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

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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.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (No. 82174086), the Beijing Natural Science Foundation (No. 7222273), the Beijing Xisike Clinical Oncology Research Foundation (Nos. Y-xsk2021-0004 and Y-XD202001-0172), the Youth Talents Promotion Project of China Association of Chinese Medicine (No. 2020-QNRC2-08), the Clinical Medicine Plus X-Young Scholars Project of Peking University (No. BMU2021MX009), and the Peking University People’s Hospital Research and Development Funds (No. RDY2020-18).

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Author notes

  1. Yancheng Cui and Rongrong Xiao have contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China

    Xiaoni Ai

  2. Department of Gastrointestinal Surgery, Peking University People’s Hospital, Beijing, 100044, China

    Yancheng Cui, Yushi Zhou, Xiaodong Yang, Zhanlong Shen, Bin Liang, Kai Shen & Yingjiang Ye

  3. Beijing Daxiang Biotech Co., Ltd., Beijing, 100195, China

    Rongrong Xiao, Jianchuang Liu & Yi Wang

  4. Merck Innovation Hub (Guangdong) Co., Ltd., Guangzhou, 510005, China

    Yi Li & Geng Xiong

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  1. Yancheng Cui
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Contributions

XA, YC, and RX contributed to conceptualization; XA, YC, RX, JL, YL, and GX provided methodology; XA, YC, RX, YZ, XY, ZS, BL, and KS provided resources; XA, YC, RX, and YW carried out data analysis; XA, YC, and YW performed writing—original draft preparation; XA performed writing—review and editing; XA and YY performed supervision; YC, XA, and YY contributed to funding acquisition. All authors have read and agreed to the published version of the manuscript.

Corresponding authors

Correspondence to Yingjiang Ye or Xiaoni Ai.

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Conflict of interest

XA is the scientific advisor at Beijing Daxiang Biotech. RX, JL and YW are current employees at Beijing Daxiang Biotech. YL and GX are current employees in Merck Innovation Hub (Guangdong) Co., Ltd..

Ethical approval

The study was conducted in accordance with the Declaration of Helsinki and approved by the ethical committees of Peking University People’s Hospital (Ethics approval number: 2021PHB148-001) and registered in ClinicalTrial.gov (NCT04996355). Informed consent was obtained from all patients for being included in the study.

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Cui, Y., Xiao, R., Zhou, Y. et al. Establishment of organoid models based on a nested array chip for fast and reproducible drug testing in colorectal cancer therapy. Bio-des. Manuf. 5, 674–686 (2022). https://doi.org/10.1007/s42242-022-00206-2

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