Advertisement

Mechanical and Microwave Resonators for Sensing and Sizing Single Cells

  • M. Selim HanayEmail author
Living reference work entry
  • 8 Downloads

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.

References

  1. 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):991–998Google Scholar
  2. Barber T, Huang L, Schmidt M, Toner M, Kapur R (2006) Devices and methods for magnetic enrichment of cells and other particles. Google PatentsGoogle Scholar
  3. Boal D, Boal DH (2012) Mechanics of the cell. Cambridge University Press, CambridgezbMATHCrossRefGoogle Scholar
  4. 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):999–1004CrossRefGoogle Scholar
  5. Burg TP, Manalis SR (2003) Suspended microchannel resonators for biomolecular detection. Appl Phys Lett 83(13):2698–2700CrossRefGoogle Scholar
  6. 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):1066CrossRefGoogle Scholar
  7. 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):7580–7585CrossRefGoogle Scholar
  8. 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):1052CrossRefGoogle Scholar
  9. 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):1613CrossRefGoogle Scholar
  10. Chaste J, Eichler A, Moser J, Ceballos G, Rurali R, Bachtold A (2012) A nanomechanical mass sensor with yoctogram resolution. Nat Nanotechnol 7(5):301CrossRefGoogle Scholar
  11. 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):4171–4177CrossRefGoogle Scholar
  12. 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 1–4Google Scholar
  13. 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):2065–2076CrossRefGoogle Scholar
  14. Coulter W (1953) Means for counting particles suspended in a fluid. US Patent, 2656508. United States Patent Office Patentiert am 20:1953Google Scholar
  15. 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):189–197CrossRefGoogle Scholar
  16. De Pastina A, Maillard D, Villanueva L (2018) Fabrication of suspended microchannel resonators with integrated piezoelectric transduction. Microelectron Eng 192:83–87CrossRefGoogle Scholar
  17. Dohn S, Sandberg R, Svendsen W, Boisen A (2005) Enhanced functionality of cantilever based mass sensors using higher modes. Appl Phys Lett 86(23):233501CrossRefGoogle Scholar
  18. 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):103303CrossRefGoogle Scholar
  19. 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 7:12947CrossRefGoogle Scholar
  20. 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):3406–3412CrossRefGoogle Scholar
  21. Ghatkesar MK, Garza HHP, Staufer U (2014) Hollow AFM cantilever pipette. Microelectron Eng 124:22–25CrossRefGoogle Scholar
  22. 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):123121CrossRefGoogle Scholar
  23. 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):387CrossRefGoogle Scholar
  24. 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):2023–2030CrossRefGoogle Scholar
  25. Grover WH, Bryan AK, Diez-Silva M, Suresh S, Higgins JM, Manalis SR (2011) Measuring single-cell density. Proc Natl Acad Sci 108(27):10992–10996CrossRefGoogle Scholar
  26. Gupta A, Akin D, Bashir R (2004) Single virus particle mass detection using microresonators with nanoscale thickness. Appl Phys Lett 84(11):1976–1978CrossRefGoogle Scholar
  27. 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.2012.119CrossRefGoogle Scholar
  28. Hanay MS, Kelber SI, O’Connell CD, Mulvaney P, Sader JE, Roukes ML (2015) Inertial imaging with nanomechanical systems. Nat Nanotechnol 10(4):339–344CrossRefGoogle Scholar
  29. Hannay J (1983) The Clausius-Mossotti equation: an alternative derivation. Eur J Phys 4(3):141CrossRefGoogle Scholar
  30. 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):2825–2828CrossRefGoogle Scholar
  31. Ilic B, Yang Y, Craighead H (2004) Virus detection using nanoelectromechanical devices. Appl Phys Lett 85(13):2604–2606CrossRefGoogle Scholar
  32. Kelleci M, Aydogmus H, Aslanbas L, Erbil SO, Hanay MS (2018) Towards microwave imaging of cells. Lab Chip 18(3):463–472CrossRefGoogle Scholar
  33. 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):2300–2303CrossRefGoogle Scholar
  34. 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):1302–1307CrossRefGoogle Scholar
  35. 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):1537–1545CrossRefGoogle Scholar
