Organ cultivation (Bioprinting, bioprinting)

Main article: 3D printing in medicine

Recovery instead of artificial prostheses

Medicine has always been a driver of technology development. Since ancient times, people have always tried to come up with something to restore the quality of life. In ancient Rome, a prosthesis was inserted into the place of the fallen tooth - this discovery was made by archaeologists.

So now, when we have a tooth, we go to the dentist and get about the same prosthesis; only it is made of titanium or ceramics, but the idea remained ancient Roman - to take and replace some part of the human body with an artificial one. At the same time, prostheses - dental, articular or artificial heart valves - over time require replacement, which means repeated complex surgery.

The idea of ​ ​ all regenerative medicine is to try to move away from using the traditional approach, when we insert artificial tissue instead of damaged tissue, which wears out over time. This area was born at the junction of several areas - biology, medicine, physics, chemistry, engineering, mathematics. The challenge is to trigger the process of tissue repair from within, so the regenerative medicine paradigm is referred to as "inside cure." This definition most capaciously shows the whole idea of ​ ​ this direction.

Extrusion and laser printing

There are two big directions in bioprinting. The first is extrusion printing. The first printer that allowed printing with cellular spheroids was developed and created in the Russian company 3D Bioprinting Solutions. There is also a laser bioprinter where a laser beam induces cell transfer from donor to acceptor plate.

Frame models: plastic in the body is replaced by living tissue

For 2019, it is too early to say that bioprinters will be used in clinics. So far, we are talking about the concept of a bio-factory, when from a computer model, using all the achievements (cellular materials for active compounds, bioreactors), we get tissue at the output that can be transplanted in the future.

After the structures are implanted in the animals, the plastic is gradually replaced by a natural structural matrix of proteins produced by the cells. Also, blood vessels and nerve tissue are gradually introduced into the implants.

The results, according to scientists, were promising. The auricles planted in mice retained their shape two months later, and also in them the content of glycozoaminoglycans, which are part of the cell matrix, increased by 20%. Muscle tissue stretched along the support structure also retained its mechanical characteristics two weeks later.

Frameless approaches: bioprinting

Another direction is frameless approaches using three-dimensional cell systems. These are technologies of tissue spheroids and cell beds, when without the use of materials we create a three-dimensional structure using different approaches. The main idea is that no additional artificial materials are added to this structure.

The essence of the bioprinting method is that the future organ is formed from two main components: living cells and a cell matrix that simulates the conditions of the intercellular environment and connective tissue.

Vladimir Aleksandrovich Mironov is the scientific director of the 3D Bioprinting Solutions laboratory, professor at the University of Virginia, candidate of medical sciences. A tissue engineer, the author of the first publication on organ printing, he laid the foundations for the development of bioprinting around the world. He first created a whole organ, the thyroid gland, on a printer that was developed by 3D Bioprinting Solutions.

The choice of cells for 3D bioprinting of tissues or organs is the most important condition for their correct functioning in the created material. In the body, tissues and organs consist of numerous types of cells with special and necessary biological properties, which must also be reproduced in the transplanted tissue.

Where can I get cells from? Bone marrow, adipose tissue, tooth pulp, cord blood - all these sources in 2019 are actively investigated and compared, which better cells are suitable for which approaches. There are a lot of cell sources in our bodies, and using them correctly can lead to us being able to recreate whatever tissue we want.

There is also a myth that all stem cells can cause cancer. That's not the case. Only undifferentiated embryonic or induced pluripotent stem cells can be a real direct cause of tumor and cancer development. For the rest of the species, there are no scientific articles supporting this myth. Mesenchymal stromal cells often used in cellular technologies do not themselves give rise to tumor or cancer cells, but they have the ability to migrate into a tumor if it is already formed in the body. Experiments are ongoing using cells as carriers to deliver a substance to a cancer tumor. If the cells are injected systemically, they will concentrate in a cancerous tumor and this can become a directed delivery of some kind of drug to this tumor.

Researches

2024

Russian scientists have proven the possibility of growing cells in space

Scientists Sechenov University confirmed the possibility of growing bioequivalents skin and other human tissues under conditions. space microgravity The experiments were conducted aboard the International MICROSEC Space Station in a specially designed space station. bioreactor The technology of growing cells in zero gravity is part of a global program to prepare for deep space exploration - 3D bioprinting and growing tissues from astronauts' own cells will effectively restore the body after injuries and diseases that will face long interplanetary flights. This was announced on September 12, 2024 by representatives of the Sechenov University. More. here

Institute of Fundamental Medicine for the Development of Bioengineering and Bioprinting opened in Russia

On July 12, 2024 Bashkir State Medical University (BSMU) Ministry of Health Russia , the official opening of the Institute of Fundamental Medicine took place at the base. The new institution is designed to become an advanced platform for research in the field of biology, medicine and bioengineering, as well as the training of modern scientists. More here

In Russia, created technology for the eternal storage of artificial organs

In early May 2024, researchers from the Peoples' Friendship University of Russia (RUDN University) announced the development of a new technology that allows artificial organs to be stored indefinitely. We are talking about a cryopreservation method, which in the future is expected to form a kind of bank of "spare parts" for patients.

