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Bio-Design and Manufacturing  2022 Vol.5 No.4 P.674-686

http://doi.org/10.1007/s42242-022-00206-2


Establishment of organoid models based on a nested array chip for fast and reproducible drug testing in colorectal cancer therapy


Author(s):  Yancheng Cui, Rongrong Xiao, Yushi Zhou, Jianchuang Liu, Yi Wang, Xiaodong Yang, Zhanlong Shen, Bin Liang, Kai Shen, Yi Li, Geng Xiong, Yingjiang Ye & Xiaoni Ai

Affiliation(s):  State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China; more

Corresponding email(s):   yeyingjiang@pkuph.edu.cn, aixn@bjmu.edu.cn

Key Words:  Organoid on chip, Patient-derived organoids, Precise oncology, Colorectal neoplasm, Drug screening


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Yancheng Cui, Rongrong Xiao, Yushi Zhou, Jianchuang Liu, Yi Wang, Xiaodong Yang, Zhanlong Shen, Bin Liang, Kai Shen, Yi Li, Geng Xiong, Yingjiang Ye & Xiaoni Ai. Establishment of organoid models based on a nested array chip for fast and reproducible drug testing in colorectal cancer therapy[J]. Journal of Zhejiang University Science D, 2022, 5(4): 674-686.

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author="Yancheng Cui, Rongrong Xiao, Yushi Zhou, Jianchuang Liu, Yi Wang, Xiaodong Yang, Zhanlong Shen, Bin Liang, Kai Shen, Yi Li, Geng Xiong, Yingjiang Ye & Xiaoni Ai",
journal="Journal of Zhejiang University Science D",
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pages="674-686",
year="2022",
publisher="Zhejiang University Press & Springer",
doi="10.1007/s42242-022-00206-2"
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%A Yancheng Cui
%A Rongrong Xiao
%A Yushi Zhou
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%A Yi Wang
%A Xiaodong Yang
%A Zhanlong Shen
%A Bin Liang
%A Kai Shen
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A1 - Yi Wang
A1 - Xiaodong Yang
A1 - Zhanlong Shen
A1 - Bin Liang
A1 - Kai Shen
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Abstract: 
The conventional microwell-based platform for construction of organoid models exhibits limitations in precision oncology applications because of low-speed growth and high variability. Here, we established organoid models on a nested array chip for fast and reproducible drug testing using 50% matrigel. First, we constructed mouse small intestinal and colonic organoid models. Compared with the conventional microwell-based platform, the mouse organoids on the chip showed accelerated growth and improved reproducibility due to the nested design of the chip. The design of the chip provides miniaturized and uniform shaping of the matrigel that allows the organoid to grow in a concentrated and controlled manner. Next, a patient-derived organoid (PDO) model from colorectal cancer tissues was successfully generated and characterized on the chip. Finally, the PDO models on the chip, from three patients, were implemented for high-throughput drug screening using nine treatment regimens. The drug sensitivity testing on the PDO models showed good quality control with a coefficient of variation under 10% and a Z' factor of more than 0.7. More importantly, the drug responses on the chip recapitulate the heterogeneous response of individual patients, as well as showing a potential correlation with clinical outcomes. Therefore, the organoid model coupled with the nested array chip platform provides a fast and reproducible means for predicting drug responses to accelerate precise oncology.

北京大学艾晓妮、北京大学人民医院叶颖江等 | 基于嵌套式微阵列芯片的类器官模型(类器官芯片)的结直肠癌药物测试体系

本研究论文聚焦新型高通量嵌套式微阵列类器官芯片模型的开发,并为临床结直肠癌药物测试体系提供了基础。传统基于孔板的类器官(patient-derived organoid, PDO)模型构建平台,因其生长速度缓慢以及类器官高变异性,导致类器官均一性差、药效结果可重复性低等弊端,在肿瘤精准医疗实际应用中表现出较大的局限性。本研究首次建立了一种基于嵌套式微阵列芯片的类器官培养体系(类器官芯片)。研究者首先构建了小鼠小肠和结肠类器官模型,通过与传统孔板平台进行对比,芯片上的小鼠类器官的生长速度和可重复性均有较大提升。芯片的结构设计可以使得Matrigel用量更少,铺展更均匀,并允许类器官以一种集中和可控的方式生长。之后,在芯片上,研究者构建了3例PDO模型用于高通量药物筛选,测试了9种不同治疗方案。PDO模型的药物敏感性测试结果展现了优异的质控效果。与传统孔板培养平台相比,类器官芯片不仅促进了类器官的生长,同时提高了培养体系的稳定性,为肿瘤精准治疗提供了一个快速、可重复性的新型药物筛选平台。

(本文第一作者为北京大学人民医院崔艳成医生,北京大橡科技有限公司肖荣荣研究员(共同一作),共同通讯作者为北京大学艾晓妮副教授和北京大学人民医院叶颖江教授)

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