3D printing organ transplant

3D-printed organs: The future of transplantation

CNN —

What if doctors could just print a kidney, using cells from the patient, instead of having to find a donor match and hope the patient’s body doesn’t reject the transplanted kidney?

The soonest that could happen is in a decade, thanks to 3D organ bioprinting, said Jennifer Lewis, a professor at Harvard University’s Wyss Institute for Biologically Inspired Engineering. Organ bioprinting is the use of 3D-printing technologies to assemble multiple cell types, growth factors and biomaterials in a layer-by-layer fashion to produce bioartificial organs that ideally imitate their natural counterparts, according to a 2019 study.

This type of regenerative medicine is in the development stage, and the driving force behind this innovation is “real human need,” Lewis said.

In the United States, there are 106,075 men, women and children on the national organ transplant waiting list as of June 10, according to the Health Resources & Services Administration. However, living donors provide only around 6,000 organs per year on average, and there are about 8,000 deceased donors annually who each provide 3.5 organs on average.

47-year-old Steve Verze is to become the first man in the world to be fitted with a 3D printed eye, according to Moorfields Eye Hospital. He tried the eye for size earlier this month, as photographed here.

Moorfields Biomedical Research Centre

British man given 3D printed eye in world first, hospital says

The cause of this discrepancy is “a combination of people who undergo catastrophic health events, but their organs aren’t high enough quality to donate, or they’re not on the organ donor list to begin with, and the fact that it’s actually very difficult to find a good match” so the patient’s body doesn’t reject the transplanted organ, Lewis said.

And even though living donors are an option, “to do surgery on someone who doesn’t need it” is a big risk, said Dr. Anthony Atala, director of the Wake Forest Institute for Regenerative Medicine. “So, living related donors are usually not the preferred way to go because then you’re taking an organ away from somebody else who may need it, especially now as we age longer.”

Atala and his colleagues were responsible for growing human bladders in a lab by hand in 2006, and implanting a complicated internal organ into people for the first time – saving the lives of three children in whom they implanted the bladders.

A bladder scaffold is seeded with cells at the Wake Forest Institute for Regenerative Medicine.

Courtesy Wake Forest Institute for Regenerative Medicine

Every day, 17 people die waiting for an organ transplant, according to the Health Resources & Services Administration. And every nine minutes, another person is added to the waitlist, the agency says. More than 90% of the people on the transplant list in 2021 needed a kidney.

“About a million people worldwide are in need of a kidney. So they have end-stage renal failure, and they have to go on dialysis,” Lewis said. “Once you go on dialysis, you have essentially five years to live, and every year, your mortality rate increases by 15%. Dialysis is very hard on your body. So this is really motivating to take on this grand challenge of printing organs.”

“Anti-hypertensive pills are not scarce. Everybody who needs them can get them,” Martine Rothblatt, CEO and chairman of United Therapeutics, said at the Life Itself conference, a health and wellness event presented in partnership with CNN. United Therapeutics is one of the conference’s sponsors.

“There is no practical reason why anybody who needs a kidney – or a lung, a heart, a liver – should not be able to get one,” she added. “We’re using technology to solve this problem.”

To begin the process of bioprinting an organ, doctors typically start with a patient’s own cells. They take a small needle biopsy of an organ or do a minimally invasive surgical procedure that removes a small piece of tissue, “less than half the size of a postage stamp,” Atala said. “By taking this small piece of tissue, we are able to tease cells apart (and) we grow and expand the cells outside the body. ”

This growth happens inside a sterile incubator or bioreactor, a pressurized stainless steel vessel that helps the cells stay fed with nutrients – called “media” – the doctors feed them every 24 hours, since cells have their own metabolism, Lewis said. Each cell type has a different media, and the incubator or bioreactor acts as an oven-like device mimicking the internal temperature and oxygenation of the human body, Atala said.

“Then we mix it with this gel, which is like a glue,” Atala said. “Every organ in your body has the cells and the glue that holds it together. Basically, that’s also called ‘extracellular matrix. ’ ”

Richard Roth with Samira Jafari

Courtesy Samira Jafari

Living organ donations save lives. This is how you become a donor

This glue is Atala’s nickname for bioink, a printable mixture of living cells, water-rich molecules called hydrogels, and the media and growth factors that help the cells continue to proliferate and differentiate, Lewis said. The hydrogels mimic the human body’s extracellular matrix, which contains substances including proteins, collagen and hyaluronic acid.

The non-cell sample portion of the glue can be made in a lab, and “is going to have the same properties of the tissue you’re trying to replace,” Atala said.

The biomaterials used typically have to be nontoxic, biodegradable and biocompatible to avoid a negative immune response, Lewis said. Collagen and gelatin are two of the most common biomaterials used for bioprinting tissues or organs.

From there, doctors load each bioink – depending on how many cell types they’re wanting to print – into a printing chamber, “using a printhead and nozzle to extrude an ink and build the material up layer by layer,” Lewis said. Creating tissue with personalized properties is enabled by printers being programmed with a patient’s imaging data from X-rays or scans, Atala said.

“With a color printer you have several different cartridges, and each cartridge is printing a different color, and you come up with your (final) color,” Atala added. Bioprinting is the same; you’re just using cells instead of traditional inks.

How long the printing process takes depends on several factors, including the organ or tissue being printed, the fineness of the resolution and the number of printheads needed, Lewis said. But it typically lasts a few to several hours. The time from the biopsy to the implantation is about four to six weeks, Atala said.

