Scientists have long been "sick" with the idea of ​​growing organs in laboratories, but science managed to achieve significant breakthroughs and achievements in these studies only in the late 90s of the last century, when bioprinting attracted everyone's attention. According to Engadget, the researchers at the Wake Forest Institute of Regenerative Medicine, who first came up with the idea by creating 3D-printed synthetic building blocks necessary for growing human bladders. As the source notes, in fact, these scientists did not print bladders. It wasn't until the early 2000s that bioengineer Thomas Boland of Clemson University began modifying conventional ink printers to use biological inks and create 3D objects from them.

In 2010, one of the world's first bioprinting companies emerged. She became Organovo. By now, Organovo has learned how to print and uses them to test new drugs and conduct new research. The company hopes to be able to create a fully functional liver in the near future. She has done a tremendous amount of work to achieve this goal, but is not yet ready for the final push.

How it works?

It should be clear right away: despite the huge difference in complexity between printing organs and printing ordinary plastic objects, both processes are very similar to each other. In both cases, special cartridges and printheads are used, which shoot ink (or biological material), laying them layer by layer on the platform. However, both systems have several key differences:

• We all know what most of our organs look like, but in order to be able to recreate them, scientists first need to perform a CT scan or MRI on each individual patient. After that, the received data is processed in a computer, and a layout is created, which serves as a hint where and how it is necessary to apply cells layer by layer.
• Instead of PVC plastic or metal, bioprinters use as ink the human cells of the organ to be produced. These cages are used with a special bonding agent that allows the creation of a one-piece structure. In addition to using cells from certain organs, bioprinters can also use stem cells, bioengineered materials (such as the polymer alginate previously used to make aortic valve tissue, for example), and other substances that would not be rejected by the human body. For example, in 2012, a titanium jaw was created on a 3D printer, which was subsequently successfully implanted in an 83-year-old woman. And since 2013, a man has been living in the USA with.
• After scientists print the sample, it must be placed in special incubation conditions so that the cells can divide and work together, as is the case with real living organs.

And it is this last part of the process that is most of the reason why we still don't see machines in our hospitals producing replacement human organs.

What is the problem?

According to Dr. Anthony Atale (leader of the Wake Forest bladder manufacturing team), the problem is multifaceted. The first aspect is the difficulty of finding those materials that can be used to produce body parts and make them subsequently grow correctly outside the body. You can't just take a newly printed organ and sew it on to a person. As mentioned above, real organs are incredibly complex machines. And if we simply force the cells of the printed copies of these organs to divide, then this does not mean at all that these cells will work as they should. Cornell University bioengineer Hod Lipson comments on the problem:

“Of course, you can just connect the cells of the heart tissue together in the right place, but where will the button be located to turn them on? The magic itself lies in the printing process.”

Lipson also points out that there is still no powerful enough software, which would be suitable for creating ideal and most accurate models of organs. But this stage is the most important before scientists will proceed directly to the printing itself.

In addition to the difficulties in creating 3D printed organs whose cells behave like real ones, scientists have faced the difficulty in reproducing blood vessels. Organs need arteries, veins, and capillaries to move blood through them and deliver nutrients that keep them alive and healthy. However, due to their length, thickness and shape, all these things are very difficult to print.

However, no one says that scientists do not try to solve this problem. This June, for example, a team of researchers at Brigham Young University used the linear polysaccharide agarose to produce a blood vessel template. Scientists from the Frauhofer Institute have also been conducting research in this direction since 2011. Harvard professor Jennifer Lewis is working on the issue of printing organs that would already have special channels for the movement of blood and nutrients through them.

The Future of Organ 3D Printing

For all the time of work on these issues, science has nevertheless been able to achieve at least partial success in printing organs. Partially, because most of the organs received were non-functional or were able to live for only a few days. For example, the same company Organovo created a miniature human liver that could actually work like a real one, with the exception of one problem - it could work no longer than 40 days. Or take the scientists from , who successfully printed heart valves and small veins in April of this year. Scientists at this institution hope to one day create a full-fledged functioning heart. Let's not forget about the bioengineers from who created an artificial (perfectly working, by the way) human ear from living cells and a special gel.

Approximately 90 percent of patients on the waiting list for organ transplants are on the waiting list for new kidneys, Atala said. Perhaps this gloomy statistics even more stimulated and pushed Chinese scientists to develop small printed kidneys, but which, unfortunately, can only remain alive and functional for four months. Atala is also looking for ways to 3D print kidneys. In one of his last public speaking at the TED medical and technology conference, he even showed a non-working model of this recreated organ (you can see it in the video below).

