Victoria Zavyalova, Russia Beyond THe headlines

Honey, I printed a thyroid gland

Russian scientists are planning the first 3D-printed organ transplant on mice. Humans could be next.
Russia's 3D Bioprinting Solutions laboratory, the first facility to successfully print a mouse's thyroid gland, is getting ready to transplant artificial organs to living mice. If successful, the experiment could pave the way for the production of 3D-printed human glands.

Back in March 2015 Moscow-based 3D Bioprinting Solutions lab (founded in 2013) became the first such facility to successfully bioprint a thyroid gland – or, to quote the scientists themselves, a "construct" of the organ. Now the researchers are preparing the transplant of several of these glands into living mice. The results of the experiment will be made public in July 2015 at the Second International Congress on Bioprinting in Singapore. The head researcher Vladimir Mironov told RBTH that he is expecting positive results.

Scientists claim they are ready to start the 3D printing of human thyroid glands. All they need for the first batch are follicular cells, which are responsible for the production and secretion of thyroid hormones.
Researchers of the 3D Printing Solutions Lab, Moscow, Russia
According to the World Health Organization (WHO), 665 million people in the world are affected by thyroid disorders. In Russia, about 140,000 people suffer from various types of thyroid disease and each year 10,000 Russian citizens have to undergo a thyroidectomy, or the surgical removal of the gland.

Thyroid dysfunction caused by cancer cannot be treated with pharmacological therapy. Not even a donor organ transplantation can help in this case, says Andrey Polyakov, the head of the microsurgery department at the Moscow Oncology Research Institute. "The reason for this is that the patients who receive organ transplants have to undergo immunosuppression therapy that can in turn speed up the development of cancer cells," Polyakov explains. According to him, the transplantation of 3D printed organs and tissues can be conducted without immunosuppression.

665 million people in the world are affected by thyroid disorders

Printing "constructs"

Scientists at 3D Bioprinting Solutions refer to the gland they created not as an organ, but as an "organ construct."
It should come as no surprise that a 3D printed gland does not fit in the conventional biological hierarchy. The existing system recognizes only molecules, tissues, organs, organ systems and organisms. The object printed at 3D Bioprinting Solutions is therefore unclassifiable.

"A tissue is a group of cells of the same kind," says Mironov. "An organ is a group of tissues. The construct we created is closer to an organ, as it consists of several types of tissues, has blood vessels and can function at the level of an organism."

The scientists chose a thyroid gland as this organ is relatively simple, making it an uncomplicated subject for research work. Besides, it was the first organ transplanted from one human being to another.

Alexander Mitryashkin, engineer, 3D Bioprinting Solutions
Elena Bulanova, Manager, 3D Printing Solution Lab

Layer by layer

The researchers adapted the existing technology of 3D printing to work with living cells
The researchers at 3D Bioprinting Solutions took the existing technology of 3D printing currently used to work with diverse materials like plastic, ceramics and metal, and adapted it to work with living cells. The process itself is called 'layer-by-layer production'.

Bioprinting looks like this: at first, the printer sprays a thin layer of gel made of fibrin, a protein involved in the clotting of blood. Embedded in the gel are microscopic spheres consisting of tissue, which subsequently form a three-dimensional structure.

Mironov came up with the idea of bioprinting when he discovered that separate ring moieties in a chicken embryo's heart was able to merge to form a tube. He understood that it was possible to form living tissues out of separate cells and groups of cells.

About Vladimir Mironov

Tissue engineering specialist and inventor of a new 3D organ printing technology. Graduated from the medical faculty of the Ivanovo State Medical University in 1977. Currently a professor at Virginia Commonwealth University, Department of Chemical and Life Science Engineering. Co-founder of two medical startups in the United States: Cardiovascular Tissue Technology and Cuspis.

Vladimir Mironov, inventor

Simpler Than You Think

A bioprinter is a simple robot that can move in three directions

The original bioprinter created by 3D Printing Solutions consists of three basic elements: a mechanical positioning device, a dispenser and a central processing unit (CPU). Essentially, a bioprinter is a simple robot that can move in three directions. It is equipped with an automated syringe that can dispense either fibrin gel or tissue spheroids.

There are, of course, other companies in the world aiming to commercialize 3D bioprinting technology, such as Organovo in the United States, Cyfuse in Japan and Regenhu in Switzerland. The technology offered by 3D Bioprinting Solutions is unique because aside from the cell-based gel, the Russian lab uses the tissue spheroids mentioned above as "building blocks."