A 3D printer seeds different types of cells onto a kidney scaffold at the Wake Forest Institute for Regenerative Medicine.

Courtesy Wake Forest Institute for Regenerative Medicine

The ultimate challenge is “getting the organs to actually function as they should,” so accomplishing that “is the holy grail,” Lewis said.

“Just like if you were to harvest an organ from a donor, you have to immediately get that organ into a bioreactor and start perfusing it or the cells die,” she added. To perfuse an organ is to supply it with fluid, usually blood or a blood substitute, by circulating it through blood vessels or other channels.

Depending on the organ’s complexity, there is sometimes a need to mature the tissue further in a bioreactor or further drive connections, Lewis said. “There’s just a number of plumbing issues and challenges that have to be done in order to make that printed organ actually function like a human organ would in vivo (meaning in the body). And honestly, this has not been fully solved yet.”

Once a bioprinted organ is implanted into a patient, it will naturally degrade over time – which is OK since that’s how it’s designed to work.

“You’re probably wondering, ‘Well, then what happens to the tissue? Will it fall apart?’ Actually, no,” Atala said. “These glues dissolve, and the cells sense that the bridge is giving way; they sense that they don’t have a firm footing anymore. So cells do what they do in your very own body, which is to create their own bridge and create their own glue.”

Atala and Lewis are conservative in their estimates about the number of years remaining before fully functioning bioprinted organs can be implanted into humans.

“The field’s moving fast, but I mean, I think we’re talking about a decade plus, even with all of the tremendous progress that’s been made,” Lewis said.

“I learned so many years ago never to predict because you’ll always be wrong,” Atala said. “There’s so many factors in terms of manufacturing and the (US Food and Drug Administration regulation). At the end of the day, our interest, of course, is to make sure the technologies are safe for the patient above all.”

Whenever bioprinting organs becomes an available option, affordability for patients and their caregivers shouldn’t be an issue.

They’ll be “accessible for sure,” Atala said. “The costs associated with organ failures are very high. Just to keep a patient on dialysis is over a quarter of a million dollars per year, just to keep one patient on dialysis. So, it’s a lot cheaper to create an organ that you can implant into the patient. ”

The average kidney transplant cost was $442,500 in 2020, according to research published by the American Society of Nephrology – while 3D printers retail for around a few thousand dollars to upward of $100,000, depending on their complexity. But even though low-cost printers are available, pricey parts of bioprinting can include maintaining cell banks for patients, culturing cells and safely handling biological materials, Lewis said.

Some of the major costs of current organ transplantation are “harvesting the organ from the donor, the transport costs and then, of course, the surgery that the recipient goes through, and then all the care and monitoring,” Lewis said. “Some of that cost would still be in play, even if it was bioprinted.”

How close are we to 3D printing organs for human transplants?

3D printed tissues for ear, skin and blood vessels are in clinical trials and research for other organs is underway too. We ask some bioprinting companies if and when humans can benefit from this technology.

Scientists and researchers across the globe are working hard to bioprint functional human organs to meet the demand of a growing list of people waiting for organ transplants across the world.

There are currently more than 106,000 people waiting for an organ transplant in the United States alone, with a new person added every 9 minutes to the list.

Many of these people are in need of critical organs such as kidneys, hearts and livers that could save their lives. However, due to limited resources, around 8,000 Americans on the waiting list die each year.

Biotechnology company Regemat 3D believes the development of bioengineered organs for human transplants is an attainable goal and that 3D bioprinting will have a main role in that accomplishment.

“We believe 3D bioprinting is and will be a key factor in the progress towards more efficient and personalised medical treatments in the upcoming future,” Sara Mico, Regemat 3D’s Business Developer and Product Specialist, told TRT World.

Since 2015, Regemat 3D has grown to become one of the top 15 3D bioprinting emerging companies worldwide, with a presence in nearly 30 countries.

“We are the only company in the world specialised in the design and development of customised 3D bioprinters and bioreactors for tissue engineering applications,” said Mico.

Some benefits of 3D bioprinting cited by Mico include the potential to accelerate the development of new drugs and shorten the time required for them to reach the market and reduce the number of animals used in research.

But how far off is the expansion of this technology to creating complex organs?

Bioprinting company nScrypt predicts this reality will emerge within the next decade, Marketing/Sales and Communications Specialist Brandon B. Dickerson told TRT World.

“We all have our crystal balls, and I say 5 to 10 years. I think soon, I’ll be saying 4 to 8 years, we are closing the gap,” said Dickerson.

In contrast, Fabien Guillemot, CEO of next-generation bioprinting company Poietis, told TRT World it’s “difficult to define when (and if) the world will be able to print organs” due to the different degree of tissue complexity compared to that of organs.

“Different 3D bioprinted tissues are entering into clinical trials (ear, skin, blood vessels). Other applications like heart patches, cornea, cartilage are also in preclinical development in many institutions and companies, worldwide.”

Guillemot said all these trials contain tissues that have a different degree of complexity, which remains lower than that of an organ's, for example some are flat tissues and some include one or two different cell types.

“But, implanting bioprinted functional tissues might be sufficient to restore and repair organ functions without changing the whole organ,” said Guillemot. “So, we anticipate that clinicians will use in routine bioprinting and bioprinted tissue products made of the patient’s own cells.”

Mico said that while the field is still “very far” from the reality of bioprinting complex organs “it is so important to invest time and resources in basic and translational research today, because today’s research will become the clinical applications of tomorrow.”