During the same presentation, Atala shared a story about a lab-grown bladder transplant surgery. He talked about the future of medicine, where special scanners will study the depth and complexity of injuries, and then print new tissue directly on the patient. However, in order to live into this future, in which there will be no shortage of new organs and anyone who needs them can afford them, the knowledge of tissue and organ bioprinting must firmly take its place in medical schools, colleges, institutes and universities.

Most recently in a British magazine The Economist An exciting article has been published about a bioprinter that will be used to print human organs!

Human organ transplant surgeons hope that one day they will be able to get all the organs they need for a transplant at the first request. A patient can now spend months, possibly years, waiting for an organ from a suitable patient. During this time, his condition may worsen. He may even die. Thanks to artificial organs, it would be possible not only to alleviate the suffering of patients, but also to save human lives. Now, with the advent of the first commercial 3D bioprinter, this possibility may become a reality.

Creation of a bioprinter

The $200,000 printer was developed as a collaboration between San Diego-based regenerative medicine companies Organovo and Melbourne-based mechanical engineering company Invetech. One of the founders of Organovo, Gabor Forzak, developed the prototype on which the new 3D printer is based. The first working samples of the printer will soon be delivered to research teams that, like Dr. Forjak, are studying ways to create artificial tissues and organs. Currently, most of this work is done manually, using existing devices.

According to Keith Murphy, director of Organovo, only simple tissues, such as skin, muscles and small sections of blood vessels, will be created in the beginning. However, immediately after testing of the test samples is completed, the production of blood vessels for operations will begin, when it is necessary to "lay" new vessels for the movement of blood to bypass the damaged ones. After further research, it will be possible to produce more complex organs. Since machines are capable of printing networks of branched vessels, it would be possible, for example, to create networks of blood vessels needed to supply blood to artificially produced organs such as the liver, kidneys, and heart.

History of bioprinting

The 3D bioprinter manufactured by Organovo uses the same operating principle as "normal" 3D printers. 3D printers work in a similar way to conventional inkjet printers, but they print the model in 3D. These printers spray polymer droplets that fuse together to form a single structure. Thus, for each pass, the printhead creates a small line of polymer on the object. As a result, step by step, the object takes on its final form. The cavities in a complex object are supported by "scaffolds" made of special water-soluble materials. These scaffolds are washed out after the object is completely finished.

The researchers found that a similar approach could be applied to biological materials as well! If you place tiny sections of cells next to each other, they begin to "melt" together. A number of technologies are currently being researched that would allow the creation of human organs from individual cells, for example, the technology of “pumping up” muscle cells using small machines.

Despite the fact that the printing industry of human organs is just emerging, scientists can already boast of successful examples of creating human organs from scratch. So, in 2006, Anthony Atala, together with his colleagues from the Wake Forest Institute for Regenerative Medicine in North Carolina, USA, created bladders for seven patients. All of them are still functioning.

The process of creating the bladder was as follows. First, the doctor took a tiny sample of the patient's bladder tissue (to prevent the immune system from rejecting the newly created organ). Then, the resulting cells were applied to the biological bladder, which was a supporting base in the form of a bladder heated to the temperature of the human body. The applied cells began to grow and divide. After 6-8 weeks, the bladder was ready for implantation in the patient.

The advantage of using a bioprinter is that it does not require a support base ("scaffold"). The Organovo machine uses stem cells derived from the bone marrow. Any other cells can be obtained from stem cells using various growth factors. 10-30 thousand of these cells are formed into small droplets with a diameter of 100-500 microns. Such droplets retain their shape well and are great for printing.

So, the first print head actually lays out droplets with cells in the right order. The second head is used to spray the support base, a sugar-based hydrogel that does not interact or adhere to cells. Once the printing is completed, the resulting structure is left for one or two days for the drops to "melt" with each other. To create tubular structures such as blood vessels, a hydrogel is first applied (inside and outside the future structure). After that cells are added. As soon as the organ is formed, the hydrogel is removed from the outside (like the peel of an orange) and pulled out from the inside, like a piece of string.

Other types of cells and supporting bases can be used in bioprinters. So, according to Mr. Murphy, liver cells can be applied to a pre-formed liver-shaped base, or layers of connective tissue can be formed to create a tooth. At the same time, the new printer has such modest dimensions that it can be safely placed in a biological cabinet to provide a sterile environment during the printing process.

Some researchers believe that machines like this one could one day be able to print tissues and organs directly into the human body! And, in fact, Dr. Atala is currently working on a printer that, after scanning the area of ​​the body where skin grafting is needed, will be able to print the skin directly on the human body! Concerning Organs bigger size, Dr. Forjac thinks they can take many forms, at least initially. For example, in order to purify the blood, an artificial kidney does not have to look like a real kidney or completely repeat it functionally. Those people who are waiting for organs will probably not worry too much about how the new organs will look. The main thing is that they work, and people feel better.

