Microfluidic system mimics 28-day female reproductive cycle

Growing tissue from cells in a petri dish is hard enough, but growing multiple types of tissue, connecting them, and keeping them alive for weeks is even more daunting. A team led by Teresa K. Woodruff of Northwestern University, collaborating with engineers at MIT’s Charles Stark Draper Laboratory, has developed a microfluidic model of the human reproductive tract that recapitulates the hormone profile of the 28-day female menstrual cycle (Nat. Commun. 2017, DOI: 10.1038/ncomms14584). The device will provide a tool for studying diseases that can affect women at different stages of their reproductive life.

The system, which they call the Evatar, includes modules containing cultured ovarian, fallopian, uterine, cervical, and hepatic tissue. The cells used to culture the ovary tissue come from mice, but the rest come from humans. Microfluidic channels connect the modules to feed nutrients to the tissues and whisk away metabolic waste.

Those channels also allow the tissues to chemically communicate using hormones. The researchers initiate the cycle by adding follicle-stimulating hormone to the circulating fluid. The ovary module responds by producing estrogen. At the cycle midpoint—day 14—the researchers add luteinizing hormone, which triggers ovulation and causes the “ovary” to stop producing estrogen and start producing progesterone. The other tissues respond to the hormones produced by the ovary as they normally would in the body.

The researchers could make the system mimic either of two possibilities at the end of the cycle. In the absence of a “pregnancy,”

progesterone levels drop, which inside the female body causes the endometrial lining to shed. To simulate a pregnancy-like state, the team added the hormone prolactin to maintain elevated progesterone levels.

Initially, the researchers weren’t sure they’d be able to maintain the system for a full 28-day cycle. “We really challenged our engineers to produce a system that would allow the dynamic changes that occur in a reproductive system,” Woodruff says.

“This integrated microfluidic model is a remarkable feat of engineering and offers an array of new capabilities that represent a major advance from traditional in vitro techniques commonly used in reproductive biology,” says Donguen (Dan) Huh, a bioengineering professor at the University of Pennsylvania who develops organ-on-a-chip systems. “The ability of the system to coculture various types of female reproductive tissues for prolonged periods in a modular and reconfigurable fashion is particularly impressive.”

The Northwestern team plans to study various diseases that affect reproductive-age women, such as fibroids and endometriosis. In addition, they have a grant from the Gates Foundation to find new forms of contraception, such as ways to block ovulation. Their ultimate goal is to grow tissue from patients’ pluripotent stem cells so individuals can have their own system for personalized medicine.

But the researchers don’t plan to limit themselves to reproductive health. They plan to add modules containing cardiac, muscular, adipose, adrenal, and hippocampal tissue.

“People sometimes think the reproductive system is important only for fertility, but reproductive system hormones inform overall biology,” Woodruff says. This device will enable biologists to study other systems in the context of cyclical hormone levels, she says.

Nor does the team intend to stop with the female reproductive system. They are building a similar model of the male reproductive system with tissues from organs such as the testis and prostate. Unsurprisingly, they plan to call that device the Adatar.

This article has been translated into Spanish by Divulgame.org and can be found here.