ABSTRACT The lack of physiologically relevant in vitro models remains a limitation in liver transplantation research. Progress in organ‐on‐a‐chip technologies enables the generation of clinically translatable data in vitro. A vascularized liver tissueoid‐on‐a‐chip (LToC) model is engineered to replicate human liver tissue's structural and functional features for modeling liver regeneration and allograft rejection. The LToC comprises a microfluidic device containing donor‐matched human hepatic progenitor cells and intrahepatic portal vein endothelial cells embedded in a fibrin matrix and maintained in dynamic culture for 49 days. The system supports self‐assembly into a perfusable microvascular network and liver lobule‐like architecture, with >95% cell viability, stable vascular integrity, and active hepatic function (albumin, urea, complement factors, and hepatocyte growth factor secretion). The mature tissueoid includes hepatocytes (CK18 + , albumin + , CYP2D6 + ), cholangiocytes (CK19 + , EPCAM + ), Kupffer cells (CD68 + ), stellate cells (PDGFR‐β + ), and endothelial cells (CD31 + ). Perfusion with allogeneic T cells induces cellular rejection, characterized by decreased viability, endothelial disruption, hepatic marker loss, HLA‐I upregulation, and a proinflammatory cytokine response (IL‐6, TNF‐α, IL‐1β, IFN‐γ, granzyme A and B, and perforin). The LToC provides a physiologically relevant platform for studying immune‐mediated liver injury, tissue regeneration, and allograft rejection, with potential applications in immunosuppressive drug testing and personalized transplant medicine.
Salih et al. (Sun,) studied this question.