Modeling the Female Reproductive Tract in 3-D: The Birth of EVATAR™
Science fiction and gaming enthusiasts are familiar with the concept of an avatar, the digital character a user creates to navigate a virtual world. Now, NIH-funded researchers are turning science fiction into scientific reality by building one. EVATAR™ is a miniaturized 3-D representation of the female reproductive tract and liver on a handheld, interconnected platform. The team of scientists from Northwestern University, Charles Stark Draper Laboratory and the University of Illinois at Chicago (UIC) is designing the model for use in drug testing and to study the basic biology of female reproduction.
Too often, laboratory and animal tests used by scientists in the early phases of research fail to predict a therapy’s effectiveness or potential side effects in humans. Use of inaccurate models can result in many years and millions of dollars being wasted while patients wait for effective treatments. Researchers need scientifically valid alternatives for predicting treatment effectiveness and safety.
Another issue is consideration of sex as a biological variable. Although women now comprise roughly half the participants in NIH-funded clinical trials, the same is not true for preclinical research. More often than not, preclinical research conducted to date has involved mostly male-derived cells and male animals. These practices have resulted in a lack of information about female physiology and women’s health.
To address these and other drug development challenges, NCATS, along with the Defense Advanced Research Projects Agency and the Food and Drug Administration, developed the Tissue Chip for Drug Screening program. Program funding is used to support scientists developing 3-D platforms with living human tissues and cells, called tissue chips or organs-on-chips. These devices are designed as accurate models of the structure and function of human organs and systems, such as the lung, liver, heart and, in this case, female reproductive tract.
A Team Effort
The EVATAR™ team at Northwestern University. (Northwestern University Photo)
Led by Northwestern University principal investigator and ovarian biology researcher Teresa Woodruff, Ph.D., the EVATAR™ team first came together in 2012 with funding from NIH’s first round of Tissue Chip program awards. At the time, each team member was working separately on 3-D models of different female reproductive organs: Woodruff on the ovaries; Joanna Burdette, Ph.D. (UIC), on the fallopian tubes; Julie Kim, Ph.D. (Northwestern), on the uterus; and Spiro Getsios, Ph.D. (Northwestern), on the cervix and vagina. Beth Sefton, Ph.D., at Northwestern, coordinates the work on EVATAR™ and ensures that the system and the investigators are all communicating in order to speed the pace and quality of the research.
“We’d each had a longstanding interest in developing 3-D organ models, and this opportunity enabled us to bridge together what we were all doing individually,” Burdette said. “For the first time, as a collaborative team, we attempted to create a 3-D model of the entire female reproductive tract.”
The Northwestern team and their partners from the Draper laboratory, Jonathan Coppeta, Ph.D., and Jeff Borenstein, Ph.D., have produced a device that enables the female reproductive tissue to interact over periods of a month or more, much like they do in the human body.
This advance solved a major technical challenge in the field: enabling organ models to communicate with each other via secreted factors, including hormones, to more closely resemble how they work together in the body.
The NCATS project, which was co-funded by the National Institute of Environmental Health Sciences, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the NIH Office of Research on Women’s Health (ORWH), and the NIH Common Fund, exemplifies the power of cooperation among NIH Institutes, Centers and Offices.
“This work is a remarkable advance for understanding female biology, and it will fill an important gap,” said Janine A. Clayton, M.D., ORWH director. “It’s a perfect example of how considering sex as a biological variable can help us develop individualized treatments and learn more about how females may metabolize drugs differently from males.”
Building EVATAR™
From puberty until menopause, the female reproductive system is capable of an amazing feat: growing a new human being. The ovaries, fallopian tubes, uterus, cervix and vagina use hormones to communicate and regulate each other. In premenopausal women, for example, every month a cascade of hormones fuels the growth and release of an egg from the ovaries; this process then triggers the other organs to prepare the fallopian tubes as the site of fertilization and the uterus for implantation of an embryo. The vagina and cervix act as the first line of defense for the female reproductive tract, protecting it from invaders that could cause infection.
Although not part of the female reproductive system, the liver serves an important role in metabolizing reproductive hormones and regulating their effects, as well as the effects of therapeutics such as chemotherapy drugs and endocrine disruptors. These hormones also circulate through the body and affect non-reproductive processes, such as bone and heart functions.
Studying the tissues as individual units limits scientists’ ability to learn how these organs work as a system. But until now, such a system did not exist.
Since 2012, the EVATAR™ group has been refining the individual organ components and building the integrated 3-D platform, which has three layers. The top layer contains multiple components that individually support the cells of each of the five organs. The bottom two layers hold the miniaturized pumps and tubes (called microfluidics) that mimic the human body environment, carrying liquids and hormones through each of the tissues. The model organs can be inserted or removed from the platform base as needed.
“We currently are working to ensure that all of the microfluidics and hormones on the platform are behaving the way we expect,” Woodruff explained.
Soon, the group will add each of the tissue types and hormones and test the entire system for the first time. The hormone fluctuations and behavior of the cells are designed to mimic a woman’s 28-day reproductive cycle.
The Future of EVATAR™
By more closely representing a woman’s reproductive biology and cycling hormones, EVATAR™ could help researchers overcome the limits of understanding female physiology using animals or cells grown in a lab. Woodruff’s group, for example, plans to use EVATAR™ to better understand the basic hormonal and cellular functioning of the reproductive tract.
The platform also could help scientists understand the various cancers, sexually transmitted infections and benign tumors that can affect female reproductive organs. In addition, researchers will be able to use EVATAR™ to predict whether a candidate drug, vaccine or biologic agent is safe or toxic in humans in a faster and more cost-effective way than is possible with current methods. The liver component will be able to process drugs, and since reproductive hormones affect how the liver works, the platform could help scientists understand how a drug will affect women with different hormone levels.
The ultimate goal is to integrate EVATAR™ with the Tissue Chip program’s other organs-on-chips to make an integrated model of a human body on a chip, enabling scientists to test the varying effects of a drug across the entire body before testing it in people.
“All of our organs are in constant dynamic communication with each other, but we’ve never been able to model that in a dish,” Woodruff said. “We’re really excited about this opportunity. For us, it’s like landing on the moon.”
Explore more about EVATAR™ and other tissue chips being developed via Chip, an online interactive model of the innovative developments from the NCATS-supported Tissue Chip for Drug Screening program. Watch the Tissue Chip for Drug Screening video to learn more about the program.
April 2017 Update
NCATS-supported scientists at Northwestern University were part of a team of researchers who recently reported on an advance relevant to the August 2015 Evatar story above. As published in Nature Communications and announced by Northwestern, the team created a miniature, working female reproductive system consisting of 3-D models of five reproductive organs: ovaries, fallopian tubes, the uterus, cervix and vagina, in addition to liver. The models communicate by way of secreted substances, including hormones, to mimic how they work together in a woman’s body in processes such as the 28-day reproductive cycle.
Posted August 2015