Multicellular hepatic in vitro models using NANOSTACKS^TM: human-relevant models for drug response prediction

Area of Science:

• Biomedical Engineering
• Drug Discovery
• Hepatology

Background:

• Drug-induced liver injury (DILI) is a major challenge in drug development, leading to trial attrition and market withdrawal.
• Current preclinical animal and in vitro models have limited accuracy in predicting human DILI.
• There is a need for more predictive in vitro models that better recapitulate in vivo liver physiology.

Purpose of the Study:

• To introduce the NANOSTACKS™ platform as a novel in vitro tool for building in vivo-relevant organ models.
• To develop and characterize advanced hepatic models using the NANOSTACKS™ platform.
• To assess the potential of these models for preclinical DILI screening.

Main Methods:

• Developed hepatic models including monocultures, tricultures (PHH, HSC, LECs), and tetracultures (PHH, HSC, LECs, KC) on the NANOSTACKS™ platform.
• Utilized static and orbital-induced mixing flow conditions for model development.
• Characterized models by assessing albumin, urea, CYP3A4, and ATP production.
• Evaluated DILI screening potential using known hepatotoxicants (zileuton, buspirone, cyclophosphamide).

Main Results:

• Successfully developed various hepatic models with different cell compositions under static and flow conditions.
• Characterization confirmed model functionality through key liver function markers.
• Orbital-induced mixing flow monoculture and triculture models demonstrated potential in identifying hepatotoxicity of tested drugs.
• The NANOSTACKS™ platform enabled the creation of complex, in vivo-relevant hepatic models.

Conclusions:

• The NANOSTACKS™ platform is a promising tool for developing advanced in vitro hepatic models.
• These models show potential for improving the prediction of drug-induced liver injury.
• The platform facilitates the creation of complex cellular models for more accurate drug response prediction.