READ MORE: Turkish biotech company develops artificial veins

From research to clinical trials

While bioprinting was initially proposed around two decades ago, its first applications have been for research and testing such as in cosmetics and pharmaceuticals, Guillemot told TRT World.

Then in 1999, a functioning human bladder was the first artificial organ made using bioprinting by scientists at the Wake Forest Institute for Regenerative Medicine.

However, to be able to start a clinical trial was challenging as companies needed “to develop a bioprinter compliant with the regulations and to develop a tissue fabrication process leveraging this bioprinter,” Guillemot explained.

Fast forward 23 years and this was achieved by 3DBioTherapeutics. A 20-year-old woman born with a rare congenital deformity in her right ear became the first person to receive a 3D-printed ear implant made from her own living cells.

The medical breakthrough made headlines this month after the New York-based medical company took a sample of cartilage cells from the patient’s ear and grew them in a lab to create an implant.

The human cells were mixed with a collagen-based bio-ink before being inserted into a 3D bioprinter, which layer-by-layer created a mirror replica of the patient’s left ear, the company’s chief scientific officer, Nathaniel Bachrach, told the New York Times.

The company’s AuriNovo implant technology is currently being used in a clinical trial to help patients with microtia, a condition where one or both outer ears are absent or underdeveloped.

CEO and co-founder of 3DBioTherapeutics Dr. Daniel Cohen called the transplant a “truly historic moment for patients with microtia,” a condition that affects around 1,500 babies in the US each year.

“And more broadly for the regenerative medicine field as we are beginning to demonstrate the real-world application of next-generation tissue engineering technology,” said Cohen.

Cohen hopes AuriNovo will become “the standard-of-care” as it is less invasive than current surgical methods for ear reconstruction that use rib cartilage.

Guillemot said that the success by 3DBioTherapeutics “shows that bioprinting is coming of age for therapeutic applications” and “can provide new solutions for patients and clinicians.”

“Being one of the few bioprinting companies engaged in the development of therapeutic applications, we (Poietis) are very enthusiastic by this news,” Guillemot said.

He said that his company plans to also start the clinical trial of its first bioprinted product Poieskin, a skin substitute, in the coming months.

READ MORE: Türkiye's shining liver transplant industry has humble origins

Bioprinting in space

But the bioprinting process comes with challenges – a lot of which comes “from biomaterial availability,” Micro explains.

“We carry out our own internal research – such as the development of a conductive bioink for peripheral nerve and spinal cord regeneration – and we identify promising biomaterials and help the research groups who developed them to bring them out into the market,” said Micro.

Other main challenges of bioprinting are related to the standardisation of tissue manufacturing process and the capacity to print more complex tissues in a way which is compatible with clinician routines and hospital constraints, according to Guillemot.

His company Poietis is addressing these challenges by developing next-generation bioprinters "which are robotised, multimodal and provide high-resolution. "

One of Poietis’s bioprinter has been installed in the Cell Therapy Center of Marseille Hospitals, as the company plans to equip cell therapy centers in hospitals “to enable them to develop and produce new applications for patients.”

“Installing bioprinters directly into hospitals, at the point of care, can reduce high costs and logistics challenges that you meet when you transfer living cells and tissues from the "factory" to the bedside,” said Guillemot.

In addition, bioprinting research is not just limited to laboratories and hospitals on Earth. Researchers at nScrypt in collaboration with Redwire’s Techshot are working on printing methods in microgravity, with the goal of eventually taking bioprinting capabilities to space.

“The first set of printing experiments is to print cardiovascular cells in microgravity to study any effects microgravity might have on printed cells,” Dickerson told TRT World.

“The bioprinter is set up to print a range of materials to include cellular and acellular materials. The intent is to allow a diverse group of scientists that want to print in microgravity this capability,” he added.

READS MORE: Are Muslims ready to accept pig organ transplants?

Aftermath of bioprinting

Another challenge faced by nScrypt’s teams and bioengineers as a whole is the aftermath of bioprinting and avoiding necrosis.

“Necrosis is the enemy, this means cells die and this occurs for many reasons, but just as your entire body needs food, oxygen and then to remove carbon dioxide and waste, so must cells and tissue,” said Dickerson explaining the importance of a vascular network for the bioprinted organs.

Companies are growing great vascularised tissue, but using thicker tissue in organs, makes it more challenging to move oxygen in and carbon dioxide out.

“Bioprinting is important, but the incubation and feeding part is where the magic happens. There is no such thing and there will be no such thing as printing an organ,” Dickerson said, adding when this is achieved then the organ growing potential will begin moving more rapidly.

Aside from organ transplants, manufacturing artificial organs with 3D printing has the potential to help several sectors in the medicine field, such as in pharmaceutical research and the training of surgeons.

Using a patient’s own cells to create the 3D printed organs also greatly reduces the risk of donor organs being rejected by the body. But as experts point out, the finances of bioprinting remain another obstacle.

“The near future of bioprinting is discovery and experimental. We talk about a big game, but we still have quite a bit in front of us,” said Dickerson. “(This) will not happen if there is not a good business model.”

“This means money. This must make money. It is easy to make the business case, ‘how much are you willing to pay for a kidney or a heart?’ It is a cruel reality, but a reality nonetheless. But before we get to that, we must ask, how much are you willing to spend to learn how to do it?”

