Thermomicrofluidic Biosensing Systems※

doi:10.6023/A21120610

Acta Chimica Sinica ›› 2022, Vol. 80 ›› Issue (5): 679-689.DOI: 10.6023/A21120610 Previous Articles Next Articles

Special Issue: 中国科学院青年创新促进会合辑

Review

基于微流控热泳的生物传感技术^※

刘超^a, 田飞^a, 邓瑾琦^a, 孙佳姝^a^,^b^,^*()

a 国家纳米科学中心北京市纳米生物医学检测工程技术研究中心北京 100190
b 中国科学院大学北京 100049

投稿日期:2021-12-31 发布日期:2022-05-31
通讯作者: 孙佳姝

作者简介:

刘超, 国家纳米科学中心研究员. 2010年6月于河北工业大学获得工学学士学位, 2016年1月于中国科学院大学获得理学博士学位, 2016年加入国家纳米科学中心. 主要研究方向为微流控分离分析与肿瘤液体活检.

田飞, 国家纳米科学中心特别研究助理. 于2011年6月获得河北工业大学工学学士学位, 于2019年6月获得河北工业大学工学博士学位. 主要研究方向为基于微流控技术的循环肿瘤靶标分离分析与病原体检测.

邓瑾琦, 国家纳米科学中心任特别研究助理. 于2016年6月在武汉大学化学与分子科学学院取得理学学士学位, 于2021年6月在中国科学院大学中丹学院取得理学博士学位, 专业为纳米科学与技术. 研究方向为基于微流控技术的生化分析.

孙佳姝, 国家纳米科学中心研究员, 国家杰出青年科学基金 (2020年)和国家优秀青年科学基金获得者(2016年). 主要研究方向为微流控分离分析技术与纳米生物医学研究. 提出了微流控热泳测量的新理念, 实现循环肿瘤标志物的高灵敏定量检测. 已发表SCI收录论文90余篇, 引用5,600余次, 并多次被Nature子刊等作为研究亮点报道. 有10余项微流控相关发明专利授权.

^※庆祝中国科学院青年创新促进会十年华诞.

基金资助:
国家重点研发计划(2020YFA0210800); 国家重点研发计划(2021YFA0909400); 国家自然科学基金(22025402); 国家自然科学基金(91959101); 国家自然科学基金(21904028); 国家自然科学基金(22104026); 国家自然科学基金(22174030); 中国科学院战略性先导科技专项(XDA16021200)

Thermomicrofluidic Biosensing Systems^※

Chao Liu^a, Fei Tian^a, Jinqi Deng^a, Jiashu Sun^a^,^b()

a Beijing Engineering Research Center for BioNanotechnology, National Center for Nanoscience and Technology, Beijing 100190
b University of Chinese Academy of Sciences, Beijing 100049

Received:2021-12-31 Published:2022-05-31
Contact: Jiashu Sun
About author:
^※ Dedicated to the 10th anniversary of the Youth Innovation Promotion Association, CAS.
Supported by:
National Key R&D Program of China(2020YFA0210800); National Key R&D Program of China(2021YFA0909400); National Natural Science Foundation of China(22025402); National Natural Science Foundation of China(91959101); National Natural Science Foundation of China(21904028); National Natural Science Foundation of China(22104026); National Natural Science Foundation of China(22174030); Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16021200)

The sensitive and specific detection of key molecules and biological micro/nanoparticles in complex biological systems is of great significance for understanding biological processes at multiple levels and scales, uncovering the mechanisms of disease onset and development, and exploring novel biomarkers. Microfluidic biosensors with advantages of microfluidics and biosensing have made significant progress in the precise detection of biological samples with small volumes. Recent years, thermomicrofluidic biosensing that combines thermophoretic migration in a temperature gradient and homogenous signal amplification strategies has realized rapid, sensitive, in situ detection of biomolecules and biological micro/ nanoparticles in complex biological systems. Different thermomicrofluidic biosensing strategies, including microscale thermophoresis (MST), thermophoresis-convection coupling, thermophoresis-diffusiophoresis coupling, and thermophoresis-electrophoresis coupling were presented. The fundamentals, features, and applications of these strategies in detecting biomolecules (protein, nucleic acids, etc.) and biological micro/nanoparticles (extracellular vesicles, viral particles, cells, etc.) were summarized. The challenge and future directions for the application of thermomicrofluidic sensing in biomedical detection were discussed.

