Vascularized liver-on-a-chip model to investigate nicotine-induced dysfunction

Area of Science:

• Biomedical Engineering
• Toxicology
• Drug Discovery

Background:

• Physiologically relevant in vitro systems are crucial for drug discovery but often fail to replicate tissue architecture and multicellular interactions.
• Incorporating microvasculature into in vitro models, especially with parenchymal cells, presents significant challenges.
• Advancements in 3D cell culture and biomimetic materials have improved in vitro models, yet vascular integration remains difficult.

Purpose of the Study:

• To systematically investigate the impact of endothelial cell seeding density on network formation within a liver-on-a-chip model.
• To assess the effects of nicotine on microvasculature and hepatic function using the developed vascularized liver-on-a-chip system.
• To establish a functional in vitro model for evaluating drug-induced hepatotoxicity and vascular dysfunction.

Main Methods:

• A systematic approach was employed to optimize endothelial cell seeding density for interconnected microvascular network formation.
• Hepatic spheroids were combined with engineered microvascular networks to create a vascularized liver-on-a-chip model.
• Nicotine exposure was used to investigate its effects on the microvasculature and hepatic functions within the chip.

Main Results:

• Optimized endothelial cell seeding density led to the formation of interconnected microvascular networks.
• Nicotine exposure resulted in interrupted adherens junctions, decreased guanosine triphosphate cyclohydrolase 1 expression, impaired angiogenesis, and reduced barrier function.
• The vascularized liver-on-a-chip model demonstrated functional xenobiotic metabolism, albumin synthesis, and urea synthesis.

Conclusions:

• The developed vascularized liver-on-a-chip model accurately replicates liver microvasculature and hepatic functions.
• Nicotine induces endothelial dysfunction, impacting vascular integrity and hepatic metabolic capacity.
• This advanced in vitro system offers a valuable tool for high-throughput assessment of drug-induced hepatotoxicity and vascular dysfunction.