Engineering Scalable Human Liver and Placenta Platforms for Drug Screening and Cell Therapy

Physiologically relevant human in vitro models are useful for drug biotransformation and toxicity screening, disease modeling, and regenerative medicine. Specifically, the liver and placenta are two critical organs with significant implications for human health. As the largest internal organ, the liver performs vital metabolic functions to maintain blood homeostasis and is highly susceptible to various metabolic diseases, including drug-induced liver injury (DILI). Primary human hepatocytes (PHHs) and induced pluripotent stem cell (iPSC)-derived hepatocytes (iHeps) are two key cell sources used to build human-relevant liver models; however, there are fundamental limitations, including the rapid decline of PHH function in conventional cultures and functional immaturity of iHeps. Advanced engineered platforms that enable the precise modulation of microenvironmental factors, such as a controlled 3D microenvironment, homotypic and heterotypic cell-cell interactions, and in vivo-like oxygen tensions, can address these limitations of PHHs and iHeps. Droplet microfluidics facilitates the high-throughput generation of 3D microtissues using natural extracellular matrix (ECM) proteins and enables cell-cell interaction with relevant non-parenchymal cell (NPC) types. Additionally, gas-permeable culture plates enable precise manipulation of pericellular oxygen tension, which ranges from ~10% to ~3% in the hepatic lobule and is known to modulate compartmentalized hepatic phenotype, called ‘zonation.’ Lastly, 3D bioprinting is useful for generating larger tissue constructs for regenerative medicine. Similarly, the placenta facilitates fetal development through biosynthesis, metabolism, and transport and is highly vulnerable to toxic chemical exposure, especially during placental implantation. This thesis synergistically explores the role of the 3D microenvironment, cell-cell interactions, and physiological oxygen tensions in engineered liver and placenta models by employing the tools above. Finally, these engineered models are utilized in applications, including protecting cells from shear stress during 3D bioprinting and developing a scalable chemical screening platform. Ultimately, these physiologically relevant liver and placenta models have utility in drug toxicity screening, disease modeling, and regenerative medicine, aiding in improved outcomes for liver- and pregnancy-related complications.