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Real-time imaging of microparticles and living cells with CMOS nanocapacitor arrays

Abstract

Platforms that offer massively parallel, label-free biosensing can, in principle, be created by combining all-electrical detection with low-cost integrated circuits. Examples include field-effect transistor arrays, which are used for mapping neuronal signals1,2 and sequencing DNA3,4. Despite these successes, however, bioelectronics has so far failed to deliver a broadly applicable biosensing platform. This is due, in part, to the fact that d.c. or low-frequency signals cannot be used to probe beyond the electrical double layer formed by screening salt ions5,6,7,8, which means that under physiological conditions the sensing of a target analyte located even a short distance from the sensor (1 nm) is severely hampered. Here, we show that high-frequency impedance spectroscopy can be used to detect and image microparticles and living cells under physiological salt conditions. Our assay employs a large-scale, high-density array of nanoelectrodes integrated with CMOS electronics on a single chip and the sensor response depends on the electrical properties of the analyte, allowing impedance-based fingerprinting. With our platform, we image the dynamic attachment and micromotion of BEAS, THP1 and MCF7 cancer cell lines in real time at submicrometre resolution in growth medium, demonstrating the potential of the platform for label/tracer-free high-throughput screening of anti-tumour drug candidates.

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Figure 1: Detection principle.
Figure 2: Insensitivity to ionic strength.
Figure 3: Sensitivity to particle electrical properties.
Figure 4: Probing living cells.

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Acknowledgements

C.L. and S.G.L. acknowledge financial support from the European Research Council. F.P. and L.S. acknowledge financial support from the EU NANOFUNCTION project (FP7-ICT, no. 257375) and the MIUR Cooperlink project. M.A.J., H.V. and F.P.W. acknowledge financial support from NanoNextNL, a micro- and nanotechnology consortium of the Government of the Netherlands and 130 partners. F.P.W. thanks E. Sterckx, K. Verheyden, D. van Steenwinckel and R. Hendricksen for technical support.

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C.L., S.G.L. and F.P.W. designed the microparticle experiments and C.L. performed them. F.P., L.S. and F.P.W. developed the numerical simulation code and F.P. executed the simulations. H.V., M.A.J. and F.P.W. designed the experiments on living cells and H.V. performed them. C.L. processed the experimental data and simulation results for the manuscript. All authors contributed to the interpretation of the results and assisted in writing the manuscript.

Corresponding author

Correspondence to F. P. Widdershoven.

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Competing interests

F.P.W declares the following financial interest. He is the (co-)inventor of multiple patents on which the CMOS nanocapacitor platform is based and is employed by NXP, where it was developed. The other authors declare no competing interests.

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Laborde, C., Pittino, F., Verhoeven, H. et al. Real-time imaging of microparticles and living cells with CMOS nanocapacitor arrays. Nature Nanotech 10, 791–795 (2015). https://doi.org/10.1038/nnano.2015.163

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