PLACENTA-ON-A-CHIP – The Future of Drug Discovery In Women’s Health
Pregnancy presents many challenges when it comes to drug development. Biological changes that a woman experiences between conception and delivery may alter the way medications are absorbed, transported, and metabolized, and certain drugs may cross the placental barrier, affecting fetal health.1 Concerns for the health of the mother and fetus have limited clinical studies in pregnant populations, so investigations into the effects of therapeutic agents during pregnancy have been virtually non-existent for decades. However, a lack of knowledge about antenatal care is also dangerous, as the vast majority of pregnant women today experience health concerns that require treatment, and often have to resort to taking unapproved medications during gestation. In addition, obstetric complications – many of which are preventable or treatable – still threaten the lives of many mothers and babies worldwide, due to a lack of research into the management of these conditions. Today, scientists are seeking innovative methods to model the physiology and pharmacology of human pregnancy. The following article will discuss the current challenges that face pregnancy therapeutics, new opportunities the field of microfluidics offers for obstetric research, and how one Canadian research group – the Labouta Laboratory – is pioneering nanotechnology drug delivery models for the safe and effective treatment of antenatal conditions.
MATERNAL HEALTH & DISEASE
The physiological effects of pregnancy are extensive, affecting almost every bodily system over the course of 39 weeks. In addition to hormonal variations, an increase in blood volume and a developing fetus, more obvious changes to a woman’s body include the expansion of the uterus – the hollow, muscular organ that supports the fetus – and the formation of the placenta in the first trimester.2
The placenta is a temporary, dynamic, and highly specialized organ attached to the wall of the uterus that plays an important role in facilitating nutrient and oxygen exchange, protecting the fetus from harmful substances in the maternal circulation, and producing hormones to support fetal development.3 Additionally, the placenta is known to play an important role in health and disease, providing immunity to the growing fetus by acting as a barrier to protect it from infections and other maternal disorders that can occur at any stage of pregnancy. Some of the most common of these health concerns are high blood pressure, gestational diabetes, pre-eclampsia, preterm labor, and miscarriage and, although the placenta can – to some extent – protect the fetus from these effects, medical management of disease during pregnancy is still essential.
TREATING FOR TWO
More than half of pregnant women currently take prescription medications or over-the-counter drugs at some point during gestation to control pre-existing illnesses or acute conditions.4 In fact, the use of pharmaceuticals during pregnancy is on the rise, partly because of advancing maternal age, as well as the growing incidence of long-term health conditions that require ongoing therapy even before women conceive. The majority of these medications appear to have little to no effect on the fetus, indicating it is possible to have a long and healthy pregnancy while medically managing maternal health. However, ethical issues surrounding the inclusion of pregnant women in clinical trials, as well as regulatory concerns about drug development for maternal and fetal conditions, means many drugs have never been directly studied in the context of pregnancy.1
BARRIERS TO RESEARCH
Many factors need to be taken into account to carry out effective pharmacological studies while prioritizing fetal and maternal health. The abundance of physical and physiological changes that occur during gestation can influence pharmacokinetics – the way in which a person’s body handles an administered drug, distributing and eliminating it from the body. This can affect how well the medicine works, and doses that are therapeutic in the non-pregnant state may have to be modified to achieve the required therapeutic levels in pregnancy. An additional consideration when treating pregnant women is potential adverse effects of drugs on the developing fetus. Congenital malformations occur in between 2% and 3% of newborn babies worldwide, with approximately 1% to 2% of this total being due to teratogenicity – the presence of certain harmful substances in medicines that can breach the placental barrier and impact normal fetal development, alter the placenta itself, or modify a pregnant woman’s physiology, harming the fetus indirectly.5,6
The potential risks of treating diseases during pregnancy, combined with ongoing controversies around the inclusion of pregnant women in clinical research, necessitate a complete shift in the way that we study pregnancy therapeutics. Researchers are therefore focusing their efforts on designing a model that effectively recapitulates the human pregnancy, so that drug testing can be carried out in vitro, without risks to the mother or fetus.
