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化学进展 2021, Vol. 33 Issue (7): 1138-1151 DOI: 10.7536/PC200717 前一篇   后一篇

• 综述 •

浓度梯度微流控芯片在药物筛选中的应用

张芳娟, 刘海兵, 高梦琪, 王德富, 牛颜冰, 申少斐*()   

  1. 山西农业大学生命科学学院 晋中 030801
  • 收稿日期:2020-07-09 修回日期:2020-10-13 出版日期:2021-07-20 发布日期:2020-12-28
  • 通讯作者: 申少斐
  • 基金资助:
    国家自然科学基金项目(31700749); 山西省高等学校科技创新计划(2019L0362); 山西农业大学科技创新基金(2016YJ02)
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Concentration-Gradient Microfluidic Chips for Drug Screening

Fangjuan Zhang, Haibing Liu, Mengqi Gao, Defu Wang, Yanbing Niu, Shaofei Shen*()   

  1. College of Life Sciences,Shanxi Agricultural University, Jinzhong 030801, China
  • Received:2020-07-09 Revised:2020-10-13 Online:2021-07-20 Published:2020-12-28
  • Contact: Shaofei Shen
  • About author:
    * Corresponding author e-mail:
  • Supported by:
    National Natural Science Foundation of China(31700749); Scientific and Technological Innovation Programs of Higher Education Institutions in Shanxi(2019L0362); Science and Technology Innovation Funds of Shanxi Agricultural University(2016YJ02)

微流控芯片技术作为21世纪极具代表性的微型分析平台技术之一,以其试剂消耗低、分析微型化、可集成化、易于控制、自动化和良好的生物相容性等优点而成为研究热点,在生物、医学、食品和环境等多个领域都有杰出表现,尤其是药物筛选领域。其中备受关注的浓度梯度微流控芯片更是取得了显著成果。本文综述了近年来用于药物筛选的浓度梯度纸基芯片、浓度梯度水凝胶芯片、浓度梯度液滴芯片、浓度梯度聚二甲基硅氧烷(PDMS)芯片的研究进展;同时对浓度梯度微流控芯片在单细胞分析、组合药物筛选、三维(3D)细胞培养和细胞微环境模拟等方面的应用及优缺点进行了阐述,并在此基础上对其发展前景进行了展望。

关键词： 微流控芯片, 浓度梯度, 药物筛选

Microfluidic chip is one of the most representative technologies of micro-analysis platform in this century. It has many advantages such as low reagent consumption, analytical miniaturization, easy control and integration, high automation and good biological compatibility. It has outstanding performances in many fields such as biology, medicine, food and environment, especially in the field of drug screening which has achieved a series of achievements with its own advantages. This article summarizes the research progress of concentration gradient microfluidic chips for drug screening in recent years, including paper chip, hydrogel chip, droplet chip and polydimethylsiloxane (PDMS) chip. Furthermore, the advantages and disadvantages of concentration gradient microfluidic chip in single cell analysis, combination drug screening, three-dimensional (3D) cell culture, cell microenvironment simulation are described. Finally, we provide a perspective for its application prospects.

