Human Liver Microphysiological System for Assessing Drug-Induced Liver Toxicity In Vitro

Area of Science:

• Drug development
• Toxicology
• Biotechnology

Background:

• Drug-induced liver injury (DILI) is a significant challenge in drug development, leading to patient risk and industry losses.
• Current 2D in vitro models have limitations in accurately predicting DILI, necessitating more translatable models.
• Early detection of DILI is crucial for patient safety and economic viability in pharmaceutical research.

Purpose of the Study:

• To develop and validate a predictive human liver microphysiological system (MPS) for assessing DILI.
• To investigate the causality and mechanistic aspects of DILI using a 3D in vitro model.
• To evaluate the utility of the MPS for assessing novel compounds and patient-specific toxicity.

Main Methods:

• A human liver MPS was created using primary human hepatocytes and Kupffer cells in 3D microtissues on an engineered scaffold under perfusion.
• Microtissues were cultured and exposed to compounds at multiple concentrations for up to two weeks.
• Functional liver-specific endpoints, including ALT, were analyzed to assess liver function and toxicity.

Main Results:

• The MPS model demonstrated the ability to assess both acute and chronic DILI.
• Validation with known hepatotoxic compounds (pioglitazone, troglitazone) showed the model's predictive capacity.
• The system successfully identified DILI and correlated it with changes in hepatic function.

Conclusions:

• The developed human liver MPS is a valuable tool for assessing DILI and its impact on liver function.
• The model can predict compound behavior in different patient subsets and disease states.
• This MPS platform offers improved translatability for DILI assessment in drug development.