RUDN specialists told the Izvestia newspaper about the proposed approach. It is noted that as of the beginning of 2024, there are methods for the long-term preservation of relatively simple biological elements, such as sperm, eggs or tissue fragments, which remain viable. However, when freezing larger objects, for example, organs, difficulties arise, since cryoprotectors (substances that protect living tissues from the damaging effect of freezing) must penetrate all structures. Russian researchers have found a way to solve the problem.

A technology has been developed that allows artificial organs to be stored indefinitely

RUDN specialists managed to maintain the viability and biological activity of cells due to the complex composition of the cryoprotective medium and accurate control of the rate of temperature change after thawing. As an object of cryopreservation, a three-dimensional matrix of biocompatible polymer polylactoglycolide was used (used in medicine, including for suturing). In the structure from this material, the scientists placed human stem cells with high regenerative potential. The resulting structures were then cooled to liquid nitrogen temperature.

Samples were stored for different lengths of time. After thawing, their properties were compared with the original control samples. In addition, the project participants checked the mechanical characteristics of the objects. It turned out that after defrosting, the material retained biological activity and strength. Moreover, after transplantation to animals in the tissues surrounding the implant, regenerative processes began. Thus, the new technology paves the way for the "eternal" storage of artificial organs.^[1]

The liver began to grow right in the body of a living person

In early April 2024, specialists from the biotechnology company LyGenesis announced the development of technology that allows you to grow mini-livers directly in the body of a living person. The method makes it possible to treat patients with hepatic impairment for whom, due to various reasons, transplantation of this organ is not available or impossible. Read more here.

Sechenov University won a grant of 300 million rubles for the creation of 3D bioprinting systems

Sechenov University won a grant from the Ministry of Education and Science of 300 million rubles to create 3D bioprinting systems. The press service of the university announced this on April 2, 2024. Read more here.

2023

How 3D printing of human organs is developing in Russia

In 2023, 15 companies specializing in the supply of products for research on human bioprinting, including bioprinters, spare parts for them, reagents, chemicals and accessories for bioprinting, worked in Russia. These include Moscow-based Diaem LLC, Analytica M LLC, Trading House Himmed LLC and St. Petersburg-based Technosnab LLC. At the same time, many Russian scientific institutes are engaged in the study of the possibilities of 3D printing of human organs. This is stated in the study, the results of which were published on February 29, 2024.

Active research in this direction is carried out by Sechenov University: in 2023, he signed an agreement with Chinese specialists on the creation of joint laboratories for three-dimensional bioprinting and regenerative medicine. And in Samara State Medical University, NTI "Bionic Engineering in Medicine" operates: scientists of this university have developed a roboruka equipped with a device for bioprinting hydrogels. The creation of promising biocompatible materials is carried out by specialists from the Laboratory of Superelastic Biointerfaces as part of Tomsk State University. According to RBC, research in this area is carried out by the Federal Research Center for Transplantology and Artificial Organs named after Academician V.I. Shumakov.

In 2023, 15 companies specializing in the supply of products for human bioprinting research worked in Russia

One of the main areas of application of 3D printing in medicine is the dental sphere. In particular, diagnostic models of teeth and jaws are made on a 3D printer. Such copies allow the orthopedic dentist to recreate the lost shape of the teeth and clearly demonstrate to the patient the future result of treatment.

3D printing is also applied in the field of plastic surgery. The use of 3D bioprinting technology could address the shortage of donor organs and improve the transplantation process. In Russia, biocompatible materials are used for organ printing, such as natural hydrogels (collagen, fibrin, hyaluronic acid), as well as synthetic polymers, which often provide higher "strength" of the printed structure. Plus, 3D printing is used to create prostheses - including fingers, hands and forearms.^[2]

The world's first bioprinting operation on a patient was carried out in Russia

The Main Military Clinical Hospital named after Academician N.N. Burdenko carried out the world's first operation using a bioprinter consisting of a roboruka, a bioprinting system and computer vision. This was announced to the medical portal Zdrav.Expert on December 26, 2023 by representatives of the MISIS University. Read more here.

The future of bioengineering. Which technologies are taking tens of billions of dollars to improve health

The convergence of biological and information technology improves human health and performance and creates innovative products and services. Against this background, investments in the field of bioengineering are growing - by the end of 2022 they reached $43 billion. This is stated in the McKinsey report, published in mid-2023.

Analysts point out that breakthroughs in biology coupled with new digital solutions are driving many industries, including health, food and agriculture, consumer goods, and energy and materials production. According to McKinsey estimates, approximately 400 options for using bioengineering achievements, almost all of which are scientifically feasible, can provide an economic effect of $2 trillion to $4 trillion per year between 2030 and 2040.

Among the key areas of development of the industry are gene therapy, tissue engineering and biomaterials. For example, cultured (artificial) meat obtained from animal cells will help solve possible food problems and reduce the cost of raising and fattening cattle. And bio-substitutes (new materials made from biologically based chemicals) compared to traditional raw materials will provide similar quality and cost, but higher environmental indicators.

