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Bio-Design and Manufacturing  2022 Vol.5 No.3 P.437-450

http://doi.org/10.1007/s42242-022-00188-1


Development of digital organ‑on‑a‑chip to assess hepatotoxicity and extracellular vesicle‑based anti‑liver cancer immunotherapy


Author(s):  Guohua Wu, Jianguo Wu, Zihan Li, Shengyu Shi, Di Wu, Xuanbo Wang, Han Xu, Hui Liu, Yixiao Huang, Rending Wang, Jia Shen, Zhihong Dong & Shuqi Wang

Affiliation(s):  The First Afliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310029, China ; more

Corresponding email(s):   jiashen@zju.edu.cn, zhdong@cdu.edu.cn, shuqi@scu.edu.cn

Key Words:  Digital, Organ-on-a-chip, Microwell array, Microspheres, Extracellular vesicles


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Guohua Wu, Jianguo Wu, Zihan Li, Shengyu Shi, Di Wu, Xuanbo Wang, Han Xu, Hui Liu, Yixiao Huang, Rending Wang, Jia Shen, Zhihong Dong & Shuqi Wang. Development of digital organ‑on‑a‑chip to assess hepatotoxicity and extracellular vesicle‑based anti‑liver cancer immunotherapy[J]. Journal of Zhejiang University Science D, 2022, 5(3): 437-450.

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Abstract: 
organ-on-a-chip systems have been increasingly recognized as attractive platforms to assess toxicity and to develop new therapeutic agents. However, current organ-on-a-chip platforms are limited by a “single pot” design, which inevitably requires holistic analysis and limits parallel processing. Here, we developed a digital organ-on-a-chip by combining a microwell array with cellular microspheres, which significantly increased the parallelism over traditional organ-on-a-chip for drug development. Up to 127 uniform liver cancer microspheres in this digital organ-on-a-chip format served as individual analytical units, allowing for analysis with high consistency and quick response. Our platform displayed evident anti-cancer efficacy at a concentration of 10 μM for sorafenib, and had greater alignment than the “single pot” organ-on-a-chip with a previous in vivo study. In addition, this digital organ-on-a-chip demonstrated the treatment efficacy of natural killer cell-derived extracellular vesicles for liver cancer at 50 μg/mL. The successful development of this digital organ-on-a-chip platform provides high-parallelism and a low-variability analytical tool for toxicity assessment and the exploration of new anticancer modalities, thereby accelerating the joint endeavor to combat cancer.

【封面文章】浙江大学王书崎等 | 构建数字化器官芯片用于评估药物肝毒性和探索基于细胞外囊泡的肝癌免疫治疗

本研究论文聚焦构建数字化器官芯片用于评估药物肝毒性和探索基于细胞外囊泡的肝癌免疫治疗。近年来,器官芯片成为评估药物毒性和开发新型抗癌药物中最具潜力的新型平台。然而,目前的器官芯片主要基于单一的培养单元也即“单罐”式的培养,通常进行整体性分析,并行处理能力较差。鉴于此,在本研究中,通过将微孔阵列与均一化的肝癌细胞微球相结合,开发了一种数字化的器官芯片,与传统“单罐”式器官芯片相比,这种包含 100 多个分析单元的数字化器官芯片将传统的整体分析单元进行分割,将传统整体性分析方式转变为数字分析。其中,每一个均一性较好的肝癌微球都可视为一个独立的肝癌培养单元,极大地增加了芯片中分析单元的并行处理能力,提高了器官芯片中药物的反应速度。同时微阵列与微球的结合也减少了分析单元之间的荧光信号干扰。利用该数字化器官芯片平台对索拉非尼杀伤肝癌的效果进行评估,结果显示,10 μM的索拉非尼显示出明显的抗癌效果,与2D条件和传统器官芯片中的药物浓度相比,数字化器官芯片中索拉非尼的抗癌作用浓度与之前报道的在体内的抗癌浓度具有一致性。此外,在本研究中,利用该数字化器官芯片平台探索了自然杀伤细胞来源的细胞外囊泡对肝癌具有一定的杀伤效果。该数字化器官芯片平台的成功开发为评估药物毒性和探索新的抗癌方法提供了高并行性和低变异性的分析工具,从而增加了药物筛选及测试的准确性和可靠性,为加速创新药物研发提供了新平台。

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