They artificially create living tissue by superimposing living cells layer by layer. Currently, all bioprinters are experimental, however, in the future they can revolutionize medicine.

Bioprinters may have different configurations, but the principle of operation is the same: they output cells from a print head that moves left-right, back-and-forth, up-down to place the cells where they are needed. Thus, in a few hours you can get an organic object, which consists of a huge number of very thin layers.

In addition to cell output, most bioprinters also output a soluble gel to support and protect cells during printing.

Pioneers of bioprinting

Several experimental bioprinters have already been created. For example, in 2002, Professor Makoto Nakamura saw that ink drops in standard inkjet printer are about the same size as human cells. After that, he adapted the technology and in 2008 created a working model of a bioprinter that prints biotubules that look like blood vessels. Professor Nakamura hopes that eventually it will be possible to literally print out internal organs ready for transplantation.

Another bioprinting pioneer is Organovo, which was created by a research team led by Professor Gabor Forgacs of the University of Missouri. Since March 2008, Organovo has set itself the goal of bioprinting functional blood vessels and heart tissue using chicken-derived cells. This work is based on a bioprinter prototype with three printheads. The first two heads expel cardio and endothelial cells, while the third one releases the collagen backing – the so-called “bio-paper” – to support the cells during printing.

Since 2008, Organovo has been working with Invetech to build commercial bioprinters called the NovoGen MMX. This bioprinter is loaded with bioink spheroids filled with tens of thousands of cells. When printed, NovoGen creates the first layer on bio-paper made from collagen, gelatin, or other hydrogels. Then bioink spheroids are introduced (injected) into it. Layer by layer is added until the final object is created.

Surprisingly, nature takes its toll and the bioink spheroids slowly merge. The biopaper is then dissolved or otherwise removed, resulting in a bioprinted tissue or organ.

As Organovo has demonstrated, when using the bioprinting process, it is not necessary to print the organ in all its details. It is enough to correctly arrange the corresponding cells in rows, and nature itself will complete the work. This process eloquently indicates that the cells contained in bioink spheroids are able to rebuild after printing. For example, experimental vessels were printed using a bioprinter using bioink spheroids and consisted of a collection of endothelial tissues, smooth muscles, and fibroblasts. After they were lined up (layered) by the bioprinter head, endothelial cells migrated into the created blood vessels, smooth muscle cells moved in the middle, and fibroblasts migrated out without additional intervention.

Cells of more complex tissues and organs, such as capillaries and other internal structures, after printing on a bioprinter, also independently assume a natural position. This process may seem almost magical. However, as Professor Gabor Forgacs explains, it is no different from the process that occurs in embryonic cells, which “know” how to properly position themselves and form complex organs. Nature has developed this amazing ability over millions of years. The corresponding cell types, once in right places somehow know what to do.

In December 2010, Organovo bioprinted the first blood vessels using cells from a single donor. The company has also successfully implanted bioprinted nerves in rats, and experiments to transplant bioprinted tissue into humans are planned for 2015. However, the first commercial application of bioprinters is expected to be in the production of simple human structural tissues for toxicological testing. This will allow scientists to test drugs on bioprinted models of the liver and other organs, thereby reducing the need for animal experiments.

Over time, once human trials are completed, Organovo hopes that bioprinters will be used to produce blood vessel grafts and be used in heart bypass surgery. The company's intentions include the large-scale development of "custom" tissue and organ technologies. To achieve this goal, researchers are currently working on creating tiny mechanical devices that can artificially train and therefore strengthen bioprinted muscle tissue before being implanted into a patient's body.

Organovo expects the first artificial human organ to be the kidney, as these organs are the most sought after for transplantation. The first bioprinted kidneys don't have to look and function the same as their natural counterparts. The main thing is that they cleanse the blood of metabolic products.

Regenerative base and bones

Another research group with a long-term goal of custom-made human organs has created the Envisiontec Bioplotter. Like Organovo's NovoGen MMX, this bioplotter outputs bioink tissue spheroids and ancillary materials including hydrogel support, collagen, and growth factors. In addition, Envisontec can also print a wider range of biomaterials - biodegradable polymers and bioceramics that can be used to support and shape artificial organs. These bioprinted materials can even be used as bone substitutes.

