Abstract 1218: A comprehensive and scalable human liver-on-a-chip model forfibrosis drug discovery and gene delivery applications

Abstract Liver cancer, or hepatocellular carcinoma (HCC), is a formidable malignancy characterized by the uncontrolled growth of cells within the liver tissue. It represents a global health concern, with risk factors including chronic viral infections (such as hepatitis B and C), excessive alcohol consumption, fatty liver disease, and certain genetic conditions. The silent progression of HCC complicates early detection, emphasizing the need for a deeper understanding of the liver tumor microenvironment, which plays a crucial role in disease development. The liver model presented here incorporates a wide array of relevant liver cell types, including hepatocytes, endothelial cells, stellate cells, and resident immune cells. This is complemented by a complete vascularization system, allowing for fluid flow across a micro vascular network that faithfully models the dimensions of liver sinusoids. All these elements are seamlessly integrated into an automated and high throughput platform known as the OrganoPlate®. To model the liver tumor microenvironment, hepatocellular carcinoma cells were integrated into healthy liver tissue model. The resulting model allowed for the observation of integrated cancer colonies, providing a more realistic platform for therapy development compared to monocultures. Simultaneously, the liver's particle clearance mechanisms were investigated using fluorescent imaging. Endothelial cell phagocytosis of E. coli particles and resident macrophages' internalization of dextran molecules were studied to explore hepatic delivery of macromolecules and nanoparticles via the systemic circulation. The integration of hepatocellular carcinoma cells within healthy liver tissue revealed the formation of integrated cancer colonies, offering insights into the complex interactions within the liver tumor microenvironment. Fluorescent imaging showcased endothelial cell phagocytosis of E. coli particles and resident macrophages' internalization of fluorescent molecules. These findings elucidate the liver's particle clearance mechanisms, providing a foundation for understanding immunological processes and designing efficient drug delivery systems. Understanding the liver tumor microenvironment is critical for developing effective therapies for HCC. The integration of hepatocellular carcinoma cells within healthy liver tissue offers a more realistic platform for therapy development compared to traditional monocultures. We believe this system holds the potential for a groundbreaking progress in liver modelling which, besides including functional hepatic cells, also reflects the cellular organization and interactions found within the liver lobule. In conjunction with its high throughput capability, this has the potential to revolutionize drug discovery and develop therapies for complex liver diseases. Citation Format: Flavio Bonanini, Roelof Dinkelberg, Tessa Hagens, Nienke Kortekaas, Nick Saites, Manuel Torregrosa, Dorota Kurek, Paul Vulto, Kristin Bircsak. A comprehensive and scalable human liver-on-a-chip model forfibrosis drug discovery and gene delivery applications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1218.