REPLICATING THE PRENATAL ENVIRONMENT
Establishing an efficient replica of obstetric physiology and pharmacology is a difficult task. Human pregnancy is a unique phenomenon; women experience a longer gestation period – even when body size is adjusted for – as well as a drawn-out labor and delivery process compared to many other animals.7 In addition, adverse pregnancy outcomes, like preterm birth and pre-eclampsia, are much more common in humans than other species. Although a number of animal models have been proposed for use in pregnancy studies, including small primates and mouse models, they typically have poor physiological relevance to human gestation, offering weak predictive power and typically requiring genetic modification in order to study human diseases.8 Another model, which has historically been used to study placental function in response to therapies, uses end-of-term human placental tissue that is discarded after delivery. However, even ex vivo models based directly on the human placenta are not truly representative of the fluctuating nature of this complex organ, which changes significantly in terms of both structure and function between the first and third trimesters.
Motivated by the challenges of existing models, scientists are now implementing new and advanced technologies to replicate human pregnancy and enhance empirical knowledge in this field. One research group, based in the Labouta Laboratory, has pioneered the use of microfluidics technologies – the manipulation of fluids in small volumes – to design a novel model of the human placenta. This lab-on-a-chip model relies on a microfluidic cell culture device containing tiny microchannels inhabited by living cells, which are arranged carefully to replicate tissue- and organ-level physiology.9 The technology has allowed researchers at the university to culture placental cells and matrices, creating a dynamic model that enables investigations into how therapeutics interact with the placental barrier. The team is using this model to develop and test safe and effective nanoparticle-based therapies to treat obstetric complications.
STUDYING PREGNANCY PHARMACOLOGY
Effective nanoparticle drug delivery has already been demonstrated for the treatment of widespread infectious diseases and cancers, in which nanoparticles – engineered particles on the nanometer scale – have been successfully exploited to load, carry, and deliver drugs to the required tissues.10 Applying these treatment methodologies in the field of obstetrics opens up new avenues for treating pregnancy-associated diseases with minimal off-target effects, because nanoparticles can be engineered to deliver drugs selectively to an organ with precise dosages, controlled release, and reduced side effects. Using another custom microfluidics system from Dolomite Microfluidics, the Labouta Laboratory is applying nanotechnology to deliver microRNAs to modelled placental tissue, enabling research into the effects of different formulations on both maternal and fetal tissues.
The placenta-on-a-chip model will allow researchers to develop a better understanding of placental function, including how nanoparticles interact with the various cellular layers of this barrier under both physiological and pathological conditions. As research progresses, this will enable selective development of drugs that target the fetus, as well as medications that cannot cross the placental barrier, depending on the aim of the project. For example, when developing a medication to treat congenital conditions, it is important that therapeutic substances can travel through the mother’s bloodstream and cross the placenta to reach the fetus. On the other hand, it is crucial that nanoparticles targeted at placental tissues or neighboring cells – to treat maternal conditions such as pre-eclampsia – have therapeutic effects on maternal physiology without transferring through the placenta or adversely affecting fetal tissues.
DEVELOPING SAFER PREGNANCY THERAPEUTICS
The main focus of the laboratory’s current work is developing an effective treatment for congenital diaphragmatic hernia (CDH), a birth defect of the diaphragm. Most congenital abnormalities are considered rare, but CDH is one of the most common of these conditions – occurring in as many as 1 in every 2,500 live births – with potentially serious outcomes, including death shortly after birth or life-long respiratory issues that require resource-intensive surveillance and medical care.11 Until now, there has been no available cure for this serious prenatal abnormality, but the team in the Labouta Laboratory is using microfluidic technologies from Dolomite to design novel therapeutic microRNA-loaded lipid nanoparticles to treat the developing fetus in the mother’s womb.
Although microfluidics is a fairly new approach to drug development, it is already considered the gold standard technique for RNA delivery, lending many benefits to the treatment of CDH. This technology enables the production of small, lipid-based vesicles to deliver therapeutic RNA directly to the impaired fetal respiratory tract. Encapsulating microRNAs within purposely formulated lipid nanoparticles offers the potential for more controlled and sustained release, while reducing toxicity and minimizing adverse side effects. In addition, downsizing particles to the nanometric scale reduces the volume of reagents needed during drug delivery, making microfluidics a cost- and resource-efficient way for the laboratory to investigate novel treatments for conditions like CDH that, until now, have remained poorly understood.
A FORWARD-THINKING APPROACH
It is essential that adequate and consistent information is available to expectant mothers about pregnancy complications and new and existing medications, so that they can make informed decisions to optimize pregnancy outcomes. Given the potential risks of including pregnant women in in vivo human studies, and the limitations of existing placental models, microfluidics offers a safer, more effective, and increasingly adaptive methodology for modelling pregnancy pharmacology. Researchers in the Labouta Laboratory continue to increase the complexity of their placenta-on-a-chip models and, as their research progresses, they are confident this technology will aid the development of novel therapies to treat a wide range of maternal and fetal conditions. The rapidly growing field of microfluidics therefore has the potential to completely transform the prenatal drug development landscape and improve the availability of pregnancy-approved medications to women across the globe.
