Organ-On-Chip Technology: The Future of Feto-Maternal Interface Research?

Lauren Richardson, Sungjin Kim, Ramkumar Menon, Arum Han, Lauren Richardson, Sungjin Kim, Ramkumar Menon, Arum Han

Abstract

The placenta and fetal membrane act as a protective barrier throughout pregnancy while maintaining communication and nutrient exchange between the baby and the mother. Disruption of this barrier leads to various pregnancy complications, including preterm birth, which can have lasting negative consequences. Thus, understanding the role of the feto-maternal interface during pregnancy and parturition is vital to advancing basic and clinical research in the field of obstetrics. However, human subject studies are inherently difficult, and appropriate animal models are lacking. Due to these challenges, in vitro cell culture-based studies are most commonly utilized. However, the structure and functions of conventionally used in vitro 2D and 3D models are vastly different from the in vivo environment, making it difficult to fully understand the various factors affecting pregnancy as well as pathways and mechanisms contributing to term and preterm births. This limitation also makes it difficult to develop new therapeutics. The emergence of in vivo-like in vitro models such as organ-on-chip (OOC) platforms can better recapitulate in vivo functions and responses and has the potential to move this field forward significantly. OOC technology brings together two distinct fields, microfluidic engineering and cell/tissue biology, through which diverse human organ structures and functionalities can be built into a laboratory model that better mimics functions and responses of in vivo tissues and organs. In this review, we first provide an overview of the OOC technology, highlight two major designs commonly used in achieving multi-layer co-cultivation of cells, and introduce recently developed OOC models of the feto-maternal interface. As a vital component of this review, we aim to outline progress on the practicality and effectiveness of feto-maternal interface OOC (FM-OOC) models currently used and the advances they have fostered in obstetrics research. Lastly, we provide a perspective on the future basic research and clinical applications of FM-OOC models, and even those that integrate multiple organ systems into a single OOC system that may recreate intrauterine architecture in its entirety, which will accelerate our understanding of feto-maternal communication, induction of preterm labor, drug or toxicant permeability at this vital interface, and development of new therapeutic strategies.

Keywords: amniochorion; extracellular matrix; fetal membrane; microfluidic lab-on-a-chip; organ-on-a-chip.

Copyright © 2020 Richardson, Kim, Menon and Han.

