Microfluidic systems have been developed that support 28 day reproductive cycles including ovarian follicle growth, ovulation, and luteinization with the accompanying changes in estradiol and progesterone. The oocytes that are released from the follicle in this setting are healthy and have the predicted nuclear and cytoplasmic maturation phenotypes of in vivo ovulated oocytes. We have integrated the ovarian tissue and cycling hormone profiles into a multiplexed microdynamic unit that includes human fallopian tube tissue, uterine endometrium, cervix, and liver organoids. We have also adapted mouse islets and separately, human testis and prostate into similarly bioactive systems. The purpose of this application is to further our work by implementing a next generation microfluidic system that has been created for the express purpose of a high throughput robotics setting that will enable drug testing of integrated organ systems that mimic a variety of reproductive diseases. The hypothesis that will be tested in that we can create an in vitro microfluidic system that represents hallmarks of polycystic ovary syndrome, a multiorgan disease that affects 8-10% of reproductive age women and for whom there is no adequate in vitro model. During the past 4 years of work, we developed the first generation microfluidic platform that permitted the hormone and tissue level function above.
In aim 1 of the present application, we will finalize a new system that was built expressly for a robotics laboratory. This system is made of materials that does not absorb steroids and has pumping profiles that are stable up to one month. Prototypes have also been handled robotically. Onboard controllers, pumps and batteries have been adapted with the goal of a low cost, reusable device that could be easily used in an incubator as well as the larger scale-screening laboratory. Our goal is to develop a device that will replace all ordinary plated culture work so that biologists can move away from studying flat cells in static waste- accumulating models.
In aim 2 we will establish models of PCOS for each organ and for the organs connected to each other and test a variety of drugs in aim 3 that will alter androgen or insulin metabolism. This will be done with Astrazeneca. Taken together, our studies will provide a next generation toolbox important to women's health and to the broader field of cell biology.

Public Health Relevance

PCOS is a highly prevalant human health crisis for women in their reproductive years but there are no good animal models of the disease. Using our expertise in microfluidic reproductive systems we have created a next generation technology that can be used in the general or high throughput tissue culture lab and will support human and mouse tissues (ovaries, fallopian tubes, uterus, cervix, adipose, liver, pancreas) under the influence of androgen. We will use this model to test drugs that target androgen production as well as existing insulin sensitizing drugs and a new class of drugs that is under development for PCOS by our pharmaceutical partner Astrazeneca.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
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Special Emphasis Panel (ZTR1)
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Reinlib, Leslie J
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Northwestern University at Chicago
Obstetrics & Gynecology
Schools of Medicine
United States
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Zink, Katherine E; Dean, Matthew; Burdette, Joanna E et al. (2018) Imaging Mass Spectrometry Reveals Crosstalk between the Fallopian Tube and the Ovary that Drives Primary Metastasis of Ovarian Cancer. ACS Cent Sci 4:1360-1370
Petukhova, Valentina Z; Young, Alexandria N; Wang, Jian et al. (2018) Whole Cell MALDI Fingerprinting Is a Robust Tool for Differential Profiling of Two-Component Mammalian Cell Mixtures. J Am Soc Mass Spectrom :