Studying preterm birth and drug transfer during pregnancy

Over one in ten babies are born prematurely, before they are 37 weeks old.  Although preterm birth may seem like a pretty common occurrence, its causes are in fact under-examined, and its symptoms can be extremely dangerous. Of the 15 million premature babies each year, about one million die from problems associated with preterm birth. Some face lifelong visual, auditory, or learning disabilities. In many countries, preterm birth rates are increasing, and preterm birth is already the leading cause worldwide for the death of children under five years old.

Premature babies can often be saved with the right medical and financial resources, but in many countries, ethese resources are not readily available. Preventing complications and preterm deaths primarily comes from having a healthy pregnancy that allows the fetus to grow properly and the mother to carry and provide sufficiently. Thus, research on possible causes and underlying mechanisms of premature birth may be necessary in order to better understand how to lower its frequency.

One of the important organs involved in fetal development is the placenta. The placenta develops in the mother’s uterus during pregnancy and controls the exchange of nutrients, oxygen, and wastes between the mother and baby’s blood. Despite decades of research, however, much remains to be learned about key mechanisms and mediators of molecular transfer across the placental barrier. Our lack of understanding on placental transport function becomes particularly problematic in drug development. While some medications can enter the fetal bloodstream, others cannot, and researchers are still unsure n how the placenta selectively allows certain molecules to pass between the mother and the fetus.

Part of this is because traditional placenta research has many limitations, and using whole organs in isolation may not be ideal for such studies. Previous experiments conducted on donated human placental tissue required hooking the live organ up to the testing apparatus, which necessitated a high level of expertise and a complicated, often messy setup. Its high likelihood of failure also meant that pharmaceutical companies were reluctant to become involved. In addition, donated placental tissue is only usable for a few hours after birth. Amidst these limitations, it seemed that performing research on placental tissue may not be feasible, but the Huh Lab at the University of Pennsylvania has paved its own way.

The Huh Lab has tackled these issues by engineering a chip that acts like a human placenta. The researchers built the first placenta-on-a-chip, which models the mother-fetus placental barrier and the transport of nutrients across it. They hope to use this chip to study drug delivery to the placenta and preterm birth.

The placenta-on-a-chip has a simple design with large potential. The chip is a small block of silicone the size of a flash drive. It contains two overlapping layers of microchannels that are lined with human cells and separated by a porous membrane. In this three-dimensional design, trophoblast cells isolated from the outer surface of the placental barrier are cultured on the upper side of the membrane, while endothelial cells derived from fetal blood vessels are grown on the lower surface of the membrane. These cells are fed fresh nutrients so that they proliferate and form a multicellular structure that resembles the maternal-fetal barrier in the human placenta. Just like in the real placenta, the two layers of cells act like a gate keeper that controls the flow and exchange of nutrients or and blocks pathogens from going between the circulatory systems of the mother and fetus. The chip system also allows for the trophoblast layer to form microvilli, small projections on the cell surfaces, which express proteins that are essential for the barrier function of the placenta.

“One of the most important functions of the placental barrier is transport, so it’s essential for us to mimic that functionality,” Huh said. In their model, the Huh Lab was able to reproduce a process called syncytialization, in which the two layers of cells in the chip continue to grow within the chip, just like placental cells would develop during a pregnancy. During a pregnancy, the trophoblast cells fuse to form syncytium tissue, which thins over the course of the pregnancy and becomes the outermost cell layer of the placenta that is in direct contact with the mother’s blood. This process is critical in pregnancy because it affects placental transport. The placenta-on-a-chip was an improvement on previous models that were not able to reproduce this change.

Not only does the chip replicate the natural growth and development of the placenta during a pregnancy, but it also has a similar glucose transfer rate across the placental barrier to that of experimental perfusion studies on donated human placenta. This consistency in glucose transfer rate is important because it shows that the chip can mimic the process of nutrient transfer through the placenta to a growing fetus and thus proves that it functions like the placental barrier. Huh and his team believe that their chip will be a good substitute for the current donated tissues used in placenta research. “The placenta is arguably the least understood organ in the human body. Much remains to be learned about how transport between mother and fetus works at the tissue, cellular and molecular levels,” Huh said. But their research has given them confidence that the placenta-on-a-chip can serve as a platform to test drug transport before use in actual the human placenta in the future.

Huh and his team look forward to using the chip system to innovate research on reproductive medicine. One of their next steps is to work with pharmacologists to simulate realistic drug transport situations. To demonstrate the feasibility of this idea, the Huh group has recently published an article in which they used the placenta-on-a-chip to simulate active placental transport of glyburide, a common medication used for gestational diabetes. Apart from drug transfer, the Huh team also wants to better understand the health impacts of taking vitamins and herbal supplements, both of which may be transferred through the bloodstream to the fetus during a pregnancy. The placenta-on-a-chip puts medicine on the path to a better understanding of mother-fetus placental transport and ultimately to improving reproductive health.