Abstract

Can a microfluidic Organ Chip model of the human cervix replicate cervical conditions to evaluate sperm translocation, motility and the efficacy of non-hormonal contraceptives?

Human Cervix Chip mimics the cervical microenvironment across the follicular and luteal phases, enabling real-time analysis of sperm translocation, motility and impact of non-hormonal contraceptives.

Traditional contraceptive testing relies on in vivo and in vitro models, which often lack human physiological relevance and reproducibility. Ex vivo cervical mucus penetration assays are limited by variability, while animal models pose ethical concerns and species differences. Microfluidic Organ chips have emerged as powerful tools to replicate human reproductive tract conditions, offering controlled, scalable environments for studying sperm behavior and drug interactions. However, their application in contraceptive research remains underexplored. A human Cervix Chip capable of mimicking the cervical microenvironment could provide a robust platform for evaluating sperm motility, translocation, and non-hormonal contraceptive efficacy.

This study used a microfluidic human Cervix that incorporated fluctuating levels of estrogen and progesterone to simulate the follicular and luteal phases of the menstrual cycle. The impact of different concentrations of non-hormonal contraceptives on sperm migration, cervical epithelial cells, and the cervical environment was assessed. The effects of healthy vaginal microbiome on contraceptive efficacy also were examined.

Primary human cervical epithelial and fibroblast cells were cultured within a 2-channel microfluidic chip to replicate cervical architecture. Sperm from multiple donors were introduced into the Cervix Chip, and sperm motility and translocation were assessed using high-resolution imaging. The effects of non-hormonal contraceptive agents on sperm function were evaluated in real time, providing insights into their potential efficacy in altering sperm behavior within the cervical environment.

Sperm translocation through the cervix-on-chip was significantly affected by non-hormonal contraceptive agent TDI-11861, a soluble adenylyl cyclase (sAC) inhibitor, demonstrating a substantial reduction in sperm motility under experimental conditions (p < 0.05). This effect was observed in Cervix Chips exposed to both follicular and luteal phase hormones, mimicking the natural hormonal fluctuations of the menstrual cycle. Additionally, sperm translocation and motility were assessed in the presence of a consortium of Lactobacillus crispatus, which mirrors the typical cervico-vaginal microbiome. The impact of TDI-11861 was dose-dependent with higher concentrations leading to significantly reduced sperm translocation (p < 0.05) and motility (p < 0.05), highlighting the potential of the Cervix Chip as a preclinical platform for evaluating the efficacy of non-hormonal contraceptive agents. These results underscore the ability of the human Cervix Chip to faithfully replicate key physiological aspects of the cervical environment, offering a promising tool for early-stage contraceptive screening. While the findings were consistent across multiple experimental replicates, further studies are required to explore the long-term effects of these agents, as well as their interaction with different microbial communities. Overall, these findings suggest the human Cervix Chip holds considerable potential in advancing contraceptive research with high translational relevance.

The model does not fully capture contributions of immune cells, endothelium, or hormonal regulation over extended periods. Further validation with larger numbers of patient-derived samples and in vivo comparisons is necessary.

This human Cervix Chip represents a scalable and ethical alternative for contraceptive research with potential applications in fertility studies and drug screening. It could facilitate the development of novel non-hormonal contraceptives with improved efficacy and safety profiles.

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