In Situ Self-Assembling Liver Spheroids with Synthetic Nanoscaffolds for Preclinical Drug Screening Applications

• Published in: ACS applied materials & interfaces 2024-05, Vol.16 (20), p.25610-25621
• Main Authors: Wu, Lina, Vllasaliu, Driton, Cui, Qi, Raimi-Abraham, Bahijja Tolulope
• Format: Article
• Language: English
• Subjects: Acetaminophen - chemistry; Acetaminophen - pharmacology; Animals; Biological and Medical Applications of Materials and Interfaces; Cell Survival - drug effects; Chemical and Drug Induced Liver Injury - metabolism; Chemical and Drug Induced Liver Injury - pathology; Drug Evaluation, Preclinical; Humans; Liver - drug effects; Polyesters - chemistry; Spheroids, Cellular - drug effects; Spheroids, Cellular - metabolism; Tissue Scaffolds - chemistry
• ISSN: 1944-8244; 1944-8252
• DOI: 10.1021/acsami.3c17384

Drug-induced liver injury (DILI) is one of the most common reasons for acute liver failure and a major reason for the withdrawal of medications from the market. There is a growing need for advanced in vitro liver models that can effectively recapitulate hepatic function, offering a robust platform for preclinical drug screening applications. Here, we explore the potential of self-assembling liver spheroids in the presence of electrospun and cryomilled poly­(caprolactone) (PCL) nanoscaffolds for use as a new preclinical drug screening tool. This study investigated the extent to which nanoscaffold concentration may have on spheroid size and viability and liver-specific biofunctionality. The efficacy of our model was further validated using a comprehensive dose-dependent acetaminophen toxicity protocol. Our findings show the strong potential of PCL-based nanoscaffolds to facilitate in situ self-assembly of liver spheroids with sizes under 350 μm. The presence of the PCL-based nanoscaffolds (0.005 and 0.01% w/v) improved spheroid viability and the secretion of critical liver-specific biomarkers, namely, albumin and urea. Liver spheroids with nanoscaffolds showed improved drug-metabolizing enzyme activity and greater sensitivity to acetaminophen compared to two-dimensional monolayer cultures and scaffold-free liver spheroids. These promising findings highlight the potential of our nanoscaffold-based liver spheroids as an in vitro liver model for drug-induced hepatotoxicity and drug screening.