JUNO Blue Perinatal Healthcare Incubator 2.0

Womb in your living room

Image credit: Juno Perinatal Healthcare

The world is approaching a technological breakthrough on the invention of an artificial womb. Scientists and doctors in the US, Israel and the Netherlands are showing it will soon be possible to save babies born extremely pre-term by keeping foetuses alive encased in bags filled with fluid. The next step would be complete ectogenesis, but what are the costs?

A romantic comedy starts production in Hollywood next year that promises to start a popular debate that has been going on for a few years now in the world of bioethicists.

Starring actors Emilia Clarke and Chiwetel Ejiofor and set in New York in the not-too-distant future, ‘The Pod Generation’ tells the story of a young couple who decide to cement their love by having a baby.

However, instead of doing it the natural way, they choose to share the burden of pregnancy using a new technology of a detachable womb.

The prospect of extra-corporal human gestation has long been the subject of dystopian fiction and film. Aldous Huxley’s 1932 classic ‘Brave New World’ opens in a ‘hatchery’, where designer humans are grown in bottles to create a new caste-based society. In the science-fiction classic ‘The Matrix’, babies are not born but grown in fluid-filled bags.

Yet the science is a long way off from the dystopian or utopian, depending on your point of view, technological capacity to make babies from egg to infancy in an artificial womb.

“Under my personal understanding I think it is several decades off as yet,” says Professor Neil Marlow, Emeritus Professor of Neonatal Medicine at University College London, one of the UK’s leading experts in premature births. Other scientists E&T spoke to agree.

Advances are being made in technologies that would make life-support systems possible for babies born so pre-term they would unlikely survive without help.

According to the World Health Organization, 15 million babies every year around the world are born prematurely, before 37 weeks. Premature delivery is the main cause of death for children under five. Between 800,000 and one million of those babies are born extremely pre-term – less than 28 weeks.

For a baby born before 22 weeks, their chances are slim. The second they take that first breath of air their lungs stop developing. Infants born in the crucial 22-to-28-week gestation period – where lungs and other organs can be damaged by premature exposure to air – could cause some type of lifelong physical or neurological disability, often at great cost to families and society.

Incubators, like the type used today to bring premature babies to term, were invented by the French obstetrician Étienne Tarnier, who, having observed the benefits of warming chambers for poultry at the Paris Zoo, had similar chambers constructed for premature infants under his care.

These warm-air incubators, introduced at L’Hôpital Paris Maternité in 1880, were the first of their kind. By the end of that century, baby incubators formed part of the exhibit on New York’s Coney Island, where people would pay to peer at the tiny infants. Yet incubators are only suitable for babies whose organs are sufficiently developed to survive without floating in amniotic fluid, attached to the placenta by the umbilical cord.

In 1955, American scientist Emanuel Greenberg patented the first ever design for an artificial womb. Like with an incubator, his womb was designed to keep the foetus at a constant temperature, immersed in fluid attached to an artificial system to provide nutrients and oxygen outside the machine.

“The blood for the placenta is circulated by means of two pumps through an artificial kidney, an oxygenating apparatus, a container where liquid food is added, and a filter which removes blood clots and other solid matter,” Greenberg wrote in his patent document. “A circulating water supply is provided which heats water to body temperature and by means of water jackets maintains the foetus chamber and the oxygenating apparatus at body temperature.”

In 1996, Yoshinori Kuwabara, chairman of the Department of Obstetrics and Gynaecology at Juntendo University in Tokyo, developed a technique called EUFI – extrauterine foetal incubation.

They removed goat foetuses from their mothers and threaded catheters through the large vessels in the umbilical cord. This supplied the foetuses with oxygenated blood while suspending them in rubber incubators that contained artificial amniotic fluid heated to body temperature.

The foetal goats survived for three weeks until they suffered circulatory failure and died. However, the EUFI showed that, sometime in the future, it would be possible to gestate human foetuses outside the mother’s body.

In 2017, researchers at the Children’s Hospital of Philadelphia in the US took a major step forward and developed a biobag using a foetal lamb, an animal whose perinatal lung development is very similar to humans.

