Regenerative Hepatology: From 3D Liver Models, Organoids and Organs-on-Chips to Bioengineering and Advanced Ex Vivo Perfusion of Livers

Chronic liver diseases represent a growing global health burden, accounting for significant morbidity and mortality worldwide. Conditions such as cirrhosis, hepatocellular carcinoma (HCC), and acute-on-chronic liver failure are responsible for over two million deaths annually, driven by diverse etiologies including metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease, viral hepatitis, and autoimmune disorders. Despite advances in clinical management, liver transplantation remains the only definitive treatment for end-stage liver disease, yet it is severely limited by donor organ shortage, high costs, and the need for lifelong immunosuppression. Consequently, there is a critical unmet need for innovative therapeutic strategies that can halt, reverse, or regenerate damaged liver tissue.A major barrier to progress in hepatology is the lack of predictive and physiologically relevant human liver models for studying disease mechanisms and evaluating novel therapies. Traditional two-dimensional (2D) cell cultures fail to recapitulate the architectural complexity, cellular heterogeneity, and the dynamic hepatic microenvironment. Similarly, animal models, while informative, often do not faithfully reproduce human liver pathophysiology or drug responses. These limitations contribute to high attrition rates in drug development and hinder the translation of promising therapies into clinical practice.In recent years, regenerative hepatology has emerged as a rapidly evolving interdisciplinary field that integrates stem cell biology, tissue engineering, microfluidics, and translational medicine. Advanced in vitro systems such as three-dimensional (3D) liver spheroids, organoids, and organs-on-chips offer unprecedented opportunities to model human liver development, disease progression, and drug responses with improved fidelity. Parallel advances in bioengineering—including decellularized scaffolds, bioprinting, and synthetic biomaterials—are enabling the generation of functional liver tissue constructs with increasing complexity and scalability.In addition, machine perfusion technologies, including normothermic and hypothermic ex vivo liver perfusion, are transforming transplantation and opening new avenues for organ preservation, assessment, and repair. These platforms not only improve graft viability but also provide unique opportunities for therapeutic interventions, including gene editing, cell therapy, and targeted drug delivery prior to transplantation.Together, these innovations are reshaping the landscape of liver research and therapy. However, significant challenges remain in standardization, scalability, vascularization, immune integration, and regulatory translation. Bridging the gap between experimental models and clinical application requires coordinated efforts across basic, translational, and clinical research domains.This Research Topic aims to bring together cutting-edge contributions that advance the development and application of regenerative approaches in hepatology. We seek to highlight innovative liver models, uncover disease mechanisms, and accelerate the discovery of effective therapies for liver diseases.We welcome Original Research, Review, Mini-Review, Case Report, and Perspective articles covering (but not limited to):• Development and characterization of 3D liver models, including spheroids and multicellular co-culture systems.• Liver organoids derived from pluripotent or adult stem cells for disease modeling and regenerative applications.• Organs-on-chips and microphysiological systems for modeling liver function, disease, and drug toxicity.• Bioengineering approaches, including 3D bioprinting, decellularized liver scaffolds, and biomaterial-based liver constructs.• Vascularization and immune system integration in engineered liver tissues.• Applications of gene editing (e.g., CRISPR-based technologies, viral vectors, etc) in liver models and regenerative therapies.• Advanced ex vivo liver perfusion technologies (normothermic, hypothermic, and subnormothermic) for organ preservation and repair.• Use of perfusion platforms for drug delivery, gene therapy, and immunomodulation prior to transplantation.• Disease modeling using regenerative platforms, including MASLD/MASH, viral hepatitis, cholestatic diseases, and genetic liver disorders.• Drug discovery and toxicology testing using advanced liver models.• Multi-omics integration (transcriptomics, proteomics, metabolomics) in engineered liver systems.• Personalized medicine approaches using patient-derived liver organoids or bioengineered tissues.• Scaling up liver tissue production and manufacturing challenges for clinical translation.• Regulatory considerations and standardization of regenerative liver technologies.• Translational and clinical studies bridging regenerative models with patient outcomes.• Ethical considerations in bioengineered organs and regenerative therapies. Topic editors: Pedro M Baptista, Roberto Gramignoli Source: https://www.frontiersin.org/research-topics/82716/regenerative-hepatology-from-3d-liver-models-organoids-and-organs-on-chips-to-bioengineering-and-advanced-ex-vivo-perfusion-of-livers