Abstract

Functional 3D Printed Human Liver Discoids for Toxicology and Pharmacology

Thomas Angelini, Associate Professor, Department of Mechanical and Aerospace Engineering, University of Florida

A persistent challenge in drug discovery and development has been our inability to predict whether compounds induce liver injury in humans, leading to costly clinical development failures, blackbox warnings, or withdrawal of drugs from the market. This limitation is broadly encountered; tests using animal models, cell monolayers, and 3D culture approaches fail to predict drug induced liver injury (DILI). Thus, to reduce costs and accelerate the development of effective drugs, there is a critical need for improved human liver tissue models. In this talk I will describe an approach for 3D bioprinting functional human liver tissue models, in which we fabricate disc-shaped structures 200 ?m in thickness and 1-3 mm in diameter, embedded in a highly permeable support medium made from packed microgels. We demonstrate that the method is precise, accurate, and scalable; up to 100 tissues per hour can be manufactured with a variability and error in diameter of about 4%. Histologic and immunohistochemical evaluation of printed discoids reveal self-organization, cell cohesion, and key liver marker expression. During 3-4 weeks in culture, the tissues stably synthesize albumin and urea at high levels, outperforming spheroid tissue models. We find the tissues express more than 100 genes associated with molecular absorption, distribution, metabolism, and excretion (ADME) at levels within the range of human liver. Finally, the liver tissue models exhibit enzymatic formation of metabolites after exposure to multiple test compounds. Together, these results demonstrate the promise of 3D printed discoids for pharmacological and toxicological application.