Constructing biomimetic microenvironments for liver regeneration

Liver regeneration is a sophisticated biological process influenced by a complex microenvironment that becomes profoundly altered in various pathological conditions. Current therapeutic approaches, including liver transplantation and pharmacological interventions, face significant limitations such as donor shortages, high costs, immune rejection, and insufficient functional recovery. Thus, alternative and innovative strategies are urgently needed. Biomimetic microenvironments constructed through tissue engineering have emerged as promising platforms, capable of recapitulating the liver's natural architecture and supporting hepatic cell functions. This review outlines key pathological features and the biological basis underlying liver regeneration, highlighting cellular plasticity, inflammation, extracellular matrix (ECM) remodeling, and immune interactions. It further discusses advanced biomimetic strategies, including 3D cell cultures, decellularized ECM hydrogels, bioprinting technologies, and dynamic culture systems like hollow fiber, fluidized-bed, and microcarrier bioreactors. These innovations facilitate accurate modeling of hepatic functions, maintain cellular differentiation, and enhance regeneration. Despite significant advancements, challenges remain in optimizing microenvironmental fidelity, ensuring clinical scalability, and translating laboratory breakthroughs into effective therapies.