Key words: thermophoresis, microfluidic, multi-physics coupling, biosensing

Cite this article

Chao Liu, Fei Tian, Jinqi Deng, Jiashu Sun. Thermomicrofluidic Biosensing Systems^※[J]. Acta Chimica Sinica, 2022, 80(5): 679-689.

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Fig. & Tab. 13

加热方式	激光波长/nm	功率密度/(mW•μm^–2)	温度梯度/(K•μm^–1)	检测温度/℃	应用	文献
水体加热	1480	—	≈0.1	<35	生物分子、EV蛋白检测	[37⇓⇓⇓-41]
水体加热	1480	≈0.01	0.3~1	28~42	EV蛋白/核酸、病毒抗原检测	[50,53 -54,56 -57,63]
Cr基底加热	1064	—	≈0.1	33	DNA检测	[64]
Cr基底加热	808	≈0.01	≈1.8	≈30	淀粉样纤维生长动力学研究	[44]
Au基底加热	532	<0.1	≈0.6	25	原位SERS	[69]
Au基底加热	532	≈0.02	5~30	33	单颗粒操控与暗场光学表征	[70]
Au基底加热	532	0.06	3.5~8.5	27	单细胞操控	[71]

Table 1. Methods of generating temperature gradient in thermomicrofluidic biosensing systems

Figure 1. Thermomicrofluidics for biosensing Figure partially created using BioRender

Figure 2. Working principle of microscale thermophoresis (MST) The quantitative detection of targets relies on the monitoring of thermophoresis-induced fluorescence distribution at the laser heating region

颗粒分子	尺寸	溶液环境	Soret系数/K^–1	文献
聚苯乙烯颗粒 (羧基修饰)	200 nm	1 mmol•L^–1 Tris	0.7	[28]
聚苯乙烯颗粒 (羧基修饰)	92 nm	水	0.23	[29]
聚苯乙烯颗粒	100 nm	10 mmol•L^–1 Tris	0.35	[60]
聚苯乙烯颗粒	100 nm	10 mmol•L^–1 Tris+PEG 6K (w=5%)	–1.5	[60]
SDS胶束	5 nm	10 mmol•L^–1 NaCl	0.024 (25 ℃)	[51]
CTAC胶束	—	水	≈0.1	[32]
HepG2 EVs	≈100 nm	PBS	0.03	[69]
Aβ40 fibril	≈2 μm	6 mmol•L^–1 NaCl (pH=8.4)	≈2.6	[44]
溶菌酶	14 kDa	100 mmol•L^–1 NaCl (pH=4.65)	0.0013 (27 ℃)	[30]
DNA (SYBR Green I 标记)	5.6 kbp	10 mmol•L^–1 Tris (pH=7.8)	0.14 (24 ℃)	[24]
λ-DNA (SYBR Green I 标记)	48.5 kbp	10 mmol•L^–1 Tris (pH=7.8)	0.4	[31]
PEG	6 kDa	10 mmol•L^–1 Tris	0.046	[60]

Table 2. Soret coefficient for common molecules and particles

Figure 3. Microscale thermophoresis (MST)-based biosensing (a) MST-detection of serum Ro antibody for the diagnosis of systemic lupus erythematosus. Reprinted with permission from Ref. [38]. Copyright © 2020 Elsevier. (b) MST for real-time detection of inorganic phosphate (Pi) during ATP turnover by myosin. Reprinted with permission from Ref. [39]. Copyright © 2020 Elsevier. (c) MST for simultaneous measurement of binding affinity and kinetics. Reprinted with permission from Ref. [40]. Copyright © 2021 Wiley-VCH GmbH.

