Just recently, the British magazine The Economist published an exciting article about a bioprinter that will be used for printing human organs!
Surgeons who perform human organ transplants hope that one day they will be able to obtain all the organs needed for a transplant at a moment's notice. Currently, a patient may spend several months, and possibly years, waiting for an organ from a suitable patient. During this time, his condition may worsen. He might 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 through a collaboration between two companies: San Diego-based Organovo, which specializes in regenerative medicine, and Melbourne-based 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 groups who, like Dr. Forjak, are studying ways to create artificial tissues and organs. Currently, much of this work is done manually using existing devices.
According to Keith Murphy, director of Organovo, at first only simple tissues such as skin, muscle and small areas of blood vessels will be created. However, immediately after testing of test samples is completed, production of blood vessels will begin for operations when it is necessary to “lay out” new vessels for blood flow to bypass damaged ones. With 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 necessary to supply blood to such artificially produced organs as the liver, kidneys, and heart.
History of bioprinting development
The 3D bioprinter, produced by Organovo, uses the same operating principle as “regular” 3D printers. 3D printers work similarly to regular inkjet printers, but print the model in three dimensions. These printers spray droplets of polymer that fuse together to form a single structure. Thus, with each pass, the print head 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 using “stages” made of special water-soluble materials. These scaffolds are washed away after the project is completely finished.
Researchers have discovered that a similar approach can be applied to biological materials! If you place tiny sections of cells next to each other, they begin to “fuse” together. A number of technologies are currently being explored that would make it possible to create human organs from individual cells, such as the technology of “pumping up” muscle cells using small machines.
Despite the fact that the human organ printing industry is just in its infancy, scientists can already boast successful examples 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 a bladder occurred 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). The resulting cells were then applied to a biological bladder, which was a supporting base shaped like a bladder heated to human body temperature. 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 supporting base (“scaffolding”) to operate. The Organovo machine uses stem cells obtained from 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 perfect for printing.
So, the first print head actually lays out droplets with cells in the desired 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 to two days to allow the droplets to “fuse” with each other. To create tubular structures such as blood vessels, a hydrogel is first applied (inside and outside the future structure). After this, cells are added. Once the organ is formed, the hydrogel is peeled off the outside (like the peel of an orange) and pulled out from the inside like a piece of rope.
Other types of cells and support bases can be used in bioprinters. So, according to Mr. Murphy, liver cells can be applied to a preformed base shaped like a liver, 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 could one day print tissue and organs directly into the human body! And, in fact, Dr. Atala is now working on a printer that, after scanning the area of the body where skin grafting is needed, will be able to print skin directly onto the human body! Regarding larger organs, Dr. Forjac believes they can take different 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 function completely like it. Those people who are waiting for organs probably won’t worry too much about what the new organs will look like. The main thing is that they work and people feel better.
UPD: The owners of the laboratory - Invitro - are now on Habré. I posted it on their corporate blog. You can contact them directly with questions.
This is from a new 3D organ printing lab. In front is an impressive microscope, then you can see two medical engineers using AutoCAD - making a mock-up of a site for the formation of tissue spheroids.
A laboratory for 3D organ bioprinting (Invitro project) recently opened here. Around her there is some kind of fierce extravaganza of misunderstanding of what exactly is being done.
In general, although I am not a microbiologist, I became interested. I made my way to the developer - V.A. Mironov. It was he who invented the technology for printing organs and patented it in the USA, participated in the development of three modifications of bioprinters, and it was he who was the “chief of science” in the new laboratory in Moscow:
V.A. Mironov (M.D., Ph.D., professor with 20 years of experience in microbiology, in particular, on the border with IT) - in the process of an hour and a half explaining to me the essence of the technology, he drew a bunch of paper.
He couldn’t talk about the press in a nutshell, because first you need to understand some of the history of the issue. For example, why did we have to discard the bright idea of raising a headless embryo in a surrogate mother, and then removing a kidney from it and placing it in a biosolution for accelerated maturation. For now, the main thing. Don’t rush to drink everything that burns: a new liver is still very far away
. Go.
