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Abstract The syncytiotrophoblast is a multinucleated structure that arises from fusion of mononucleated cytotrophoblasts, to sheath the placental villi and regulate transport across the maternal–fetal interface. Here, we ask whether the dynamic mechanical forces that must arise during villous development might influence fusion, and explore this question using in vitro choriocarcinoma trophoblast models. We demonstrate that mechanical stress patterns arise around sites of localized fusion in cell monolayers, in patterns that match computational predictions of villous morphogenesis. We then externally apply these mechanical stress patterns to cell monolayers and demonstrate that equibiaxial compressive stresses (but not uniaxial or equibiaxial tensile stresses) enhance expression of the syndecan-1 and loss of E-cadherin as markers of fusion. These findings suggest that the mechanical stresses that contribute towards sculpting the placental villi may also impact fusion in the developing tissue. We then extend this concept towards 3D cultures and demonstrate that fusion can be enhanced by applying low isometric compressive stresses to spheroid models, even in the absence of an inducing agent. These results indicate that mechanical stimulation is a potent activator of cellular fusion, suggesting novel avenues to improve experimental reproductive modelling, placental tissue engineering, and understanding disorders of pregnancy development.

Organs-on-a-chip have emerged as next-generation tissue engineered models to accurately capture realistic human tissue behaviour, thereby addressing many of the challenges associated with using animal models in research. Mechanical features of the culture environment have emerged as being critically important in designing organs-on-a-chip, as they play important roles in both stimulating realistic tissue formation and function, as well as capturing integrative elements of homeostasis, tissue function, and tissue degeneration in response to external insult and injury. Despite the demonstrated impact of incorporating mechanical cues in these models, strategies to measure these mechanical tissue features in microfluidically-compatible formats directly on-chip are relatively limited. In this review, we first describe general microfluidically-compatible Organs-on-a-chip sensing strategies, and categorize these advances based on the specific advantages of incorporating them on-chip. We then consider foundational and recent advances in mechanical analysis techniques spanning cellular to tissue length scales; and discuss their integration into Organs-on-a-chips for more effective drug screening, disease modeling, and characterization of biological dynamics.