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.

中文翻译：

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具有合成纳米支架的原位自组装肝球体用于临床前药物筛选应用


药物性肝损伤（DILI）是急性肝衰竭最常见的原因之一，也是药物退出市场的主要原因。人们对先进的体外肝脏模型的需求日益增长，这些模型可以有效地概括肝功能，为临床前药物筛选应用提供强大的平台。在这里，我们探索了在电纺和冷冻研磨聚己内酯（PCL）纳米支架存在下自组装肝球体作为新的临床前药物筛选工具的潜力。这项研究调查了纳米支架浓度对球体大小、活力以及肝脏特异性生物功能的影响程度。使用全面的剂量依赖性对乙酰氨基酚毒性方案进一步验证了我们模型的功效。我们的研究结果表明，基于 PCL 的纳米支架在促进尺寸小于 350 μm 的肝球体原位自组装方面具有强大的潜力。基于 PCL 的纳米支架（0.005 和 0.01% w/v）的存在改善了球体活力和关键肝脏特异性生物标志物（即白蛋白和尿素）的分泌。与二维单层培养物和无支架肝球体相比，具有纳米支架的肝球体显示出改善的药物代谢酶活性和对对乙酰氨基酚更高的敏感性。这些有希望的发现凸显了我们的基于纳米支架的肝球体作为体外肝脏模型用于药物诱导的肝毒性和药物筛选的潜力。