Evolution of methods So, at first there was gene therapy: the patient was administered the appropriate complexes. Certain cells were isolated, the necessary genes were introduced into them, and then the cells were placed in the human body. There was not enough insulin - this is the gene that produces it. We take a cell complex, modify it, and inject it into the patient. The idea is great, although it has one fundamental drawback: the patient is cured immediately, and there is no need to buy anything after the operation. That is, guess who it was in the throat. The case was difficult, and then one of the patients died - and a typical US wave of lawsuits and bans began, as a result of which the research had to be curtailed. As a result, there is a method, but it has not been properly tested. The next trend was cell therapy
- use of embryonic stem cells. The method is excellent: “universal” cells are taken, which can be developed to whatever the patient needs. The problem is that to get them somewhere, you need an embryo. The embryo is obviously consumed in the process of obtaining cells. And this is a moral and ethical problem that caused a ban on the use of such cells. Further - tissue engineering - this is when you take a base, put cells on it, put it all into a bioreactor, and at the output you get the result (organ) that the patient needs. Like a prosthesis, only alive. Here: the main difference from a prosthesis is that the prosthesis is initially made of inorganics, and is unlikely to ever integrate into the body “like a native one.” You can't scratch a wooden leg.
Tissue engineering methods are frame– when a leached (deprived) cadaveric organ is used, which is then “populated” with the patient’s cells. Other scientific groups have tried to work with porcine protein organ scaffolds (human donors are not needed, but immunocompatibility is fully realized). The frames can be artificial - from different materials; some scientific groups have even experimented with sugar.
Mironov himself practices frameless technology(using hydrogel as a base). In his method, the polymer base quickly degrades and ultimately only cellular material remains. Simply put, first a neogranic frame with placed cells is inserted, and then the frame “dissolves” and its functions are taken over by the cells of the already grown organ. The same material is used for the frames as for surgical sutures: it easily and simply degrades in the human body.
The main question here is why 3D printing is needed. To understand this, let's dig a little deeper into the available tissue engineering methods.
Getting closer to the goal
In general, the idea of inserting a pre-grown organic organ into a person is excellent. Let's look at three options for technology development:- You take an inorganic frame, seed it with cells, and you get a finished organ. The method is rough, but it works. This is what we are talking about in most cases when they say “we printed an organ.” The problem is that somewhere you need to take the “building material” - the cells themselves. And if they exist, then it is stupid to use some kind of external frame when it is possible to simply assemble an organ from them. But the most painful problem is incomplete endothelialization. For example, for bronchi done this way, the level is about 70%. This means that the superficial vessels are thrombogenic - by curing a patient, you immediately introduce a new disease to him. Then he must live on heparin or other drugs, or wait for a blood clot and embolism to form. And here US lawyers are already waiting impatiently, ready to play out according to the old scenario. And the problem of endothelialization has not yet been solved. Possible variant– isolating bone marrow progenitor cells using mobilization with special preparations and homing on the organ, but this is still a fantasy very far from practice.
- The second method is extremely original and very pleasing in its cynicism. We take a patient’s cell (fibroblast) and add 4 genes. We put the resulting cell into a blastocyst (an animal embryo) and begin to grow the animal. It turns out, for example, a pig with a human pancreas - the so-called chimera. The organ is completely “native”, only the entire infrastructure around it – blood vessels, tissues, and so on – comes from a pig. And they will be rejected. But nothing. We take a pig, cut out the desired organ (the pig is completely consumed), and then we remove all the pig tissue using special processing - we get a sort of organic frame of the organ that can be used to grow a new one. Some researchers went further and proposed the following lifehack: let's replace the pig with a surrogate mother. Here it is: in addition to 4 genes, another one is added to the cell, which is responsible for acephaly (lack of a head). A surrogate mother is hired to carry our mutual embryo friend. It develops without a head; acephalians do this well. Then - an ultrasound, finding out that the child is defective, and a legally permitted abortion. No head - no person, which means we didn’t kill anyone. And then - once! - we now have a theoretically legal biomaterial with the patient’s undeveloped organs. Let's implant them quickly! Of the obvious disadvantages - well, besides the moral side - organizational complexity and possible legal complications in the future.
