Self-Organized Vascularized Hepatic Organoids in Microcapsules for Liver Regeneration.

Hepatic organoids represent a promising strategy for liver regeneration; however, challenges remain in flexibly tailoring them to achieve complex architectures and vascularized structures for enhanced functionality. Here, we propose a novel system of self-organized vascularized hepatic organoids (SOVHOs) encapsulated in hydrogel microcapsules with biomimetic features for liver regeneration. The hydrogel shell microcapsules encapsulating human umbilical vein endothelial cells and hepatic organoids derived from human induced pluripotent stem cells were generated using microfluidic encapsulation technology. The hydrogel shell provides a 3-dimensional culture environment that supports the formation of uniform hepatocyte spheroids with vascular networks inside the microcapsules. The SOVHOs exhibit liver-specific functions, including drug metabolism, urea synthesis, and serum protein production. In rats with acute liver failure, we demonstrated that the SOVHOs markedly enhanced survival rate and normalize the inflammatory response after transplantation, indicating their remarkable repopulation capacity in facilitating injured liver recovery. Furthermore, SOVHOs remained viable in the host liver for at least 7 days post-implantation, exhibiting low immunogenicity and no detectable adverse effects in rats during this period. These results suggest that our SOVHOs are potentially valuable for clinical application in liver disease treatment.