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Mechanical and Microwave Resonators for Sensing and Sizing Single Cells

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Handbook of Single Cell Technologies

Abstract

Repeated size measurements on a single cell can provide critical information about its physiological state. The growth and decay rates of cellular size can be used to assess viability and drug susceptibility in a rapid manner. Although optical microscopy provides size information of single cells, its precision and throughput are not yet sufficient for personalized medicine approaches. Moreover, optical microscopy and Coulter counters provide area and volume information, which do not necessarily reflect how much material has been internalized by the cell. Rather, the mass, or alternatively total dielectric polarization, of the cell can be used to assess total material accumulation. There are emerging technologies based on resonant sensors for obtaining cell size with high sensitivity and throughput. There are two classes of such sensors based on mechanical and microwave resonators, both of which can be integrated with microfluidics delivery systems. Mechanical sensors, in the form of suspended microchannel resonators, measure the buoyant mass of a cell compared to the medium. While suspended microchannel resonators are efficient for measuring suspended cells, adherent cells can be measured, albeit with less resolution, by microelectromechanical systems working inside liquid. On the other hand, microwave sensors measure the polarizability and dielectric constant difference of cells compared to the medium. In this chapter, we first explain the fundamental principles for these sensor technologies and then survey recent biomedical results obtained with these sensors.

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References

  • Afshar S, Salimi E, Braasch K, Butler M, Thomson DJ, Bridges GE (2016) Multi-frequency DEP cytometer employing a microwave sensor for dielectric analysis of single cells. IEEE Trans Microwave Theory Tech 64(3):991–998

    Google Scholar 

  • Barber T, Huang L, Schmidt M, Toner M, Kapur R (2006) Devices and methods for magnetic enrichment of cells and other particles. Google Patents

    Google Scholar 

  • Boal D, Boal DH (2012) Mechanics of the cell. Cambridge University Press, Cambridge

    Book  MATH  Google Scholar 

  • Bryan AK, Goranov A, Amon A, Manalis SR (2010) Measurement of mass, density, and volume during the cell cycle of yeast. Proc Natl Acad Sci 107(3):999–1004

    Article  Google Scholar 

  • Burg TP, Manalis SR (2003) Suspended microchannel resonators for biomolecular detection. Appl Phys Lett 83(13):2698–2700

    Article  Google Scholar 

  • Burg TP, Godin M, Knudsen SM, Shen W, Carlson G, Foster JS, Babcock K, Manalis SR (2007) Weighing of biomolecules, single cells and single nanoparticles in fluid. Nature 446(7139):1066

    Article  Google Scholar 

  • Byun S, Son S, Amodei D, Cermak N, Shaw J, Kang JH, Hecht VC, Winslow MM, Jacks T, Mallick P (2013) Characterizing deformability and surface friction of cancer cells. Proc Natl Acad Sci 110(19):7580–7585

    Article  Google Scholar 

  • Cermak N, Olcum S, Delgado FF, Wasserman SC, Payer KR, Murakami MA, Knudsen SM, Kimmerling RJ, Stevens MM, Kikuchi Y (2016) High-throughput measurement of single-cell growth rates using serial microfluidic mass sensor arrays. Nat Biotechnol 34(10):1052

    Article  Google Scholar 

  • Cetin AE, Stevens MM, Calistri NL, Fulciniti M, Olcum S, Kimmerling RJ, Munshi NC, Manalis SR (2017) Determining therapeutic susceptibility in multiple myeloma by single-cell mass accumulation. Nat Commun 8(1):1613

    Article  Google Scholar 

  • Chaste J, Eichler A, Moser J, Ceballos G, Rurali R, Bachtold A (2012) A nanomechanical mass sensor with yoctogram resolution. Nat Nanotechnol 7(5):301

    Article  Google Scholar 

  • Chen T, Dubuc D, Poupot M, Fournie J-J, Grenier K (2012) Accurate nanoliter liquid characterization up to 40 GHz for biomedical applications: toward noninvasive living cells monitoring. IEEE Trans Microwave Theory Tech 60(12):4171–4177