- And finally, there is a third method, which is what we are talking about. It is also the most modern - three-dimensional printing of organs. And this is exactly what they are doing in the new laboratory. The point is this: there is no need for inorganic scaffolds (the cells support themselves perfectly well), there is no need to take organs from someone. The patient donates a little of his adipose tissue (everyone has it; during the experiments, only skinny Japanese complained), from which the necessary structural elements are obtained by sequential processing of cells. A three-dimensional model of the organ is created, converted into a CAD file, then this is given to a 3D printer, which can print with our cells and understands at which point in three-dimensional space it needs to be “placed” specific type cells. The output is a tissue construct that must be placed in a special environment before problems with hypoxia begin. In the bioreactor, the tissue construct “ripens”. The organ can then be “transplanted” into the patient.
- Obtaining a model of an organ. You need to get a diagram somewhere. It's pretty simple.
- Obtaining the cells themselves. Obviously, we need material to print the organ.
- Assembling a printer so that cells can be printed (a lot of problems with the formation of an organ structure).
- Hypoxia (lack of oxygen) during organ creation.
- Implementation of nutrition of the organ and its maturation to readiness.
Organ model
So, a CAD file is taken (now in stl format) with a model of the organ. The easiest way to obtain a model is to make a three-dimensional scan of the patient himself, and then refine the data manually. Currently, current designs are modeled in AutoCAD.
Modeling is visible. The 3D structure is like a regular part - only instead of plastic there will be fabric spheroids.
Material
The material is taken - tissue spheroids, which will be used for sealing. A hydrogel is used as a base and acts as a connecting structure. The 3D printer then prints the organ from these tissue spheroids.
The first experiment confirming that a whole organ can be assembled from pieces: scientists cut the heart of a chicken into fragments and fused it back together. Successfully.
Now the question is where to get the cells for this material. The best are human embryonic stem cells, from which cells can be made for any tissue by sequential differentiation. But, as we know, you can’t touch them. But you can take iPS - induced pluripotent stem cells. They can be made from bone marrow, dental pulp or the patient's normal fat tissue - and they are produced various companies Worldwide.
The scheme is as follows: a person goes to the clinic, undergoes liposuction, the adipose tissue is frozen and placed in a repository. If necessary, it is obtained, the necessary cells are made from it (ATDSC, there is one such complex in Russia) and then differentiated according to their intended purpose. For example, iPS can be made from fibroblasts, renal epithelium can be made from them, and then functional epithelium can be made.
Machines for automatically producing such cells are produced by General Electric, for example.
Centrifuge. The first stage of separation of material from adipose tissue.
From these cells balls are formed in special micro-grooves on hard material. A cell suspension is placed into a recess on the mold, then the cells grow together to form a ball. More precisely, a not very smooth spheroid.
Processing of structural blocks
The next problem is that the cells in the cartridge are eager to grow together. Tissue spheroids must be isolated from each other, otherwise they will begin to grow together prematurely. They need to be encapsulated, and for this purpose hyaluronic acid is used, obtained from blood serum. You need very little of it - just one thin layer. It also “goes away” quickly after printing.Seal
The 3D printer head has three extruders: two nozzles with gel and a device that produces tissue spheroids. The first nozzle with gel contains thrombin, the second nozzle contains fibrinogen. Both gels are relatively stable until they touch. But when the protein fibrinogen is cleaved by thrombin, fibrin monomer is formed. It is with this that tissue spheroids are held together like concrete. With a layer depth corresponding to the diameter of the spheroid, you can sequentially apply the material row by row - make a layer, fix it, move on to the next one. The fibrin is then easily degraded in the medium and washed away during perfusion, leaving only the desired tissue.
This is how the tubes will be printed
The printer prints in layers of 250 micrometers: this is a balance between the optimal block size and the risk of hypoxia in the spheroid. In half an hour, you can print a tissue-engineered structure of 10x10 centimeters - but this is not yet an organ, but a tissue-engineered structure, “snot” in the jargon. For a structure to become an organ, it must live, have a clear form, and perform functions.
A microscope with a huge focal length looks at a glass cube with a 3D printer.
Printhead. The complex is currently being tested on plastic. The printer is now printing consumables, plastic molds for creating spheroids. At the same time, tests are being carried out on a sterile box for a 3D printer with the electronic device running.