Their system used a unique fluid-filled container attached to custom-designed machines. The lambs grew in a temperature-controlled, near-sterile environment, breathing amniotic fluid mimicking what would happen naturally in the womb. Their hearts pumped blood through the umbilical cord into a gas exchange machine outside the bag. Electronic monitors were attached to measure blood flow and other vital functions. Over the next four weeks, the lambs grew wool hair, gained weight, and opened their eyes. If that was applied to a human foetus born prematurely, it would give them an extra few weeks for their lungs to develop.

In a paper published in Nature in spring 2021, scientists at Israel’s Weizmann Institute of Science in Israel took five-day-old embryos from mice uteruses and grew them for six more days in an artificial womb made of glass. The embryos were attached to a ventilation system and a bag of nutrient fluid.

Now, a cross-disciplinary group of scientists in the European Union have taken up the baton and are working on an artificial womb for premature infants born during the crucial 22-28-week phase of development.

Based at the Eindhoven University of Technology in the Netherlands, the first phase of development of the Perinatal Life Support System (PLS), or incubator 2:0 (as they like to call it), is being developed by a cross-disciplinary consortium of engineers and doctors from the Netherlands, Italy and Germany. The first phase is funded with a €2.9m grant from the EU’s Horizon 2020.

Led by Professor Frans van de Vosse from the Department of Biomedical Engineering and Professor Guid Oei, a gynaecologist from the Máxima Medical Center, a teaching hospital in southern Holland, the project also involves researchers from the Politecnico di Milano and the Rheinisch-Westfälische Technische Hochschule Aachen in Germany. Dutch neonatal start-up Juno Perinatal Healthcare is involved with the entrepreneurial, intellectual property rights and funding side of the project.

The PLS scientists were prompted to begin work by earlier research at the Children’s Hospital of Philadelphia, led by Professor Alan Flake.

The system established requires two loops. One has the foetus attached by the umbilical cord to the infant’s circulation system, providing nutrients, oxygen and – if required – medication. The second loop keeps fresh amniotic fluid circulating in the biobag as it would in the mother’s womb.

“The principle is what we have in mind for our support system – that you keep the infant in water, so the lungs don’t start breathing,” says van de Vosse.

The idea is that the baby is floated in a liquid where the lungs were filled with an artificial amniotic fluid, and the infant is supplied with oxygen and nutrients just like in the natural womb, via an external oxygenator attached to the umbilical cord.

Human physiology is very different from animals and testing on foetuses is only legally possible in the first two weeks of life.

To get over this and to carry out tests on the incubator they are developing, the PLS team have come up with the concept of doing all the main testing on a robot foetus.

By using a 3D baby robot rather than a natural foetus, human or animal, they avoid the ethical difficulties of testing on potential humans, as well as animal rights issues. To protect human rights of the unborn foetus whose physiology was reproduced in the robot copy, some data will be removed.

The mannequins will be created from a 3D-printed silicon mould made from using footage from a magnetic resonance imaging (MRI) scan of a real 24-week-old human foetus (MRI scans produce detailed images from inside the body) and, after the robot is printed to the right shape, the team will put in actuators, to make sure everything works correctly, like leg movement.

The umbilical cord will be attached to an artificial placenta and an oxygenator outside the womb bag to supply the foetus with nutrition and hormones and take over the oxygenation of the blood. The incubator itself will be filled with fluid.

The robotic mannequin will be able to show measurable life signs, such as measuring a fake heart rate, simulated blood pressure, artificial breathing, and even change colour if there are changes to blood oxygenation levels.

“The mannequins will also make it easier to learn what standards we need to use, for example the right nutrients in the placenta, and also to train people to use the device and the monitoring system and act accordingly to signals that are there and test monitoring devices,’ says van de Vosse.

“By linking big data as well as patient data to the mannequin model, we can also simulate the effect of different treatments to make sure doctors make the best choices,” he adds.

One big problem the team face right now is connecting the umbilical cord to the artificial placenta.

There are two arteries and one vein in umbilical cords. Yet in a human foetus, as soon as the umbilical cord is cut, the veins and artery go into spasm.

This makes is very difficult to cannulate to the artificial placenta, a process that must be done in three minutes so as not to cause any damage to the premature baby.

Another even bigger challenge for the researchers is to prevent coagulation of blood that goes from the umbilical cord to an oxygenator and back.