    Article  Google Scholar 

  • Chen T, Artis F, Dubuc D, Fournie J, Poupot M, Grenier K (2013) Microwave biosensor dedicated to the dielectric spectroscopy of a single alive biological cell in its culture medium. In: 2013 IEEE MTT-S international microwave symposium digest (MTT). IEEE, Seattle, pp 1–4

    Google Scholar 

  • Chien J-C, Ameri A, Yeh E-C, Killilea AN, Anwar M, Niknejad AM (2018) A high-throughput flow cytometry-on-a-CMOS platform for single-cell dielectric spectroscopy at microwave frequencies. Lab Chip 18(14):2065–2076

    Article  Google Scholar 

  • Coulter W (1953) Means for counting particles suspended in a fluid. US Patent, 2656508. United States Patent Office Patentiert am 20:1953

    Google Scholar 

  • Dalmay C, Cheray M, Pothier A, Lalloué F, Jauberteau M, Blondy P (2010) Ultrasensitive biosensor based on impedance spectroscopy at microwave frequencies for cell scale analysis. Sensors Actuators A Phys 162 (2):189–197

    Article  Google Scholar 

  • De Pastina A, Maillard D, Villanueva L (2018) Fabrication of suspended microchannel resonators with integrated piezoelectric transduction. Microelectron Eng 192:83–87

    Article  Google Scholar 

  • Dohn S, Sandberg R, Svendsen W, Boisen A (2005) Enhanced functionality of cantilever based mass sensors using higher modes. Appl Phys Lett 86(23):233501

    Article  Google Scholar 

  • Dohn S, Svendsen W, Boisen A, Hansen O (2007) Mass and position determination of attached particles on cantilever based mass sensors. Rev Sci Instrum 78(10):103303

    Article  Google Scholar 

  • Etayash H, Khan M, Kaur K, Thundat T (2016) Microfluidic cantilever detects bacteria and measures their susceptibility to antibiotics in small confined volumes. Nat Commun 7:12947

    Article  Google Scholar 

  • Ferrier GA, Romanuik SF, Thomson DJ, Bridges GE, Freeman MR (2009) A microwave interferometric system for simultaneous actuation and detection of single biological cells. Lab Chip 9(23):3406–3412

    Article  Google Scholar 

  • Ghatkesar MK, Garza HHP, Staufer U (2014) Hollow AFM cantilever pipette. Microelectron Eng 124:22–25

    Article  Google Scholar 

  • Godin M, Bryan AK, Burg TP, Babcock K, Manalis SR (2007) Measuring the mass, density, and size of particles and cells using a suspended microchannel resonator. Appl Phys Lett 91(12):123121

    Article  Google Scholar 

  • Godin M, Delgado FF, Son S, Grover WH, Bryan AK, Tzur A, Jorgensen P, Payer K, Grossman AD, Kirschner MW (2010) Using buoyant mass to measure the growth of single cells. Nat Methods 7(5):387

    Article  Google Scholar 

  • Grenier K, Dubuc D, Chen T, Artis F, Chretiennot T, Poupot M, Fournie J-J (2013) Recent advances in microwave-based dielectric spectroscopy at the cellular level for cancer investigations. IEEE Trans Microwave Theory Tech 61(5):2023–2030

    Article  Google Scholar 

  • Grover WH, Bryan AK, Diez-Silva M, Suresh S, Higgins JM, Manalis SR (2011) Measuring single-cell density. Proc Natl Acad Sci 108(27):10992–10996

    Article  Google Scholar 

  • Gupta A, Akin D, Bashir R (2004) Single virus particle mass detection using microresonators with nanoscale thickness. Appl Phys Lett 84(11):1976–1978

    Article  Google Scholar 

  • Hanay MS, Kelber S, Naik AK, Chi D, Hentz S, Bullard EC, Colinet E, Duraffourg L, Roukes ML (2012) Single-protein nanomechanical mass spectrometry in real time. Nat Nanotechnol 7(9):602–608. https://doi.org/10.1038/nnano.2012.119