From 2018 to 2022, the number of vacancies in the field of bioengineering technologies more than doubled, and a sharp increase occurred during the COVID-19 pandemic. However, then, against the background of a reduction in funding for a number of projects, the number of proposals for finding employees in this area began to decline: in 2022 it decreased by 19% compared to the previous year. There are issues of regulation of bioengineering technologies and certain ethical problems, which slows down the development of the market.^[3]

A bioprinter for printing with live cells was tested in Russia right in the operating room

A bioprinter modified by scientists at MISIS University in the form of a roborook, which can print live cells directly on a patient in the operating room, has successfully passed animal tests in the preclinical research laboratory of the P.A. Herzen MNII and is ready for further stages of research. This was announced on September 22, 2023 by Zdrav.Expert representatives of MISIS. This in situ bioprinting technology, that is, directly into a defect, may in the future become a progressive therapeutic method for the treatment of burns, ulcers and extensive soft tissue injuries. Read more here.

For the first time in Russia, the animal was returned to hearing using an eardrum printed on a 3D bioprinter

On August 14, 2023, the First Moscow State Medical University named after I.M. Sechenov of the Ministry of Health of the Russian Federation (Sechenov University) announced a unique operation to restore hearing in an animal using an analogue of an eardrum printed on a 3D bioprinter.

Russian experts say that the cause of damage to the eardrum can be both injuries and the consequences of infectious diseases, including chronic purulent otitis media, which affects millions of people around the world. The problem is solved exclusively by surgery: cartilage, supracartilage and fascia are used, from which the implant is formed. However, it does not always take root, which is why the operation has to be repeated. In addition, the fabrics used are not intended to conduct sound. A new domestic development allows you to bypass existing difficulties.

Scientists from the Institute of Regenerative Medicine at Sechenov University have created an analogue of the eardrum based on spheroids - "balls" from cells. For such an implant, it is not necessary to use the patient's own tissues, and the operation itself is less traumatic and goes faster than a traditional procedure.

In the manufacture of an analogue of the eardrum, a collagen membrane and bio-ink are used. The membrane is used as a substrate for 3D printing. The composition of the ink includes biopolymers gelatin and fibrin, as well as the cellular component - spheroids from human mesenchymal stromal cells. The implant starts the process of regeneration of the eardrum, which lasts about a month. The collagen substrate is gradually resorbed, and spheroids stimulate repair processes during which the implant is replaced with new tissue.

During the experimental operation, the scientists returned the chinchilla hearing. The eardrum of this animal is similar in characteristics to the human one, so it is great for practicing the technique and observing the results. According to Russian specialists, the technology is almost ready to be introduced into clinical practice to restore hearing in people.^[4]

A new method of 3D printing of human organs has been developed

On August 7, 2023, Australian specialists from the University of Sydney and the Children's Medical Research Institute in Westmead announced the development of a new technology for the formation of human organs by 3D printing.

Scientists have used 3D photolithographic printing to create a complex environment for assembling tissues that mimic the architecture of an organ. Using bioengineering and cell culture tools, the researchers were able to convert stem cells derived from blood or skin into specialized cells that can assemble into an organ-like structure.

The project participants note that a set of detailed instructions is required to create tissues from cells. Without them, cells will unpredictably group together as part of the wrong structures. Experts have proposed a step-by-step process, thanks to which each building block is directed to a strictly defined place and connected to certain elements. As a result, it becomes possible to form organized structures. In particular, during experiments, the researchers created a bone-fat complex resembling natural bone and a set of tissues similar to those generated during the processes of early mammalian development.

With this bioengineering technology, we can direct stem cells to form certain types of cells and organize them correctly in time and space, thereby repeating the process of real development of the organ, "said Professor Patrick Tam, one of the authors of the work.

The researchers hope that the proposed method will help in the future in the treatment of genetic diseases and age-related ailments. In particular, the technology may have the potential to correct vision caused by conditions such as macular degeneration.^[5]

In Russia, learned to grow brain cells from auxiliary living tissue

In Russia, they learned to grow brain cells from auxiliary living tissue. Scientists from the Institute of Cytology of the Russian Academy of Sciences (INC RAS) shared their achievement in August 2023 with colleagues from St. Petersburg Polytechnic University Peter the Great.

To develop and test medical drugs, live cells are needed, on which the effectiveness of drugs could be tested. Unlike cells of other human organs, neurons are quite difficult to obtain, they cannot simply be taken from a living brain.

One widely used way is to grow neurons from human stem cells. However, there are diseases for which this method is not suitable. There is a more complex method - this is reprogramming the cells of the human body taken from connective tissue - fibroblasts. The problem is that they are susceptible to rapid death - when reprogrammed into nerve cells, only 3-10% of fibroblasts survive.

Scientists of the INC RAS and St. Petersburg Polytechnic University Peter the Great have achieved that up to 80% of all these cells survive, and the method they have created is potentially applicable to reprogramming not only fibroblasts, but also other types of cells, TASS reports citing the press service of the institute. Thanks to this, the cost of such experimental human cells for pharmaceutical companies will decrease, and developers will be able to expand the scope of work on the search for drugs.