The development of medicines to treat maternal and fetal conditions has historically been limited by a lack of knowledge of pregnancy physiology and pharmacokinetics, combined with ethical and regulatory concerns regarding the inclusion of pregnant populations in clinical trials. Microfluidics technologies offer significant potential to the field of pregnancy therapeutics, because nanoparticles can be engineered to minimize fetal drug exposure when required, and deliver therapies safely to intended tissues. Similarly, placenta-on-a-chip technology offers high potential for testing the antenatal safety of therapeutics. Researchers in the Labouta Laboratory are developing increasingly complex microfluidics models of the placenta, and these studies have the potential to improve both maternal and fetal survival rates – as well as quality of life after birth – providing novel and exciting opportunities to an area of research that has long been overlooked.
- David, A.L. et al. 2022. Improving development of drug treatments for pregnant women and the fetus. Therapeutic Innovation & Regulatory Science, 56(6):976–990. doi: 10.1007/s43441-022-00433-w.
- Pascual, Z.N. and Langaker, M.D. 2023. Physiology, Pregnancy. StatPearls Publishing. Available at: https://www.ncbi.nlm.nih.gov/books/NBK559304/.
- Weinberg, D.H. 2022. Human placenta project, Eunice Kennedy Shriver National Institute of Child Health and Human Development. U.S. Department of Health and Human Services. Available at: https://www.nichd.nih.gov/research/supported/human-placenta-project/default.
- Gunatilake, R. and Patil, A.S. 2023. Drug use during pregnancy, MSD Manual Consumer Version. MSD Manuals. Available at: https://www.msdmanuals.com/home/women-s-health-issues/drug-use-during-pregnancy/drug-use-during-pregnancy.
- Leung, C. et al. 2022. Principles of drug use and management in pregnancy. Pharmaceutical Journal, 309(7963). doi: 10.1211/pj.2022.1.150391.
- Tetro, N. et al. 2018. The placental barrier: The Gate and the fate in drug distribution. Pharmaceutical Research, 35(4). doi: 10.1007/s11095-017-2286-0.
- Mika, K. et al. 2021. Evolutionary transcriptomics implicates new genes and pathways in human pregnancy and adverse pregnancy outcomes. eLife, 10. doi: 10.7554/elife.69584.
- Carter, A.M. 2020. Animal models of human pregnancy and placentation: Alternatives to the mouse. Reproduction, 160(6). doi: 10.1530/rep-20-0354.
- Bhatia, S.N. and Ingber, D.E. 2014. Microfluidic organs-on-chips. Nature Biotechnology, 32(8):760–772. doi: 10.1038/nbt.2989.
- Pritchard, N. et al. 2020. Nanoparticles in pregnancy: The next frontier in Reproductive Therapeutics. Human Reproduction Update, 27(2):280–304. doi: 10.1093/humupd/dmaa049.
- The Children’s Hospital of Philadelphia. 2014. Congenital diaphragmatic hernia (CDH). Available at: https://www.chop.edu/conditions-diseases/congenital-diaphragmatic-hernia-cdh.
Dr. Hagar Labouta is the Keenan Research Chair of Nanomedicine at Unity Health Toronto, and an Assistant Professor in the Leslie Dan Faculty of Pharmacy at the University of Toronto. Previously, her laboratory was affiliated with the College of Pharmacy at the University of Manitoba. She has extensive research experience in the areas of nanomedicine, drug delivery, and biomedical engineering, as well as a strong publication record, and is a co-inventor of an international patent for the development of carrier systems for intracellular drug targeting. She earned her PhD in Pharmaceutical Nanotechnology at Saarland University in Germany under the supervision of Professor Marc Schneider, followed by post-doctoral research under the supervision of Professor Claus-Michael Lehr in the Drug Delivery Department at the Helmholtz Institute for Pharmaceutical Research. After emigrating to Canada, she continued her post-doctoral studies at the University of Calgary, where she focused on other areas of nanomedicine in the Departments of Chemistry and Biomedical Engineering, under the supervision of Professors David Cramb and Kristina Rinker, respectively. The Labouta Laboratory is supported by several local, national, and international funds.
Total Page Views: 1364