by using a patient’s cells, rather than a donor, the risk of rejection is minimized or completely eliminated.

Not surprisingly, researchers are also exploring evidence data collection. The Wake Forest team is partnering with technology company Oracle to capture organoid data and analyze it with artificial intelligence. The project, generally known as the body-on-a-chip system, involves printing living tissue on a microchip to allow the toxicity and efficacy of the drugs to be studied even before clinical trials begin. The chips can be the size of a dime or a quarter, which is large enough to hold 10 to 12 miniature organs.

“We work extensively with researchers, pharmaceutical companies, and biotech companies, and we are trying to sow breakthroughs as quickly as possible, analyze data, and develop new drugs,” said Rebecca Laborde, the chief principal scientist in Oracle’s health science division. . “This is the most exciting project I have worked on in a long time.”