Liver lobule models incorporating the space of Disse and their applications

The space of Disse is a key liver microenvironment positioned between endothelial cells and hepatocytes, filled with an extracellular matrix, where molecular exchange occurs. Its structure dynamically shifts between physiological and pathological conditions, influencing liver function and disease progression. Due to its critical role, in vitro models of the space of Disse are essential for studying liver physiology, disease mechanisms, and therapeutic interventions. This review provides a comprehensive analysis of current bioengineering strategies for modeling the space of Disse. First, we examine different cellular sources and tissue configurations developed in these models, ranging from 2D cultures and sandwich systems to layered 3D tissues and spheroids. Next, we explore recent advancements in engineering approaches, including the integration of microfluidics, microfabrication techniques, and novel biomaterials to enhance model reliability. Finally, we discuss five key applications of these models: investigating the space of Disse physiology and cellular interactions, studying oxygen gradients, modeling liver pathologies, improving hepatotoxicity prediction in the drug screening process, and developing transplantable liver grafts. By synthesizing these advancements, this review highlights the current state, challenges, and future directions of the space of Disse in vitro modeling.