Figure 4. Mechanism of biosensing based on thermophoresis-convection coupling The thermophobic thermophoresis and toroid natural convection induced by the localized temperature gradient result in rapid accumulation of biomolecules and bioparticles at the cold bottom region

Figure 5. Detection of proteins of extracellular vesicles (EVs) by thermophoresis-convection coupling (a) Thermophoretic aptasensor (TAS) for profiling surface proteins on tumor EVs in EV-based liquid biopsy. Reprinted with permission from Ref. [51,53]. Copyright © 2019 Nature Publishing Group and © 2021 Nature Publishing Group. (b) Thermophoresis-mediated DNA computation for the detection of multiple protein markers on single EVs. Reprinted with permission from Ref. [54]. Copyright © 2021 American Chemical Society.

Figure 6. Detection of EV RNAs by the coupling of thermophoresis-convection coupling (a) Thermophoretic sensor implemented with nanoflares (TSN) for in situ detection of EV miRNAs and detection of estrogen receptor-positive (ER+) breast cancer. Reprinted with permission from Ref. [56]. Copyright © 2020 American Chemical Society. (b) Thermophoretic sensor implemented with FRET-based DNA tetrahedron (DTTA) for in situ, sensitive detection of EV mRNA and precise diagnosis of prostate cancer. Reprinted with permission from Ref. [57]. Copyright © 2021 Elsevier.

Figure 7. Mechanism of biosensing based on thermophoresis-diffusiophoresis coupling Localized temperature gradient induces a solute concentration gradient, and the resulting diffusiophoresis drives particles toward the hot region.

Figure 8. Biosensing mediated by the thermophoresis-diffusiophoresis coupling (a) One-step PEG-enhanced thermophoretic assay for detection of SARS-CoV-2 viral particles. Reprinted with permission from Ref. [63]. Copyright © 2021 American Chemical Society. (b) PEG-enhanced thermophoretic detection of target DNA by the size-dependent accumulation of sandwiched hybrid of target DNA, DNA-modified AuNP, and FITC-labeled DNA. Reprinted with permission from Ref. [64]. Copyright © 2015 American Chemical Society.

Figure 9. Mechanism of biosensing based on thermophoresis-electrophoresis coupling Localized temperature gradient can induce a thermoelectric field upon the differentiated thermophoretic mobility of positive and negative charge, subsequently resulting in electrophoresis of analyte for manipulation and sensing.

Figure 10. Sensing and bioparticle manipulation based on thermophoresis-electrophoresis coupling (a) Thermophoretic tweezer for plasmonic nanoparticle assembly and in situ surface-enhanced Raman scattering (SERS). Reprinted with permission from Ref. [69]. Copyright © 2016 American Chemical Society. (b) Thermophoretic tweezer for real-time and programmable manipulation of cells and lipid vesicles. Reprinted with permission from Ref. [71,72]. Copyright © 2017 American Chemical Society and Copyright © 2018 American Chemical Society.

传感原理	优势	局限性	适用靶标与应用场景	主要设计因素	文献
微量热泳技术	应用靶标范围广	灵敏度较低、方法单一	蛋白、核酸、生物小分子、 EV测量	探针类型、基团修饰、缓冲液性质	[37⇓⇓⇓-41]
热泳-对流耦合	灵敏度高、无需复杂前处理	依赖靶标自身热泳性质	EV蛋白/核酸检测	靶标与探针尺寸差别、芯片高度、导热性质	[50,53 -54,56 -57]
热泳-扩散泳耦合	不依赖靶标自身热泳性质、检测速度快	汇聚范围小、灵敏度较低	病毒颗粒、DNA检测	靶标与探针尺寸差别、 PEG浓度、分子量	[63-64]
热泳-电泳耦合	单颗粒操控、空间分辨率高	芯片成本高、激光光路设计复杂	单细胞、单纳米颗粒操控	颗粒自身电学性质、电解质种类	[69⇓⇓-72]

Table 3. Summary of different thermomicrofluidic biosensing strategies

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基于微流控热泳的生物传感技术^※

Thermomicrofluidic Biosensing Systems^※

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基于微流控热泳的生物传感技术※

Thermomicrofluidic Biosensing Systems※

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Knowledge

Abstract

Cite this article

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Fig. & Tab. 13

References 72

Related Articles 13

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基于微流控热泳的生物传感技术^※

Thermomicrofluidic Biosensing Systems^※