To achieve this result, the scientists found the most optimal method - they synchronized connective tissue cells with each other before starting to reprogram them into neural cells. In addition, genetic changes are introduced smoothly and in a gentle mode, in the same way the cells are treated with antibiotics necessary to maintain the process.^[6]

Russian scientists were the first in the world to print cell spheroids using a laser bioprinter

Specialists from Sechenov University and the Institute of Photonic Technologies of the Russian Academy of Sciences (RAS) were the first in the world to develop a technology for the transfer of viable cellular spheroids (spherical structures) using a laser bioprinter. The press service of the university told about this achievement at the end of July 2023. Read more here.

In Russia, an analogue of the eardrum from living cells and collagen was printed on a bioprinter

Scientists at Sechenov University printed an analogue of the eardrum from living cells and collagen on a bioprinter. The press service of the university told about this on August 3, 2023.

As Polina Bikmulina, a junior researcher at the Institute of Regenerative Medicine, explained, scientists took as a basis the previously developed biochernils containing a biocompatible hydrogel and cellular spheroids. Then, using a 3D bioprinter on biobumag, which was collagen matrices, experts printed constructs.

We took an animal with a persistent perforation of the membrane, injected bioequivalent at the site of the defect and began to observe the results. When a month later we began to study the membrane through the endoscope with an increase, we could not find the point where the bioequivalent was introduced - it recovered so much. Moreover, all layers were restored in it, and histologically it became indistinguishable from the natural, natural membrane. What is especially important is that it transmits vibration in the same way as the native membrane does. For us, this has become a big, significant event, - said Valery Svistushkin, head of the department, professor, director of the Clinic for Ear, Throat and Nose Diseases of the UKB No. 1 of Sechenov University.

Deafness and hearing loss are a common problem and an important challenge for otolaryngologists, he said. The perforation of the eardrum affects millions of people around the world, it leads to hearing loss, which means a violation of professional and social adaptation and loss of quality of life, the specialist explained.

It is expected that the new technique will allow people to return hearing within one month. Thanks to the technology, the operation will take place several times faster than usual - about 40 minutes. It is noted that the operation using the new technology of scientists at Sechenov University is a prevention of complications of chronic purulent otitis, which will bring a number of advantages to both patients and the health care system.^[7]

ITMO opened a mobile laboratory to create an artificial heart

ITMO created the first mobile cube laboratory in Russia to work with cells. It will grow cell cultures, create databases and conduct advanced research in the field of tissue engineering using artificial intelligence. In the future, ITMO scientists plan to grow myocardial cells to create a full-fledged artificial heart. This was announced on July 19, 2023 by representatives of ITMO. Read more here.

Learned to grow lungs from stem cells

In mid-June 2023, Rockefeller University researchers announced the development of a cell culture platform in which mini-lungs can be grown from human embryonic stem cells.

The tiny structures are similar to the mini-lungs that form during fetal development and contain tiny airways and alveoli. The researchers create these structures in a bioreactor equipped with microfluidic chips that grow lungs. The team has developed a number of growth factors that can stimulate embryonic cells to differentiate the lungs, and hopes to use the system to study the behavior of respiratory infections and find new treatments. Mini-lungs are genetically identical to conventional lungs, which reduces the biological variability inherent in such trials and allows researchers to conduct experiments without using test animals.

This will allow us to respond to the next pandemic with much greater speed and accuracy! We can quickly use this information to make the virus visible and develop therapies much faster than we did for COVID-19. It can be used to screen drugs, compounds, vaccines, monoclonal antibodies and more directly in human tissues. The technology is ready to confront all kinds of threats that could hit us in the future, "said Rockefeller University bioengineering professor Ali Brivanlu.

Scientists at Rockefeller University are all better at creating mini-organs in the lab. Such organoids are extremely useful for studying the mechanisms underlying diseases and testing new treatments. The COVID-19 pandemic has pushed scientists to a deeper understanding of respiratory diseases - after all, some of the most contagious diseases spread through the air, so understanding how they become infected and develop in the lung tissue will help researchers better prepare for the next pandemic.

Mini-lungs developed by researchers can be created by thousands, which allows scientists to simultaneously study thousands of individual SARS-CoV-2 infections, for example. The lungs have exactly the same DNA signature. So scientists don't have to worry that one patient's response will be different from the other's. Quantification allows researchers to keep genetic information unchanged and measure a key variable - the virus.^[8]

A device has been developed for bioprinting human tissues inside the body

In mid-June 2023, a regenerative medicine research team from Canada's Victoria University announced the development of a portable device that prints biocompatible human tissue inside patients. Read more here.

Copies of human embryos from stem cells created for the first time in the world

In mid-July 2023, scientists at the University of Cambridge created synthetic human embryos using stem cells, a revolutionary move to dispense with the use of eggs or sperm.

According to Professor Magdalena Jernicka-Goetz, model embryos resemble embryos in the early stages of human development and can become an important source of information about the consequences of genetic diseases and the biological causes of repeated miscarriages. However, this study raises serious ethical and legal questions. This is because laboratory-grown organisms are not covered by the current legislation of most countries, including the UK. These structures do not have a heart and brain, but usually contain cells that form the placenta, the yolk sac, and the embryo itself.