READ MORE: Türkiye's liver transplants are changing lives beyond borders

Source: TRT World

Organ printing: how 3D bioprinting technology has advanced and what is hindering its development In research centers and hospitals around the world, advances in 3D printing and bioprinting are providing new opportunities for human treatment and scientific research. In the coming decades, bioprinting could be the next major milestone in healthcare and personalized medicine. nine0003

Let's talk about bioprinting technology, the latest advances in the industry and the limitations that professionals face.

How a 3D printer works

Traditional printers, like the one you have at home or office, work in two dimensions. They can print text or images on a flat surface (usually paper) using the x (horizontal) and y (vertical) dimensions. 3D printers add another dimension - depth (z). During the printing process, the printer heads can move up and down, left and right, back and forth, but instead of delivering ink to paper, they distribute various materials - polymers, metal, ceramics and even chocolate - until the "print" of a holistic, voluminous object , layer by layer in a process known as "additive manufacturing". nine0003

To create a 3D object, you need a blueprint for it, a digital file created with modeling software. After its creation, the computer-generated model is sent to the printer. Your chosen material is loaded into the machine and ready to be heated to easily flow out of the printer nozzle. As the printer reads the plan, its head moves, depositing successive layers of the selected material to create the final product.

As each layer is printed, it is solidified either by cooling or by mixing two different solutions delivered by the printer head. The new layers precisely lay down on the previous ones to make a stable, cohesive element. In this way, you can create almost any shape, including a moving one. nine0009

3D printing allows you to create objects with geometric structures that would be difficult or impossible to make in other ways. A wide range of products are already being created using 3D printers, including jewelry, clothing, toys, and high-end industrial products. Even a 10-year-old Moscow schoolboy has learned how to work with a 3D printer: he prints 3D figures to order and sells them through Instagram.

How a bioprinter works

Bioprinters work in much the same way as 3D printers, with one key difference - they deposit layers of biomaterial, which can include living cells, to create complex structures such as blood vessels or skin tissue. nine0003

Living cells? Where do they get them? Every tissue in the body is made up of different types of cells. The required cells (kidney, skin, and so on) are taken from the patient and then cultured until there are enough of them to create "bio-ink" that is loaded into the printer. This is not always possible, therefore, for some tissues, stem cells are taken that are capable of becoming any cell in the body (organism), or, for example, porcine collagen protein, seaweed and others.

Often used in bioprinting is chitosan, a polysaccharide obtained from the external skeleton of mollusks (eg shrimp) or by fermenting fungi. This material has high biocompatibility and antibacterial properties. Its disadvantage is the low rate of gelation. Another popular material is a polysaccharide isolated from seaweed called agarose. Its advantages are high stability and the possibility of non-toxic cross-linking during research. However, this biomaterial does not decompose and has poor cell adhesion (the ability of cells to stick together with each other and with other substrates). nine0003

Collagen, a primary structural protein found in the skin and other connective tissues, has a high biological significance. It is the most abundant protein in mammals and a major component of connective tissue. Its disadvantages for bioprinting include the property of acid solubility. More information about biomaterials can be found here.

Based on computer designs and models, often scans and MRIs taken directly from the patient, the printer heads place the cells exactly where they are needed and within a few hours an organic object is built from a large number of very thin layers. nine0009

Organovo bioprinter creates tissues that mimic the structure and composition of various human organs

Source: Pbs.org

Scaffolding for ear or nose replacement at Wake Forest University in Winston-Salem, North Carolina

Source: CBS News

Computer displays an image of a "scaffold" for the human ear, created in the laboratory of Wake Forest University in Winston-Salem, North Carolina

Source: CBS News

Usually more than just cells are needed, so most bioprinters also supply some kind of organic or synthetic "glue" - a soluble gel or collagen scaffold to which cells can attach and grow. This helps them form and stabilize in the correct shape. Surprisingly, some cells can take the correct position on their own without any "scaffolding". How do they know where to go? How do embryonic cells develop in the uterus, or does adult tissue move to repair damage? Same here. nine0003

Universities, researchers and private companies around the world are involved in the development of bioprinting technologies. Let's take a look at some of the amazing things they are working on.

Bioprinting in Russia

3D Bioprinting Solutions is a biotechnology research laboratory founded by medical company INVITRO. The activity of the laboratory is the development and production of bioprinters and materials in the field of three-dimensional bioprinting and scientific research. August 23, 20193D Bioprinting Solutions laboratory sent a new batch of cuvettes to the ISS to continue experiments on bioprinting in space, which began in 2018. This was reported in the press center of the laboratory. This time it is planned to use organic and inorganic components to assemble bone tissue on the world's first space bioprinter Organ.Aut.

Symposium "Biofabrication in Space"

Source: Zdrav.Expert

Organ.Aut magnetic bioprinter

Source: Zdrav.Expert

The astronauts will also grow protein crystals and experiment with printing biofilms of bacteria to study their behavior in zero gravity. Russian scientists expect to receive unique scientific data that can be applied in the development of new drugs.

Scientific director of 3D Bioprinting Solutions and leading researcher of the Institute of Regenerative Medicine, Candidate of Medical Sciences Vladimir Mironov, in his speech at the Department of Anatomy of Sechenov University on September 2, noted: “Living cells, tissues and human organs will be synthesized already in the current century. To do this, morphological sciences, such as microscopic anatomy and histology, must be digitized or digitalized, that is, digitized and made available for computer programs of robotic bioprinters, since without digital models it is impossible to print human tissues and organs. ” nine0009

Bioprinting around the world

Every year, millions of people around the world need bone grafting. Modern bone grafts often use cement-based synthetic material in combination with the patient's own bone. However, the use of these materials has a number of limitations - some transplants caused rejection and inflammatory processes in patients. Reproduction of the natural bone-cartilage "interface" has also been problematic.

