On October 3, Japan’s “Asahi Shimbun” broadcast footage of several special sharks swimming in a water tank. Under the orange-red culture light, their body surface emits a faint blue light. According to Japanese media, this is the first time that humans have used an artificial womb to breed and give birth to a shark. This move takes the practical application of artificial womb technology one step further. In December last year, an 8-minute short video of an artificial womb factory sparked heated discussion. According to the video description, women will be free from the pain of childbirth in the future, and tens of thousands of babies will be born in the laboratory every year.
There have been a lot of recent developments in the field of artificial womb technology. “Nature” magazine published a special report on September 14, saying that human trials of artificial wombs may soon start. On September 19, the U.S. Food and Drug Administration (FDA) held a two-day independent advisory meeting to discuss how to transfer artificial womb research from animals to humans. The technology has been tested on hundreds of lambs and some piglets worldwide.
Unlike the predictions of “Nature”, the FDA meeting did not disclose specific human trial plans. In fact, in the future, the primary goal of artificial wombs is to save premature babies rather than replace the womb. Ann Massaro, chief neonatologist in the FDA’s Office of Pediatric Therapeutics, spoke at the meeting and said that the most challenging question at the moment is “how much uncertainty can we accept.” Many experts attending the meeting said that the conversion of animal models to human trials will take time, and many key technical details and ethical regulations need to be improved.
Lack of long-term cultivation solutions
A company in Okinawa, Japan, has been researching artificial uterus devices since 2017. This year, it successfully used it to cultivate fetuses of thin-tailed lantern sharks and performed “artificial delivery.” The thin-tailed lantern shark is only 40 to 50 centimeters long as an adult. It is a small deep-sea shark that is widely distributed in the Pacific. What makes them emit blue light is a special light-emitting organ located on the surface of the body. Currently, the IUCN classifies it as “data deficient” and there are no long-term breeding records. This move by Japanese researchers is intended to provide new solutions for the protection of the pintail shark.
Matthew Kemp, associate professor of obstetrics at the National University of Singapore, is also developing an artificial uterine system. He has expressed professional opinions on public consultation items issued by the FDA’s Pediatric Advisory Committee. This item was opened on the FDA official website in July this year, with the theme of evaluating the safety and effectiveness of artificial uterus technology equipment. This consultation paved the way for the FDA advisory meeting in September. In his reply to China News Weekly, Kemp said that artificial womb technology has developed slowly and has only made many breakthroughs in the past ten years. Artificial reproduction of rare species is one of the emerging application fields of this technology. He pointed out that Juntendo University in Japan carried out the breeding of fetal sheep 20 years ago, and the earliest artificial uterus model can be traced back to the 1950s. So far, researchers around the world have spent a long time filling in the various technological gaps.
The artificial uterus does not look complicated from the outside. It’s a liquid-filled, sterile, temperature-controlled “bag” that resembles a miniature version of a traditional nursery or incubator. This “bag” is usually made of polyethylene plastic and is used to provide a sterile environment. The bag is filled with artificial amniotic fluid, simulating the intrauterine environment, and connected to the catheter system. In addition, the “bag” is also connected to the blood circulation system, replacing the nutrient supply and metabolic functions of the umbilical cord. Researchers can directly observe the development of the fetus inside through this translucent bag. Kemp said that a 2009 study at the University of Michigan in the United States pioneered this “bag” model, and subsequent artificial uterine structures have been based on this model. In this study, researchers used a pumpless catheter system to avoid fetal damage from mechanical pumps and successfully allowed full-term lambs to survive outside the womb for 4 hours.
The Children’s Hospital of Philadelphia (CHOP) is at the forefront of expanding the “bag” model. In 2017, the CHOP team conducted trials with eight fetal sheep and released a video demonstrating the results. In the video, a hairless, pale lamb is lying on its side in a bag, wrapped in turbid artificial amniotic fluid, with its eyes closed and its nose and limbs twitching frequently. The sheep spent its 28th day in the artificial womb and was able to breathe and swim normally, physiologically equivalent to a human fetus at 23 to 24 weeks of gestation. In 2019, several members of the CHOP team joined the startup Vitara Biomedical to raise $100 million for the optimized development of artificial uterine devices. The optimized device was named “Extrauterine Environment for Neonatal Development”, or EXTEND. This year, the CHOP team applied to the FDA with EXTEND, hoping to approve the first human clinical trial of artificial uterus.