    Article  Google Scholar 

  • Hanay MS, Kelber SI, O’Connell CD, Mulvaney P, Sader JE, Roukes ML (2015) Inertial imaging with nanomechanical systems. Nat Nanotechnol 10(4):339–344

    Article  Google Scholar 

  • Hannay J (1983) The Clausius-Mossotti equation: an alternative derivation. Eur J Phys 4(3):141

    Article  Google Scholar 

  • Ilic B, Czaplewski D, Zalalutdinov M, Craighead H, Neuzil P, Campagnolo C, Batt C (2001) Single cell detection with micromechanical oscillators. J Vac Sci Technol B Microelectron Nanometer Struct Process Meas Phenom 19(6):2825–2828

    Article  Google Scholar 

  • Ilic B, Yang Y, Craighead H (2004) Virus detection using nanoelectromechanical devices. Appl Phys Lett 85(13):2604–2606

    Article  Google Scholar 

  • Kelleci M, Aydogmus H, Aslanbas L, Erbil SO, Hanay MS (2018) Towards microwave imaging of cells. Lab Chip 18(3):463–472

    Article  Google Scholar 

  • Khan M, Schmid S, Davis ZJ, Dohn S, Boisen A (2011) Fabrication of resonant micro cantilevers with integrated transparent fluidic channel. Microelectron Eng 88(8):2300–2303

    Article  Google Scholar 

  • Khan MF, Kim S, Lee D, Schmid S, Boisen A, Thundat T (2014) Nanomechanical identification of liquid reagents in a microfluidic channel. Lab Chip 14(7):1302–1307

    Article  Google Scholar 

  • Kim J, Song J, Kim K, Kim S, Song J, Kim N, Khan MF, Zhang L, Sader JE, Park K (2016) Hollow microtube resonators via silicon self-assembly toward subattogram mass sensing applications. Nano Lett 16(3):1537–1545

    Article  Google Scholar 

  • Kouh T, Hanay M, Ekinci K (2017) Nanomechanical motion transducers for miniaturized mechanical systems. Micromachines 8(4):108

    Article  Google Scholar 

  • Laborde C, Pittino F, Verhoeven H, Lemay S, Selmi L, Jongsma M, Widdershoven F (2015) Real-time imaging of microparticles and living cells with CMOS nanocapacitor arrays. Nat Nanotechnol 10(9):791

    Article  Google Scholar 

  • Lee J, Shen W, Payer K, Burg TP, Manalis SR (2010) Toward attogram mass measurements in solution with suspended nanochannel resonators. Nano Lett 10(7):2537–2542

    Article  Google Scholar 

  • Lee J, Bryan AK, Manalis SR (2011) High precision particle mass sensing using microchannel resonators in the second vibration mode. Rev Sci Instrum 82(2):023704

    Article  Google Scholar 

  • Lee D, Kim J, Cho N-J, Kang T, Kauh S, Lee J (2016) Pulled microcapillary tube resonators with electrical readout for mass sensing applications. Sci Rep 6:33799

    Article  Google Scholar 

  • Lissandrello C, Inci F, Francom M, Paul M, Demirci U, Ekinci K (2014) Nanomechanical motion of Escherichia coli adhered to a surface. Appl Phys Lett 105(11):113701

    Article  Google Scholar 

  • Longo G, Alonso-Sarduy L, Rio LM, Bizzini A, Trampuz A, Notz J, Dietler G, Kasas S (2013) Rapid detection of bacterial resistance to antibiotics using AFM cantilevers as nanomechanical sensors. Nat Nanotechnol 8(7):522

    Article  Google Scholar 

  • Maloney N, Lukacs G, Jensen J, Hegner M (2014) Nanomechanical sensors for single microbial cell growth monitoring. Nanoscale 6(14):8242–8249

    Article  Google Scholar 

  • Malvar O, Ruz J, Kosaka PM, Domínguez CM, Gil-Santos E, Calleja M, Tamayo J (2016) Mass and stiffness spectrometry of nanoparticles and whole intact bacteria by multimode nanomechanical resonators. Nat Commun 7:13452

