Hepatic organoids for microfluidic drug screening.

Area of Science:

• Biotechnology
• Drug Discovery
• Toxicology

Background:

• Early-stage drug development requires reliable methods to predict drug toxicity.
• Current 2D cell culture models inadequately mimic in vivo liver function.
• Hepatotoxicity screening is crucial for a "fail early, fail cheaply" strategy.

Purpose of the Study:

• Introduce the microfluidic organoids for drug screening (MODS) platform.
• Develop and validate 3D hepatic organoids for drug screening.
• Assess the MODS platform's utility in identifying drug-induced toxicity.

Main Methods:

• Digital microfluidic system for generating individually addressable, free-floating 3D hydrogel microtissues (organoids).
• Formation of hepatic organoids using co-cultures of HepG2 and NIH-3T3 cells within hydrogel matrices.
• Analysis of organoid contractile behavior, albumin secretion, and cytochrome P450 3A4 activity.
• Screening acetaminophen's effects on apoptosis and necrosis using the MODS platform.

Main Results:

• Successfully generated arrays of hepatic organoids exhibiting fibroblast-dependent contractile behavior.
• Organoids demonstrated superior mimicry of in vivo liver function compared to 2D cultures, evidenced by albumin secretion and CYP450 3A4 activity.
• The MODS platform effectively identified acetaminophen-induced apoptosis and necrosis in a dose-dependent manner.

Conclusions:

• The MODS platform provides a robust method for generating 3D hepatic organoids for drug screening.
• MODS offers a more physiologically relevant model for hepatotoxicity assessment than traditional 2D systems.
• The platform holds potential as a cost-effective tool for early-stage drug development, aligning with the "fail early, fail cheaply" paradigm.