  36. Kouh T, Hanay M, Ekinci K (2017) Nanomechanical motion transducers for miniaturized mechanical systems. Micromachines 8(4):108CrossRefGoogle Scholar
  37. 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):791CrossRefGoogle Scholar
  38. 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):2537–2542CrossRefGoogle Scholar
  39. 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):023704CrossRefGoogle Scholar
  40. 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 6:33799CrossRefGoogle Scholar
  41. 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):113701CrossRefGoogle Scholar
  42. 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):522CrossRefGoogle Scholar
  43. Maloney N, Lukacs G, Jensen J, Hegner M (2014) Nanomechanical sensors for single microbial cell growth monitoring. Nanoscale 6(14):8242–8249CrossRefGoogle Scholar
  44. 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 7:13452CrossRefGoogle Scholar
  45. 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):500CrossRefGoogle Scholar
  46. 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 1–4Google Scholar
  47. 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):13124–13129CrossRefGoogle Scholar
  48. Naik AK, Hanay M, Hiebert W, Feng X, Roukes ML (2009) Towards single-molecule nanomechanical mass spectrometry. Nat Nanotechnol 4(7):445CrossRefGoogle Scholar
  49. Nerguizian V, Alazzam A, Stiharu I, Burnier M Jr (2017) Characterization of several cancer cell lines at microwave frequencies. Measurement 109:354–358CrossRefGoogle Scholar
  50. 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):034103CrossRefGoogle Scholar
  51. 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):1310–1315CrossRefGoogle Scholar
  52. Olcum S, Cermak N, Wasserman SC, Manalis SR (2015) High-speed multiple-mode mass-sensing resolves dynamic nanoscale mass distributions. Nat Commun 6:7070CrossRefGoogle Scholar
  53. 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):1034–1041CrossRefGoogle Scholar
  54. 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):20691–20696CrossRefGoogle Scholar
  55. Park K, Mehrnezhad A, Corbin EA, Bashir R (2015) Optomechanical measurement of the stiffness of single adherent cells. Lab Chip 15(17):3460–3464CrossRefGoogle Scholar
  56. Park Y, Depeursinge C, Popescu G (2018) Quantitative phase imaging in biomedicine. Nat Photonics 12(10):578CrossRefGoogle Scholar
  57. 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–C544CrossRefGoogle Scholar
  58. Poudineh M, Sargent EH, Pantel K, Kelley SO (2018) Profiling circulating tumour cells and other biomarkers of invasive cancers. Nat Biomed Eng 2(2):72CrossRefGoogle Scholar
  59. Pozar DM (2011) Microwave engineering. WileyGoogle Scholar
  60. Sader JE, Hanay MS, Neumann AP, Roukes ML (2018) Mass spectrometry using nanomechanical systems: beyond the point-mass approximation. Nano Lett 18(3):1608–1614CrossRefGoogle Scholar
  61. 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 6:6482CrossRefGoogle Scholar
  62. Schmid S, Dohn S, Boisen A (2010) Real-time particle mass spectrometry based on resonant micro strings. Sensors 10(9):8092–8100CrossRefGoogle Scholar
  63. 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):910CrossRefGoogle Scholar
  64. 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):757–763CrossRefGoogle Scholar
  65. 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):1161CrossRefGoogle Scholar
  66. 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):224104CrossRefGoogle Scholar
  67. Tamayo J, Kosaka PM, Ruz JJ, San Paulo Á, Calleja M (2013) Biosensors based on nanomechanical systems. Chem Soc Rev 42(3):1287–1311CrossRefGoogle Scholar
  68. 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):3512–3518CrossRefGoogle Scholar
  69. 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 1–4Google Scholar
  70. 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
  71. 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):553–555CrossRefGoogle Scholar
  72. Yuksel M, Orhan E, Yanik C, Ari AB, Demir A, Hanay MS (2019) Nonlinear nanomechanical mass spectrometry at the single-nanoparticle level. Nano Lett 19:3583CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd 2020

Authors and Affiliations

  1. 1.Department of Mechanical EngineeringBilkent UniversityAnkaraTurkey
  2. 2.Institute of Materials Science and Nanotechnology (UNAM)Bilkent UniversityAnkaraTurkey

Personalised recommendations