Researchers create ovulation on a chip

Researchers have created ovulation in the lab, with a simulated female reproductive system that behaves almost like the real thing over twenty eight days (New Scientist, 2017).

Every twenty eight days, the ovary, cultured on a small plastic chip, releases an egg and starts producing hormones to prepare for pregnancy (Nature, 2017). The hormones travel through a series of tiny channels that mimic Fallopian tubes and into a uterus-like chamber made of human tissue. The system, described in a study published today in Nature Communications, is the latest in a series of organs-on-chips.

There is no good animal model for the twenty eight day human reproductive cycle, said Teresa Woodruff, a reproductive scientist at Northwestern University in Chicago, and a co-author of the study. She said the system fills an “urgent unmet need for us.” The organ-on-a-chip system may improve understanding of the causes of recurrent miscarriage and fuel new research into birth control and other drug development (Scientific American, 2017). The work may also help move toward a future where fertility experts could simply grow a sample of an individual woman’s cells, place them in this system and determine the best treatment.

Teresa Woodruff and her colleagues named their system Evatar, a portmanteau of Eve and avatar. To model the female reproductive system, the researchers took lab-grown human and mouse cells from five organs and cultivated them in a network of interconnected cubes. The cubes were fed by tubes that allowed blood and hormones to flow through them, mimicking the fluids’ movement throughout the body. Valves and pumps also controlled the units’ pressure and airflow. This environment allowed cells that would normally die in a petri dish, suffocating amid their own cellular waste, to stay alive for a standard twenty eight day reproductive cycle.

The Fallopian tubes, uterus and cervix are made from human tissues obtained from women undergoing hysterectomies. The ovaries, however, are from mouse tissue, because healthy ovaries are rarely removed from women. Tissue for the fifth organ, the liver, comes from humans. To start the reproductive cycle, the researchers added follicle-stimulating hormone, which drove the mouse ovaries to produce oestrogen. Fourteen days later, the researchers added luteinising hormone, which stimulated the ovaries to release an egg and begin to produce progesterone.

The egg stayed in the ovary chamber, but a second chamber lined with tissue from human Fallopian tubes began to act as though the egg were passing through it. In the model, as in women, the tissue in the Fallopian tubes contain hair-like structures called cilia, which beat back and forth to waft the egg to the uterus. The third and fourth chambers, lined with human uterine and cervical tissue, respectively, then produced receptors for the hormones. The researchers connected Evatar to a human liver-on-a-chip, which can metabolises drugs that the researchers are testing.

“I think this is as an extraordinarily important, beautiful piece of work,” said John Wikswo, a physiologist at Vanderbilt University in Nashville, Tennessee. He has been leading an effort to link at least ten organ systems together to form a complete human-on-a-chip. He said the simulated organs in the Evatar system function correctly only when the right amounts of signalling factors and hormones are carried in the right amount of fluid and each organ plays a part.

Jon Hennebold, a reproductive scientist at Oregon Health and Science University in Portland, said the main advantage of the new system is that it will allow researchers to quickly screen several drugs at once, testing them for toxicity and for their effects on the reproductive system. But he said even an integrated set of organs-on-chips can’t entirely replace animal or clinical studies, because it is impossible to know which organs will be relevant in a disease or during drug treatments.

“Right now organs-on-a-chip cannot account for something like an early-life [toxic] exposure that might affect future reproductive health,” said Kevin Osteen, a professor obstetrics and gynaecology at Vanderbilt University School of Medicine who was not involved in the study but works on other reproductive chip models. The chip system also does not include the placenta, which is key to supporting pregnancy, nor does it factor in how inflammation due to a viral infection would affect reproductive organs.

Teresa Woodruff said her system opens possibilities for studying a wide range of conditions, such as diseases of the cervix, which cannot be modelled in mice because their cervical cells are completely different from the human variety. She said “This system will allow us to study infection in that organ in way we haven’t been able to do in the past.”

She said her lab is planning to study various diseases by seeding the Evatar system with cells from people with conditions such as ovarian cancer, or by infecting Evatar with human papilloma virus, which can cause cervical cancer. The group is also making a male reproductive system called Adatar, and a testis–prostate system called DudeKube. The researchers plan to eventually link these systems with ten other organs, including brains-on-a-chip, which produce signalling steroids and hormones, and the surprisingly complex system of human fat-on-a-chip, which can affect metabolism, the immune system and the reproductive cycles.

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