A team led by Jeremy Mao at Columbia University's Tissue Engineering and Regenerative Medicine Lab is working on using bioprinters to replace teeth and bones. At present, a 3D lattice structure in the form of a cutter has been experimentally created and implanted in the jawbone of a rat. This structure consists of microchannels that are filled with substances that stimulate the development of stem cells. Just nine weeks after implantation, they caused the growth of the periodontal ligament and the formation of the alveolar process. Over time, these studies could enable people to have new bioprinted teeth or get them by stimulating the body to form new teeth of its own.

In another experiment, Mao's team implanted a lattice structure created with a bioprinter into the femur region of several rabbits. Once again, this construct was saturated with growth factors. Within four months, all rabbits had developed new, fully functional joints around this lattice, the medical journal The Lancet reported. Some rabbits even began to move around and put weight on their new joints as early as a few weeks after surgery. In the next decade, people in need of arthroplasty will already be able to get new hip joints and other bones created using bioprinting technology. A team at the University of Washington recently reported the results of four years of work using a 3D printer to create a bone-like material that could be used to repair damaged human bones in the future.

In Situ Bioprinting

The aforementioned scientific progress will eventually allow organs to be obtained in laboratories using bioprinters from the patient's own cells, which could lead to a revolution in medicine. However, other researchers have tried to go further and develop methods to print a new tissue or organ directly onto the body. In the next decade, doctors will be able to scan wounds and apply layers of cells to heal them quickly.

Now, a team of bioprinting researchers led by Anthony Alata at the Wake Forrest School of Medicine has developed a skin-creating printer. In their initial experiments, they took 3D scans of test injuries inflicted on mice and used that data to control a bioprinter head that sprays skin cells, coagulants and collagen onto the wound. The results of this experiment were also very promising: wounds healed in just two to three weeks (about five to six weeks in the control group).

The bioprinter skin project is partly funded by the US military, which is pushing for in situ bioprinting to treat wounds in combat. Currently, the work is still in the preclinical testing phase. Alata develops technology by experimenting on pigs. However, trials in burn victims could be carried out within the next five years.

The potential for using bioprinters to repair damaged tissues and organs in our body in situ is enormous. Perhaps in the next decade it will possible creation a robotic surgical arm with a tip in the form of a bioprinter head that will penetrate the body and repair damage at the cellular level. Patients will still need to rest and recuperate for several days while the material created by the bioprinter becomes fully mature living tissue. However, most patients will eventually be able to recover from very major surgery in less than a week.

Use in cosmetology

Same as recovery internal organs bioprinter through a small incision on the patient's body, the use of this technology has great prospects in the field of cosmetology. For example, bioprinters can be created to print human faces. They will vaporize existing tissues and simultaneously replace them with new cells, creating a new face at the request of the patient.

Even mentioning that the cells of your face are being slowly burned out by a laser and printed to order suggests a terrible torture that no one will ever want to endure. However, many people today go under the knife to achieve much less cosmetic results. When the technology becomes available to bioprint new faces, not to mention printers that can print new muscles without spending time training them, it is very likely that it will be in demand in the cosmetic market.

The material was prepared by the editors of the Technolife website based on information obtained from open sources. Sources: www.organovo.com, www.envisiontec.de. Any use of this material by Internet publications is possible only with an active link to the Technolife website.

Since 2012, it has been possible to print prostheses and implants of the human musculoskeletal system on 3D printers. Vertebrae and intervertebral disks made of plastic and rubber are already quite well mastered and a more complex level is gradually being mastered - printing human organs and body parts at the cellular level. In clinics in the USA, Europe and Japan, which are ahead of the rest in scientific research in medicine, right now they are experimenting with stem cells in order to create such body parts that would be completely implanted in the human body.

To give you a better idea of ​​the scale of progress, we can cite Oxford Performance Materials data, which speak of 450,000 patients worldwide and investments of $ 2 billion. The use of stem cells and human own cells is questionable, but it is precisely such a material that completely eliminates the risk of rejection. . Stem cells are not the only resource for a 3D printer, scientists are already working on a combination of plastic fibers and living cells, without which the creation of truly complex organs is unthinkable. Agree, it is one thing to print a bone prosthesis, and another part of the liver or heart.

So far, such complex organs cannot be completely made, but, for example, printed skin is already being used with might and main for transplantation in the US burn center. Patrons and just businessmen all over the world are investing in medical 3D printing, according to a study by Grand View Research, by 2020 the 3D printing market will be more than a billion dollars, the printers themselves will rapidly become cheaper, and there it’s a stone’s throw before the release of mass, home models .

What successes can medicine provide us with at the moment?

Scull

In March last year, surgeons replaced 75% of a person's skull with a plastic prosthesis. Separate bones, like the jawbones, have been “mounted” in a person’s head before, but no one has yet made such a replacement, especially in one stage and using a 3D printer.