CHOP fetal surgeon Alan Fleck, who is in charge of this work, said at the FDA meeting that human trials are “very necessary” for the purpose of obtaining clinical evidence of the safety and effectiveness of this technology. He believes that if human trials are successful, most premature babies will not need to be placed on a ventilator and can continue to grow in artificial wombs. Fleck also introduced the current stability performance of EXTEND, saying that the team has conceived more than 300 lambs in artificial wombs, and the trials have gone very smoothly. When asked how far the technology had progressed, he declined to answer, choosing instead to discuss trial arrangements with the committee privately. Before the meeting, Flake also declined an interview with Nature magazine, citing “conflicts of interest” and “restrictions on proprietary information.”
Many research teams around the world are seeking breakthroughs in this field. The Eindhoven University of Technology in the Netherlands completed the development of a similar fetal sheep model in 2019. In 2021, “Nature” published the results of the Weizmann Institute of Science in Israel on the extrauterine culture of mouse embryos. In the same year, the First Affiliated Hospital of Zhengzhou University successfully carried out the first domestic in vitro cultivation trial of artificial uterus for fetal sheep. Zhao Gaofeng, chief physician of the hospital’s lung transplant surgery department, is the person in charge of this trial. He told China News Weekly that one of the reasons for the slow development of artificial womb technology is that there is currently a lack of long-term culture solutions.
Zhao Gaofeng said that there are five major technical difficulties in artificial uterus. One is constant temperature, which is no longer a problem under current technical conditions. The second is oxygen supply. The oxygen required by the fetus in the amniotic fluid does not need to be obtained through breathing, but is delivered through the umbilical cord blood. In the artificial uterus, it is obtained through extracorporeal membrane oxygenation (ECMO). This system relies on vascular cannulation to drain the blood, oxygenate it in an artificial lung outside the body, and then infuse it back into the fetus. However, due to the limitations of intubation itself, various complications may occur in the fetus during ECMO operation, which affects the oxygen supply efficiency. The third and fourth are nutrition and excretion respectively. The transportation of nutrients required for fetal development and the process of waste metabolism are all realized through the circulatory system in the artificial womb. The maintenance and stability of the circulatory system itself still needs to be optimized, and this process is likely to bring about the fifth difficulty – infection.
Zhao Gaofeng recalled that the fetal sheep test he led went through a long period of time and failed many times, with a total of more than 10 test sheep. During the experiment, artificial amniotic fluid needs to be constantly replaced. If bacteria are accidentally mixed in, fetal sheep can easily become infected and cause sepsis when broad-spectrum antibiotics are ineffective. The CHOP team can cultivate fetal sheep in artificial wombs for 28 days, while the domestic team can only cultivate fetal sheep for about a week. The difference in infection prevention level brought about by the advanced equipment of the former is the key. He believes that there are still technical shortcomings around the world in maintaining the stability of artificial uteruses for the long term.
Researchers from a Japanese company said that in the early stages of the experiment, sharks cultured in artificial wombs were placed directly into seawater tanks for culture after the incubation period. However, they all died within a few days. They believe that shark babies cannot adapt to the sea environment in time after giving birth. Since then, researchers have developed a seawater adaptation plan to gradually shift the environment in the artificial uterus to seawater before birth, and then transfer it to a seawater tank for cultivation. One of the new batch of sharks survived the program for more than seven months, the longest time this species has ever been kept in captivity. This also means that long-term culture of fetuses in artificial wombs usually has higher technical requirements.
