Acute-on-chronic liver failure (ACLF) and acute liver failure (ALF) are life-threatening conditions marked by severe hepatic dysfunction combined with overwhelming systemic inflammation. Mortality remains extremely high because no available therapy can simultaneously control inflammation and replace lost liver function, leaving liver transplantation as the only definitive option for a limited number of patients.
Acute-on-chronic liver failure (ACLF) and acute liver failure (ALF) are life-threatening conditions marked by severe hepatic dysfunction combined with overwhelming systemic inflammation. Mortality remains extremely high because no available therapy can simultaneously control inflammation and replace lost liver function, leaving liver transplantation as the only definitive option for a limited number of patients.
This study introduces UTOpiA, an integrated whole-blood extracorporeal bioartificial liver system designed to address both pathophysiologic drivers of liver failure. The system combines granulocyte–monocyte apheresis (GMA) to reduce systemic inflammation with human induced pluripotent stem cell–derived hepatocyte-like cell (iHLC) organoids engineered to lack key HLA molecules, minimising immune recognition. Importantly, the tandem design allows direct whole-blood perfusion, avoiding plasma separation and improving efficiency.
In rat models of ACLF and ALF, a single UTOpiA treatment significantly improved survival compared with GMA alone, iHLCs alone, or earlier hepatoma-based devices. Treated animals showed reduced coma severity, improved liver biochemistry, lower ammonia and bilirubin levels, and marked suppression of inflammatory cytokines. Beyond metabolic support, UTOpiA also promoted liver regeneration: iHLC-derived α-fetoprotein enhanced hepatocyte cell cycling, while restoration of key hepatic transcription programs supported functional recovery.
These findings demonstrate that integrating immunomodulation with hepatic metabolic and regenerative support can reverse severe liver failure in preclinical models. While clinical translation will require further validation, UTOpiA represents a major conceptual advance toward an off-the-shelf bioartificial liver therapy for patients with otherwise fatal liver failure.
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