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Text｜Hu Xiangyun

Editor｜Hai Ruojing

The "artificial womb" technology has been pushed to the forefront of public opinion.

Recently, the First Affiliated Hospital of Zhengzhou University announced the completion of an "ECMO-free (extracorporeal membrane oxygenation) artificial uterus animal experiment". A 4-month-old fetal lamb was placed in a "special device" and connected to the mother. With the mother's vital signs maintained, it successfully survived for 90 minutes.

Zhao Gaofeng, the director of the lung transplant surgery department of the First Affiliated Hospital of Zhengzhou University and the person in charge of the experiment, mentioned in an interview with the media that this idea of ​​eliminating ECMO in artificial uterus technology is "the first in my country". This means thatIn the case of the same blood type, both the father and the mother can play the role of nurturing the fetus.。

The concept of "anyone can have a baby" has given people unlimited imagination. On social media, discussions about "baby factories on assembly lines" and "male pregnancy and childbirth" once surpassed the technology itself.

Will the application prospects of artificial wombs really become the "brave new world" in science fiction novels?

Original intention: to save extremely premature babies, not to make men pregnant

In the 1920s, British biologist Haldane first proposed the concept of "ectogenesis", bringing the first comprehensive discussion about artificial wombs to mankind. In his vision, the 21st century will no longer be an era of using traditional instincts to give birth, but a more "rational, enlightened, and completely in vitro" pregnancy process will replace it; by 2074, the proportion of babies born through "natural pregnancy will be less than 30%."

Today, such ideas are even more radical in some ways. Musk and other "tech geeks" have publicly stated that with the global population declining, they should invest in artificial womb technology to "make children faster, easier and cheaper."

On domestic social media, after the research of the team from the First Affiliated Hospital of Zhengzhou University was announced, the majority of comments were about "male fertility".

The United States, Australia, Japan, Israel and other countries all have research teams working on artificial uterus technology.From the earliest silicone membrane blood oxygenators and artificial amniotic fluid incubators to the ECMO technology that began to be used in the 21st century and the "ECMO-free" solution launched by the Chinese team today, in fact, scientific research teams around the world have not studied it as a device to replace pregnancy and realize uterine function, but as a method that can "provide a feasible alternative for neonatal intensive care."。

Schematic diagram of a fetal sheep in an artificial womb (Source: EA Partridge et al./Nature Commun. (CC BY 4.0))

The head of the artificial womb research team at the University of Michigan even publicly stated in a paper that the idea of ​​"a baby growing completely outside the womb is 'technological ignorance and an ideological daydream'."

Zhao Gaofeng also corrected that the artificial womb is not for "mass production of babies, but to allow fetuses that cannot stay in the womb to continue to survive."

The scientific community emphasizes this issue because the treatment of premature babies still faces many difficulties both at home and abroad. In medicine, premature babies are those with a gestational age of less than 37 weeks, and those with a gestational age of less than 28 weeks are considered extremely premature babies. To this day, their medical treatment is still a recognized problem; and with the increase in the number of elderly mothers in China in recent years and the application of assisted reproductive technologies, the premature birth rate may rise.

For individual families, this also means a heavy financial burden. According to the survey data of Beijing Chunmiao Charity Foundation, more than 85% of families with premature babies have "catastrophic health expenses", and the cost of treatment exceeds 40% of the family's ability to pay.

A doctor who has been engaged in reproductive work for decades explained to 36Kr that breathing and infection are the main problems. Take breathing as an example. When the fetus is in the womb, the fetal lungs are filled with amniotic fluid, and the oxygen it needs is obtained from the placenta through the umbilical cord. After the umbilical cord is cut short, it starts to breathe on its own. If it is a premature baby whose organs are not fully developed, the spontaneous breathing is unstable, and even if a ventilator is used, it is easy to have lung infection, bronchopulmonary dysplasia and other problems. The younger the child, the longer he or she will rely on oxygen.

But if it can continue to develop in the artificial womb, theoretically "its lungs will develop better."

This has also become a point that all teams have emphasized in the current experiments of artificial uterus technology. For example, in 2017, the experimental results published by the team of Children's Hospital of Philadelphia in the United States mentioned that in the uterine environment simulated by the biological bag they designed (including a transparent plastic bag and an extracorporeal circulation device), 8 premature lambs equivalent to 23-24 weeks of human gestational age "developed normally and even grew wool" during the 4 weeks of survival;

The University of Michigan team's solution is to inject a special liquid into the lungs of experimental animals, then use a system to drain the heart blood through the jugular vein, and then oxygenate it outside the body before returning it. The research results also mentioned that the experimental fetus "survived for 116 days, and the lungs, brain and other organs developed well."

"IfTraditional premature infant rescue is to provide children with more advanced life support, while artificial uterus technology can provide them with an environment that simulates the mother's body so that they can continue to develop, increasing the possibility of premature infants' survival and healthy development.” The aforementioned doctor believes.

A Chinese team created a world first: What does "going ECMO" mean?

At present, the artificial uterus technology team with the fastest progress in the world has already embarked on the path of setting up offices and attracting venture capital; in September 2023, the US FDA was even holding a meeting to discuss the issue of human trials.

In comparison, why did the team from the First Affiliated Hospital of Zhengzhou University, which had just completed an animal experiment, attract such strong attention?

The concept of "de-ECMO" is the biggest highlight of the experiment. In some media reports, this is also called "the world's first successful case."

Over the past few decades, breaking through the blood oxygen problem has been an important node in the core progress of artificial uterus technology, and the key lies in the application of ECMO. Because ECMO can supply oxygen to the fetus separated from the mother, this method allows blood to "bypass" the heart and lungs, allowing the organs to rest and heal.