"Last year we filed a patent for our bioprinter design and for the methods of printing we invented," Mironov told RBTH.

The original bioprinter created by 3D Printing Solutions

Mice pioneers

The printed 'organ constructs' are soon to be transplanted into mice.
The printed "organ constructs" will soon be transplanted to mice. The procedure will be no different than a regular organ transplant. The mice used in the experiment have already been subjected to a treatment of radioactive iodine that shut down their thyroid glands, causing hormone deficiency.

Scientists will monitor the mice over the course of a month to determine if their thyroid glands are no longer functioning. "We will review the levels of thyroxine that are supposed to go down significantly because of the suppression of thyroid activity," reports Elena Bulanova of 3D Printing Solutions.

The researchers will transplant the printed glands to the mice and will observe them to see if the hormone levels are restored. If they are, this will mean the artificial organs work. It will take a month for the grafts to be integrated completely into the bodies of the mice.

The experiment will involve outbred mice of the so-called CD1 strain. "Those mice have minimal variations in morphology and behavior," says Bulanova. "Twelve animals will be used in total; six of them will form the control group, which will not receive the transplant, and the other six will get the grafts."

Chances of success

The printed organ constructs are already widely used by pharmaceutical companies
"We are certain that the gland is functional," says Mironov. "In fact, we are mostly concerned by the perspective of the graft hyperactivity, which can cause hyperthyroidism." According to Mironov, the laboratory conducted all necessary theoretical calculations and morphometric studies before beginning the experiment.

Elizaveta Kudan, senior research associate, 3D Bioprinting Solutions
"We are certain that the gland is functional"
The printed organ constructs are already widely used by pharmaceutical companies for toxicological studies, says Youssef Hesuani, the executive director of 3D Printing Solutions. For instance, California-based Organovo cooperated with the international healthcare company F. Hoffmann-La Roche AG to test an unnamed medication. "We know that while the drug showed no toxicity during the tests involving a monolayer of cells, the experiments on a 3D liver construct provided the opposite results," Hesouani told RBTH.

Youssef Hesuani
Executive director of 3D Printing Solutions
A Q&A with Vladimir Mironov, 3D Bioprinting Solutions: "Printed organs will become affordable with time"
Which organs do you expect to be printed in the next two or three years?

V.M.: Thyroid glands, blood vessels, skin and hair, as well as cartilage, bone and adipose tissue. Some organs from this list have in fact already been printed.

By your estimates, a printed organ will cost between 200,000 and 250,000 dollars. Does this mean that only the wealthy will be able to afford them?

V.M.: The history of technological progress shows that once a hi-tech product enters mass production by automated means and starts to be widely used on the market, it becomes tens, scratch that, thousands of times cheaper. So there is no doubt that 3D printed organs will become more affordable with time.

Do you expect foreign clients?

V.M.: Yes, our product is capable of entering the global market. In China alone there are 1.5 million people in need of an organ transplant.

Do you think Russia will be able to create an infrastructure for printed organ transplantation?

V.M.: It is possible, yes. But the government will need to cooperate with private businesses. This will require millions of dollars of investment, but will in time allow the healthcare system to save a lot of money on the treatment of patients. Besides, a country that does not invest in the development of such technologies today will later have to buy it from others, which will be much more expensive.

Short history of bioprinting

The scientists promised to create a fully-functional human liver by 2019

In 2013 a team led by Takanori Takebe, a stem-cell biologist at Yokohama City University in Japan, successfully transplanted tiny "liver buds" constructed from human stem cells to mice. The scientists have promised to create a fully functional human liver by 2019.

In 2014 Sabine Costagliola, a researcher at the Free University of Brussels, regenerated thyroid tissue using the embryonic stem cells of mice. The tissue was later transplanted to a mouse and started producing thyroxine. Dr. Terry Davies, an endocrinologist from New York City, has recently managed to do the same – regenerate thyroid tissue – with human embryonic stem cells.

Researchers at 3D Printing Solutions are currently waiting for the results of research involving the regeneration of thyroid tissue from induced pluripotent stem cells – i.e. adult cells that have been genetically reprogrammed to an embryonic stem-cell state.

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Story by Victoria Zavyalova. Edited by Joseph Crescente & Vsevolod Pulya.
Photos provided by 3D Bioprinting Solutions lab.
Video edited by Vladimir Stakheev.
Design and layout by Victoria Zavyalova & Vsevolod Pulya.
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