Contents

1 Introduction

2 Characteristics of concentration-gradient microfluidic chip

3 Type of concentration-gradient microfluidic chip

3.1 Paper chip

3.2 Hydrogel chip

3.3 Droplet chip

3.4 PDMS chip

4 Application of concentration-gradient microfluidic chip

4.1 Single cell analysis

4.2 Combination drug screening

4.3 3D cell cultures

4.4 Simulated cell microenvironment

5 Conclusion and outlook

Key words: microfluidic chip, concentration gradient, drug screening
()
图1 纸基微流控纸芯片:(A) 3D打印纸基微流控芯片集成平台[25];(B) 用于药物筛选的纸基多通道微流控芯片[26]
Fig. 1 Microfluidic paper chip. (A) The hybrid 3D-printed and paper-based microfluidic platform[25]; (B) A paper-based multichannel microfluidic chip for drug screening[26]
图2 水凝胶微流控芯片:(a) 水凝胶二维表面梯度和三维表面梯度示意图[34];(b) 基于对流扩散的梯度药物形成微流控系统[37];(c) 多浓度梯度水凝胶装置[38];(d) 具有多梯度生化浓度和水凝胶屏障的微流控平台[39]
Fig. 2 Hydrogel microfluidic chip: (a) Schematic diagram of 2D and 3D surface gradients of hydrogel[34]; (b) Convection-diffusion based gradient drug fluid generating microfluidic system[37]; (c) Multi-concentration gradient hydrogel device[38]; (d) Microfluidic platform with multi-gradient biochemical concentration and hydrogel barrier[39]
图3 液滴微流控芯片:(a) 液滴微反应器示意图[42];(b) 产生移动液滴阵列的微流控装置示意图[44];(c) 具有浓度梯度的液滴阵列芯片示意图[45]
Fig. 3 Droplet microfluidic chip. (a) Droplets microreactor formed by microfluidic channels[42]; (b) Schematic diagram of a microfluidic device for generating an array of moving droplets[44]; (c) Schematic diagram of droplet array chip with concentration gradient[45]
图4 PDMS微流控芯片:(a) 双重浓度梯度PDMS芯片构建示意图[16];(b) 自动化细胞培养PDMS芯片平台[51];(c) 用于研究环境污染物引起的支气管上皮损伤的浓度梯度PDMS芯片平台[52]
Fig. 4 PPDMS microfluidic chip. (a) Schematic diagram of PDMS chip of double concentration gradient construction[16]; (b) PDMS chip platform of automated cell culture[51]; (c) A PDMS chip platform for the study of bronchial epithelial injury caused by environmental pollutants[52]
图5 用于单细胞分析的微流控平台:(a) 用于单细胞跟踪和克隆的微流体平台[58];(b) 用于单细胞研究的多浓度梯度微流体装置[59];(c) 用于实时监测分析单细胞反应的微流控平台[60];(d) 包含单细胞捕获阵列的微流控梯度装置[61];(e) 用于单个CTCs表型相关药物敏感性分析的DS芯片[62]
Fig. 5 Microfluidic platform for single cell analysis. (a) Microfluidic array platform for single cell tracking and cloning[58]; (b) Multi-concentration gradient microfluidic device for single cell research[59]; (c) Microfluidic platform for real-time monitoring and analysis of single cell reaction[60]; (d) Microfluidic gradient device containing single cell capture array[61]; (e) Schematics showing the workflow for phenotype-related drug sensitivity analysis of single CTCs using the DS-Chip[62]
图6 组合药物筛选:(a) 单药治疗和组合治疗比较[70];(b) 用于产生不同药物组合的微流控阵列示意图[71];(c)组合抗生素测试的微流控平台[72];(d) 用于三重浓度梯度产生的微流控装置示意图[15]
Fig. 6 Combination drug Screening. (a) Comparison between monotherapy and combination therapy[70]; (b) Schematic diagram of a microfluidic array for generating different drug combinations[71]; (c) Microfluidic platform of combined antibiotic testing[72]; (d) Schematic diagram of microfluidic device for generating triple concentration gradient[15]
图7 3D细胞培养:(a) 细胞在二维和三维基底上的生长情况[74];(b) 3D芯片用于同时给药多种药物浓度[75];(c) 进行球体培养的液滴微流控平台[76]
Fig. 7 3D cell culture. (a) Graphical representation of a growing cell on a 2D and 3D substrate[74]; (b) The 3D chip is used for simultaneous delivery of multiple drug concentrations[75]; (c) Droplet-microfluidic platform for the culture of spheroids[76]
图8 模拟细胞微环境:(a) 微流控芯片模拟肿瘤微环境[81];(b) 用于药物筛选研究的仿生体外肿瘤微组织的微流控模型[83];(c) 用于细胞捕获和肿瘤球形成的微肿瘤模型[84]
Fig. 8 Simulated cell microenvironment. (a) The microfluidic chip simulates the tumor microenvironment[81]; (b) Microfluidic model of bionic tumor micro-tissue in vitro for drug screening research[83]; (c) Microtumor model for cell capture and sphere formation[84]
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