器官芯片与工程化人体组织在药物研发中的应用前景

doi:10.3969/j.issn.2095-4344.2711

中国组织工程研究 ›› 2020, Vol. 24 ›› Issue (29): 4717-4723.doi: 10.3969/j.issn.2095-4344.2711

• 组织构建综述 tissue construction review • 上一篇下一篇

器官芯片与工程化人体组织在药物研发中的应用前景

陈沛杉，张海燕

首都医科大学基础医学院细胞生物学系，北京市 100069

收稿日期:2019-11-16 修回日期:2019-11-20 接受日期:2019-12-26 出版日期:2020-10-18 发布日期:2020-09-15
通讯作者: 张海燕，教授，博士生导师，首都医科大学基础医学院细胞生物学系，北京市 100069
作者简介:陈沛杉，女，1997年生，北京市人，汉族，首都医科大学2016级长学制临床医学专业在读。
基金资助:

国家自然科学基金面上项目(81770616)

Organs-on-a-chip and engineered human tissues in drug development

Chen Peishan, Zhang Haiyan

Department of Cell Biology, Basic Medical College, Capital Medical University, Beijing 100069, China

Received:2019-11-16 Revised:2019-11-20 Accepted:2019-12-26 Online:2020-10-18 Published:2020-09-15
Contact: Zhang Haiyan, Professor, Doctoral supervisor, Department of Cell Biology, Basic Medical College, Capital Medical University, Beijing 100069, China
About author:Chen Peishan, Department of Cell Biology, Basic Medical College, Capital Medical University, Beijing 100069, China
Supported by:
the National Natural Science Foundation of China, No. 81770616

摘要/Abstract

摘要：

文题释义：

器官芯片(Organs-on-a-chip，OOC)：是指在体外建立的模拟人体生理或病理状态的小型组织或器官，是将细胞培养组装成为具有功能的、与器官结构功能类似的三维组织结构器官模型，通过简单的设计兼有传统人类细胞培养和器官培养系统的高生物保真度水平，来实现预测器官水平反应的功能组织单位。

复合器官芯片的整合：细胞和器官通过分泌可溶性因子、胞质信号分子，来介导与外周循环系统之间的可溶性物质交换。不同的器官芯片个体之间通过模仿体内血液灌注的微流体相互连接，并建立动态平衡。这些连接激活重点器官之间的物质、信息交换，创造出更贴近真实药物传输和摄入情况的方法。

背景：器官芯片是指在体外建立的模拟人体生理或病理状态的小型组织或器官。

目的：综述单器官芯片和复合器官芯片的设计理念，讨论其在药物发展和精准医疗中的潜力、应用前景，以及目前尚未解决的问题。

方法：通过计算机检索在PubMed数据库、CNKI中国期刊全文数据库收录的相关文献。英文检索词为“Organs-on-a-chip, drug development, cell culture, Organoids, microfluidic systems, induced pluripotent stem cells, liver”，中文检索词为“器官芯片，药物研发，肝脏，微流控系统，血脑屏障，肿瘤”，最终纳入68篇文献进行归纳总结。

结果与结论：器官芯片技术集合了工程化人体组织工程、半导体制造以及不同来源的成人体细胞培养等领域的最新研究进展，突破了现有细胞和动物模型的限制，将整个器官或系统的活动、力学特性、生理反应等体现在3D微流体细胞培养芯片上。通过将人类细胞与生理相关微环境相整合，模拟体外的人类生理或病理状态，使得它们有望用于补充并减少药物、医学设备及生物材料的临床应用前的动物实验，也为筛选药物的不良反应提供有利的体外平台。

ORCID: 0000-0001-5256-6792(陈沛杉)；0000-0001-9005-5774(张海燕)

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

关键词: 器官芯片, 组织工程, 干细胞, 药物研发, 诱导多潜能干细胞, 肝实质细胞, 细胞培养, 3D培养

Abstract:

BACKGROUND: Organs-on-a-chip (OOC) is a chip that miniatures tissues or organs in vitro to simulate human physiological or pathological activities.

OBJECTIVE: To review the design considerations of single and multi-OOCs, expound its achievements, potential and application prospect in drug development and precision medicine, as well as the remaining challenges.

METHODS: We searched relevant articles in PubMed and CNKI databases with the keywords of “organs-on-a-chip, liver, blood-brain barrier, tumor” in Chinese and “organs-on-a-chip, drug development, cell culture, organoids, microfluidic systems, induced pluripotent stem cells, liver” in English, respectively. Finally, 68 articles were analyzed in this review.

RESULTS AND CONCLUSION: OOC is a breakthrough technology that benefits from progresses in engineered human tissue engineering, semiconductor fabrication and adult somatic cell culture, exceeding the limitations of current cell and animal models. The activities, mechanical properties and physiological reactions of the whole organ or human system can be embodied in the 3D microfluidic OOC. As it can simulate physiological or pathological states in vitro by integrating human cells with physiology-related microenvironments, OOCs are expected to supplement and reduce the pre-clinical trials of drugs, medical devices and biological materials, offering a favorable in vitro platform for screening drug-related adverse reactions.