Post-processing
The main question is that cells, in general, would benefit from having access to oxygen and nutrients. Otherwise, they begin, roughly speaking, to rot. When the organ is thin, there are no problems, but from a couple of millimeters this is important. True, an elephant, for example, has cartilage up to 5 millimeters - but they are mounted where a lot of pressure is created due to the mass of the rest of the elephant. So, to prevent the printed organ from deteriorating during the fabrication process, microcirculation is needed. This is done by printing real vessels and capillaries, plus using the finest perfusion holes made by inorganic instruments (roughly speaking, building blocks arrive on a polymer “skewer”, which is then removed).
Fabric seal
Tissue association of several cell types without mixing
The future organ is placed in a bioreactor. This, to greatly simplify, is a jar with a controlled environment in which the necessary substances are supplied to the inputs and outputs of the organ, plus accelerated maturation is ensured due to the influence of growth factors.
Here’s what’s interesting - the architecture of an organ is usually similar to an encapsulated object familiar from OOP – an entry artery, an exit vein – and a bunch of functions inside. It is assumed that the bioreactor will provide the required input and output. But this is still a theory; not a single one has been collected yet. But the project has been developed to the stage “you can assemble a prototype.”
It hung in the laboratory. The first stage is visible: obtaining basic elements, the second is a 3D printer with three extruders, the third is moving from a prototype to an industrial model, then testing on animals, then going to an IPO and installing it in people.
Entire line - cell sorter, tissue spheroid fabricator, printer, perfusion unit
Markets
Now who needs all this at the stage when the organs themselves are not there?The first ones large clients– military. Actually, as you might guess, DARPA visits all scientists working on this topic. They have two uses - testing (there are many things that cannot be tested on living people, but I would like to - a separate organ would be very useful) and therapeutic. For example, a democracy fighter’s arm is torn off, and it takes a day to crawl to the hospital. It would be nice to close the hole, relieve the pain, give him the opportunity to shoot for another 5 hours, and then come to the nurse on his own. In theory, either robots are possible that will assemble all this in place, or patches from human tissue, which are already being seriously considered for use on burns.
Second client – pharma. There, drugs are tested for 15 years before entering the market. As Americans joke, it is easier to kill a colleague than a mouse. On a mouse you need to collect a bunch of documents as thick as your hand. Certified mice end up being very expensive. And the results for animals differ from those for humans. Current flat cell and animal testing models are not sufficiently relevant. The laboratory told me that approximately 7% of new drug formulations in the world do not make it to clinical trials due to nephrotoxicity detected during preclinical testing. Of those that did, about a third had toxicity problems. That is why, by the way, one of the first tasks is to test the functionality of nephrons made in the laboratory. Tissues and organs from the printer will significantly speed up the development of drugs, and this is a huge amount of money.
The third client is hospitals. The kidney transplant market in the USA, for example, is worth 25 billion dollars. At first, the plan is to simply sell 3D printers to hospitals so that patients can get what they need. The next (theoretical) step is to create complexes for printing organs directly inside the patient. The fact is that it is often much easier to deliver a miniature print head inside a patient than a large organ. But these are still dreams, although the necessary robots exist.
This is roughly how it should work
Yes, there is another important topic here: in parallel, research is being conducted on the control of tissue spheroids due to magnetic levitation. The first experiments were simple - iron “nanofilks” were inserted into the fabric, and the spheroids actually flew as they should in the magnetic field and were delivered to the location. But differentiation suffered. It is difficult to perform the necessary functions with sawdust. The next logical step is metal in the encapsulating layer. But even cooler are microscaffolds with magnetic particles. These scaffolds cover the spheroid and can also act as a frame-connector that fits right into place, which provides enormous scope for the rapid printing of organs.
3D printing of a human organ may one day become a medical routine. At the 3D Bioprinting Solutions company, an ITAR-TASS correspondent got acquainted with the achievements of domestic bioprinting.
Employee of the Laboratory of Biotechnological Research "3D Bioprinting Solutions"
Three stages of bioprinting
In the 3D Bioprinting Solutions laboratory, under the glass of a laminar (sterile box), there is a device that, at first glance, resembles an ordinary 3D printer: mechanical drives, and cartridges in the form of glass tubes: they contain “ink”. The printer rustles, unfolds the cartridges, something is squeezed onto the glass stand - some tiny gelatinous structure gradually appears. In this case, an elementary drop of ink is not just cells, but so-called tissue spheroids - micron-sized balls containing up to 2 thousand living cells of the required type. Considering that the organ consists of cells of different types, there are also several cartridges. Biopaper, that is, the place where bioink is fixed, is a hydrogel.