However, a team at Swansea University in 2014 developed a bioprinting technology that allows the creation of an artificial bone prosthesis in the exact shape of the desired bone, using a biocompatible material that is both durable and regenerative. At the same time, scientists from the University of Nottingham in England were working on similar studies. nine0003

It takes about two hours to print a small bone. Therefore, surgeons can do it right in the operating room. This part of the bone is then covered with adult stem cells that can develop into almost any other type of cell. This is combined with bio-ink from the printer, a combination of polylactic acid (which provides mechanical strength to bone) and alginate, a gel-like substance that serves as a shock-absorbing material for cells. The end product is then implanted into the body, where it will completely disappear within about three months and be replaced by new bone. nine0003

Researchers hope that in the future, bioprinted bones can be created with sufficient reliability to support complex spinal reconstruction, and that the bone material will be further improved to increase its compatibility with cartilage cells.

Source: ETH Zurich

Successful 3D printing of human cartilage may soon completely replace artificial implants for people in need of reconstructive surgery. Back in 2015, scientists in Zurich developed technology that would allow hospitals to print a full-size human nose implant in less than 20 minutes. They believe that any cartilage implant can be made using their technique. nine0003

Researcher Matti Kesti described the technology as follows:

“

“A serious car accident can cause the driver or passenger to suffer complex nose injuries. The nose can be restored by creating a 3D model on a computer. At the same time, a biopsy of the patient is performed and cartilage cells are removed from the victim's body, such as from a knee, a finger, an ear, or fragments of a broken nose. The cells are spawned in the laboratory and mixed with the biopolymer. From this suspension, a model of nasal cartilage is created using a bioprinter, which is implanted into the patient during surgery. In the process, the biopolymer is used simply as a mold. It is subsequently broken down by the body's own cartilage cells. And in a couple of months it will be impossible to distinguish between the graft and the person’s own nasal cartilage.” nine0003

Matti Kesti

Since the implant was grown from the body's own cells, the risk of rejection will be much lower than for an implant made of, say, silicone. An additional advantage is that the bioimplant grows with the patient, which is especially important for children and young adults.

If a person is severely burned, healthy skin can be taken from another part of the body and used to cover the affected area. Sometimes intact skin is missing. nine0003

Researchers at Wake Forest School of Medicine have successfully designed, built and tested a printer that can print skin cells directly onto a burn wound. The scanner very accurately determines the size and depth of damage. This information is sent to a printer and skin is printed to cover the wound. Unlike traditional skin grafts, it only takes a patch of skin one-tenth the size of a burn to grow enough cells to print. While this technology is still in the experimental stage, the researchers hope that it will be widely available within the next five years. nine0003

As already mentioned, 3D printers print products in layers, and since the skin is a multi-layered organ with different types of cells, it is well suited for this type of technology. However, researchers still have a lot of problems to solve, in particular, how to prevent damage to cells from the heat generated by the printer. And of course, like most parts of the human body, the skin is more complex than it first appears—there are nerve endings, blood vessels, and a host of other aspects to consider. nine0009

Blood vessels

Biomechanical engineer Monica Moya holding a petri dish with printed alginate-based biotubes. Biotubes can act as temporary blood vessels similar to blood vessels that help create a patch of living tissue.

Source: embodi3D

With tens of thousands of miles of veins, arteries and capillaries in the human body, researchers are working to replace them if they ever wear out. The creation of viable blood vessels is also essential for the proper functioning of all other potential bioprinted body parts. nine0003

Biomechanical Engineer Monica Moya of Livermore National Laboratory. Lawrence uses bioprinting to create blood vessels. The materials created by her bioprinters are engineered to allow small blood vessels to develop on their own.

This development takes time, so vials of cells and other biomaterials are printed to help deliver vital nutrients to the printed environment. After a while, self-assembled capillaries connect with bioprinted tubes and begin to deliver nutrients to cells on their own, mimicking the work of these structures in the human body. nine0009

Internal organs

Many researchers hope that in 20 years the lists of patients waiting for organ transplants will become a thing of the past. They envision a world where any organ can be printed and transplanted in just a few hours, without rejection or complications, because these organs will be created from body cells according to the individual characteristics of each patient. Currently, bioprinting of fully functional complex internal organs is not possible, but research is ongoing (and not without success). nine0009

Bladder

For example, the bladder is already printed. In 2013, at Wake Forest University in the US, researchers successfully took cells from a patient's original, poorly functioning bladder, cultured them, and added additional nutrients. The 3D shape of the patient's bladder was then printed and the cultured cells soaked through it. The form was placed in an incubator and, when it reached the desired condition, it was transplanted into the patient's body. The mold will eventually collapse, leaving only the organic material. The same team successfully created viable urethras. nine0009

Physicians and scientists at the Wake Forest Institute for Regenerative Medicine (WFIRM) were the first in the world to create laboratory-grown organs and tissues that were successfully transplanted into humans. Right now they are working on growing tissues and organs for more than 30 different areas of the body, from the kidneys and trachea to cartilage and lungs. They also aim to accelerate the availability of these treatments to patients.

