Microfluidic organoid-slice-on-a-chip system for studying anti-cholangiocarcinoma drug efficacy and hepatorenal toxicity.

IF 6.1 2区 工程技术 Q1 BIOCHEMICAL RESEARCH METHODS
Lab on a Chip Pub Date : 2025-03-28 DOI:10.1039/d4lc00902a
Jie Liu, Guohua Wu, Di Wu, Lin Wu, Chenwei Sun, Wenlong Zhang, Qijun Du, Qinrui Lu, Wenqi Hu, Hongyu Meng, Zhi Luo, Guangzhi Liu, Bangchuan Hu, Haijie Hu, Shuqi Wang
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Abstract

Organ-chip technology, in contrast to cell culture and animal models, offers a promising platform for accelerating drug development. However, current chip designs simulate human organ functions and there is a lack of multi-organ chip designs that can simultaneously study drug efficacy and hepatorenal toxicity. Here, we developed a novel microfluidic multi-organ chip that integrated cholangiocarcinoma organoids (CCOs) with recellularized liver slices (RLS) and recellularized kidney slices (RKS), to simultaneously assess anti-cholangiocarcinoma drug efficacy and hepatorenal toxicity. Co-culture of patient-derived CCOs with RLS and RKS was successfully achieved for 7 days under flow conditions with enhanced liver and renal cell functions. Furthermore, an in vitro biomimetic model showed IC50 values of trastuzumab emtansine (T-DM1) of around 6.42 ± 7.34 μg mL-1 in four clinical cases, with one outlier of 77.77 μg mL-1 due to patient variability. Post-treatment, RLS and RKS cell viability remained high at 75.67% and 81.03%, respectively, suggesting low hepatorenal toxicity of T-DM1 for treating cholangiocarcinoma. Our study demonstrates the use of an organoid-slice-on-a-chip (OSOC) platform for personalized drug efficacy and toxicity assessment, particularly aiming at leveraging anticancer drugs for off-label use to save patient lives.

用于抗胆管癌药物疗效和肝肾毒性研究的微流控类器官切片芯片系统。
与细胞培养和动物模型相比,器官芯片技术为加速药物开发提供了一个有前途的平台。然而,目前的芯片设计模拟人体器官功能,缺乏能同时研究药物疗效和肝肾毒性的多器官芯片设计。在此,我们开发了一种新型的微流控多器官芯片,将胆管癌类器官(CCOs)与再细胞化肝片(RLS)和再细胞化肾片(RKS)结合起来,同时评估抗胆管癌药物疗效和肝肾毒性。患者源性CCOs与RLS和RKS在流动条件下成功共培养7天,肝脏和肾脏细胞功能增强。此外,体外仿生模型显示,曲妥珠单抗emtansine (T-DM1)在4例临床病例中的IC50值约为6.42±7.34 μg mL-1,由于患者的差异,1例异常值为77.77 μg mL-1。治疗后,RLS和RKS细胞活力保持较高,分别为75.67%和81.03%,提示T-DM1治疗胆管癌的肝肾毒性较低。我们的研究展示了一种用于个性化药物疗效和毒性评估的类器官切片(OSOC)平台的使用,特别是旨在利用抗癌药物的超说明书使用来挽救患者的生命。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Lab on a Chip
Lab on a Chip 工程技术-化学综合
CiteScore
11.10
自引率
8.20%
发文量
434
审稿时长
2.6 months
期刊介绍: Lab on a Chip is the premiere journal that publishes cutting-edge research in the field of miniaturization. By their very nature, microfluidic/nanofluidic/miniaturized systems are at the intersection of disciplines, spanning fundamental research to high-end application, which is reflected by the broad readership of the journal. Lab on a Chip publishes two types of papers on original research: full-length research papers and communications. Papers should demonstrate innovations, which can come from technical advancements or applications addressing pressing needs in globally important areas. The journal also publishes Comments, Reviews, and Perspectives.
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