Bioprinting functional hepatocyte organoids derived from human chemically induced pluripotent stem cells to treat liver failure.

Background: To treat liver failure, three-dimensional (3D) bioprinting is a promising technology used to construct hepatic tissue models. However, current research on bioprinting of hepatic tissue models primarily relies on conventional single-cell-based bioprinting, where individual functional hepatocytes are dispersed and isolated within hydrogels, leading to insufficient treatment outcomes due to inadequate cell functionality.

Objective: Here, we aim to bioprint a hepatic tissue model using functional hepatocyte organoids (HOs) and evaluate its liver-specific functions and .

Design: Human chemically induced pluripotent stem cells (hCiPSCs) were used as a robust and non-genome-integrative cell source to produce highly viable and functional HOs (hCiPSC-HOs). An oxygen-permeable microwell device was used to enhance oxygen supply, ensuring high cell viability and promoting hCiPSC-HOs maturation. To maintain the long-term biofunction of hCiPSC-HOs, spheroid-based bioprinting was employed to construct hepatic tissue models (3DP-HOs). 3DP-HOs were intraperitoneally implanted in mice with liver failure.

Results: 3DP-HOs demonstrated enhanced cell viability when compared with a model fabricated using single-cell-based bioprinting and exhibited gene profiles closely resembling hCiPSC-HOs while maintaining liver-specific functionality. Moreover, 3DP-HOs implantation significantly improved survival in mice with CCl-induced acute-on-chronic liver failure and also mice with liver failure. 3DP-HOs significantly reduced liver injury, inflammation and fibrosis indices while promoting liver regeneration and biofunction expression.

Conclusion: Our bioprinted hepatic tissue model exhibits remarkable therapeutic efficacy for liver failure and holds great potential for clinical research in the field of liver regenerative medicine.