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化学进展 2023, Vol. 35 Issue (9): 1357-1368 DOI: 10.7536/PC230116 前一篇   后一篇

• 综述 •

基于微流控芯片的体外三维肝脏生理模型的构建及应用

卢雪萍, 赵亮, 汪夏燕, 郭广生*()   

  1. 北京工业大学 环境安全与生物效应卓越中心 环境与生命学部 化学系 北京 100124
  • 收稿日期:2023-02-03 修回日期:2023-04-01 出版日期:2023-09-24 发布日期:2023-04-20
  • 基金资助:
    国家自然科学基金项目(22174007); 国家自然科学基金项目(22127805); 北京市卓越青年科学家项目(BJJWZYJH01201910005017)
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Construction and Application of 3D Microfluidic Liver-On-A-Chip

Xueping Lu, Liang Zhao, Xiayan Wang, Guangsheng Guo()   

  1. Center of Excellence for Environmental Safety and Biological Effects, Faculty of Environment and Life, Department of Chemistry, Beijing University of Technology,Beijing 100124, China
  • Received:2023-02-03 Revised:2023-04-01 Online:2023-09-24 Published:2023-04-20
  • Contact: *e-mail: gsguo@bjut.edu.cn
  • Supported by:
    The National Natural Science Foundation of China(22174007); The National Natural Science Foundation of China(22127805); The Beijing Outstanding Young Scientist Program(BJJWZYJH01201910005017)

肝脏是身体内最重要器官之一,是生化代谢和合成过程最主要的器官。因此,深入了解肝脏生理生化过程、病理机制等,对于研究、预防、诊断、治疗肝脏相关或代谢相关疾病具有重要意义。肝脏体外培养模型是研究肝脏相关生物学机制的重要实验基础。传统体外细胞培养难以重现肝脏复杂的生理结构和微环境,且缺乏肝脏组织构造的基本三维特征。更重要的是,平面培养过程中细胞的组织形态架构、基因表达、物质代谢过程等与体内相比具有较大差异。微流控技术可以通过精巧设计与布局在微通道结构中培养相应细胞来模拟肝脏的生理结构,结合三维细胞培养技术,可以在微流控芯片上实现更类似于体内肝脏微环境以及与其他组织器官相互作用的体外肝器官模型。本文总结了基于微流控技术构建体外三维肝脏芯片的方法和最新进展,包括基于多孔膜培养、水凝胶培养、细胞团簇培养及生物打印的三维肝脏模型。进一步,我们也探讨了三维培养的肝脏芯片在重塑肝脏生理结构、探究机理和病理机制以及药物筛选和毒性测试方面的应用,并对三维肝脏微流控器官芯片的潜在价值及其面临的挑战进行了展望。

关键词： 微流控芯片, 三维培养, 器官芯片, 肝脏芯片, 药物筛选

As the largest internal organ in the human body, the liver plays an essential role in the metabolism. The liver or relevant diseases are one of the leading causes of death in the world, with the number of cases surging each year. Therefore, an in-depth understanding of the physiological and biochemical processes and pathological mechanisms of the liver is of great significance for the research, prevention, diagnosis, and treatment of liver-related or metabolism-related diseases. The in vitro liver culture model is an important experimental platform for the study of liver-related biological mechanisms. However, the traditional two-dimensional in vitro cell culture model makes it difficult to reproduce the complex physiological structure and microenvironment of the liver, and lack of disease characteristics. More importantly, the cell structure, gene expression, substance metabolism, and so on in the process of planar culture are significantly different from those in vivo. Microfluidic technology can simulate the physiological structure of liver by designing appropriate micro-structure, providing a microenvironment more like that in vivo by combining with three-dimensional liver tissue culture. Therefore, this paper summarizes the methods and latest progress in constructing 3D liver chips in vitro based on microfluidic technology, including porous membrane culture, hydrogel culture, cell spheroid-based culture, and 3D bioprinting. The applications of 3D cultured liver microchips in remodeling liver physiological structure, exploring mechanism and pathological mechanism, drug screening, and toxicity testing are further summarized. Finally, the potential value and challenges of 3D liver-on-a-chip are discussed.

