This is how a human embryo is implanted: Spanish scientists record the 'miracle of life' for the first time.

The 'miracle of life' is much more complex than uniting an egg with a sperm. The resulting embryo must implant in the uterus, and this is where science has hit a blind spot until now. During the first five days after conception, the human embryo is very microscopic and free. During this period, it can be studied in assisted reproduction clinics or research laboratories. But, from the fifth day onward, it must adhere to the walls of the maternal uterus. And, from that moment until it can be seen by ultrasound, weeks later, nothing is known about how it develops. This is a key aspect, since implantation failure is one of the main causes of infertility and accounts for 60% of spontaneous abortions. Now, researchers from the Institute for Bioengineering of Catalonia (IBEC), in collaboration with Dexeus University Hospital, have achieved a milestone: capturing unparalleled images of the implantation of a human embryo . This is the first time that the process has been recorded in real time and in 3D .

"What happens during implantation is a black box for us. What we were trying to do was open that black box, and to do so, we developed a system in which the embryo not only implanted but we could record and view it," Samuel Ojosnegros , principal investigator of the Bioengineering for Reproductive Health group at IBEC and leader of the study, explained to ABC.

The seed of this work lies in Ojosnegros's time at the California Institute of Technology (Caltech), the same school where the protagonists of the popular series " Big Bang Theory " studied. Back in 2012, while working in the center's microscopy laboratory, the Spanish researcher created a "very rudimentary" system to observe how embryos implant. But it wasn't until 2014, the year he arrived at the Institute for Bioengineering of Catalonia and teamed up with embryologist Anna Seriola, an IBEC researcher and co-first author of the study, that the project really took off.

"We have observed that human embryos insert themselves into the uterus, exerting considerable force during the process. These forces are necessary because the embryos must be able to invade the uterine tissue and fully integrate into it. It is a surprisingly invasive process . Although it is known that many women experience abdominal pain and slight bleeding during implantation, this process itself has never been observed before," says Samuel Ojosnegros.

To carry out the study, the results of which are published in the journal Science Advances, they used embryos donated for research by patients at Dexeus University Hospital who had completed their assisted reproduction cycles. "Without the generosity of the patients, we couldn't do anything," emphasizes Samuel Ojosnegros.

The researchers reproduced a matrix composed of collagen , the main component of the maternal uterus, so that the embryo would be in a near-physiological environment; and culture media with richer serums derived from human plasma, which more closely resemble what a real embryo encounters for development. "We've given it the nest it finds in nature, the nutrients from the mother, and we've done all of this in a system that can be used under a microscope. The embryo can develop, and we can observe it," the researcher notes.

Experiments were conducted with human and mouse embryos to compare the two implantation processes. "We've seen that the human embryo is very invasive; it digs a hole and buries itself inside, and once inside, it begins to pull on the uterus and grow. The mouse embryo, however, remains on the surface of the uterus and expands across that surface," Ojosnegros explains.

Another surprising thing they've seen is that the human embryo is "mechanosensitive," the researcher describes. This means it's capable of sensing tension. " If you pull on the uterus at specific points, it senses the tension and shifts the implantation axis to that signal. We hypothesize that there are microcontractions in the uterus that are capable of guiding embryo implantation," he notes.

" Human reproduction is quite inefficient ; only a third of conceptions become fully born babies, a third of embryos never implant, and another third are lost shortly after implantation. So, we can consider implantation to be a limiting factor in human reproduction," says Amélie Godeau, a researcher with the Ojosnegros group and co-lead author of the study.

The system used by the researchers in this work will allow them to study the implantation process in vitro to make it more efficient , to know which embryos implant and which do not, or to develop vitamin or protein supplements that improve the process.

From now on, according to the researcher, there are two challenges: one of basic science and one of technology. On the one hand, understanding how the embryo implants, why it exerts this force, and what mechanism it uses to tear, make a hole, and invade the womb; and on the other, ensuring that industry can adopt the system to continue research that will lead to new discoveries in both diagnostics and compounds that improve implantation.