A “regular” 3D printer will surprise few people: it was invented in 1985 by American Chuck Hall. Three decades later, 3D printers are being mass-produced, and their main commercial use today is printing 3D prototypes of everything from buildings to airplanes. There are also household models that allow you to print, for example, a cup. 3D printing has also been used in medicine for a long time: in surgery, dentistry for the manufacture of prostheses or implants. But the prospects for bioprinting, the next evolutionary step in 3D printing, look truly revolutionary. When humanity learns to print new organs using living cells to replace worn-out ones, life will never be the same.
Russian scientist Vladimir Mironov wondered in 2003 at the University of North Carolina: why not, using exactly the same principle by which a 3D printer produces polymer structures, not recreate biological structures using cells instead of plastic as “ink”. In the same 2003, he developed a general technology for the so-called “organprinting” and published an article, after which the terms “bioprinter”, “biopaper”, “bioink” came into use. Today Vladimir Mironov is the scientific director Russian company"3D Bioprinting Solutions", a resident of the Skolkovo Biomedical Technologies cluster.
It’s not visible to the eye, but, as they explain to me, the bioprinter is also equipped with an ultraviolet source: radiation is necessary for hardening the biodegradable hydrogel.
“Note that we are not engaged in cultivation, but in assembly, that is, assembling organs. It all starts with a digital 3D model of the organ - it is necessary to virtually cut it into layers, set the distribution of cells of different types in these layers, and provide for the placement of hollow spheroids inside, from which vessels are formed,” says Vladimir Mironov. The screen shows what exactly the printer was doing right before my eyes: a layer of spheroids is laid out on the hydrogel base (different colors of the balls are different cells), then again a layer of hydrogel, and on top of that is the next layer of spheroids. But in the three-dimensional model, cylindrical holes have formed - these are vascular channels. The printed structure is not yet a finished organ. For now, this is simply a design in which the cell spheroids are supported by a hydrogel located between them: hence the appearance of the jelly. The next stage is tissue maturation, that is, the fusion of spheroids together with the simultaneous release of the hydrogel. This process takes place in a special bioreactor: a small chamber placed in an incubator cabinet that maintains the required temperature and humidity. “What you saw is, in fact, the three main stages of assembling an organ: creating a digital model, the printing process and maturation. Each of them in itself is a separate complex area of research,” notes Vladimir Mironov. 
Vladimir Aleksandrovich Mironov, scientific director of the Laboratory of Biotechnological Research “3D Bioprinting Solutions”
Cellular technologies
It is clear that each organ must be printed from cells suitable for a particular patient. The raw materials for the production of “bioink” are stem cells from three sources. From them you can grow cells for any organ. The first, most accessible one is the patient’s own adipose tissue. Another source is embryonic stem cells. These cells are isolated from umbilical cord blood after childbirth and stored in special cryobanks. But few patients have such a reserve. Therefore, there is a third source: induced stem cells, that is, with a high degree of approximation, grown for the patient using donor cells.
“We are not engaged in the production of aluminum - we are building airplanes,” Vladimir Mironov finds more and more words, explaining that the task of the laboratory is to develop technology for assembling organs, and not to obtain cells (there are specialized companies for this). However, elementary cells from adipose tissue are obtained directly here. And most importantly, spheroids for experiments are produced directly in the 3D Bioprinting Solutions laboratory. I am shown plastic molds with a mesh structure for making spheroids. A spheroid is a droplet of 200-250 microns. Under a microscope you can see that there are many cells in the shell of the ball. Spheroids are made both manually (applied with a pipette) and using a special machine created by 3D Bioprinting Solutions: the automated technology is still being tested.
An automated microfluidic method for scaling spheroids will provide a bioprinter with ink for a large tissue construct: 1 thousand spheroids per second.