“In adult heart and lung machines, you use a coating to circumvent coagulation, but this isn’t good for the brain,” explains van de Vosse. “So, we have to come up with something else, but I think we will manage that.”

They will also need to try out what the right kinds of nutrition and hormones are needed for the placenta. This part of the project is being tasked to medical researchers in Aachen, Germany.

Another issue that can cause life-long injury for babies born extremely prematurely is brain damage.

In Milan experts in biomedical optics are working hard on a device to measure the amount of oxygen going to the baby’s brain.

Led by electronic engineer Alessandro Torricelli, they have developed a system based on two advanced light-measuring or photonic techniques: diffuse correlation spectroscopy (DCS) and time-resolved reflectance spectroscopy (TRS). Both technologies work in the near-infrared wavelength range, specifically in the so-called ‘physiological window’ where light absorption by tissue constituents such as blood, water and lipid is low enough to allow light to reach deeper tissue layers, sampling at the depth of the cerebral cortex or skeletal muscle.

DCS provides information about tissue blood flow and TRS locally measures optical tissue properties, allowing oxygen saturation and haemoglobin saturation to be measured. By this innovative combination of TRS and DCS, a set of information for monitoring the local tissue oxygen metabolism becomes accessible.

Eindhoven University’s van de Vosse is hoping to also be able to use these photonic technologies to measure what is going on in the baby’s brain. “If an infant is in stress, there will be a difference in the amount of oxygen that goes to brain and the blood that leaves it,” he says.

It is hoped that within two or three years, the researchers will be ready, having run all tests through the baby robot, and be able to test the prototype womb on an animal foetus. It will then be another six years for a device that is safe to use in hospital, and Jasmijn Kok, co- founder of Juno Perinatal Healthcare, is also working on finding new funding for this.

“We don’t want to be the first one we want to try this; we will take our time because we want to get it right” says van de Vosse.

“The most challenging part is going to be that we cannot make mistakes,” says Kok. “It’s like shooting a rocket to the Moon. You can’t get it wrong the first time because it is so important,” she adds.

What will Incubator 2:0 look like? When the PLS project was launched, designer Lisa Mandemaker was commissioned to create a prototype. She came up with red expandable balloons.

“We made these prototypes to help people decide what we expect from a technology rather than have these images put into our heads by Hollywood,” says Mandemaker.

“The scientists said it is not good for the baby’s development to have it see through – it’s a privacy thing and more a thing for the baby than the parent. There is concern what the emotional impact would be having movement and noise around and people peering at you.”
This year, the PLS team have come up with a more advanced model, more like a pod, with a closed case that shuts down onto a bag with the baby and fluid inside.

The advances in artificial womb technology are being scrutinised intensely by bioethicists. Even though complete ectogenesis of humans, from in-vitro egg fertilisation to birth, is still decades away, many argue it is never too early to start the discussion.

Some argue outsourcing pregnancies could improve gender equality. Not only would women be spared unpleasant side effects of hormonal changes when carrying a baby, but in many cultures, pregnancy is still viewed by many as a disability, and often can be if a pregnant mother is too sick to work. It has also been considered as a way for two gay men or a transgender woman to have a baby without needing a surrogate womb, a practice already outlawed in some countries like China because of the danger of female exploitation. It would also help women who were born without a uterus or may have lost it to cancer.

Others, including some feminists, fear it may deprive women of the greatest power they have over men: the ability to bear children. There are also issues such as the emotional development of a child.

“This technology has the potential to do wonderful things – especially for people experiencing dangerous pregnancies, and entities delivered or potentially delivered prematurely,” says Elizabeth Romanis, Assistant Professor in Biolaw at Durham University.

While this technology is in the early stages of development, it is important that we start having discussions about the ethico-legal questions arising from artificial placentas. We need to have thought through these problems in advance of its development to prevent the reaction to them being one of either misplaced overenthusiasm without concern of implications for individuals in some circumstances, or excessive fear limiting access to a life-changing technology for many.

The PLS scientists see these debates as being a little like, well, science fiction for now.

“What we are doing is to trying to replace the incubator by another one, so there is nothing different, only we improve the current incubator,” says van de Vosse.

“I always argue it would not be ethical not to do it if there is a chance we can improve the quality of life for those extreme pre-term babies. Would it be ethical to let them die if we know how to save them?”

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