Scientists in Australia are doing similar research as well. They used human stem cells to grow a kidney organ that contains all the necessary cell types for a kidney. Such cells can serve as a valuable initial source for bioprinting more complex kidney structures. nine0009

MD, Professor of Urology, Professor of the Institute of Regenerative Medicine Anthony Atala shows a kidney created by a bioprinter. A modified desktop inkjet printer sprays cells instead of ink. The cells were cultured from the patient and the structural template for the kidney was obtained from the MRI (so it is the correct size and shape).

Using this technology, back in 2001, Atala printed and successfully transplanted a bladder into a young man, Jake.

Source: TedEd

Heart

Heart cells, laboratory-grown organelles. Source

Surprisingly, it is the human heart that can become one of the easiest organs to print, since, in fact, it is a pump with tubes. Of course, everything is not so simple, but many researchers believe that humanity will learn to print hearts before kidneys or liver.

Researchers at the Wake Forest Institute for Regenerative Medicine in April 2015 created "organoids" - 3D printed fully functional, beating heart cells. nine0009

In April 2019, Israeli scientists printed the world's first 3D heart. It is still very small, the size of a cherry, but it is able to perform its functions. The 3D heart with blood vessels uses personalized "ink" of collagen, a protein that supports cell structures, and other biological molecules.

A Tel Aviv University researcher holds the world's first 3D printed heart on April 15, 2019.
Source: Haaretz

“This is the first time anyone anywhere has successfully designed and printed a whole heart with cells, blood vessels, ventricles and chambers,” said Tel Aviv University scientist Professor Tal Dvir.

So far, scientists have been able to print tissue from cartilage and the aortic valve, for example, but the challenge has been to create tissue with vascularity—the blood vessels, including capillaries, without which organs cannot survive, let alone function. nine0003

The Tel Aviv scientists started with human adipose tissue and separated the cellular and non-cellular components. They then reprogrammed the cells to become undifferentiated stem cells, which could then become cardiac or endothelial. Endothelium - a single layer of flat cells lining the inner surface of the heart cavities, blood and lymphatic vessels. Endothelial cells perform many functions of the vascular system, such as controlling blood pressure, regulating the components of blood clotting, and the formation of new blood vessels. nine0003

Non-cellular materials, including a large amount of proteins, were processed into a "personalized hydrogel" that served as "printing ink".

It will be years before this technology can create organs for efficient transplantation. However, the achievements of scientists in Tel Aviv are a huge milestone along the way.

Medical research and pharmacology

One of the key potential uses for bioprinted living materials is in the field of medical and drug research. Bioprinted tissues have several cell types with different densities and key architectural features. This allows researchers to study the impact of various diseases on the body, the stages of disease progression and possible treatments in the natural microenvironment. nine0003

One of the most impressive developments in recent years is the development of a desktop brain at the ARC Center of Excellence in 2016. The researchers were able to use a 3D printer to create a 3D printed six-layer structure that includes nerve cells that mimic the structure of brain tissue.

This opens up huge potential benefits for researchers, pharmaceuticals and private companies, because it will allow them to test new products and drugs on tissue that accurately reflects the responses of human brain tissue, as opposed to animal samples, which may cause a completely different response. The desktop brain can also be used to further investigate diseases such as schizophrenia or Alzheimer's. nine0003

We are far from printing the brain, but the ability to arrange cells to form neural networks is a significant step forward. By allowing researchers to work with human tissue in real time, testing processes can be greatly accelerated and results can be more realistic and accurate. It will also reduce the need to use laboratory animals for medical tests and potentially dangerous human testing.

Medical simulators and data registries

Source: Simbionix

About 3,000 medical simulators are currently in use around the world to help doctors practice complex procedures. Virtual blood vessels, 3D printed organs... and no animal suffers!

The American company 3D Systems created an industry segment called VSP (Virtual Surgical Planning). This approach to personalized surgery combines expertise in medical imaging, surgical simulation and 3D printing. Surgeons using the Simbionix medical simulator for the first time often report feeling physical pain while empathizing with their virtual patient - the experience is so realistic. Organs and tissues look completely real. When stitching an organ, the surgeon sees on the screen a needle that enters the tissue, and pulls the thread. If the doctor does something wrong, the virtual blood vessels break and the organ begins to bleed. These simulators were developed by the Israeli company Symbionix, which was acquired by 3D Systems in 2014. nine0003

On September 3, 2019, the Radiology Society of North America (RSNA) and the American College of Radiology (ACR) announced the launch of a new 3D Medical Printing Clinical Data Registry to collect data on treatment outcomes using 3D printing at the point of care. This information will be a powerful tool to assess and improve patient care in real time, drive ongoing research and development, and inform patients and healthcare professionals about the best course of care. nine0009

“

“The creation of a joint RSNA-ACR 3D printing registry is essential to the advancement of clinical 3D printing. The registry will collect data to support the appropriate use of this technology and its implications for clinical decision making. ”

William Widock, Professor of Radiology at the University of Michigan and Chairman of the RSNA 3D Printing Special Interest Group (SIG)

According to the RSNA, the information in the registry will allow for the necessary analysis to demonstrate the clinical value of 3D printing. Due to the wide variety of clinical indications, different technologies for creating physical models from medical images, and the complexity of the models, it is problematic to choose the optimal treatment method. The registry will help solve this problem. nine0009

Bioprinting software

Bioprinter and bioprinting software manufacturer Allevi introduced Allevi Bioprint Pro software on September 5, 2019. Built-in model generation and integrated slicing will allow you to focus more on experimenting, rather than setting up the printer. The program runs entirely in the cloud, which means you can create your biostructures, define materials, and track prints right from a web browser on any computer. nine0003

According to the development team, the new bioprinter with the above software is powerful and easy to use and represents another piece of the puzzle on the way to 3D printed organs.

