Microengineering Approaches To Study The Human Placenta

The placenta is essential to the progression of a successful pregnancy. This specialized organ develops along with the fetus and mediates the transfer of all substances between mother and baby, thus dictating fetal growth and development. Despite its critical importance, there is very little known about the development and physiology of the placenta in utero. The initial steps of placentation early in gestation involve the migration of trophoblasts from the growing placenta into the maternal decidua where they undergo a coordinated process of vasculature remodeling. Abnormal trophoblast invasion can lead to adverse pregnancy outcomes or even pregnancy loss. The regulation of this invasion and remodeling is poorly understood due to the lack of predictive research platforms. Throughout the course of pregnancy, the kinetics of placental transport are also crucial. The placenta must effectively and efficiently allocate resources like nutrients between the maternal and fetal circulations. However, it also is the barrier against fetal exposure to potentially harmful xenobiotics, like drugs. There is a need for a platform that can accurately model these transport processes to understand how the placenta controls these dynamics. We have leveraged organ-on-a-chip technology to create biomimetic microsystems that reconstitute these physiological processes of implantation and placental transport. We have first developed a model of the placental barrier, or “placenta-on-a-chip” that recapitulates the multilayered structure of the maternal-fetal interface. This platform was utilized to study i) transplacental transport of glucose and xenobiotics and ii) the effect of hemodynamic shear stress on the placental barrier. Next, we have developed a microphysiological model of implantation to mimic and mechanistically investigate the process of extravillous trophoblast invasion. This platform incorporates key decidual cell types to elucidate their regulatory roles in the process of spiral artery remodeling. The work presented in this dissertation represents a significant contribution to the placental biology community and will improve our fundamental understanding of the placenta