Abstract

Spectral imaging of a single cell with terahertz (THz) wave is valuable in determination of its physiological state for cell-based precision diagnosis, as THz photon energy is in tune with the vibration-rotation and conformation related excitations of cellular material, and THz absorption is extremely sensitive to the state and degree of hydration of a cell. Because of the severe mismatch between the cell size and the THz wavelength, such imaging has to be carried out in the near-field modality. To make the design and performance assessment of a THz near-field spectral imager effective and systematic, we simulate the scattering THz near-field signals of tumor cells by strictly controlling cell model parameters with representative physiological states. The results demonstrate that the specific physiological characteristics from intracellular hydration state, nucleocytoplasmic ratio, and cell geometric morphology of tumor cells can be characterized quantitatively by their discrepant dielectric response in the THz band, correlating THz near-field scattering signal from a cell with the latter’s corresponding physicochemical state.

© 2020 Optical Society of America under the terms of the OSA Open Access Publishing Agreement

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    [Crossref]
  38. A. G. Markelz, A. Roitberg, and E. J. Heilweil, “Pulsed terahertz spectroscopy of DNA, bovine serum albumin and collagen between 0.1 and 2.0 THz,” Chem. Phys. Lett. 320(1-2), 42–48 (2000).
    [Crossref]
  39. F. Keilmann and R. Hillenbrand, “Near-field microscopy by elastic light scattering from a tip,” Philos. Trans. R. Soc., A 362(1817), 787–805 (2004).
    [Crossref]
  40. O. M. Ramahi, “Stable FDTD solutions with higher, rder absorbing boundary conditions,” Microwave & Opt. Techn Lett. 15(3), 132–134 (1997).
    [Crossref]
  41. J. P. Berenger, “A perfectly matched layer for the absorption of electromagnetic waves,” Appl. Spectrosc. Rev. 53(10), 806–835 (2018).
    [Crossref]
  42. M. Chaplin, “Do we underestimate the importance of water in cell biology?” Nat. Rev. Mol. Cell Biol. 7(11), 861–866 (2006).
    [Crossref]
  43. C. Cametti, S. Marchetti, C. M. C. Gambi, and G. Onori, “Dielectric relaxation spectroscopy of lysozyme aqueous solutions: analysis of the δ-dispersion and the contribution of the hydration water,” J. Phys. Chem. B 115(21), 7144–7153 (2011).
    [Crossref]
  44. P. C. Ashworth, E. Pickwell, E. Provenzano, S. E. Pinder, A. D. Purushotham, M. Pepper, and V. P. Wallace, “Terahertz pulsed spectroscopy of freshly excised human breast cancer,” Opt. Express 17(15), 12444–12454 (2009).
    [Crossref]
  45. L. Sterczewski, K. Nowak, B. Szlachetko, M. Grzelczak, B. S. Szczesniak, S. Plinska, W. Malinka, and E. Plinski, “Chemometric evaluation of THz spectral similarity for the selection of early drug candidates,” Sci. Rep. 7(1), 14583 (2017).
    [Crossref]
  46. M. Papetti and I. M. Herman, “Mechanisms of normal and tumor-derived angiogenesis,” Am. J. Physiol. Cell Physiol. 282(5), C947–C970 (2002).
    [Crossref]
  47. Z. Zang, J. Wang, H. L. Cui, and S. Yan, “Terahertz spectral imaging based quantitative determination of spatial distribution of plant leaf constituents,” Plant Methods 15(1), 106 (2019).
    [Crossref]
  48. Z. Song, S. Yan, Y. Zang, Y. Fu, D. Wei, H. L. Cui, and P. Lai, “Temporal and spatial variability of water status in plant leaves by terahertz imaging,” IEEE Trans. Terahertz Sci. Technol. 8(5), 520–527 (2018).
    [Crossref]

2020 (2)

Z. Li, S. Yan, Z. Zang, G. Geng, Z. Yang, J. Li, L. Wang, C. Yao, H. L. Cui, C. Chan, and H. Wang, “Single cell imaging with near-field terahertz scanning microscopy,” Cell Proliferation 53(4), e12788 (2020).
[Crossref]

X. Chen, X. Liu, X. Guo, S. Chen, H. Hu, E. Nikulina, X. Ye, Z. Yao, H. Bechtel, M. Martin, G. Carr, Q. Dai, S. Zhuang, Q. Hu, Y. Zhu, R. Hillenbrand, M. Liu, and G. You, “THz near-field imaging of extreme subwavelength metal structures,” ACS Photonics 7(3), 687–694 (2020).
[Crossref]

2019 (5)

G. Dai, G. Geng, X. Zhang, J. Wang, T. Chang, and H. L. Cui, “W-Band near-field microscope,” IEEE Access 7, 48060–48067 (2019).
[Crossref]

G. Geng, G. Dai, D. Li, S. Zhou, Z. Li, Z. Yang, Y. Xu, J. Han, T. Chang, and H. L. Cui, “Imaging brain tissue slices with terahertz near-field microscopy,” Biotechnol. Prog. 35(2), e2741 (2019).
[Crossref]

