Recent Progress in 2D, 3D, and On-a-Chip Models of the Placenta

Background: The placenta is a temporary organ that develops throughout pregnancy, connecting a developing fetus to the maternal uterine wall. The placenta’s structure is species-specific and complex, necessitating the advancement of in vitro models to study this dynamic organ. The main cell types composing the placenta, trophoblast cells, serve several roles and have been incorporated within biomaterials and devices to recapitulate the placental microenvironment. Summary: This review highlights in vitro 2D, 3D, and on-a-chip models of two placental interfaces: the interface between the endometrium and extravillous trophoblast cells and the interface between the chorionic villi and intervillous space. First, an overview of placental cell types and in vitro model types used in the discussed studies is provided. Next, models of invasive trophoblasts cells at the endometrium where the placenta is anchored and the spiral arteries are remodeled are discussed. Next, the review highlights models of the chorionic villi and intervillous space, an interface of high gas and nutrient exchange where cytotrophoblast cells fuse into syncytiotrophoblasts. Finally, we discuss key takeaways and future directions in creating representative placental models. Key Messages: Combining biomaterial and engineering approaches has led to the development of physiologically relevant models, allowing placental trophoblast functions to be investigated with more clarity. Each cell type (e.g., trophoblast cell line vs. stem cells vs. primary placental cells) and biomaterial system (e.g., organoid vs. on-a-chip) that is selected for a given model has a unique combination of advantages and limitations, which are detailed within this review. Overall, the placental models discussed enable trophoblast cell behavior to be studied in vitro with the inclusion of extracellular matrix materials, growth factors, and other environmental cues. While one model alone does not fully recapitulate every function of the placenta, individual models are tailored to inform on specific placental trophoblast behaviors.