Center for Biomedical Engineering, University of Science and Technology of China, Hefei, 230027, China.
Chinese Integrative Medicine Oncology Department, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
Acta Biomater. 2021 Oct 15;134:228-239. doi: 10.1016/j.actbio.2021.07.013. Epub 2021 Jul 13.
Nonalcoholic fatty liver disease (NAFLD) has emerged as a public health concern. To date, the mechanism of NAFLD progression remains unclear, and pharmacological treatment options are scarce. Traditional animal NAFLD models are limited in helping address these problems due to interspecies differences. Liver chips are promising for modeling NAFLD. However, pre-existing liver chips cannot reproduce complex physicochemical microenvironments of the liver effectively; thus, NAFLD modeling based on these chips is incomplete. Herein, we develop a biomimetic liver lobule chip (LC) and then establish a more accurate on-chip NAFLD model. The self-developed LC achieves dual blood supply through the designed hepatic portal vein and hepatic artery and the microtissue cultured on the LC forms multiple structures similar to in vivo liver. Based on the LC, NAFLD is modeled. Steatosis is successfully induced and more importantly, changing lipid zonation in a liver lobule with the progression of NAFLD is demonstrated for the first time on a microfluidic chip. In addition, the application of the induced NAFLD model has been preliminarily demonstrated in the prevention and reversibility of promising drugs. This study provides a promising platform to understand NAFLD progression and identify drugs for treating NAFLD. STATEMENT OF SIGNIFICANCE: Liver chips are promising for modeling nonalcoholic fatty liver disease. However, on-chip replicating liver physicochemical microenvironments is still a challenge. Herein, we developed a liver lobule chip with dual blood supply, achieving self-organized liver microtissue that is similar to in vivo tissue. Based on the chip, we successfully modeled NAFLD under physiologically differentiated nutrient supplies. For the first time, the changing lipid zonation in a single liver lobule with the early-stage progression of NAFLD was demonstrated on a liver chip. This study provides a promising platform for modeling liver-related diseases.
非酒精性脂肪性肝病（NAFLD）已成为一个公共健康关注点。迄今为止，NAFLD 进展的机制仍不清楚，且药物治疗选择有限。由于种间差异，传统的动物 NAFLD 模型在帮助解决这些问题方面存在局限性。肝脏芯片在模拟 NAFLD 方面具有广阔的应用前景。然而，现有的肝脏芯片无法有效地再现肝脏的复杂物理化学微环境，因此，基于这些芯片的 NAFLD 建模并不完整。在此，我们开发了一种仿生肝小叶芯片（LC），并在此基础上建立了一种更准确的肝芯片 NAFLD 模型。我们自主研发的 LC 通过设计的肝门静脉和肝动脉实现了双重血液供应，且在 LC 上培养的微组织形成了多个类似于体内肝脏的结构。在此基础上，我们成功地模拟了 NAFLD。成功诱导了脂肪变性，更重要的是，首次在微流控芯片上证明了随着 NAFLD 的进展，肝小叶中的脂质分区发生变化。此外，该诱导的 NAFLD 模型的应用已初步在有前景的药物的预防和逆转中得到验证。本研究为理解 NAFLD 进展和鉴定治疗 NAFLD 的药物提供了一个有前景的平台。