”Nature” magazine mentioned in a special report that EXTEND may be the closest solution to human trials at present. However, the FDA meeting failed to vote as scheduled. Kemp pointed out that in order to approve the trial, FDA officials need to be convinced that the fetus will benefit from EXTEND and that developmental performance should be no worse than that of fetuses receiving the current standard of care, which is difficult to extrapolate from animal testing. He believes that progress will continue to be made in this field, but that it is currently impossible to justify starting human trials. There is still a lot of duplication of work before considering the application of this technology.
In addition, some analysts pointed out that the current artificial womb simulation environment is not stable enough and the device complexity is not enough. It is still far from the idea of ”artificial womb factory” in the hotly discussed video. Even if this idea can be realized in theory, it will face many practical and ethical barriers.
Stephanie Kukkola, a neonatologist at the Children’s Mercy Center in Kansas City, USA, said in a reply to China News Weekly that the gestation period of lambs is different from that of humans, and the timing of organ development is also different. The lamb model was chosen mainly to imitate human lung development at 22 to 24 weeks of gestation, and fetal sheep at relevant developmental stages are suitable for operation. In fact, at this stage, fetal sheep are much larger than human fetuses, and their brains are at a different stage of development. Therefore, EXTEND’s current data do not confirm that human trials will be as successful as those in fetal sheep.
Left: A 107-day gestation lamb on day 4 of survival in an artificial womb; right: The same lamb on day 28 showing somatic cell growth and maturation. Picture/”Nature Communications”
Artificial uterus is not “assembly line creation”
At the FDA meeting, experts agreed that developing artificial womb technology is critical to helping save the lives of some premature babies, especially extremely premature babies. When premature babies are placed in the incubator used in traditional care, they need to breathe with their own immature lungs, which can easily cause lung damage and infection. The CHOP team also said that the most fundamental purpose of this technology is to simulate the natural uterus and improve ultrasonic health. Outcomes of premature infants.
The World Health Organization (WHO) defines preterm birth as birth before 37 weeks of gestation, while ultra-preterm birth refers to fetuses born before 28 weeks of gestation that are not full term. Premature birth may occur naturally, or it may occur due to special circumstances such as infection, hormone imbalance, high blood pressure, or diabetes, which render the uterus unsuitable for the fetus to survive. In May this year, the latest report jointly released by multiple agencies, including the WHO, stated that in 2019, premature birth had become the largest cause of death and disability among children under the age of 5. Complications related to premature birth resulted in approximately 900,000 deaths that year. In 2020, there were approximately 13.4 million premature births worldwide, of which nearly 1 million died from complications of premature birth.
The report points out that the mortality rate is closely related to the gestational age of the baby at birth. Generally, the longer a fetus remains safely in the womb, the better its chances of long-term survival and health. 22 weeks or before is considered a critical period for fetal viability, with few fetuses surviving outside the womb during this period. By 28 weeks, most are viable, but often require extensive life support. The CHOP team said the lungs and brain are the last fully mature organs in humans, so long-term health issues after birth need to be monitored.
In 2022, the Journal of the American Medical Association published a study by the team of Edward Bell, a researcher at the University of Iowa. They constructed a case data set from many places in the United States from 2013 to 2018, and proposed that the 1-year survival rates of extremely premature infants who were actively treated at 22, 23, 24, 25, and 26 weeks of gestation were 30%, 55.8%, 71.4%, and 71.4%, respectively. 79.9% and 88.1%. In other words, at 24 weeks gestation, 71.4% of babies survive to be 1 year old. The Bell data set and its conclusions were repeatedly mentioned at FDA meetings as strong evidence for promoting artificial wombs. But Kemp believes that current data shows that the use of the untested artificial uterine system for babies with a gestational age of 24 weeks or more cannot be advocated because it will be difficult to compete with the survival rate of more than 70%.
Zhao Gaofeng believes that the purpose of artificial womb technology is to remove fetuses that require surgery from the mother’s body, making in vitro surgery possible. The artificial uterus can provide a stable surgical environment and extend the operable time from a few minutes to half an hour inside the body to several hours outside the body. From a clinical perspective, this has important implications for infants with conditions such as congenital malformations. When congenital lesions develop to a certain extent, they will endanger the life of the fetus, so the deformity or defect needs to be treated at the appropriate time. In vitro treatment can avoid the risk of miscarriage caused by intrauterine surgery. Therefore, artificial wombs are of great significance for the care of premature infants with defects.