Zhernitska-Goetz also said that in the near future synthetic embryos cannot be used for clinical purposes. It would be illegal to implant them in a patient's uterus, and it is not yet clear whether these structures can continue to mature after the earliest stages of development. For June 2023, we can create human embryo-like models by reprogramming cells. The motivation for the work is for scientists to understand the development period of the "black box," so named because scientists are only allowed to grow embryos in the lab to the legal limit of 14 days. They then learn about the course of development much later, studying pregnancy shots and embryos donated for research.

In 2022, the Zhernitskaya-Goetz team and a rival group from the Weizmann Institute in Israel showed that mouse stem cells could be induced to self-assemble into early embryonic-like structures with intestinal tract, brain buds and beating heart. Since then, the race has begun to transfer this work to human models, and several groups have managed to reproduce the earliest stages of development.

This event highlights how fast science in this area is ahead of the law, and scientists in the UK and other countries have already begun to develop voluntary guidelines to regulate work on synthetic embryos. The question of whether these structures in theory can grow into a living being also remains unanswered. Synthetic embryos grown from mouse cells have been reported to be nearly identical in appearance to natural embryos. But when they were implanted in the wombs of female mice, they did not develop into living animals. In April 2023, researchers from China created synthetic embryos from monkey cells and implanted them in the wombs of adult monkeys, several of which showed the first signs of pregnancy, but none of which continued to develop for longer than a few days. Researchers say it's unclear whether the barrier to more advanced development is merely technical or has a more fundamental biological cause.^[9]

Sechenov University has developed a technology for 3D bioprinting of human tissue from living cells

In early June 2023, it became known about the creation in Russia of a technology for three-dimensional bioprinting of human tissue from living cells, this achievement allows printing organs and tissues for a specific person. We are talking about the development of scientists from the First Moscow State Medical University (MGMU) named after Sechenov and the Semenov Center for Chemical Physics of the Russian Academy of Sciences. Read more here.

Artificial cornea created in Russia

At Sechenov University, an artificial cornea based on collagen was created. The press service of the university announced this on May 17, 2023.

The basis for the development of a new corneal repair technology was a new generation collagen matrix, which is used in reconstructive dentistry. Scientists managed to achieve a high degree of transparency of the prototype (up to 90%). The prosthetic material is fully biocompatible.

The artificial cornea was obtained using the electrophoretic deposition method. It has a high light-transmitting ability, while scientists can regulate its thickness and swelling depending on the patient's pathology. A unique development is planned to be used for corneal transplantation for injuries and eye diseases.

Scientists want to test the biocompatibility of the artificial cornea and evaluate the results of transplantation after surgery. They will then begin research on dogs, cats and other animals. In parallel, preclinical research will be launched together with industrial partners. When the full cycle of tests on animals is completed, this technique will be used in humans, added to the press service of Sechenov University.

The university noted that by May 2023, the restoration of the cornea by regenerative medicine is in great demand. For its replacement, only tissues taken from donors are used. However, the demand for donor corneas exceeds the supply, and according to world statistics, only one in 70 patients in need receive treatment. But there was no completely artificial material, the structure of which coincides with the native one. Meanwhile, corneal injury or disease is fraught with a significant decrease in visual acuity, up to and including its complete loss. ^[10]

A robot has been created that can print new tissues inside the body

In late February 2023, engineers from the University of New South Wales unveiled a miniature and flexible soft robotic F3DB arm that could be used to 3D print biomaterials directly on organs inside the human body. Read more here.

Artificial penis shows encouraging results

In early January 2023, it became known that scientists from the South China University of Technology in Guangzhou developed synthetic tissue that heals penis injuries and restores its normal functions. Read more here.

2022

Russian scientists have created material for the "cultivation" of organs and tissues

Scientists at NUST MISIS together with colleagues from Tomsk Polytechnic University have proposed a way to modify biopolymers for tissue engineering. This was announced on December 9, 2022 to the medical portal Zdrav.Expert by representatives of MISIS. Adding a small amount of reduced graphene oxide particles to the material contributes to improved mechanical properties and shape memory effect, the scientists said. In the future, such material can be used for soft tissue regeneration, for example, for nervous tissue and skin. Read more here.

Method of growing mini-organs, including intestines, discovered

In early December 2022, researchers from the Tokyo Medical and Dental University discovered that spheroids grown in suspension, when transferred to a bioreactor, turn into a human organ intestine and differentiate into complex intestinal tissue during transplantation.

Growing human body parts in a laboratory setting is a common technique in horror films and science fiction books. But growing miniature organ-like tissues in the lab is already within our reach. Researchers in Japan have developed a new approach that makes it easier and more efficient to grow mini-intestinal organs in the lab. This opens up huge prospects for regenerative medicine.

In a study, scientists from Tokyo Medical and Dental University (TMDU) have shown that the use of several specialized laboratory techniques allows the cultivation of intestinal-like tissues of predictable size and composition.

In order to develop a more reliable and consistent way of creating, the researchers explored the possibility of using cell culture plates made using an ultra-low-attachment polymer to stimulate cells to separate and grow in suspension. They also tested the effect of growing the resulting spheroids in a bioreactor - a specialized incubator that maintains constant movement of the growth medium to improve cell health.