Employee of the Laboratory of Biotechnological Research "3D Bioprinting Solutions"
On the threshold of practice
There are only 16 people at 3D Bioprinting Solutions, including researchers and management. According to executive director Youssef Khesuani, the company was created in early 2013, and since that time hundreds of thousands of dollars have been invested in the creation of laboratories and research. It is noteworthy that the investor is the well-known INVITRO laboratory chain. As Vladimir Mironov noted, it usually takes 15-30 years from an idea to a finished technology. According to his forecasts, the implantation of the first bioprinted organs (at first relatively simple ones like the thyroid gland) will begin around 2030. The simplicity or complexity of an organ is determined by the presence of various “options” such as channels, valves and other elements that are often difficult to print. “In the future, a “bioprinting” department at every hospital will be as common as an X-ray room or an operating room,” Vladimir Mironov is sure. “We needed some kind of organ—they printed it on the spot.”
However, it is possible to monetize bioprinting technologies without waiting for this bright future. “Here we created the first Russian commercial bioprinter; today we can create such ones to order. We have applications from different countries,” says Yousefa Khesuani. Bioprinters in the world cost from $250 thousand to $1 million. Biological structures printed on them are used, for example, by pharmaceutical companies to test new drugs.
The first Russian bioprinter created by 3D Bioprinting Solutions differs from foreign analogues, firstly, in its special solution for ultraviolet irradiation, which hits the hydrogel without touching the cells. Secondly, this is the only multifunctional printer - it combines all known printing methods (with cells, spheroids, in hydrogel, without hydrogel).
And finally, the specialists of 3D Bioprinting Solutions made their printer small, that is, it fits into a standard serial laminar - for Western analogues, you usually have to order separate laminars, which cost $20 thousand. “We are going to engage in joint scientific research on our printer with scientific groups from all over the world, work on various projects that can be commercialized,” says Youssef Khesuani. “To act as a technological platform for testing bio-ink and bio-paper, to establish bio-printing technologies, to make custom samples of materials, etc. Including, to sell our machine and molds for the production of spheroids.” Today there are less than two dozen companies in the world that have ready-made bioprinters. But the world believes in the prospects of a trend that promises a revolution in health care: the production of bioprinters American company
“The project to create a 3D Bioprinter has two stages of commercialization. Initially, the printer will be offered for sale to science-2-science, and printing of biological tissues and organ models can be used for the development of medicines, says Kirill Kayem, vice president of the Skolkovo Foundation, executive director of the biomedical technology cluster. “We expect that, thanks to the ecosystem effect, the developments of 3D Bioprinting Solutions will be in demand by other Skolkovo residents. At the second stage of commercialization, we expect that the successful development of the system will make it possible within a few years to print organs for use in clinical practice, including at the Research Medical Center on the territory of Skolkovo. The 3D Bioprinting Solutions project is at the forefront of science and practice. There are only a couple of dozen developments of this kind in the world, and, unlike the Skolkovo resident’s project, quite a large part of them are focused specifically on printing tissues, and not whole organs.”
Vladimir Mironov is confident that already in next year his team will be able to print the first full-fledged organ - the thyroid gland.
Bioprinting is one of the most revolutionary areas of 3D printing. The future of medicine depends on how this technology develops.
What is meant by the word “bioprinting”?
Today, 3D printers are being actively developed for printing food products - chocolate, sugar, jelly, etc. At the same time, another direction is developing - scientists are trying to grow meat or fiber based on algae in the laboratory. Bioprinting falls somewhere in between these approaches—between genetics and 3D printing.
3D technologies have already influenced the development of medical implants. Today, doctors calculate transplants that are ideal for the patient by 3D scanning the damaged area, creating a 3D model, and printing it on a 3D printer.
But medicine, for its part, also influenced the young 3D printing industry: new materials for printers are being created - with hypoallergenicity, high biocompatibility and low rejection. As a rule, this is ceramics or special biocompatible plastic.
Organ seal
Organs are different - some are easier to print, some are more difficult. Let's start with simpler processes and move on to complex ones:
- Flat structures, usually with one or two types of cells, that is, the creation of human skin for transplantation into damaged areas, such as burns;
- Tubular structures, mainly with two types of cells, to create blood vessels;
- Hollow organs. Difficulties arise in the stomach or bladder, when they perform complex functions and interact with other organs.
