Scientists at the Wyss Institute for Biologically Inspired Engineering at Harvard University and the University of California, Davis, have developed a microfluidic model of the human cervix. This “Cervix-on-a-Chip” (Cervix Chip) replicates the epithelial-stromal interface and microbiome interactions of the human cervix, offering a powerful new tool for studying women’s health issues such as bacterial vaginosis (BV).

“Our engineered cervix model and the breadth and depth of analysis it allows sets a new standard in research that is well in line with existing clinical observations, while offering first new insights into cervix functionality and vulnerability,” said first author Zohreh Izadifar, PhD, lead author of a new report in Nature Communications. Izadifar is now at Boston Children’s Hospital and Harvard Medical School (HMS). 

The new study demonstrates how this microfluidic device can simulate the complex tissue environment of the cervix, including mucus production, and hormone responsiveness in healthy tissue and in response to bacterial infection. The Wyss team’s paper is titled, “Mucus production, host-microbiome interactions, hormone sensitivity, and innate immune responses modeled in human cervix chips.”  

More than 25% of reproductive-aged women experience a BV infection, which causes significant discomfort and increases the risk of sexually transmitted infections (including HIV), spontaneous abortion, pre-term birth, and other complications. Current antibiotic treatments are often ineffective and fail to prevent recurrence in more than 60% of cases. As the mechanisms behind these statistics are currently unknown, the research team decided to create an in vitro model that is true to in vivo clinical conditions.

Creating an in vitro cervix

The Cervix Chip offers a new approach to understanding and treating this condition by allowing a detailed study of the cervix’s response to healthy and pathogenic microbial communities. The research team, led by Donald Ingber, MD, PhD, founding director of the Wyss Institute and co-founder of Emulate, a Boston organs-on-chip biotech company, grew human cervical epithelial cells and fibroblast cells in a microfluidic device the size of an SD card. The device contains two channels separated by a porous membrane with fibroblasts below epithelial cells, mimicking the tissue interactions in a real cervix.

“We leveraged critical findings that we had made in a previously developed Vagina Chip to create a platform that now enables researchers to find answers to additional long-standing questions in women’s health,” said Ingber. The hope is that “the Cervix Chip can be used alongside the Vagina Chip to evaluate the efficacy of potential new treatments in the form of live biotherapeutic products.”

cervix chip figure
The team modeled the cervical wall by growing human cervical epithelial cells in one of two parallel channels running through a microfluidic device the size of a USB memory stick and cervical fibroblast cells in the adjacent channel. The channels are separated by a porous membrane which allows the two cell types to communicate similarly as in a woman’s body. [Wyss Institute at Harvard University]
The Cervix Chip replicated not only the structure but also the function of a real cervix. In vivo, the cervical epithelium responds differently to constant or pulsated mucus release, as do the epithelial layers of the Cervix Chip. Further, hormonal changes to the chip environment result in mucosal and cellular responses that match the responses in vivo. “All of these findings closely reflect cervix physiology described from clinical observations,” said Izadifar.

Next, the team explored the utility of the Cervix Chip to study interactions with a healthy microbiome as well as an infectious state. When exposed to healthy bacteria like Lactobacillus crispatus, the Cervix Chip showed enhanced mucus quality and epithelial integrity. This again was reflective of natural physiological conditions.

Conversely, exposure to Gardnerella vaginalis, the bacteria that causes BV, resulted in compromised epithelial barrier functions and expression of proteins associated with inflammation. “Interestingly, we identified specific mucus structural and sugar modifications that could help explain the deterioration of the mucus’s quality related to BV, and indirectly could have an impact on downstream pathological processes,” said Izadifar. “We also hope to use the chip to identify new treatments for other infectious diseases of the female reproductive tract,” said Ingber.

This work represents an advance in the field of women’s health research. Izadifar concluded, “In the future, our bottom-up approach to reconstituting the female cervix and its in vivo-like responsiveness will allow us to comprehensively investigate the relevance of the cervix’s distinct tissue and microbial components in diverse pathologies.”

Previous articleMultiomic Mosaics Cell by Cell, Pixel by Pixel
Next articleNoncoding Gene Identified as Cause of Intellectual Disability Affecting Thousands