Spine

As already written above, the replacement of vertebrae and intervertebral discs is almost mastered, but more recently, the Chinese have made a new breakthrough and replaced a vertebra with a tumor of the spinal cord for a 12-year-old boy. The material was made porous, so you don’t have to constantly change the vertebra - it will simply acquire new bone tissue and become an integral part of the body.

Ear

The bionic ear was created from calf cells, a polymer gel, and silver nanoparticles. As a result, doctors at Princeton University have created a real "ear of the future", which is able to perceive radio waves that are not picked up by the ordinary human ear. According to scientists, they may well master the “connection” of such an ear to the neurons of the brain so that it can perceive what it hears.

germ

Not quite a living organ, however, Japanese company Fasotec is printed using a magnetic resonance imaging scanner in a transparent cube that mimics the womb, an exact copy of your unborn child. It looks fantastic and frightening at the same time, but so far doctors like this thoroughly commercial project, because with its help it will be possible to observe the correct development of the fetus, practically holding the model of the child in their hands.

Arms

When South African-born Richard Van Yes had the fingers of his right hand cut off in a carpentry shop, he found Ivan Owen of Washington, DC, who built prototypes of mechanical hands. Together they founded Good Enough Tech, developed Robohands, and mastered 3D printing of "robohands", significantly reducing the cost of the final product. With the help of Makerbot, who lent them both printers and printing resources, these two enthusiasts have already helped more than 200 people around the world.

Liver

It is not yet possible to print a complete organ, due to its complexity, however, printing of liver tissue from hepatocytes, stellate cells and epithelial cells has already been mastered. This success dates back to 2013, so a scientific breakthrough to the "printing" of the whole liver is quite possible in the near future.

Nose

Korean doctors and researchers have successfully reconstructed a 3D-printed artificial nose for a six-year-old boy. Nerkha, a boy from Mongolia, was born without a nose and nostrils, which is extremely rare. Babies born without a nose can breathe properly and most die within 12 months. Doctors from Seoul, where the parents brought the boy, created an airway support structure using 3D printing technology. In a series of operations, doctors restored Nerja's nose. The patient's nostrils were created using his own bone tissue. Now he can breathe normally and looks much better.

"Printing" human organs on a 3D printer

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Reduced copy of the human ear from biogel

Wake Forest Institute for Regenerative Medicine

Scientists at Wake Forest Medical School have unveiled a bioprinter that prints human tissues from living cells that can retain their shape and take root in the body. In the future, bioprinted tissues and organs could replace artificial prostheses. The work of the researchers was published in the journal Nature.

To create organs and tissues, the printer uses a special hydrogel and plastic biodegradable material. The hydrogel is a combination of gelatin, fibrinogen, hyaluronic acid and glycerin with a fairly high concentration of living cells. First, the printer carefully creates three-dimensional objects from it layer by layer, and then coats them with an outer shell of degradable polymer. This shell helps keep organs and tissues in shape.

After the tissues are transplanted into the body, the polymer shell gradually decomposes. At the same time, the cells begin to independently release the matrix, which provides mechanical support for the cells, and, ultimately, the need for supporting material disappears. The entire volume of artificial tissue is permeated by a network of microchannels through which oxygen and nutrients enter the cells.

On the this moment The scientists created a gel analogue of a rat calvarium bone based on human stem cells from amniotic fluid, reduced copies of a human ear from rabbit chondrocytes, and several “muscles” using C2C12 mouse myoblast. The researchers tested all samples in the laboratory and in vivo, implanting them under the skin of rats and mice.

The results, according to scientists, were promising. The auricles implanted in mice retained their shape after two months, and the content of glycosaminoglycans, which are part of the cell matrix, increased by 20 percent. Muscle tissue, stretched along the support structure, also retained its mechanical characteristics after two weeks. The peroneal nerve implanted in the implant also retained its integrity, and nerve contacts with α-BTX+ inside the implant were observed in the tissue. In the gel analogue of the calvarium bone in rats, vascularized bone tissue formed five months later.

According to the authors, it is now necessary to find out how safe bioprinted implants are for humans. Most likely, cartilage structures, that is, the auricles, will be tested first, since, unlike muscles and bones, cartilage does not require an extensive system of blood vessels.

The idea of ​​3-D printing of organs, in general, is not new. Scientists are actively working on this technology, as it will not only allow the creation of bioimplants for human transplantation, but also, for example, conduct clinical trials of drugs on individual organs and tissues. So, the company Organavo is currently engaged in 3D printing of kidney tissue for drug testing.

Kristina Ulasovich