Instrumenting a Fetal Membrane on a Chip as Emerging Technology for Preterm Birth Research

Abstract

Preterm birth (PTB) is clinically defined as process of giving birth before 37 weeks of gestation and is a leading cause of death among neonates and children under the age of five. Prematurity remains a critical issue in developed countries, yet our understanding of the pathophysiology of PTB remains largely unknown. Among pregnancy complications, subclinical infections such as chorioamnionitis (CAM) are implicated in up to 70% of PTB cases. Specifically, CAM is characterized by the infection of the fetal membranes that surround the developing fetus and extend from the placenta, and is often associated with preterm, premature rupture of the fetal membranes (PPROM). The fetal membrane plays a key structural role in maintaining the fetal and maternal compartments of the gravid uterus. However, our understanding of the mechanisms of PPROM and the spatio-temporal progress of CAM remains vastly unknown. A lack of human-derived models have hindered our understanding of the mechanism that govern spontaneous PTB. Thus, in this short review, we discuss the emerging microfabrication technologies, specifically, organ-on-chip (OoCs) models, that seek to recapitulate the cellular and molecular context of the gestational membranes in vitro. These models show promise to facilitate the investigation of pathologic mechanisms that drive these disease conditions by mimicking the interactive contribution of the major cell types that make up the microenvironment of the fetal membrane and enable high throughput screening. Herein, we histologically characterize the microenvironment of the fetal membrane as a metric for scaling to recapitulate the functional components of the human fetal membrane. We review the current OoC models of the gravid uterus and conceptualize an "Instrumented Fetal Membrane on a Chip" (IFMOC) design as a prototype for PPROM and CAM research. Lastly, we discuss further applications of these OoC models for toxicological or pharmacological screening and personalized medicine. Fetal membrane OoCs offer an innovative and valuable platform to explore complex interactions between multiple drug types, toxic substances, and/or pathogenic microbes and their potential impacts on pregnancy outcomes. Further work will be required by integrating technological and analytical capabilities in order to characterize the fetal membrane microenvironment for preterm birth research.

Decidual stromal cell‐derived PGE2 regulates macrophage responses to microbial threat

“…These data also support the use of microfluidic devices to model cell-cell interactions 45 . Importantly, we used conditioned cell supernatants to establish that the immune modulating factor(s) derived from dTHESC cells could suppress TNF-α production by THP-1 cells in response to LPS in a paracrine fashion and independent of cell-cell contact.…”

“…Traditional cell culture uses high media-to-cell volume ratios, which potentially dilutes mediators and masks relevant physiological effects 45 . We applied a microfluidic organotypic model 45 to assess the responses of dTHESC and THP-1 cells to LPS and define the extent to which such a model recapitulates traditional cell culture findings (Figure 2A).…”

“…We applied a microfluidic organotypic model 45 to assess the responses of dTHESC and THP-1 cells to LPS and define the extent to which such a model recapitulates traditional cell culture findings (Figure 2A). Individual cell and co-culture experiments performed in single-chamber organ-on-chip devices illustrated a statistically significant increase in TNF-α production by THP-1 cells after a 24 h exposure to LPS and suppression of the TNF-α response when co-cultured with dTHESC cells (Figure 2B), confirming the results from traditional plate-based culture experiments.…”

“…These data also support the use of microfluidic devices to model cell-cell interactions. 45 Importantly, we used conditioned cell supernatants to establish that the immune modulating factor(s) derived from dTHESC cells could suppress TNFα production by THP-1 cells in response to LPS in a paracrine fashion and independent of cell-cell contact. Furthermore, we also found that supernatants from human gestational membranes cultured ex vivo could also blunt the same TNFα response to LPS by the THP-1 macrophages, suggesting that such events could occur in situ.…”

Amnion membrane organ‐on‐chip: an innovative approach to study cellular interactions

“…The female reproductive tract (37), placenta (38), and endometrium-on-chip (39) have been developed and used to study multiple aspects of reproductive health, which have highlighted the importance of cell-cell and cell-blood interactions in vitro. Although development of a fetal membrane-on-chip has been postulated (22), no work has been reported yet. We first focused on creating an in vitro culture model of the amnion membrane because it is a key component of the fetal membrane.…”