Kukkola stressed that people tend to overestimate the potential applications of artificial wombs. This technology is an alternative treatment option for neonatal intensive care, not the so-called “machine surrogacy” or “fetal factory”, nor can it completely replace the normal pregnancy process. For example, she said that usually ultra-preterm infants are prone to respiratory failure due to incomplete lung development and need to receive mechanical ventilation, which means using a ventilator to provide air pressure to the lungs. While life-saving, it can also cause trauma to delicate lung tissue, risking scarring and inflammation in the long term, leading to conditions such as bronchopulmonary dysplasia (BPD). Babies with severe BPD may require long-term hospitalization and sometimes long-term respiratory support. The artificial uterus uses ECMO for extracorporeal oxygenation, which is expected to eliminate tissue damage caused by mechanical ventilation, reduce the incidence of BPD, and improve survival rates.
The CHOP team hopes that EXTEND will reduce other complications in premature infants, such as brain hemorrhages, but animal trials do not yet support a link between these symptoms and treatments. The FDA pointed out in the meeting briefing that artificial womb research is promising in the field of premature infants, but regulatory and ethical issues require further discussion, so no more information will be made available to the media and the public.
Currently, the 28-day survival time of fetal sheep has reached the ethical upper limit recognized by academic circles. The fetal sheep were euthanized after the experiment. When asked about the ethical issues that artificial wombs may bring, many interviewees believed that a reasonable trial design would help alleviate the ethical challenges of this research, and screening cases is an important step. Kukola said initial controlled trials are needed to exclude patients who are likely to have good results with conventional treatment. Therefore, the screening mechanism should be strict, and based on this, the safety and necessity of using an artificial uterus should be estimated, such as whether there is a higher risk of complications, whether the ventilator can no longer fully support the patient’s breathing, etc. In addition, ultra-premature caesarean section will bring additional risks to the mother and her future births, which is also an issue that needs to be considered in the trial design.
Kukkola also stressed the need to ensure trial participants fully understand the risks and benefits of the technology. Existing research shows that patients sometimes blindly agree to participate in research because of excessive trust in a treatment or the possibility of a cure, even when researchers explain the associated risks. Institutional review boards and stakeholders need to jointly participate in trial design to ensure that information is equal between participants and researchers and to avoid risks to the greatest extent.
Zhao Gaofeng pointed out that domestic human trials are still in the exploratory stage. The development of all new technologies, especially clinical research, needs to pass ethical standards. For example, he said that in recent years, many cases of xenogeneic organ transplantation have been performed in the United States, including two cases of heart transplantation and two cases of kidney transplantation. They were all treated as special cases and the ethical review was very fast. He hopes that China will be more open and inclusive in terms of ethics in some pioneering fields.
This year, the First Affiliated Hospital of Zhengzhou University, where Zhao Gaofeng is located, will join forces with the teams of the Second Affiliated Hospital of Zhejiang Medical University and the Third Affiliated Hospital of Zhengzhou University to jointly apply for the national-level project “Basic Research and Clinical Application of Artificial Uterus”, with a view to improving artificial uterus. to discuss the possibility in more depth. Zhao Gaofeng said that this subject will leave the scope of fetal sheep and move towards human trials, striving for a major breakthrough within two years. However, the ethical aspects are currently yet to be reviewed.
In addition to ethical uncertainties, Kemp believes that more information is needed about fetal immunity, endocrine and organ growth before human trials can be considered. Regulatory agencies should define standardized metrics, including body weight, endocrine maturity, circulating volume, etc., to facilitate the use of artificial uterine systems. At present, this type of definition is still blank, and the lack of standardization of experimental data from different systems will limit the objectivity of system evaluation. More attention should be paid when artificial wombs are used in premature fetuses with growth restriction, infection and inflammation, because abnormal indicators need to be more precise than normal indicators to assess the actual health status of the fetus.