At the same time, CELLINK, the first bio-ink company, announced the launch of a new product to become the most flexible bio-printing platform on the market. The BIO X6 bioprinter, which has no analogues at the moment, has the ability to combine more bioprinting materials, cells and tools. nine0009

Why is this taking so long?

Complex body structure

The human body and its various components are much more complex than a plastic toy. The human organ has a complex network of cells, tissues, nerves, and structures that must be arranged in specific ways to function properly. From placing thousands of tiny capillaries in the liver to actually getting a printed heart that "beats" and contracts in the human body, there is still a lot of research and testing. nine0003

Legal regulation

In addition, bioprinting technologies, like all new medical treatments, must pass safety tests and due process of regulation before they become available.

Special software and hardware

It also takes time to develop special software and hardware. These programs can be written only with the appropriate data (medical, clinical, statistical, mathematical, and so on), which someone must first collect, analyze, systematize and digitize. nine0009

Working through all of these steps requires the integration of technologies from various fields, including engineering, biomaterials science, cell biology, physics, mathematics, and medicine. So we need to be a little more patient.

The main thing is to know that those who work in the field, doctors and engineers, programmers and scientists are making progress every day both in bioprinting technology itself and in understanding how it can be used and improved. Although we are not quite there yet, there is no doubt that medicine will be very different in 10-20 years, thanks also to bioprinting. nine0009

In brief

Bioprinting is an extension of traditional 3D printing.

Bioprinting can produce living tissue, bones, blood vessels, and possibly entire organs for use in medical procedures, medical training, and testing.

The cellular complexity of a living organism has made 3D bioprinting slower to develop than conventional 3D printing.

Bioprinting technology could enable the generation of patient-specific tissues to develop precise, targeted and fully personalized treatments. nine0003

We still have a long way to go before we can create fully functioning and viable organs for human transplantation.

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Cover photo: etonastenka, Depositphotos

Printing organs: how ears, skin and noses are made with a 3D printer

Natalka Pisnya
BBC Russian Service , USA

March 23, 2018

Photo copyright, Masela family archive

Photo caption,

Luc Masela with his parents one month after the artificial bladder transplant. year 2001. nine0003

Luc Masela, now 27, is an athlete with a degree in economics, works for a large exhibition company, travels a lot and recently met, in his words, "the most beautiful girl in the world." Both she and most of his current friends were extremely surprised when they learned that 17 years ago he survived a dozen and a half operations.

Luke was born with spina bifida - and although he was able to walk, his bladder was severely damaged. By the age of 10, he almost did not leave hospitals: due to improper functioning of the bladder, fluid began to return to the boy's kidneys, doctors diagnosed an irreversible pathology of the organ. nine0003

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Video caption,

3D printed organs are here intestinal segment. This would guarantee Luke several years of medically supervised life and a high risk of developing cancer.

The urologist who was taking care of the boy invited the Masela family to take part in an experimental program: to grow a new bladder from his own cells. Then, in 2001, it sounded like science fiction: only nine people took part in the program before Luke. Despite this, his family agreed. nine0003

"The essence of the operation was reduced to two stages: first, a piece of bladder tissue was taken from me, and over the next two months, cells were grown in the laboratory in order to grow a new healthy bladder from them," says Luke.

Photo copyright, Masela family archive

Photo caption,

Luc Masela, 17 years after the artificial bladder transplant

Next was the transplant operation, which, according to him, lasted 16 hours. “I opened my eyes and saw a cut through my entire stomach, tubes of all possible sizes were sticking out of me, except for them - four IVs and a bottle-feeding machine,” he recalls. “I stayed in the hospital for another month, I was prescribed bed rest, after that I stayed at home for another month. nine0003

The operation was performed by Dr. Anthony Atala, Pediatric Regenerative Surgeon. In two months, out of a hundred patient cells, scientists created one and a half billion. Further, an engineering structure was created on a collagen frame: the bladder was “sculpted” like a two-layer pie, the core of which dissolved over time, and it started working like a normal organ, taking root thanks to Luke’s own cells.

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Luke and Dr. Atala haven't seen each other for 10 years after being discharged from the hospital. Once a dying child became the champion of the school wrestling team and went to college.

The professor took charge of the Wake Forest Institute of Regenerative Medicine in North Carolina in those 10 years, but he never forgot about Luke: his bladder was one of the most challenging and most successful projects in his early practice.

By 2018, Atala won the Christopher Columbus Award for "work on a discovery that will have a significant impact on society"; The Times and Scientific American magazines at various times named him "Physician of the Year", he was also recognized as "one of the 50 scientists on the planet who in the next 10 years will change the way we live and work."

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In the mid-2000s, Atala's team turned their attention to an ordinary household 3D printer and wrote special software for it, later specialized machines were created for the laboratory. Now the laboratory "grows" up to 30 different types of cells and organs, as well as cartilage and bones.

One of the team's latest achievements is ears and noses grown outside the human body. nine0003

The main customer and sponsor of Atala's developments is the US Department of Defense, and many of the patients are military victims of military operations.

It works like this: first, a CT scan of the ear or nose is done. One of Atala's assistants, Joshua Corpus, jokes that at this stage, people often ask to "improve" the shape of the nose if they thought theirs was too wide or hooked, and the ears if they were too wide.