Although some overseas scientists believe that ECMO is not suitable for extremely premature infants, most of the improvement ideas are still centered around the equipment; in fact, even the team of the First Affiliated Hospital of Zhengzhou University used ECMO when they first conducted experiments. At that time, they also compared ECMO to "a vital role in the artificial uterus system, playing the role of lungs for premature infants."

36Kr learned that this is because the use of ECMO does not involve "any other additional blood circulation" and can "confine" the blood circulation within the fetus itself.

In the results recently disclosed, the team did not explain why they gave up this mature path, but mentioned the idea of ​​"ECMO-free" for living replacement, which is to connect the sheep's umbilical artery and umbilical vein "with the artery and vein in the mother's neck to establish a parallel circulation similar to ECMO." In the view of the team, the "ECMO-free" solution helps to avoid risks such as thrombosis and infection, and no longer needs to pay high equipment maintenance costs.

Fu Shibo, a doctor at a tertiary hospital in Shanghai (Zhihu medical science author "Dr. Philip"), told 36Kr, "Although the expression "removing ECMO" does not explain the specific connection method, it should also "use a converter, such as a membrane structure similar to dialysis, to establish a certain connection between the blood flow of the mother/father and the fetus", so as to avoid the mother/father's immune system identifying the fetus as a foreign body and attacking it, while ensuring that the gas, nutrients and metabolic waste in the blood are exchanged across the membrane.。

In terms of effectiveness, the advantages and disadvantages of this experimental idea are relatively obvious.

The first is cost reduction. In an interview with Health Times, Zhao Gaofeng mentioned that the "startup cost and daily operating cost of ECMO are 60,000 to 70,000 yuan and 10,000 to 20,000 yuan respectively." For a research team still in its infancy, the cost burden is heavy.

"The 'ECMO-free' plan will help reduce dependence on overseas high-end equipment and its supporting membrane consumables, especially when there are no domestic alternatives to related consumables. In addition, although it has not been announced to the public, a certain membrane structure device used in the 'ECMO-free' plan is most likely a self-developed device with independent intellectual property rights, which means that the overall equipment cost will be lower." Dr. Fu Shibo believes.

In addition, from the perspective of experimental structure design, the ECMO in the overseas team's plan is only responsible for oxygenation, and "other nutrients must be added to the fetus's blood through injection"; while the Chinese team's plan solves the problems of gas and nutrition at the same time, which is simpler.

However, the doctor also mentioned that the membrane structure equipment used in the "ECMO-free" program is effective in blocking blood typeAntibodyIn terms of functions, it still cannot be compared with the natural placenta, and may cause problems such as neonatal hemolysis. Therefore, there will be many limiting factors. For example, the team itself mentioned that "the blood type of the fetus must be consistent with that of the father/mother."

"Overall, I think both solutions have their own advantages. From the perspective of clinicians, we hope that the research of the First Affiliated Hospital of Zhengzhou University can be published in papers so that everyone can understand it earlier and in more detail. Of course, we also hope that the Chinese solution can lead the research in this field."

Expecting a lamb to be born alive

Currently, a breakthrough in the process of artificial uterus technology becoming a reality is that the survival time of experimental animals continues to increase.

In 2017, the longest survival time of the experimental lambs of the Philadelphia Children's Hospital team reached 4 weeks; in 2023, another data released by Japanese scientists stated that 6 surviving lantern sharks were successfully born using artificial womb technology, and the longest surviving one lasted 7 months.

In China, the team of the First Affiliated Hospital of Zhengzhou University previously used ECMO to achieve a survival time of 7 days for the experimental fetus; in this "ECMO-free" plan, the fetus survived in the artificial womb for 90 minutes. "The domestic team has indeed provided a new technical path that reduces dependence on equipment.However, the earliest report on artificial uterus was in 2017. Domestic scholars started relatively late, and the experimental observation time was also relatively short.Doctor Fu Shibo believes that this is also a regrettable point in the experiment conducted by the First Affiliated Hospital of Zhengzhou University.

However, the question that both domestic and overseas teams have not been able to answer is: although it is claimed that the fetal lambs developed normally in the artificial womb, they were basically euthanized in the end, and no "successful, living lambs were born, or even lived for a period of time."

"This actually confuses me a little bit," the doctor said.If according to the experimental results, the various systems of the fetal sheep develop normally, why not observe them for a longer period of time, especially after "birth"?There may still be some inherent flaws that cannot be resolved, such as how to induce the first spontaneous breath of the fetus when it is removed from the amniotic fluid; if a similar caesarean section method is used to stimulate it after removal, is it successful? These have not yet been announced. "

On the other hand, all current research progress remains at the stage of animal experiments. From the perspective of clinical practice, doctors mentioned that the most concerning issue is still "to what extent it can serve human premature infants with relevant needs."

In September 2023, the US FDA held an independent advisory meeting to discuss how to better evaluate the safety and effectiveness of artificial uterus technology, such as the limitations of animal data and the ethical difficulties of human trials. However, the specific human trial plan was not announced to the public during this discussion.

According to foreign media reports,The Children's Hospital of Philadelphia team has submitted an application to the FDA for human trials of related equipment; and the University of Michigan team also mentioned that they hope to advance human clinical trials within 3-4 years.But they also mentioned that there are "fundamental gaps in the scientific community's understanding of how a human fetus grows in an artificial womb, which requires focused research before formal trials."

Ethics is also a question that scientists are thinking about. Some overseas scholars mentioned that transplant operations involving extremely premature babies are often performed in the early stages of pregnancy, and the uterine incision is relatively larger than that in full-term pregnancy. There are risks such as uterine rupture and abnormal placental implantation, which involves the issue of informed consent. "We worry that parents will do anything desperately after being informed of the dire situation of the fetus, even if these technologies are completely untested and risky."