Microscale 3D Liver Bioreactor for In Vitro Hepatotoxicity Testing under Perfusion Conditions

Area of Science:

• Hepatotoxicity and Toxicology
• Biomedical Engineering
• In Vitro Models

Background:

• Accurate prediction of drug-induced liver injury (hepatotoxicity) is crucial for clinical trial success.
• Existing preclinical animal models often fail to predict human responses.
• Validated human in vitro models are needed to bridge the gap between animal studies and clinical trials.

Purpose of the Study:

• To investigate the response of primary human liver cells to toxic drug exposure.
• To evaluate a perfused microscale 3D liver bioreactor as a model for hepatotoxicity testing.
• To assess the dose-dependent effects of acetaminophen (APAP) on liver cells in vitro.

Main Methods:

• Primary human liver cells were cultured in a perfused microscale 3D liver bioreactor.
• Bioreactors were treated with varying concentrations of acetaminophen (5, 10, or 30 mM).
• Biochemical markers (lactate, ammonia, prostaglandin E2), gene expression, and histology were analyzed.

Main Results:

• Acetaminophen exposure induced dose-dependent toxicity, evidenced by decreased lactate production and increased ammonia release.
• Increased prostaglandin E2 release indicated an inflammatory response to cellular stress.
• Histological analysis showed disintegration of cell aggregates and loss of hepatocyte-specific markers upon APAP treatment.
• Gene expression related to drug metabolism, antioxidant response, urea synthesis, and apoptosis was altered.

Conclusions:

• The microscale 3D liver bioreactor is a suitable in vitro model for detecting drug-induced hepatotoxicity.
• Perfusion conditions in the bioreactor enhance the physiological relevance of the model.
• This model shows promise for improving the accuracy of preclinical drug safety assessments.