Key words: organs-on-a-chip, tissue engineering, stem cells, drug development, induced pluripotent stem cells, hepatic parenchymal cells, cell culture, 3D culture

中图分类号:

陈沛杉, 张海燕. 器官芯片与工程化人体组织在药物研发中的应用前景[J]. 中国组织工程研究, 2020, 24(29): 4717-4723.

Chen Peishan, Zhang Haiyan. Organs-on-a-chip and engineered human tissues in drug development[J]. Chinese Journal of Tissue Engineering Research, 2020, 24(29): 4717-4723.

图/表（结果） 3

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引言

材料方法

讨论

通过体外模仿患者的遗传学和病理生理学特点，器官芯片可用于预测疾病、对患者特异性的健康和疾病的建模，帮助药物开发并使其更具有特异性，促进它们在系统生物学精准医疗中的应用。

自2012以来，美国一直引领着器官芯片技术的发展。通过组织芯片(2012-2014)的初步开发、集成器官芯片的进展(2014-2017)、当前器官芯片的独立验证(2016-2018)，使用组织芯片进行疾病模拟和药物功效测试的倡议正在进行。日本与欧洲国家关于3R(减少(Reduction)、替代(Replacement)、优化(Refinement))的广泛推进增强了器官芯片的技术支持^[64]。政府、工业、学术研究、实验室、商业实体和监管机构之间的合作，将加快器官芯片进入标准工业流程的速度。

药物开发是一个低效、资源高度集中的过程，且在大多数情况下，并不能开发出一种新药。由于许多药物在Ⅲ期试验或在上市后表现出严重不良反应^[7]，开发新药的平均成本常常超过10亿美元^[65]。动物模型的不可预测性使得90%的候选药物在人体试验时失败^[66]。同样的，由于药物在动物身上发生的不良反应不一定转化到人类身上，这种筛查试验可能忽略了一些有效药物。这些假阳性和假阴性读数造成了巨大的经济负担，也导致在决策一种药物潜在的盈利能力时，更看重其是否存在潜在的风险，而非药物治疗疾病的潜力。器官芯片促进药物发展的关键在于决策。应进一步开发哪些药物并进行测试，应停止开发哪些会对人体产生毒性的药物？如果一种药物最终会伤害人，更早的决定其能否进入市场可以节省更多的健康效益，金钱和时间^[35]。

在药物的临床前筛选中，器官芯片可以确认药物没有毒性(例如，通过评估心血管、肝脏或皮肤毒性)，预估治疗的预期效果。微流控多器官器官芯片脉管系统适用于非靶点的临床前毒性测定。可以重新设计早期识别脱靶效应的药物，以降低患者的风险和开发成本。

器官芯片可以加快药物进入临床试验阶段的进程。器官芯片有潜力为目前被排除在临床试验之外的特殊群体患者提供“临床阶段试验-芯片”，帮助其寻找治疗靶点。器官芯片可用于早期确定疗效，且对患者没有风险。使用患者特异性细胞能对不同亚群的患者进行建模，尽早识别药物副作用或药物之间的交互作用。患者专用器官芯片也可用于了解临床试验上观察到的阴性结果，进一步确定是否存在患者特异性药物敏感性不明或考虑到患者的特异性重新定向设计临床试验。

药物西沙必利进入人体释放入血后突发的致死作用可表明应用器官芯片的重要性。后续研究发现，约56%出现不良反应的患者同时服用了抑制肝脏内细胞色素P450 3A4酶的药物，从而影响了西沙必利代谢，导致患者血清中西沙比利浓度的增加^[67]。受影响的患者群体则有潜在的心脏病或心律失常史，这使他们更容易发生西沙必利引起的原发性心律失常^[11]。如果使用患者的生理性特异细胞器官芯片系统能够预测或评价药物如何潜在的影响每个患者或一组患者，这种潜在的结果原本是可以避免的。同时，需要在药物上市时提供处方药的适当信息，从一开始就避免潜在的药物间相互作用与并发症。

由于器官芯片可以用来研究在多个人体器官中的靶向机制，它们能提供更真实的人体疾病模型^[68]。使用特定患者的人类诱导多能干细胞和基因编辑技术，如CRISPR-Cas(CRISPR associated- Clustered Regularly Interspaced Short Palindromic Repeats)，将可以研究基因突变对器官功能的影响，以及随后治疗方法的作用途径与效果。这些器官芯片模型能为疾病进展和药物作用机制提供新的见解。

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

器官芯片与工程化人体组织在药物研发中的应用前景

Organs-on-a-chip and engineered human tissues in drug development

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