There is currently a lack of safety information regarding engineered nanomaterial toxicity during pregnancy, posing a risk to both the mother and the developing fetus. Both restricted clinical testing in pregnant women and limitations of animal models to predict human tissue response contribute to this lack of information regarding chemical safety during pregnancy. In particular, the transport dynamics of nanomaterials across the placenta, which serves as the barrier between maternal and fetal circulations, is still not well understood. Therefore, there is a great demand for innovative methods to predict exposure-related developmental toxicity. Organs-on-chips have emerged as in vitro tools to recapitulate human cellular and tissue response for pharmacology and disease modeling in a variety of organs, including the heart and lungs. However, in vitro models of the placenta fail to capture critical structural and functional hallmarks of the barrier. We therefore propose to build a placental exposure chip that mimics the native cellular structure and microenvironment to better predict developmental exposure risk of engineered nanomaterials. We propose to screen engineered nanomaterial toxicity using a custom placental exposure chip that recreates key structural and functional features of the maternal-fetal interface. In this system, we will combine mechanical and extracellular matrix cues that mimic the native microenvironment to guide trophoblast fusion and endothelial barrier formation in a multicellular model of the placental barrier. We will use this system to assess the effects of select engineered nanomaterial exposure on molecular, structural, and functional metrics of placental trophoblasts and endothelial cells across multiple spatial scales. Specifically, we will measure the impact of engineered nanomaterials on placental cell endocrine activity, structural integrity, and barrier permeability in a dose-dependent manner. The developed system can be used alone or in tandem with existing organs-on-chips, such as cardiac and airway models, to assess the coupled effects of potential exposure and developmental toxicity. Upon completion of this project, we will gain a better understanding of the effects of engineered nanomaterials on placental cell viability, structure, and function. Importantly, we hope to present a valuable and flexible tool that will enable researchers to simultaneously predict chemical exposure risk during pregnancy and developmental toxicity in a human-relevant model.
This project aims to evaluate nanomaterial toxicity in an in vitro model of the maternal-fetal barrier that mimics key structures and function of the human placenta. This developed system would allow researchers to understand the impact of engineered nanomaterials on the health of the placenta alone or in combination with existing organ-on-a-chip systems. The results of this study will allow researchers to better predict developmental exposure risks during pregnancy and develop comprehensive biological response profiles of engineered nanomaterials.
| Ahn, Seungkuk; Ardoña, Herdeline Ann M; Lind, Johan U et al. (2018) Mussel-inspired 3D fiber scaffolds for heart-on-a-chip toxicity studies of engineered nanomaterials. Anal Bioanal Chem : |
