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Bioanalysis in single cells: current advances and challenges

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  • ReceivedJan 17, 2020
  • AcceptedMar 16, 2020
  • PublishedApr 14, 2020

Abstract

Cells, basic units of living structures and functions, build up a complicated small world, and their order and complexity resemble a small universe. The detailed understanding and elucidation of the matter transport and energy conversion mechanisms within a single cell will expand our knowledge about the origin and evolution of life, the disease mechanisms and much more. In past decades, single-cell analysis has been rapidly and significantly improved and various methodologies have been developed to reveal the complexity of mass, energy, and information within single cells. In this review, we focused on the methods developed in recent years for single-cell analysis, including electrochemical method, optical method, and mass spectrometry method. We reviewed the recent advances and representative studies in this research field, and also discussed the strengths and limitations of each method. Finally, we presented the existing technical challenges and further directions for single-cell analysis.


Funded by

the National Natural Science Foundation of China(21327902)

the Excellent Research Program of Nanjing University(ZYJH004)


Acknowledgment

This work was supported by the National Natural Science Foundation of China (21327902) and the Excellent Research Program of Nanjing University (ZYJH004). Bin Kang and Dechen Jiang organized the initial draft, and Yuling Wang, Pei Song, Lei Xing, Zhaoshuai Gao, Jun Hu, Xiaohong Wang, He Gao contributed to summarize each subsection.


Interest statement

The author declares no conflict of interest.


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  • Figure 1

    (a) Schematic representation of a hollow Pt nanoelectrode for the detection of the glucosidase activity in isolated single lysosomes from a single cell, adapted with permission from Ref. [42], copyright by National Academy of Sciences (2018); (b) schematic representation of the 30 nm nanopipette functioned with G-quadruplex DNAzyme to detect the subcellular ROS generation, adapted with permission from Ref. [43], copyright by Wiley (2018) (color online).

  • Figure 2

    (a) Schematic representation of the surface-confined ECL-based microscopy with a Ru(II)-labeled ECL probe for the imaging of cellular antigens [49], copyright by American Chemical Society (2018). (b) Luminol as ECL probe for measuring small molecules in single cells [34], copyright by American Chemical Society (2015). (c) Cell-sized microwells electrode for the rapid measurement of intracellular glucose in single cells [50], copyright by American Chemical Society (2016). (d) ECL-based capacitance microscopy for visualizing antigens on plasma membranes [52], copyright by American Chemical Society (2019) (color online).

  • Figure 3

    Visualization of the cell structure by an SRM image. (a) Actin distribution captured by live cell STED in neurons at different developmental stages, adapted with permission from Ref. [71], copyright by Elsevier (2015). (b) All synaptonemal complexes in a spermatocyte at uniform resolution, adapted with permission from Ref. [72], copyright by Elsevier (2016). (c) Graphene protected cell retain cell fluorescence. Scale bars: 50 μm, adapted with permission from Ref. [77], copyright by Elsevier (2015) (color online).

  • Figure 4

    pH probes used to map the intracellular H+ concentration in a single cell. (a) Two types of fluorescent pH probes were fabricated to evaluate the variation of the intra- and extracellular H+ concentration in biological processes, adapted with permission from Ref. [94], copyright by American Chemical Society (2018). (b) Aminofluorescein and ethidium bromide embedded in mesoporous SiNPs were synthesized as fluorescent pH probes with stable ratio to measure the H+ concentration in cellular lysosomes and mitochondria, adapted with permission from Ref. [100], copyright by American Chemical Society (2016). (c) A novel pH probe was developed to monitor the change in the H+ concentration in lysosomes during cellular autophagy and apoptosis by SERS imaging, adapted with permission from Ref. [105], copyright by American Chemical Society (2019) (color online).

  • Figure 5

    Mapped intracellular viscosity by rotor molecular viscosity probes. (a) Three typical basic structures of molecular rotors, adapted with permission from Ref. [135], copyright by American Chemical Society (2009). (b) Structures of RY3 and related compounds. (c) Fluorescence ratio image and FLIM of RY3 revealing the viscosity values in MCF-7 cells, adapted with permission from Ref. [134], copyright by American Chemical Society (2011) (color online).

  • Figure 6

    Principle of AFM force spectrum and its application to a “push-pull” experiment. The AFM cantilever close to the surface was used to apply local forces to quantify the force transduction or measure the cell mechanics, adapted with permission from Ref. [158], copyright by the Royal Society of Chemistry (2013) (color online).

  • Figure 7

    (a) Schematic representation of an ESI-IMS-MS platform for single-cell micro-sampling, ESI, and ion separation by IMS, adapted with permission from Ref. [178], copyright by American Chemical Society (2015). (b) Schematic representation of the experimental setup of label-free mass cytometry (CyESI-MS) for high-throughput single-cell MS, adapted with permission from Ref. [185], copyright by American Chemical Society (2019) (color online).

  • Figure 8

    (a) Schematic representation of the combination of microscopy-guided MALDI-MS analysis and ICC analysis, adapted with permission from Ref. [192], copyright by Wiley (2019); (b) LDI-MS using NAPA for the metabolic analysis of single baker’s yeast cells, adapted with permission from Ref. [194], copyright by Wiley (2013); (c) LDI-MS-based signal amplification assay for low-abundance biomarkers, adapted with permission from Ref. [195], copyright by Wiley (2018) (color online).

  • Figure 9

    (a) Micrograph of an aggregate of human buccal mucosa cells. (b) Distribution of an IB-1 protein fragment bound to groups of aggregated cells, adapted with permission from Ref. [203], copyright by American Chemical Society (1997).

  • Figure 10

    (a) SIMS images of the amiodarone-doped macrophages at various depths, adapted with permission from Ref. [219], copyright by American Chemical Society (2015). (b) NanoDESI imaging of a papillary human renal cell carcinoma tissue (4.5 mm×2.5 mm), adapted with permission from Ref. [221], copyright by American Chemical Society (2017). (c) VUVDI-MSI of a single HeLa cell, adapted with permission from Ref. [222], copyright by American Chemical Society (2018) (color online).

  • Table 1   Spatial and temporal resolutions of the typical electrochemical approaches for single-cell analysis

    Electrochemical strategy

    Spatial resolutions

    Temporal resolutions

    Nanoelectrode

    5 nm[27]

    10 µs [28]

    Electrode array

    20 nm[29]

    10 µs [29]

    SECM

    32 nm[30]

    Low

    SICM

    3 nm[31]

    Low

    SPR-EM

    200 nm[32]

    2.6 ms[32]

    ECL-M

    0.8 µm[33]

    5 sec [34]

  • Table 2   Representative methods for cellular force measurements

    Force sensitivity

    Temporal resolution

    Spatial resolution

    Throughput

    Ref.

    Traction force microscopy

    nN

    ms-sec

    ~1 μm

    high

    [151]

    Micropillar

    pN

    sec

    ~1 μm

    high

    [155]

    Single molecule methods

    pN

    ms

    N/A

    low

    [157159]

    Molecular tension probes

    pN

    ms

    ~20 μm

    high

    [160,161]

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