These organoids were surrounded by mesenchyma, which is a type of tissue found between organs in the human body. Importantly, when the organoids were transplanted into mice, they continued to grow and differentiate, developing a complex tissue architecture that reflected that of the mature gut.

Given that more complex intestinal tissues have been created with traditional methods, it is likely that this new approach could easily be adapted to create more complex organoids, such as intestinal-like tissue containing blood vessels or nerves. These lab-grown tissues will be invaluable for future applications in regenerative medicine.^[11]

Biotech companies begin work to grow embryos for human organs

In August 2022, Israeli biotech company Renewal Bio said it had successfully used advanced stem cell technology and artificial uteruses to grow mouse embryos that had continued to develop for several days. The study was conducted with the aim of facilitating transplantation and treating diseases such as infertility, genetic diseases and aging, the researchers say. Read more here.

The Moscow Polytechnic proposed a method for contactless diagnosis and management of hydrogels during bioprinting

On January 23, 2021, the Moscow Polytech announced that scientists from the Faculty of Chemical Technology and Biotechnology have developed a technique and special equipment that allows using an optical method to monitor and control processes inside hydrogels during their 3D bioprinting. Read more here.

2021

Lab-grown stomachs now produce acid as real

In early December 2021, scientists at Cincinnati Children's Hospital announced the successful creation of a stomach organoid so complex that it has separate glands and nerve cells that can control smooth muscle contractions. This achievement is a significant step forward in the field of regenerative medicine.

According to the researchers, this achievement demonstrates that individual layers and parts of complex organs can be grown from individual human pluripotent stem cell (UCS) lines and combined for further development. The approach used to create these multi-layered stomach organoids could also be used to create more complex versions of other lab-grown organs. The results of the study were published Dec. 1, 2021, in the journal Cell Stem Cell by Wells and lead author Alexandra Eicher, PhD.

This advance in tissue engineering is important because we can now collect complex organ tissues from separately produced components, similar to an assembly line. Given that this technology could be widely applicable to other organs, it is possible that engineered tissues could be a source of material to repair elements of the upper gastrointestinal tract damaged by congenital diseases or acute injuries. Team members, thanks to a grant from Cincinnati Children's Hospital, are working to expand the production of therapeutic-quality organoid tissues with the goal of transplanting them to patients by early 2030, says Ph.D. author James Wells.

Most organoids created before the end of 2021 can form three-dimensional structures that include several types of cells. In laboratory utensils, these tiny organs perform real-world functions, giving new opportunities to study diseases and develop drugs. But, as a rule, they lack various types of cells that are necessary to create a full-length functional organ. Some may lack key nerve fibers, internal blood vessels, or other important ducts and glands needed to communicate the organ with the rest of the body's systems. This new gastric organoid does not yet have all the necessary cell types, but it represents a significant leap forward.

Importantly, the development of these human mini-stomachs was not limited to a thin layer of medium in a laboratory dish. Once the organoids reached the critical stage, at about 30 days, the team performed microsurgical surgery to transplant the organoids into a mouse, which provided blood flow and biological space for much greater growth. Instead of cell spheres that look like dots in a dish, these organoids grew a thousand times in volume inside mice and formed mini-organs visible to the naked eye. In fact, the lab-grown tissue is very similar to natural human tissue at similar stages of development. Brunner's iron even began to develop in this new organoid, which releases alkaline mucus that protects the duodenum, the upper intestine, from the acidity of the stomach contents.

We started with cells from three primary germ layers - neuroglial, mesenchymal and epithelial gastric progenitors - all separately derived from the PSC. Of these, we created stomach tissue containing acid-producing glands surrounded by layers of smooth muscle containing functional enteral neurons that controlled contractions of engineered antrum gastric tissue, said study lead author Alexandra Eicher.

The team also found that all of these individual components are necessary to form stomach tissue with proper complexity and function. Each component helps to form the other components correctly. For example, the authors found that if you do not add nerves during the assembly process, then the gastric glands and muscles will not form properly. In addition to demonstrating a three-layer approach to creating gastric organoids, the team also took a similar approach to create a more complex esophageal organoid.

Helmrat's lab at Cincinnati Children's Hospital has begun work to expand this line of research beyond mice. Although this approach will provide important information at the laboratory level, the research team does not believe that the use of animals as hosts for the further cultivation of human organs will be the final method of transplanting organoid tissues to patients.^[12]

Creation of a method of 3D printing materials with living cells for the creation of human organs

In mid-March 2021, researchers at the University of Buffalo in New York developed a new technique that allows for fast 3D printing of hydrogel materials with viable cells. Researchers hope the new method will pave the way for 3D printing of organs in the future.

The current limitations are due to the slow pace of 3D printing, which reduces the viability of such printed structures. The new method, called fast stereolithographic hydrogel printing (FLOAT), significantly reduces environmental exposure to encapsulated cells typical of other techniques.

The technology we developed is 10-50 times faster than industry standards and works with large samples that were previously very difficult to obtain, said researcher Ruogang Zhao.

Thanks to strict control of photopolymerization conditions, this method allows the creation of centimeter-sized hydrogel structures in a matter of minutes. The team also evaluated the new 3D printer's ability to print cells and embedded blood vessel networks, which will be critical to the proper functioning of 3D print organs. According to the report of the researchers, the new method brilliantly coped with the task.