    Article  Google Scholar 

  • Martínez-Martín D, Fläschner G, Gaub B, Martin S, Newton R, Beerli C, Mercer J, Gerber C, Müller DJ (2017) Inertial picobalance reveals fast mass fluctuations in mammalian cells. Nature 550(7677):500

    Article  Google Scholar 

  • Meyne N, Cammin C, Jacob AF (2014) Accuracy enhancement of a split-ring resonator liquid sensor using dielectric resonator coupling. In: 2014 20th international conference on microwaves, radar and wireless communications (MIKON). IEEE, Gdansk, pp 1–4

    Google Scholar 

  • Mir M, Wang Z, Shen Z, Bednarz M, Bashir R, Golding I, Prasanth SG, Popescu G (2011) Optical measurement of cycle-dependent cell growth. Proc Natl Acad Sci 108(32):13124–13129

    Article  Google Scholar 

  • Naik AK, Hanay M, Hiebert W, Feng X, Roukes ML (2009) Towards single-molecule nanomechanical mass spectrometry. Nat Nanotechnol 4(7):445

    Article  Google Scholar 

  • Nerguizian V, Alazzam A, Stiharu I, Burnier M Jr (2017) Characterization of several cancer cell lines at microwave frequencies. Measurement 109:354–358

    Article  Google Scholar 

  • Nikolic-Jaric M, Romanuik S, Ferrier G, Bridges G, Butler M, Sunley K, Thomson D, Freeman M (2009) Microwave frequency sensor for detection of biological cells in microfluidic channels. Biomicrofluidics 3(3):034103

    Article  Google Scholar 

  • Olcum S, Cermak N, Wasserman SC, Christine KS, Atsumi H, Payer KR, Shen W, Lee J, Belcher AM, Bhatia SN (2014) Weighing nanoparticles in solution at the attogram scale. Proc Natl Acad Sci 111(4):1310–1315

    Article  Google Scholar 

  • Olcum S, Cermak N, Wasserman SC, Manalis SR (2015) High-speed multiple-mode mass-sensing resolves dynamic nanoscale mass distributions. Nat Commun 6:7070

    Article  Google Scholar 

  • Park K, Jang J, Irimia D, Sturgis J, Lee J, Robinson JP, Toner M, Bashir R (2008) ‘Living cantilever arrays’ for characterization of mass of single live cells in fluids. Lab Chip 8(7):1034–1041

    Article  Google Scholar 

  • Park K, Millet LJ, Kim N, Li H, Jin X, Popescu G, Aluru N, Hsia KJ, Bashir R (2010) Measurement of adherent cell mass and growth. Proc Natl Acad Sci 107(48):20691–20696

    Article  Google Scholar 

  • Park K, Mehrnezhad A, Corbin EA, Bashir R (2015) Optomechanical measurement of the stiffness of single adherent cells. Lab Chip 15(17):3460–3464

    Article  Google Scholar 

  • Park Y, Depeursinge C, Popescu G (2018) Quantitative phase imaging in biomedicine. Nat Photonics 12(10):578

    Article  Google Scholar 

  • Popescu G, Park Y, Lue N, Best-Popescu C, Deflores L, Dasari RR, Feld MS, Badizadegan K (2008) Optical imaging of cell mass and growth dynamics. Am J Phys Cell Phys 295(2):C538–C544

    Article  Google Scholar 

  • Poudineh M, Sargent EH, Pantel K, Kelley SO (2018) Profiling circulating tumour cells and other biomarkers of invasive cancers. Nat Biomed Eng 2(2):72

    Article  Google Scholar 

  • Pozar DM (2011) Microwave engineering. Wiley

    Google Scholar 

  • Sader JE, Hanay MS, Neumann AP, Roukes ML (2018) Mass spectrometry using nanomechanical systems: beyond the point-mass approximation. Nano Lett 18(3):1608–1614

    Article  Google Scholar 

  • Sage E, Brenac A, Alava T, Morel R, Dupré C, Hanay MS, Roukes ML, Duraffourg L, Masselon C, Hentz S (2015) Neutral particle mass spectrometry with nanomechanical systems. Nat Commun 6:6482

