Biomimetic Vascularized iPSC‐Hepatocyte Spheroids for Liver Regeneration

Human induced pluripotent stem cell derived hepatocytes (hiPSC-heps) hold promising value for acute liver failure (ALF) treatment, while their therapeutic efficacy is usually limited by low cell bioactivity and untargeted in vivo accumulation. Here, inspired by vascularity supporting cellular architectures in the tissues and organs, a novel vascularized hiPSC-heps spheroid based on microfluidic microcapsules is presented for liver repair via orthotopic transplantation. The microcapsules are comprised of aqueous cores that facilitate hiPSC-hep aggregating into spheroids, and hybrid hydrogel shells of sodium alginate and hyaluronic acid methacryloyl (HAMA). By selectively degrading the alginate, the microcapsules are imparted with porous HAMA shells, which not only allowed human umbilical vein endothelial cells (HUVECs) to attach and form vascularized networks, but also facilitated communication between HUVECs and hiPSC-heps. The specific spatial distributions of these cells in the vascularized hiPSC-hep spheroids can provide nutrition support, promote the hepatic functions, and avoid immune cell attacks. Based on these features, it is illustrated that the vascularized hiPSC-hep spheroids can repair the acute failing liver more effectively, indicating their practical values in clinical liver repair.