Figures

FIGURE 1
FIGURE 1
Intra-uterine tissue anatomy. An illustration of the anatomy of the intra-uterine tissue broken down into maternal and fetal components. Maternal tissues comprise of the uterus (i.e., Myometrium), cervix, and vagina, while the fetal tissues include the placenta, umbilical cord, fetus, and fetal membranes.
FIGURE 2
FIGURE 2
Illustration of both feto-maternal interfaces in utero. (A) The left side represents the placenta, the site of nutrients, oxygen, and waste exchange for the growing fetus. The placenta is attached to the maternal side by the decidua basalis next to myometrium (gray) and the fetal side through the fetal membranes (amnion in blue and chorion in yellow). This image highlights the tertiary chorionic villi and arteries (red) and veins (blue), respectively. (B) Overview of the two feto-maternal interfaces in relation to the fetus. The top box outlines the cross-section of the placenta and the bottom box outlines the cross-section of the fetal membrane. (C) The description starts from the innermost layer (amnion) and ends at the maternal decidua. Amnion epithelial cells (blue) are connected to the first layer of the ECM called the basement membrane/compact layer (green strips). The fibroblast (top), spongy (middle), and reticular layers (bottom) follow, containing amnion and chorion mesenchymal cells (purple). The chorion (yellow) is connected to the ECM through a basement membrane (green stripes and is made up of two types of cells: chorion laeve cells and chorion trophoblast cells. The chorion interfaces with the maternal decidua (green), connecting the fetal layers to the maternal compartments of the uterus.
FIGURE 3
FIGURE 3
Diagram of fetal membranes anatomical differences between species. (A) Illustration representing the human fetal membrane. The human fetal membrane, or feto-maternal interface, starts with the innermost layer (amnion) facing the amniotic cavity and ends with the maternal decidua. Within the intrauterine cavity, the amnion epithelial cells (AECs) connected to the basement membrane (green stripes) are bathed in amniotic fluid (yellow) and comprise the first layer. Below AECs, the ECM is comprised of compact, fibrous, spongy, and reticular layers, all containing mesenchymal cells derived from the amnion and chorion (purple). Chorion trophoblast cells (CT; yellow) are attached to the ECM via another layer of the basement membrane on its apical side and to the maternal decidua (green) on its basal side. (B) Schematic of non-human primate (NHP) fetal membranes, currently the best animal model used in the field. It is almost identical to human fetal membranes; however, specific to NHPs, the AEC layer interfaces with a thick, fibrous, collagen layer termed “microfibers” (Owiti et al., 1989) before the basement membrane/compact layer of the ECM. (C) The amniotic sac of a mouse is comprised of two epithelial layers; amnion epithelial monolayer (blue) and a multilayer of chorion trophoblast cells (yellow). Between these layers, loose collagen fibers support mesenchymal cells (purple) and maternal blood vessels in the ECM. This tissue does not contain a maternal interface (i.e., decidua) as other mammalian models.
FIGURE 4
FIGURE 4
Illustration highlighting the differences between vertical and planar co-culture OOC designs. (A) 3D view of two cell culture chambers, stacked on top of each other, to form a “vertical co-culture” OOC device. These two chambers are separated by a semipermeable synthetic membrane (tan structure; black arrow), which contains small pores for cell migration and signal propagation, but too small for cells to freely move between the layers. Blue ellipses are grown on top of the membrane, while red ellipses are grown on the bottom glass substrate. Red and blue ellipses represent two distinct cell populations. (B) 3D view of two cell culture chambers aligned next two each other and separated by a set of microchannel arrays to form a “planar co-culture” OOC device. These two chambers are separated by microchannels that can be filled with collagen (pink; black arrow), providing an actual cell–collagen interface. Both blue and red ellipses are grown the bottom glass substrate but in separate chambers. Red and blue ellipses represent two distinct cell populations. The sizes of the microchannels are small enough to prevent cells from freely moving between the culture compartments but large enough for actively migrating cells and biochemicals to move between the compartments. Alternatively, these microchannel arrays can be replaced with a porous gel barrier.
FIGURE 5
FIGURE 5
Currently developed OOCs mimicking components of the fetal membranes and feto-maternal interface. (A) Device layout—schematic of the two-chamber fetal membrane-organ-on-chip (FM-OOC) developed to study fetal and maternal cell interactions at the fetal membrane interface adapted from Richardson et al. (2019a). The FM-OO-C is comprised of two stacked PDMS cell culture chambers that are coated with Matrigel (pink). Primary AECs (blue) are placed in the top chamber and grown on top of a polycarbonate semipermeable synthetic membrane, while primary decidual cells (green) are placed in the lower chamber and grown on the glass substrate. (B) Images of the fabricated FM-OO-C chips and cells being cultured within each compartment. Bright-field microscopy images of primary human AECs in the top chamber (purple) and primary decidual cells in the bottom chamber (red) are shown. The yellow outline visualizes the cellular morphology. (C) Endpoint assays—Left: Fluorescein isothiocyanate stain (yellow) is seen in the two horizontal columns feeding into the top AEC chamber. Media were collected from the bottom vertical columns to measure membrane permeability. Center: Bottom chamber showing representative senescence-associated β-galactosidase (SA-β-Gal) stained decidual cells and the semipermeable membrane containing blue staining representing SA-β-Gal + AECs. Right: Image of the FM-OO-C containing media from both amnion and decidual cells, which can be used to measure cytokine kinetics. (D) Device layout—the amnion membrane organ-on-chip (AM-OOC) is designed to recreate the amnion component of the fetal membrane by co-culturing AECs (blue) in an outer circular PDMS chamber and AMCs (purple) in the inner circular chamber. This planar two-chamber model is separated by a type IV collagen-filled (pink) microchannel array (mimicking the basement membrane). (E) The outer chamber of the AM-OOC was filled with red dye, and the inner chamber was filled with blue dye for visualization. Bright-field microscopy images of AEC morphology and AMC morphology inside an AM-OOC device. Microchannels filled with Type IV collagen Matrigel (stained with Masson trichrome), connecting the two culture chambers, are also shown. (F) Endpoint assay—confocal images showing native AECs (green) and AMCs (red), which have transitioned, migrated, and integrated into the opposite population. Middle right panel highlights (yellow) GFP-AECs that have migrated through the type IV collagen-filled microchannel, re-localized vimentin, and transitioned into a mesenchymal morphology indicative of EMT. Middle left panels highlight (yellow) RFP-AMCs that have migrated through the type IV collagen-filled microchannel, down-regulated vimentin, and transitioned into an epithelial morphology indicative of MET. The bottom panel is a schematic representing AECs (green) and AMCs (red) undergoing cellular transitions. Gray arrows highlight the migration direction. Pink, vimentin; green, histone 2B AEC; red, histone 2B AMCs. This figure is a rendition of Richardson et al. (2019b). All figures reused with permission.
FIGURE 6
FIGURE 6
Schematic of proposed OOCs better mimicking the full fetal membrane and feto-maternal interface. (A) A rendition of the proposed fetal membrane on a chip (IFMOC) by Gnecco et al. (2017) designed to create an infectious preterm birth model to study fetal membranes. This device contains four chambers culturing AECs (blue) on top, CTs (yellow) along with immune cells (orange) in the second chamber, decidua (green) and immune cells in the third chamber, and bacteria (red) in the bottom chamber. Each chamber is separated by a polycarbonate semipermeable synthetic membrane. (B) The proposed feto-maternal interface organ-on-chip (FMI-OOC) here is designed to mimic the feto-maternal interface, including the fetal membranes and maternal decidua. The FMI-OOC contains four co-centric circular cell culture chambers separated by arrays of microchannels. The cells are seeded following the in vivo structure; AECs (blue), AMCs (purple), CMCs/CTs (yellow), and decidua cells (green), respectively. Primary fetal membrane collagen and Matrigel (pink) can enable culturing AMCs and CMC/CTs in a 3D format. To recreate cell–collagen interfaces, microchannels can be filled with type IV collagen (pink) to mimic the basement membrane of the amnion and chorion layers, while the choriodecidua interface is left open (gray). All figures reused with permission. A comparison of both proposed OOC models can be found in Table 3.

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