- Functional organs consisting of many types of cells that interact with each other in complex ways. First of all, these are the heart, liver and kidneys.
Regenerative medicine has already proven that it can successfully implant lab-grown versions of the first three types of organs. Researchers hope that as the 3D printing industry develops, organ transplants can be mass produced.
To date, lab-grown skin, bladders and tracheas have been implanted - body parts slowly grown through a combination of artificial scaffolds and living human cells. 3D printing technologies offer greater speed and computer precision in the formation of a layer of living cells.
Creating complex organs using a 3D printer remains a fantasy for now. No one has yet succeeded in printing a heart or liver from a patient's cells, although the first careful steps have already been taken: 3D technologies are used to create tiny pieces of organs.
How organs are printed
Artificial supports are created to grow organs. They are identical in shape to the organ itself. Living cells are seeded onto their surface.
Using this method, artificial bladders were grown for the first implantations in patients in 1999. More than 10 years have passed, 3D printers have become more advanced, and now they can print both artificial supports and living cells at the same time.
Some laboratories predict that it will soon be possible to do without artificial supports, using the tendency of living cells to “self-organize.” The supporting material will eventually simply dissolve (for which a hydrogel, a viscous aqueous composition, can be used), without affecting living cells, but leaving the original tissue structure in a given position. The problem is the strength and integrity of the created structure.
Scientists at Organovo are experimenting with creating tiny pieces of liver to act as building blocks. The company's 3D printers can already arrange blocks in layers, allowing living cells to grow together. A patient's stem cells could provide material for 3D printing an organ that the body won't reject.
Existing problems
The ability to print full-size, functioning organs depends on whether scientists can create full-fledged blood vessels. The vessels will supply the organs with blood rich in nutrients and oxygen, which will keep the tissue healthy. So far, no laboratory has been able to create 3D printed organs with a network of blood vessels.
Organovo is experimenting with 3D printing blood vessels 1mm or larger in diameter. They were able to build tissues containing tiny blood vessels measuring 50 microns in size. This is enough to support a millimeter-thick organ fragment.
Even the best 3D printers cannot create systems on the smallest scale for building blood vessels and organs. Many researchers believe that the solution lies in studying the tendency of living cells to self-organize. This will allow tissue to be printed in tens or hundreds of microns, and then the cells will independently develop and organize themselves correctly.
Prospects for bioprinting
So what is bioprinting? This is an industry that will save the lives of millions in the future by creating custom implants and organs. According to researchers, this will happen in 10-15 years.
Tiny fragments of the heart, liver and kidneys are currently being created. They are used to test all kinds of drugs or the effects of diseases and toxic substances on tissue.
Once upon a time it was science fiction, but today it is a scientific fact - 3D printing of human organs is used in medicine.
At first glance, the very idea of producing organs “to order” using 3D printing seems like the plot of a science fiction film. However, technology that can create living human tissue, replace vital organs, and quickly heal open wounds is much more feasible than you might imagine.
3D printed organs are already being used as teaching aids for future surgeons to sharpen their skills before facing real life emergencies. 3D printed bone replacements have also been successfully transplanted, but printing living tissue will become next step in the development of this innovative technology.
Process
As with any other 3D printing, the object is printed layer by layer, but unlike PLA or ABS 3D technologies, living cells that are in a gel-like mass are used to create living tissue. After this, the cells grow and develop, turning into living tissue, bones and even entire organs. The promise of what this technology can do for humanity is truly enormous. There is an acute shortage of donor organs in the world, and 3D bioprinting could be a solution to this problem.
Early developments
Although 3D bioprinting technology is not yet ready for commercial use, its application is already producing mind-blowing results.
Using the RepRap 3D printer, a team of bioengineers from the University of Pennsylvania created working blood vessels. Bioengineers around the world are confidently moving towards the fact that it will be possible to print organs from patient cells, but on this thorny and complex path there are still many difficulties and problems that have yet to be overcome. A key challenge facing bioengineers is creating a system of blood vessels that can exchange nutrients and remove waste from internal tissue cells. Since there is no way to create such blood vessels, the internal cells will quickly suffocate and die. But a team from Pennsylvania has come up with a surprising solution to the problem.