Contents

1 Introduction

2 Construction methods for 3D microfluidic liver-on-a-chip

2.1 Porous membrane

2.2 Cell spheroids

2.3 Gel-based 3D culture

2.4 3D bioprinting

3 Application of 3D microfluidic liver-on-a-chip

3.1 Disease models

3.2 Drug screening

4 Conclusion and prospects

Key words: microfluidic chip, 3D cell culture, organ-on-a-chip, liver-on-a-chip, drug screening
()
表1 不同体外肝脏实验模型之间优缺点的比较
Table 1 Comparison of different liver models: the advantages and limitations
in vitro
liver models		 Advantages/benefits Limitations The throughput/Similarity ref
2D hepatocytes culture (monolayer) Easy to handle; low cost; high accessibility Hard to recapitulate native liver tissue and microenvironment; different cell morphology and gene expression with native liver; loss of cell diversity High/Low
69
3D hepatocytes culture 3D cell organization enables cell-cell interactions and similar architecture of native tissue; enhanced cellular functions Incapable of controlling nutrient and oxygen gradient; inappropriate for mimicking liver sinusoid architecture High/Medium 24,25,26
31,37,43
3D liver-on-a-chip Capable of recapitulating similar hepatic structure (liver sinusoid); able to imitate liver microenvironment and chemical gradient; highly spatial and temporal controllable manner Difficult to fabricate the chip and seed the cell; high costs; require sophisticated equipment; limited testing assays Medium/High

80
3D bioprinting Feasible reconstruction of organ/tissue in vitro;providing an experimental platform that simulates the real environment and improve the efficiency of biomedical research Technical limitations; high cost; requiring the stability and sustainability of materials Medium/High 52,53,54,55
图1 几种在体外利用微流控技术构建三维肝脏生理模型的方法。(A) 基于多孔膜的方法[35];(B) 基于细胞团簇培养[42];(C) 基于凝胶胶原中的细胞培养[49];(D)基于 3D生物打印的构建方法[54]
Fig.1 Microfluidic-based approaches to construct 3D liver-on-chip in vitro. (A) using porous permeable membrane[35]; (B) applying cell spheroids[42]; (C) the gel-based 3D culture[49]; (D) the 3D-printing based construction[54]
图2 基于微流控技术的体外肝脏模型用于肝脏功能与病理机制的研究。(A) 基于微流控技术的酒精肝三维体外模型[57];(B) 基于微流控技术的非酒精性脂肪肝药物高通量筛选平台[61];(C) 基于微流控多类器官系统用于研究肝脏代谢类疾病II型糖尿病[62];(D) 基于微流控芯片研究乙型肝炎病毒感染过程[64]
Fig.2 The microfluidic-based 3D liver-on-chip for studying the hepatic diseases. (A) the microfluidic technology-based 3D liver-on-chip for simulating alcoholic liver disease (ALD)[57]; (B) the microfluidic technology-based high-throughput screening platform for emulating nonalcoholic fatty liver disease (NAFLD)[61]; (C) the microfluidic multi-organoid system for recapitulating type II diabetes mellitus (T2DM)[62]; (D) the liver-on-chip platform for studying the hepatitis B virus (HBV) infection process[64]
图3 基于微流控技术的体外肝脏器官芯片模型用于药物代谢与筛选以及安全性评估研究。(A)基于二维培养原代肝细胞、诱导分化的心肌细胞以及不同肿瘤细胞共同构成的多器官芯片用于药物研究[69];(B) 基于集成多孔膜方法的三维肝脏器官芯片用于测试药物对于不同物种(人、鼠、狗)细胞的毒性[70];(C) 集成有微电极的高通量数字化微流控芯片装置用于肝脏器官芯片的研究[72];(D) 利用阵列微孔设计的集成高通量肝脏-肿瘤器官芯片用于多种前体药物活性和效用的研究[77];(E) 集成化器官芯片用于原代肝细胞、诱导分化的心肌细胞的药物生物效应的研究。芯片上集成有包括电化学传感器在内的多种生物传感器[80]
Fig.3 3D liver-on-chip system for drug metabolism and efficacy screening. (A) a multi-organ chip system for studying drug efficacy and safety. Different cells including primary hepatocytes, iPSC derived cardiomyocytes, and tumor cells can be cultured on a single chip[69]; (B) the porous membrane was used to construct 3D liver-on-chip for testing drug toxicities to different species (human, rat, dog)[70]; (C) a high throughput digital microfluidic device for study of liver-on-chip[72]; (D) an integrated high throughput biomimetic system for studying liver and tumor interaction. The device was designed with array microwells for testing prodrug activity and efficacy[77]; (E) multisensor-integrated organs-on-chips for studying the drug induced biological effects in primary hepatocytes and induced differentiation of cardiomyocytes. The chip integrated various microbioreactors including electrochemical biosensors[80]
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