Engineered Perfusable Hepatic Fibrosis Model via Embedded Sacrificial Bioprinting Recapitulates Stiffness‐Driven Fibrogenesis

ABSTRACT Hepatic fibrosis, as the common pathological endpoint of chronic liver diseases, is characterized by a self‐perpetuating vicious cycle comprising extracellular matrix (ECM) driven liver tissue stiffening and sustained hepatic stellate cell (HSC) activation. Although existing studies have simulated fibrotic microenvironments using 2D models with tunable matrix stiffness or static 3D cultures, these models lack engineered hepatic sinusoidal vasculature and dynamic mechanical stimulation within 3D ECM contexts. This study employed embedded sacrificial bioprinting to construct functional liver sinusoid‐mimetic vascular networks within hydrogel matrix of precisely tunable elastic modulus, establishing a dynamically perfused in vitro liver fibrosis model. Experimental validation demonstrated that matrix stiffness directly drives HSC activation, inducing marked myofibroblastic transdifferentiation. Furthermore, compared to static models, 3D dynamic perfusion significantly enhanced hepatocyte sensitivity to high‐stiffness matrix, more accurately replicating the functional decline of hepatocytes in fibrotic microenvironments observed in vivo. More critically, the biomimetic in vitro platform established in this study presents a potential avenue for evaluating pharmacotherapeutic interventions against liver fibrosis. Through targeted inhibition of key signaling hubs, we achieved partial reversal of HSC activation on stiff matrix and partial recovery of liver tissue function. Overall, by simultaneously integrating matrix stiffness modulation, 3D multicellular interactions, and hemodynamic stimulation, this work effectively addresses the insufficient responsiveness of hepatocytes to mechanical cues in conventional models due to inadequate mechanical stimulation. This approach provides a robust framework for faithfully recapitulating the pathophysiological progression of liver fibrosis in vitro through precise tuning of ECM mechanical properties, thereby offering a promising platform for future drug screening and therapeutic assessment.