Rapid Volumetric Bioprinting Coupled with Dynamic Perfusion Enhances Human Hepatic Organoid Toxicity Testing

Area of Science:

• Biomedical Engineering
• Hepatology
• Drug Discovery

Background:

• Drug-induced liver injury (DILI) is a significant cause of acute liver failure and market drug withdrawals.
• Three-dimensional (3D) hepatic in vitro systems offer enhanced functionality and drug sensitivity over 2D cultures.
• The role of dynamic perfusion in improving hepatotoxicity testing sensitivity and reproducibility remains unclear.

Purpose of the Study:

• To develop and evaluate a perfusion-based 3D bioprinted hepatic model for enhanced hepatotoxicity testing.
• To assess the impact of dynamic perfusion on the sensitivity and reproducibility of drug-induced liver injury (DILI) assessment.

Main Methods:

• Development of a custom perfusion platform for volumetric bioprinted hepatic constructs.
• Incorporation of intrahepatic cholangiocyte organoids (ICOs) differentiated towards hepatocytes within a gelatin methacryloyl bioresin.
• Exposure of hepatocyte-like ICO constructs to subtoxic acetaminophen (10 mM, 7 days) under static and perfused conditions.

Main Results:

• The perfusion system maintained and enhanced hepatocyte differentiation, indicated by upregulated hepatic markers.
• Perfused constructs exhibited significantly elevated cellular injury and liver injury markers following acetaminophen exposure compared to static controls.
• The dynamic perfusion platform demonstrated increased sensitivity in detecting acetaminophen-induced hepatotoxicity.

Conclusions:

• The developed perfusion-based 3D bioprinted hepatic model is a viable platform for hepatotoxicity risk assessment.
• Dynamic perfusion enhances the physiological relevance and sensitivity of in vitro liver injury models.
• This technology holds potential for improving drug discovery and regenerative medicine applications through more accurate toxicity testing.