Microengineering the Liver: Strategies for Constructing Functional Liver‐on‐a‐Chip Devices

ABSTRACT Reliable in vitro liver models are indispensable for researching liver diseases and developing medications. Present 2D/3D cell cultures and animal models inadequately replicate the intricacy of living systems and in vivo conditions, resulting in impaired cellular functions. They also fail to emulate tissue‐like architectures, which undermines their precision. Meanwhile, animal models present species differences, making real‐time observation of dynamic results inconvenient and raising serious ethical concerns. Therefore, there is an urgent need to develop alternative tissue models with biomimetic human pathophysiology to bridge the gap between clinical trials and traditional human and animal models. Liver‐on‐a‐chip (LOC) technology, based on microfluidics, is an innovative in vitro modeling device that can replicate the microstructures and tissue‐tissue interfaces of specific liver functional units, simulating organ and tissue‐level physiological activities. This review summarizes recent strategies and breakthroughs in LOC technologies, from biomimetic tissues and extracellular matrix construction in liver microphysiological systems to diverse LOC development approaches. Furthermore, we highlight key advances in functional LOC platforms, including 3D bioprinting, vascularization strategies, and the incorporation of liver buds and organoids to enhance physiological relevance. The integration of deep learning and sensor technologies for intelligent, real‐time monitoring is also discussed. Finally, we examine LOC applications in drug screening and disease modeling, assess challenges in clinical translation, and offer perspectives on future directions in biomedical research and personalized medicine.