Liver Microarchitecture-Guided Design of Biomimetic Scaffolds: Biomaterials, Dynamic Culture Systems, and Emerging...

Liver tissue engineering (TE) has emerged as a promising strategy to address the growing burden of liver disease and the shortage of donor organs, while also providing physiologically relevant in vitro models for drug development and disease research. This review synthesizes current knowledge on how native liver microarchitecture and extracellular matrix (ECM) organization can inform the rational design of liver-mimetic scaffolds. We first describe the hepatic acinus as the functional unit underlying metabolic zonation, highlighting regional differences in oxygen and nutrient gradients, cellular composition, and ECM specialization as key design cues for scaffold composition, stiffness, and spatial patterning. We then survey major classes of biomaterials, and discuss their physicochemical requirements and associated fabrication strategies. Particular attention is given to studies that have fabricated liver lobule or acinus-like architectures and to combinatorial strategies that integrate multiple fabrication methods with dynamic culture. Dynamic culture systems, including perfusion bioreactors and microfluidic liver-on-a-chip platforms, are examined as essential tools that provide physiological perfusion, controlled gradients, and mass transport to sustain hepatocyte function and metabolic zonation in engineered tissues. We further review organoid and lab-grown liver models, with emphasis on the self-organization processes by which stem cell-derived constructs recapitulate aspects of acinar architecture, and discuss their convergence with scaffold-based approaches as modular building blocks. Finally, we discuss the current status of clinical translation and commercialization, including the use of normothermic machine perfusion, and outline key scientific, manufacturing, cost, scalability, and regulatory challenges that must be addressed to achieve clinically applicable engineered liver tissues. We conclude that the convergence of acinar-inspired spatial design, liver-specific ECM biochemistry, physiological perfusion, and organoid-derived cell sources, supported by scalable, cost-effective manufacturing and clear regulatory pathways, will be essential to translate biomimetic liver constructs from laboratory prototypes to clinically applicable grafts and predictive in vitro models.