Bioengineers at the University of Pennsylvania tried to solve this problem by using a 3D printer called RepRap to print a network of blood vessels from sugar. Once a special network of blood vessels is introduced into a group of cells, the sugar simply dissolves, leaving a functioning vascular network.
Bioengineering scientist Jordan Miller says the idea came to him while visiting an exhibition. “The first time this thought came to me was when I was at the Body Worlds exhibition, where you can see individual plastic molds and casts of organs of the cardiovascular system.”
When the sugar hardens, a gel-like mass containing liver cells is added to the mold. This gel coats and envelops the blood vessels. Once the gel has hardened, it can be removed from the mold. The sugar form remains inside until the gel is washed off with water, at which time the sugar dissolves completely. Liquid sugar flows through the same blood vessels that were created with its help, without causing any harm to the cells.
“From a cell perspective, this new technology makes tissue generation simple and easy,” says Christopher Chen, professor of innovation in the Department of Bioengineering.
Breakthrough
Surgeon Anthony Atala is the director of the Wake Forest Institute for Regenerative Medicine, and he and his team have made significant strides in 3D organ printing. Using living cells, Atala is working on 3D printing kidneys for transplantation. And although everything is still on early stage, Atal's team has already made significant progress toward solving one of the biggest challenges facing transplantation - the worldwide shortage of donor kidneys.
More than 10 years ago, Atala successfully transplanted an artificial bladder into his patient Luke Massella, so he, like few others, knows how this technology can change lives.
Anthony Atala asks, “Can we grow organs instead of transplanting them?” His laboratory at the Wake Forest Institute for Regenerative Medicine is doing just that, creating more than 30 tissues and entire organs.
Practical use
In addition to organ transplantation, 3D printing can be used in various fields of medicine. This will not only help produce donor organs, but also provide better healing and recovery for patients, and better medical education for existing professionals and students. Some practical examples where such technologies can be applied:
1. Organs
The most obvious use for 3D printed organs: transplantation. The ability to create new organs directly from a patient's own cells cannot be overstated. This could save tens of thousands of lives every year.
2. Skeletal support
Manufacturing complex and detailed objects is one of the strengths 3D printing, so 3D printers are already being used to create biodegradable structures to support the skeleton to help and facilitate patient healing and tissue growth.
3. Replacement of bones
When combined with 3D scanning, 3D printers can create bone, such as a femur, which is ideal for those who need new bone tissue. Creating replacement bones specifically tailored to each patient greatly reduces patient discomfort and improves mobility after grafting.
4. Practice of operations
Whenever you visit a doctor, you want to know that you are in experienced hands. Nobody wants to be the first one to be operated on by this doctor. With 3D printed organs, future surgeons could perform dozens or even hundreds of surgeries before performing the same surgery. to a real person. Surgeons' ability to gain better practice means the resulting surgery will take less time and recovery will be faster.
5 . Testing of medical products
Nobody likes the idea of testing drugs, whether on animals or humans. But again, we all want to know that our medications are tested and safe. With the proliferation of 3D bioprinting, printed organs and tissues could be tested for side effects or negative reactions to a given drug in development. If you see a side effect from a drug on a bottle or package of medicine, it means that someone has already experienced this side effect while testing and studying the drug. With 3D printing, we will forever forget about testing medications on humans and animals. This will also contribute to the continuous development of medicine.
Leading Researchers
One of the main developers of 3D printing of organs is the San Diego company Organovo. Their website states:
"At Organovo, we design and create fully functional human tissue using our proprietary 3D bioprinting technologies. Our goal is to create living human tissue that functions like natural human tissue. With 3D tissue that closely matches human biology, we make it possible to use innovative treatment methods:
In collaboration with biopharmaceutical companies and academic medical centers, we design, create and test engineered tissues for disease modeling and toxicology studies.
We're giving researchers something they've never had before: the ability to test drugs on functional human tissue before administering the drug to a living person; this will help bridge the existing gap between preclinical and clinical trials.
We create functional, three-dimensional tissues that can be implanted into the human body to treat or replace damaged or diseased tissue."
The company was recently registered on the New York stock exchange. Organovo has already proven the commercial value of this very new field of activity, which will undoubtedly grow and develop in the future.
Although personal 3D printers are not far behind and, according to experts, they can radically affect the field of medicine.
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