UC San Diego

Drug-induced liver toxicity is the leading cause of acute liver failure and post-market drug withdrawals. In addition, liver associated chronic diseases are major contributors of morbidity and mortality in the United States. Conventional animal models are often costly and unreliable in translation to human studies. Therefore, effective in vitro human liver models that can recapitulate native liver function and disease states are highly demanded to better understand disease mechanism and serve as drug screening platforms.

Over the past decades, liver tissue engineering has made significant progress towards the establishment of in vitro liver models for both fundamental pathophysiological studies and drugscreening. However, current platforms are still limited of in terms of their inability to reproduce complex liver microarchitecture, maintain long-term liver functions and reproduce cellular behaviors in diseased conditions. Rapid 3D bioprinting technology, with its potential to pattern cells and biomaterials in a precise manner, provides a great tool to build novel and biomimetic liver models with increasing structural complexity.

In this dissertation, I present the application of digital light processing (DLP)-based rapid 3D bioprinting technology to build in vitro liver tissue constructs for modeling healthy and disease conditions. To address the need of liver models for personalized drug screening, I developed a 3D triculture model that embeds human induced pluripotent stem cell (iPSC)-derived hepatic cells with supporting cells in a biomimetic hexagonal architecture. In comparison with 2D monolayer culture and a 3D hepatic cell-only model, the 3D triculture model demonstrates enhancements in liver-specific gene expression, functions and drug metabolism potential. Furthermore, to study liver cancer progression in fibrotic matrix conditions, a liver cancer invasion model possessing tissue-scale organization and patterning of distinct regional stiffness was developed. Tumor cells in cirrhotic condition demonstrated reduced growth along with upregulated invasion markers compared to healthy controls. Cancer stromal invasion from the nodule with cirrhotic stiffness was also visualized using the cancer invasion model. Overall, these models demonstrate the capability of DLP-based 3D bioprinting to build novel and complex structure that mimic native liver tissues in various conditions, and the potential to be applied to in vitro drug testing and disease modeling.