    Article  Google Scholar 

  • Schmid S, Dohn S, Boisen A (2010) Real-time particle mass spectrometry based on resonant micro strings. Sensors 10(9):8092–8100

    Article  Google Scholar 

  • Son S, Tzur A, Weng Y, Jorgensen P, Kim J, Kirschner MW, Manalis SR (2012) Direct observation of mammalian cell growth and size regulation. Nat Methods 9(9):910

    Article  Google Scholar 

  • Son S, Kang JH, Oh S, Kirschner MW, Mitchison T, Manalis S (2015) Resonant microchannel volume and mass measurements show that suspended cells swell during mitosis. J Cell Biol 211(4):757–763

    Article  Google Scholar 

  • Stevens MM, Maire CL, Chou N, Murakami MA, Knoff DS, Kikuchi Y, Kimmerling RJ, Liu H, Haidar S, Calistri NL (2016) Drug sensitivity of single cancer cells is predicted by changes in mass accumulation rate. Nat Biotechnol 34(11):1161

    Article  Google Scholar 

  • Tamayo J, Ramos D, Mertens J, Calleja M (2006) Effect of the adsorbate stiffness on the resonance response of microcantilever sensors. Appl Phys Lett 89(22):224104

    Article  Google Scholar 

  • Tamayo J, Kosaka PM, Ruz JJ, San Paulo Á, Calleja M (2013) Biosensors based on nanomechanical systems. Chem Soc Rev 42(3):1287–1311

    Article  Google Scholar 

  • Tamra A, Dubuc D, Rols M-P, Grenier K (2017) Microwave monitoring of single cell monocytes subjected to electroporation. IEEE Trans Microwave Theory Tech 65(9):3512–3518

    Article  Google Scholar 

  • Tamra A, Rols M-P, Dubuc D, Grenier K (2019) Impact of a chemical stimulus on two different cell lines through microwave dielectric spectroscopy at the single cell level. In: 2019 IEEE MTT-S international microwave biomedical conference (IMBioC). IEEE, Nanjing, pp 1–4

    Google Scholar 

  • Watts C, Hanham S, Armstrong J, Ahmad M, Stevens M, Klein N (2019) Microwave dielectric sensing of free-flowing, single, living cells in aqueous suspension. IEEE J Electromagnetics RF Microwaves Med Biol https://doi.org/10.1109/JERM.2019.2932569

  • Yang Y, Zhang H, Zhu J, Wang G, Tzeng T-R, Xuan X, Huang K, Wang P (2010) Distinguishing the viability of a single yeast cell with an ultra-sensitive radio frequency sensor. Lab Chip 10(5):553–555

    Article  Google Scholar 

  • Yuksel M, Orhan E, Yanik C, Ari AB, Demir A, Hanay MS (2019) Nonlinear nanomechanical mass spectrometry at the single-nanoparticle level. Nano Lett 19:3583

    Article  Google Scholar 

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Authors and Affiliations

  1. Department of Mechanical Engineering, Bilkent University, Ankara, Turkey

    M. Selim Hanay

  2. Institute of Materials Science and Nanotechnology (UNAM), Bilkent University, Ankara, Turkey

    M. Selim Hanay

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  1. M. Selim Hanay
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Correspondence to M. Selim Hanay .

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Editors and Affiliations

  1. Department of Engineering Design, Indian Institute of Technology Madras, Chennai, India

    Tuhin Subhra Santra

  2. Department of Engineering and System Science, National Tsing Hua University, Hsinchu, Taiwan

    Fan-Gang Tseng

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Hanay, M.S. (2020). Mechanical and Microwave Resonators for Sensing and Sizing Single Cells. In: Santra, T., Tseng, FG. (eds) Handbook of Single Cell Technologies. Springer, Singapore. https://doi.org/10.1007/978-981-10-4857-9_25-1

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  • DOI: https://doi.org/10.1007/978-981-10-4857-9_25-1

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