Three-Dimensional Bioprinted hiHeps Hepatorganoids with Improved Hepatic Functions for the Treatment of Acute / Chronic Liver failure and for the Promotion of Liver Regeneration
The liver's intricate architectural organization and regenerative capacity have long posed challenges in developing therapeutic strategies for severe hepatic injuries and functional recovery. Three-dimensional bioprinting provides a unique platform to reconstruct biomimetic liver tissues through spatially orchestrated cellular and extracellular matrix integration. Here, we engineered three-dimensional (3D)-bioprinted hepatic units derived from human induced hepatocytes (hiHeps), which recapitulated native lobular zonation and exhibited enhanced metabolic functions, including glucose/lipid homeostasis and albumin synthesis. These bioengineered units demonstrated robust regenerative potential: they reversed chronic liver fibrosis by resolving pathological collagen deposition, rescued acute liver failure (ALF) through rapid functional compensation, and accelerated liver regeneration in partial hepatectomy models by stimulating endogenous hepatocyte proliferation. Preclinical validation in Bama minipigs revealed that implantation of hiHeps units following extensive liver resection restored coagulation profiles, improved synthetic function, and significantly enhanced survival rates compared to controls. By integrating patient-specific cells with tunable 3D microenvironments, our platform achieved superior functional integration and regenerative efficacy over conventional approaches. This work establishes a paradigm for bioengineered liver grafts that actively drive tissue repair and functional restoration. As a scalable and physiologically relevant solution, these bioprinted hepatic units pioneer a transformative strategy in regenerative hepatology, addressing critical challenges in treating liver failure and post-resection recovery while illuminating microenvironmental cues essential for organ-level regeneration. Overall design: RNA-seq profiling of human induced hepatocytes (hiHeps) and three-dimensional (3D)-bioprinted hepatic units derived from hiHeps at Day7.