Human fallopian tube-on-a-chip for preclinical testing of non-hormonal contraceptives with living human sperm

Technical Summary: Human Fallopian Tube-on-a-Chip for Preclinical Testing of Non-Hormonal Contraceptives

Problem Statement
The fallopian tube (FT) plays a critical physiological role as a sperm reservoir and the primary site of oocyte fertilization. However, there is a lack of human-relevant preclinical models capable of accurately replicating the complex microenvironment of the FT to study its physiology or test contraceptive efficacy. Existing models, such as epithelial organoids cultured in gel, fail to recapitulate the specific tissue architecture and functional dynamics observed in vivo, particularly the formation of abundant tissue folds and the interaction between living human sperm and the tubal environment.

Methodology
The authors developed a microfluidic organ-on-a-chip model (FT Chip) designed to mimic the human fallopian tube. The system was constructed using primary human epithelial cells and stromal fibroblasts derived specifically from the human FT ampulla. A key feature of the methodology was the induction of tissue morphology; the chip environment facilitated the formation of abundant tissue folds lined by hormone-responsive epithelial cells, a structural characteristic that closely resembles the in vivo state but was absent in control epithelial organoids cultured in gels.

To validate the model, the researchers conducted comparative time-resolved analyses. They introduced human sperm and oocyte-sized microparticles into the epithelial channel of the chip. These experiments were performed under two conditions: in the presence of estradiol to simulate hormonal influence, and in acellular chips as a baseline control. Furthermore, the model was utilized to test the efficacy of a specific non-hormonal contraceptive candidate, TDI-11861, by administering the compound to the chip and observing its effects on sperm behavior.

Key Results
The study yielded several distinct findings regarding the functionality of the FT Chip:

1. Structural Fidelity: The FT Chip successfully supported the formation of complex tissue folds lined by hormone-responsive epithelial cells, a feature not achieved in standard gel-cultured organoids.
2. Differential Particle Dynamics: In the presence of estradiol, the movement of human sperm was significantly reduced within the epithelial channel compared to movements in acellular chips. Conversely, the movement of oocyte-sized microparticles increased under the same conditions. This suggests the model can distinguish between the motility patterns of biological sperm and inert particles within a hormone-responsive environment.
3. Contraceptive Efficacy: When the non-hormonal contraceptive TDI-11861 was introduced, the chip demonstrated a dose-dependent inhibition of human sperm motility, confirming its utility in screening contraceptive agents.

Significance and Claims
The paper posits that the FT Chip serves as a viable human preclinical tool for studying fallopian tube physiology. Specifically, the authors claim that this model offers a platform to assess both the efficacy and the mechanism of action of contraceptives, particularly non-hormonal options, using living human sperm. By bridging the gap between in vitro cell cultures and in vivo physiology, the FT Chip provides a more accurate environment for evaluating how contraceptive agents interact with the human reproductive tract.