Women’s health advocates have long argued that far more research is needed on women's bodies and health – and the first-ever “vagina on a chip” could go a long way to making that happen.
“Women’s health has not received the attention it deserves,” Dr Don Ingber, who led the team at Harvard’s Wyss Institute for Biologically Inspired Engineering, that created the vagina chip, which was reported in the journal Microbiome in November.
But researchers hope for more than headlines, seeing the chip as a way to facilitate vaginal health research and open the door to vital new treatments.
“Organ on chips” are tiny devices about the size of a flash drive, designed to mimic the biological activity of human organs. The glass chips contain living human cells within grooves that allow the passage of fluid to either maintain or disrupt the cells’ function.
So far, Ingber and his team at the Wyss Institute have developed more than 15 organ chip models, including some that mimic the lung, intestine, kidney and bone marrow.
The idea to develop a vagina chip grew out of research, funded by the Gates Foundation, on a childhood disease called environmental enteric dysfunction, an intestinal disease most commonly found in low-resource nations and which is the second leading cause of death in children under five.
That’s when Ingber discovered just how much the child's microbiome influences this disease, reports Medscape.
Stemming from that work, the Gates Foundation turned its attention to newborn health, in particular, the impact of bacterial vaginosis, an imbalance in the vagina’s bacterial makeup. Bacterial vaginosis occurs in one out of four women worldwide and has been linked to premature birth as well as HIV, HPV persistence and cervical cancer.
Upon establishing the Vaginal Microbiome Research Consortium, the foundation asked Ingber to engineer an organ chip that mimicked the vagina’s microbiome. The goal was to test “live biotherapeutic products”, or living microbes like probiotics, that might restore the vagina’s microbiome to health.
No other pre-clinical model exists to perform tests like that, says Ingber. “The vagina chip is a way to help make some advances,” he told Medscape.
Pushing for more women’s health research
The Gates Foundation recognised that women’s reproductive health is a major issue, not only in low-income nations, but worldwide. As the project evolved, Ingber began hearing from female colleagues about how neglected women’s reproductive health is in medical science.
“I realised this is just the starting point,” Ingber said.
For an example, bacterial vaginosis: since 1982, treatment has revolved around the same two antibiotics, partly because there is no animal model to study. No other species has the same vaginal bacterial community as humans do.
That makes developing any new therapy “incredibly challenging”, said Dr Caroline Mitchell, an OB/GYN at Massachusetts General Hospital and a member of the consortium.
It turns out that replicating the vagina in a lab dish is, to use the technical term, very hard.
“That’s where a vagina chip offers an opportunity,” said Mitchell. “It’s not super high-throughput, but it’s way more high-throughput than a (human) clinical trial.”
As such, the vagina chip could help scientists find new treatments much faster.
Like Ingber, Mitchell also sees the chip as a way to bring more attention to the largely unmet needs in female reproductive medicine.
“Women’s reproductive health has been under-resourced, under-prioritised, and largely disregarded for decades,” she added. And the time may be ripe for change: she said she was encouraged by the National Institutes of Health’s Advancing NIH Research on the Health of Women conference, held in 2021 in response to a congressional request to address women’s health research efforts.
Beyond bacterial vaginosis, Mitchell imagines the chip could help scientists find new treatments for vaginal yeast infection (candidiasis), chlamydia and endometriosis. As with bacterial vaginosis, medicines for vaginal yeast infections have not advanced in decades.
Efforts to develop a vaccine for chlamydia – which can cause permanent damage to a woman’s reproductive system – have dragged on for many years. And endometriosis, an often painful condition in which the tissue that makes up the uterine lining grows outside the uterus, remains under-researched despite affecting 10% of childbearing-age women.
While some mouse models are used in chlamydia research, it’s hard to say if they’ll translate to humans, given the vaginal and cervical bacterial differences.
“Our understanding of the basic physiology of the environment of the vagina and cervix is another area where we’re woefully ignorant,” Mitchell said.
To that end, Ingber’s team is developing more complex chips mimicking the vagina and the cervix. One of his team members wants to use the chips to study infertility. The researchers have already used the chips to see how bacterial vaginosis and mucous changes impact the way sperm migrates up the reproductive tract.
The lab is now linking vagina and cervix chips together to study viral infections of the cervix, like HPV, and all types of bacterial diseases of the vaginal tract. By applying cervical mucus to the vagina chip, they hope to learn more about how female reproductive tissues respond to infection and inflammation.
As they make the chips more complex, perhaps by adding blood vessel cells and female hormones, Ingber foresees being able to study the response to hormonal changes during the menstrual cycle.
“We can begin to explore the effects of cycling over time as well as other types of hormonal effects,” he says.
Ingber also envisions linking the vagina chip to other organ chips. He’s already succeeded in linking eight different organ types together. But for now, the team hopes the vagina chip will enhance our understanding of basic female reproductive biology and speed up the process of developing new treatments for women’s health.
Study details
Vaginal microbiome-host interactions modelled in a human vagina-on-a-chip
Gautam Mahajan, Erin Doherty, Tania To, Arlene Sutherland, Jennifer Grant, Abidemi Junaid, Aakanksha Gulati, Nina LoGrande, Zohreh Izadifar, Sanjay Sharma Timilsina, Viktor Horváth, Roberto Plebani, Michael France, Indriati Hood-Pishchany, Seth Rakoff-Nahoum, Douglas Kwon, Girija Goyal, Rachelle Prantil-Baun, Jacques Ravel & Donald Ingber.
Published in Microbiome on 22 November 2023
Abstract
Background
A dominance of non-iners Lactobacillus species in the vaginal microbiome is optimal and strongly associated with gynaecological and obstetric health, while the presence of diverse obligate or facultative anaerobic bacteria and a paucity in Lactobacillus species, similar to communities found in bacterial vaginosis (BV), is considered non-optimal and associated with adverse health outcomes. Various therapeutic strategies are being explored to modulate the composition of the vaginal microbiome; however, there is no human model that faithfully reproduces the vaginal epithelial microenvironment for preclinical validation of potential therapeutics or testing hypotheses about vaginal epithelium-microbiome interactions.
Results
Here, we describe an organ-on-a-chip (organ chip) microfluidic culture model of the human vaginal mucosa (vagina chip) that is lined by hormone-sensitive, primary vaginal epithelium interfaced with underlying stromal fibroblasts, which sustains a low physiological oxygen concentration in the epithelial lumen. We show that the Vagina Chip can be used to assess colonization by optimal L. crispatus consortia as well as non-optimal Gardnerella vaginalis-containing consortia, and to measure associated host innate immune responses. Co-culture and growth of the L. crispatus consortia on-chip was accompanied by maintenance of epithelial cell viability, accumulation of D- and L-lactic acid, maintenance of a physiologically relevant low pH, and down regulation of proinflammatory cytokines. In contrast, co-culture of G. vaginalis-containing consortia in the vagina chip resulted in epithelial cell injury, a rise in pH, and upregulation of proinflammatory cytokines.
Conclusion
This study demonstrates the potential of applying human organ chip technology to create a preclinical model of the human vaginal mucosa that can be used to better understand interactions between the vaginal microbiome and host tissues, as well as to evaluate the safety and efficacy of live biotherapeutics products.
Medscape article – Scientists Create ‘Vagina on a Chip’: What to Know (Open access)
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Microbiome therapy reduces recurrent bacterial vaginosis in trial
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