A microfluidic culture model of the human reproductive tract and 28-day menstrual cycle
BOSTON — So-called “organs on a chip” — small blobs of tissue growing in lab dishes that mimic the function of their human counterparts — have promise for basic science and drug development. And those efforts are scaling up. On Tuesday scientists unveiled a five-organ female reproductive system on a chip small enough to hold in your hand, and showed that it could simulate a 28-day menstrual cycle.
The chip is part of an effort funded by the National Institutes of Health to build an entire human body-on-a-chip — a creation that would involve all of the organ systems and allow researchers to run unprecedentedly precise experiments on human tissue. Other research groups are also working on chips that mimic multiple organs, for instance the liver, heart, and blood vessels.
In this case, the “chip” is about the size of a hardcover book and studded with Lego-like blocks, each of which is hollowed-out and holds bits of tissue growing on plastic scaffolding: ovary, fallopian tube, uterus, cervix, liver. (The ovary samples come from mice — ovaries are rarely removed from healthy women — while the tissue for the fallopian tubes, uterus, and cervix comes from women who had hysterectomies.) The blocks are connected by minuscule tubes to simulate how the real organs communicate with each other in the human body.
Those tubes allow hormones to flow between the miniature organs. By feeding the right cocktail of hormones into the ovary block, the researchers were able to coax the miniature organ to release an egg, and to produce hormones that flowed into each organ downstream, causing them to behave similarly to how they do in the human body.
This is the first menstrual cycle “on-a-chip,” said Teresa Woodruff, the study’s primary investigator and a professor of obstetrics and gynecology at Northwestern University Feinberg School of Medicine.
The results were published Tuesday in Nature Communications.
All about EVATAR
The chip — dubbed “EVATAR,” a portmanteau of the biblical “Eve” and a representative “avatar” — could someday be used to test the effects of drugs on human tissues before putting them into the human body. Right now, animals play that role — but scientists wonder if animals’ different physiology might be one reason that so many drugs never make it into the clinic.
Building the EVATAR was a team effort, with multiple groups working to build the organ systems and a crack team of biomedical engineers in Cambridge, Mass., handling the design of the chip itself.
Jonathan Coppeta, a biomedical engineer at the Charles Stark Draper Laboratory, was part of that team, which built the piping system that moves fluid between the organ blocks. It’s controlled by 62 pumps that can be turned on and off independently. Each of those pumps uses a pinky-sized electromagnet to move about a millionth of a liter of fluid at a time.
Such a precisely controllable system allows scientists to do things that wouldn’t be possible to do in a real person, like change the rate at which hormones flow from one organ to another, to study the effect of that hormone on the organs.
“Could it potentially be better than an animal model?” said Jeffrey Borenstein, a biomedical engineer at Draper. “Yes, because you’re using human cells. Is it perfect? No, because there are always going to be limitations.”
Reproductive biology researchers unaffiliated with the project noticed one particular limitation in the team’s model of a uterus. The lining of a human uterus consists mainly of two types of cells — but on the chip it’s primarily one type of cell, pointed out Warren Nothnick, vice chairman of the department of molecular and integrative physiology at the University of Kansas Medical Center. Nothnick said that could hinder the system’s human veracity, because the underrepresented cell type gives rise to endometrial cancer. But altogether, he said, the paper is “really groundbreaking.”
Dr. Julie Kim, a Northwestern professor who led the team that built the uterus block, said that encouraging this particular type of cells — known as endometrial cells — to grow properly in lab-built organs is an open challenge. She hopes to build more life-like uteri in the future: “My dream is to create a menstruating uterus in a dish.”
Pharma showing interest
One of Woodruff’s next steps is building personalized EVATARs, whose miniature organs are grown out of stem cells from individual people. That could allow researchers to test how a drug would impact a particular person, based on their biology.
Men have to wait, but perhaps not long — within a year, Woodruff hopes to have more results to share about the male version of the project, nicknamed ADATAR.
Already pharmaceutical companies are starting to show interest — Woodruff said that she has tested some AstraZeneca drug candidates to gauge their impact on the female reproductive system.
Draper’s chip can support up to 12 organs, so researchers could use this chip to simulate different organ systems. The lab is also using similar technology to build custom chips for pharmaceutical companies like Pfizer.
Meanwhile, Woodruff is looking for participants to provide stem cells that could be used to make custom organ systems, which she said should happen over the next year.