Degree Type

Dissertation

Date of Award

2019

Degree Name

Doctor of Philosophy

Department

Mechanical Engineering

Major

Mechanical Engineering

First Advisor

Nicole Hashemi

Abstract

The human placenta is a gender-specific, interim endocrine organ that grows in the uterus during pregnancy, with the placenta attaching the evolving fetus to the uterine wall through the umbilical cord to supply oxygen and nutrients. The placenta is also responsible for facilitating removal of waste products and carbon dioxide from the fetus, and with protecting the fetus from infectious agents and foreign substances that can be introduced across the placental barrier. Until the revelation of thalidomide-induced birth defects in the late 1960s, the human placenta was assumed to be an impenetrable barrier shielding the fetus from xenobiotics transfused from the maternal bloodstream. Thereafter, the placenta became a very contentious subject within the scientific community and the pharmaceutical industry because of concerns related to uncertainty associated with usage of xenobiotics and prescribed drugs during pregnancy. Many in vivo, ex vivo, and in vitro models and platforms for conducting placental drug screening have been developed by researchers, but despite these numerous attempts, a lack of physiological functions exhibited by those models and platforms have restricted the modeling of realistic human-placenta responses for conducting accurate drug-transport studies. This dissertation aims to present a microfluidic platform that has been developed to mimic structural phenotypes and physiological characteristics of a human placenta that can be used to simulate near-transport studies of xenobiotics and pharmaceutical drugs across the human placenta.

The usage of pregnant animal subjects has been a previously-preferred method for in vivo experimentation, but ex vivo experimentation has mostly been conducted on perfusion models of human placentas derived from post-delivery. Because of differences between humans and animals with respect to physiological characteristics of placentation, current in vivo drug transport studies of the human placenta have mostly produced erratic outcomes and the ex vivo perfusion models used lack representation of physiological characteristics over the course of pregnancy. Chapter 2 highlights how the placenta-on-a-chip, a micro-engineered device fabricated utilizing microfluidic technology, has revolutionized the processes of overcoming many issues previously experienced for both in vivo and ex vivo models.

Following fabrication and verification of the placenta-on-a-chip, it was initially used to study caffeine transport across the placental barrier in vitro. Caffeine, primarily found in natural sources such as coffee, tea, and cocoa, is one of the most widely-consumed psychoactive drugs in the world. Because of absence of enzymes responsible for metabolizing caffeine in the fetal liver, concerns have been raised that a high maternal caffeine intake might harm the fetus. Chapter 3 presents a study conducted to quantify fetal caffeine concentration and rate of caffeine transfer from a continuous maternal perfusion of 0.25 mg mL-1 over a span of 7.5 h. There is limited information about the safety of using naltrexone (NTX), a common form of medication, prescribed for treating opioid addiction during pregnancy, and concerns have been raised about the effects of this drug on the fetus and its brain. Chapter 4 is a near-transport study of NTX and its major metabolite, 6β-naltrexol, across the placental barrier to the fetus and its brain.

While the placenta-on-a-chip device and associated transport studies summarized in the following chapters suggest this device as a possible in vitro placental drug-testing platform, further studies are required to achieve a sufficiently accurate model for the pharmaceutical industry to use in performing placental drug transport studies.

Copyright Owner

Rajeendra Lakruwan Pemathilaka

Language

en

File Format

application/pdf

File Size

138 pages

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