[Быстрая printing] significantly reduces sample deformation and cellular damage caused by prolonged exposure to environmental stresses, which is often seen with traditional 3D printing techniques, explained another researcher, Chi Zhou.]

The printed networks of vessels within the hydrogel structures allow the nutrient solution to penetrate deep into the structures, which is a decisive factor in the production of viable printing organs.^[13]

Launch of Enlight - Pancreatic 3D Printing Project

At the end of February 2021, the European Enlight project was launched, which is to develop a pancreatic model for testing drugs for diabetes. This model will be created using 3D printers made by Readily3D, using tomographic printing to create microstructures in less than 30 seconds. The research will be conducted at UMC Utrecht and EPFL academic centers, which in 2019 were the first to use bulk printing using specialized stem cells. UMC Utrecht is the initiator of this project. Read more here.

2020

Printing the heart on a bioprinter. Video

Bioprinter endoscope printed with living cells on the wall of a stomach model

On August 14, 2020, it became known that the Chinese scientists they created a prototype of a bioprinter that can treat defects in the stomach wall by printing patches on it containing hydrogels cells of the corresponding tissues. It is delivered inside the stomach along the esophagus in a similar way, and to the endoscope then opens the folded parts and begins to apply layers of hydrogels. The authors of the development showed the work of a bioprinter on a stomach model by printing layers of epithelium cells and smooth muscle on its inner surface. The article was published in the journal Biofabrication. More. here

In Armenia, mastered bioprinting of human tissues

On August 4, 2020, it became known that a team of young doctors in Armenia mastered the technology of growing tissues of the human body using bioprinting. This was told in the company FoldInk, where such research is carried out. Read more here.

On board the ISS conducted an experiment on 3D printing of the meniscus

On May 15, 2020, it became known that the American research company Techshot conducted its first experiment on 3D printing of human tissues in zero gravity conditions on the BFF bioprinter, developed in conjunction with nScrypt and delivered aboard the International Space Station in July 2019. Read more here.

Russian cosmonauts conduct an experiment on bioprinting bone tissue

On April 12, 2020, Zdrav.Expert learned that Russian astronauts on the ISS began an experiment to print inorganic components of rat bone tissue. Printing will take several days. Read more here.

3D printing of bone tissues will be tested on the ISS

On March 4, 2020, Zdrav.Expert learned that from April 10, 2020, the crew of the International Space Station will begin experiments on 3D printing of bone tissues for subsequent recrystallization and transplantation to rats. The research uses the magnetic bioprinter Organ.Auth, authored by the Russian company 3D Bioprinting Solutions. Read more here.

2019

In Russia, for the first time, a tissue implant was printed during surgery

On December 7, 2019, Zdrav.Expert learned that in Russia, for the first time, a tissue implant was printed during surgery.

The operation was carried out on rats and took place MNII named after P.A. Herzen in (branch of the Federal State Budgetary Institution ") NMSC of Radiology Ministry of Health RUSSIAN FEDERATION in conjunction with the company. 3D Bioprinting Solutions More. here

Bone fragments were grown on the ISS using a 3D bioprinter

On November 25, 2019 TAdviser , it became known that the Russian astronauts working on, using International Space Station bio ","printer Body.Avt created fragments of an artificial bone structure with tissues from calcium-phosphate ceramics. More. here

In China, hundreds of patients are treated with cellular technology

For 2019, there are many methods for forming three-dimensional structures. You can create any object, with any structure, from any material. Further it is already a matter of details - the rate of destruction of the material, mechanical properties, etc. Cell sources can be converted into different types of cells and tissues by exposure to biologically active substances. First of all, growth factors are used that accelerate, for example, vascular formation, nanoparticles, hormones, vitamins, low molecular weight compounds are also used.

With the number of cells that we can use for regenerative medicine, with the number of methods, there is a lot of research to be done on biologically active substances. Since 2000, many scientific groups have been trying to make such a development that would first show itself well in a test tube, then on an animal, and then eventually found clinical use.

Around regenerative medicine, a myth has formed that cellular technologies will not soon come to clinical practice. This is not so - just look at the number of registered clinical studies.

For 2019, China is becoming a global leader not only in conducting and testing animals, but also in implementation in clinics. In the Celestial Empire, hundreds of patients are treated using cellular technologies.

2018

The cornea was printed on a 3D printer for the first time

In May 2018, it became known about the first creation of the cornea of ​ ​ the eye using a 3D printer. This achievement was boasted at Newcastle University. They can now use volumetric printing to form corneas from stromal cells for each individual, the researchers said.

According to the Financial Times, employees of Newcastle University have created special biochernils consisting of cells of the living donor corneal stroma, alginate (polysaccharide) and collagen, the protein that forms the basis of the body's connective tissue. By loading this substance into a regular 3D printer, it was possible to print a healthy cornea in just 10 minutes. Moreover, after printing, more than 90% of the cells remained viable, and on the seventh day - 83%.