After that, a special computer code is written, and the printing of the basis of the organs begins. nine0003

For this, a bioabsorbable polymer, polycaprolactam, is used. At the same time flexible and durable, in the human body it disintegrates within four years.

After printing, the layers of polycaprolactam resemble lace; after transplantation, their place will be taken by a person's own cartilage tissue in a few years.

Polycaprolactam is then saturated with a gel created from the patient's cells, cooled to -18 degrees Celsius - so the cells, according to scientists, are not damaged, they are "alive and happy." nine0003 Image caption,

Printing a test kidney sample on a bioprinter

In order for the polymer and gel structure to take shape and become something more durable, ultraviolet light is used in the laboratory - it does not damage cells.

The future implant is printed for 4-5 hours, then it is finally formed and inserted under the epidermis.

Skin can also be grown: children affected by fires were the first to take part in the early trials of Atala - after the "printing" of the skin, scientists observed the patients for several more years. The new skin did not crack, did not burst, and grew with the children. nine0003

The most difficult work, according to the scientist, is facial wounds: it is not enough just to stretch the skin, you need to accurately calculate the geometry, align the swelling, the structure of the bones, and understand how a person will look after that.

In addition to the skin and ears, Atala can "print" the bones of the jaws, grow blood vessels and cells of some organs - the liver, kidneys, lungs.

This technology is especially appreciated by oncologists: on the basis of patient cells, it is possible to recreate the body's response to various types of chemotherapy and observe the reaction to a particular type of treatment in the laboratory, and not on a living person. nine0003

But the liver, kidneys, lungs and heart are still being tested. Atala says he raised them in miniature, but creating organs from various tissues to real size requires a lot of additional research.

But, according to him, cells were grown in the laboratory and a vagina was created for a girl who was born several years ago with a congenital deformity of the genital organs - several years have passed since the transplant.

Image caption,

Bioprinted polycaprolactam ear implant base

Atala smiles and adds that his team is also working on a working penis. This research has been going on for several years, and the most troublesome for scientists is the complex structure of tissues and the specific sensitivity of the organ itself.

Among others, Igor Vasyutin, a Russian post-graduate student of the First Moscow State Medical University (MSMU) named after Sechenov, is working on this under laboratory conditions. He is a cell biologist, Atala's right hand. nine0003

Vasyutin has been in the USA for about a year - he came on an exchange. He is ready to talk about the behavior of stem cells for hours, but becomes less verbose when it comes to Russian science.

Vasyutin's alma mater has not reached mass regeneration of human organs and is still training on animals: local scientists "printed" a mouse thyroid gland on a 3D printer.

Research on human organs, however, is also being done there. According to the head of the Institute of Regenerative Medicine at MSMU Denis Butnar, several years ago the Institute recreated a special engineering design of the buccal mucosa. She functioned perfectly for the first six months, but subsequently had to undergo a second operation. nine0003 Image caption,

Test sample of an ear implant under ultraviolet light

In Russia, however, over the past few years, the Italian surgeon-transplantologist Paolo Macchiarini has been practicing, the man who was the first in history to perform a synthetic organ transplant operation - a plastic tube that replaced the patient trachea.

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However, seven of his nine patients died, and the breathing tubes implanted in the remaining two subsequently had to be replaced with donor ones. nine0003

Several criminal cases were brought against him, including on charges of pressure on patients and fraud, and the leading doctors of the world called Macchiarini's operations "ethical Chernobyl".

Will printed organs replace donors?

At the zenith of his career, Macchiarini argued that a new perspective is opening up for humanity: you can "print" any human organ on a printer, create an engineering structure from it, enriched with the patient's stem cells, and get the perfect prosthesis. nine0003

Be that as it may, complex human organs - the liver, kidneys, heart, lungs - have not yet been able to grow any regenerative surgeon.

Bioprinting of the so-called simple organs, however, is already available in the US, Sweden, Spain and Israel - at the level of clinical trials and special programs.

The US government is actively investing in such programs - in addition to Wake Forest, cooperating with the Pentagon, the Massachusetts Institute of Technology also receives significant amounts to recreate the work of the liver, heart and lungs. nine0003 Image caption,

Skin application test on a burnt wound

According to Professor Jorge Raquela, a gastroenterologist at the Mayo Clinic Research Center, "Bioprinting is one of the most exciting branches of modern medicine, it has huge potential, and the turning point of the most important discoveries is already close."

Meanwhile, Pete Basillier, head of R&D at analytics firm Gartner, insists technology is advancing much faster than understanding the implications of 3D printing. nine0003

Such developments, according to Basilière, even if created with the best of intentions, give rise to a set of questions: what will happen when "improved" organs are created, the basis of which will not only be human cells - will they have "superpowers"? Will a regulatory body be created to monitor their production? Who will check the quality of these organs?

More than 150,000 Americans are on the waiting list for organ transplants every year, according to a report from the US National Library of Medicine. Donor organs will receive only 18% of them; every day in the United States, without waiting for a transplant, 25 people die. Organ transplants and subsequent rehabilitation cost insurance companies and patients $300 billion in 2012 alone. nine0003

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Most Americans are potential donors: upon obtaining a driver's license, they voluntarily answer the question of whether they agree to donate their organs in the event of a car accident or other dangerous incident . In case of consent, a small "heart" and the word "donor" appear in the corner of the document. nine0003

Prof. Atala's driver's license is like that - in spite of all his achievements and faith in the "publishing organs", he is ready to share his with those around him.