The composition of the ink should be plastic, but at the same time rigid enough that the finished cornea retains its shape. It's also important that the cells stay alive. So far, not a single scientific group has been able to combine all three conditions. But now we have ready-to-use bio-containing stem cells, "said Che Connon, professor at the Department of Tissue Engineering Technology at Newcastle University, who led the work on 3D printing of corneas.

This most convex transparent part of the eyeball can suffer from infections, burns, mechanical injuries and other causes. By May 2018, about 10 million people around the world need a corneal transplant to avoid vision loss, and another 5 million people have already gone blind, but have a chance to recover from such a transplant. Unfortunately, donor material is always lacking, but the development of Newcastle University scientists can solve this problem. True, the technology still has to pass clinical trials, and about 5 years can pass before mass use, researchers say.^[14]

3D printer printing sugar tissue for growing organs created

In May 2018, it became known about the creation of a 3D printer that prints tissues from sugar for growing organs and studying tumors. This is a development of the University of Illinois.

You can already find 3D printers on the market that can print objects made of sugar. Unlike these devices, the new equipment uses isomalt, a sugar substitute derived from beets and commonly found in lollipops for sore throats and coughs.

After dissolution and volumetric printing, the sugar structures cool and solidify, creating a strong scaffold carrier supports on the basis of which the cultivation of living cells takes place. Here, one of the problems is getting material that will "go away" not earlier and not later than the desired time.

3D printing using sugar becomes difficult when it comes to regenerating heart tissue. Too much pressure causes the structure to lose shape, and excessive heat leads to crystallization or burning of the tissue. Isomalt is less susceptible to crystallization than conventional sugar and is not susceptible to discoloration upon dissolution.

Professor Rohit Bhargava, who works at the Cancer Tumor Treatment Center in Illinois, says the unique method makes it possible to produce structures from thin tubes with a circular cross section. Previously, this was not possible for polymers. Soluble sugar helps to create cylinders and tunnels that resemble blood vessels. It is through these vessels that nutrients can be transported to tissues or cells. The development of a new method will also allow the creation of channels in microfluidic devices.

Illinois State University technology could find applications in areas such as medical research, biomedical engineering and manufacturing. Experts hope that in some time their 3D printer will be able to print human organs from scratch.^[15]

3D model of cardiac ventricle created to study consequences of myocardial infarction

In 2018, researchers created a 3D model of the heart ventricle specifically for experiments. On it, they studied the consequences of myocardial infarction and the influence of individual chemicals.

2016: Russia adopts law on biomedical cell products

If we talk about the development of regenerative medicine in Russia, then it is worth noting a long-standing problem - in our country until 2016 there were no laws related to this industry. In 2016, a law on biomedical cell products was adopted in Russia, which was designed to provide Russian scientists and manufacturers with regulation that is competitive in the international arena and helps attract investments in biotechnology companies registered in Russia.

The law introduced very strict restrictions, so the result so far has been a temporary decrease in the number of new clinical studies in regenerative medicine. According to the law, all biomedical cell products must be produced in GCP (good clinical practice) and GMP (good manufacturing practice) standards.

This is a complex requirement, and by 2019, just one company has registered a site for the production of biomedical cell products. It is very important that the law regulates the import and export of biomaterials (tissues, body fluids, etc.). Around the world, this is a well-known practice - to legislate the surrender of biomaterial to create biomedical cell products.

The second was a problem - the direction was practically not supported by the state, but in 2019 money is allocated for these studies within the framework of the project of the national project "Health," including funds - the Russian Foundation for Basic Research, the Russian Scientific Foundation.

According to the Scopus and Clinicaltrials databases, the number of Russian publications in the field of regenerative medicine has increased more than 6-7 times over ten years. Publishing activity is observed in Tomsk,, Novosibirsk, To Moscow St. Petersburg.

There are a lot of studies on the use of cells in Russia, and there are practically no studies on the use of materials and cells. This is due to the fact that groups of researchers are currently scattered: we do not have an association of materials scientists, biologists, etc. While 11% is dedicated to tissue-engineering scaffolds, it is hoped that this figure will only grow.

2015: Copy of protein chains printed to seek relief from cancer patients' chemotherapy process

in 2015, scientists printed a copy of protein chains to study how to facilitate the chemotherapy process for cancer patients.

1999: Dr Atala transplants a bladder grown from stem cells into patients

In 2006, Professor Anthony Atal's group published a paper on bladder repair. Back in 1999, Atala transplanted several patients with a bladder grown using stem cells, but did not publish the results then to make sure that the operation was successful in a distant period of time. Since then, by 2019, about 30 similar operations have been carried out in the world.

For 2019, Atala is one of the world leaders in a new direction in medicine, which is called tissue engineering. In his laboratories, work is underway to artificially obtain many tissues and organs, not only urological (despite the fact that Atala is the author of a large work Stem Cell in Urology, published in 2008). Cartilage, bones, vessels, urethra and many other organs, tissues are grown here.

They are also trying to work here on kidneys, which are much more difficult to grow than the bladder. Professor Atala himself has high hopes for 3D printing technology, through which the organ can simply be printed from the corresponding cell cultures. However, simpler cases of cell failure are trying to treat by injecting stem cells into the kidney that begins to malfunction^[16]

Notes