Z. Yao, V. Semenenko, J. Zhang, S. Mills, X. Zhao, X. Chen, H. Hu, R. Mescall, T. Ciavatti, and S. March, “Photo-induced terahertz near-field dynamics of graphene/InAs heterostructures,” Opt. Express 27(10), 13611–1362 (2019).
[Crossref]

Y. Liu, H. Liu, M. Tang, J. Huang, W. Liu, J. Dong, X. Chen, W. Fu, and Y. Zhang, “The medical application of terahertz technology in non-invasive detection of cells and tissues: opportunities and challenges,” RSC Adv. 9(17), 9354–9363 (2019).
[Crossref]

Z. Zang, J. Wang, H. L. Cui, and S. Yan, “Terahertz spectral imaging based quantitative determination of spatial distribution of plant leaf constituents,” Plant Methods 15(1), 106 (2019).
[Crossref]

2018 (5)

Z. Song, S. Yan, Y. Zang, Y. Fu, D. Wei, H. L. Cui, and P. Lai, “Temporal and spatial variability of water status in plant leaves by terahertz imaging,” IEEE Trans. Terahertz Sci. Technol. 8(5), 520–527 (2018).
[Crossref]

X. Han, S. Yan, Z. Zang, D. Wei, H. L. Cui, and C. Du, “Label-free protein detection using terahertz time-domain spectroscopy,” Biomed. Opt. Express 9(3), 994–1005 (2018).
[Crossref]

J. P. Berenger, “A perfectly matched layer for the absorption of electromagnetic waves,” Appl. Spectrosc. Rev. 53(10), 806–835 (2018).
[Crossref]

Z. Yi, L. Qiao, Y. Xia, H. Hua, L. Jiang, D. Liang, L. Ze, Z. Jian, and Z. Li, “Label-free monitoring of cell death induced by oxidative stress in living human cells using terahertz ATR spectroscopy,” Biomed. Opt. Express 9(1), 14–24 (2018).
[Crossref]

G. Dai, Z. Yang, G. Geng, M. Li, T. Chang, D. Wei, C. Du, H. L. Cui, and H. Wang, “Signal detection techniques for scattering-type scanning near-field optical microscopy,” Appl. Spectrosc. Rev. 53(10), 806–835 (2018).
[Crossref]

2017 (2)

X. Lin, N. Wan, L. Weng, and Y. Zhou, “Light scattering from normal and cervical cancer cells,” Appl. Opt. 56(12), 3608–3614 (2017).
[Crossref]

L. Sterczewski, K. Nowak, B. Szlachetko, M. Grzelczak, B. S. Szczesniak, S. Plinska, W. Malinka, and E. Plinski, “Chemometric evaluation of THz spectral similarity for the selection of early drug candidates,” Sci. Rep. 7(1), 14583 (2017).
[Crossref]

2016 (3)

S. Sawallich, B. Globisch, C. Matheisen, M. Nagel, R. J. B. Dietz, and T. Gobel, “Photoconductive terahertz near-field detectors for operation with 1550-nm pulsed fiber lasers,” IEEE Trans. Terahertz Sci. Technol. 6(3), 365–370 (2016).
[Crossref]

S. Yamaguchi, F. Yasuko, O. Kubota, T. Itsuji, T. Ouchi, and S. Yamamoto, “Brain tumor imaging of rat fresh tissue using terahertz spectroscopy,” Sci. Rep. 6(1), 30124 (2016).
[Crossref]

R. J. Heath, A. Ribas, and P. S. Mischel, “Single-cell analysis tools for drug discovery and development,” Nat. Rev. Drug Discovery, 15(3), 204–216 (2016).
[Crossref]

2015 (3)

P. L. Fale and K. L. A. Chan, “Non-destructive label-free monitoring of drug intake in live cells using ATR FT-IR spectroscopy,” Biophys. J. 108(2), 493a (2015).
[Crossref]

K. Shiraga, T. Suzuki, N. Kondo, K. Tanaka, and Y. Ogawa, “Hydration state inside HeLa cell monolayer investigated with terahertz spectroscopy,” Appl. Phys. Lett. 106(25), 253701 (2015).
[Crossref]

H. Jian, Y. Zhongbo, W. Dongshan, D. Chunlei, and C. Hong-Liang, “Enhancement effects of the terahertz near-field microscopy,” Appl. Sci 5(4), 1745–1755 (2015).
[Crossref]

2014 (2)

M. Eisele, T. Cocker, M. A. Huber, M. Plankl, L. Viti, D. Ercolani, L. Sorba, M. S. Vitiello, and R. Hober, “Ultrafast multi-terahertz nano-spectroscopy with sub-cycle temporal resolution,” Nat. Photonics 8(11), 841–845 (2014).
[Crossref]

K. Shiraga, Y. Ogawa, T. Suzuki, N. Kondo, A. Irisawa, and M. Imamura, “Characterization of dielectric responses of human cancer cells in the terahertz region,” J. Infrared, Millimeter, Terahertz Waves 35(5), 493–502 (2014).
[Crossref]

2013 (2)

K. Shiraga, Y. Ogawa, T. Suzuki, N. Kondo, A. Irisawa, M. Imamura, and K. Shiraga, “Determination of the complex dielectric constant of an epithelial cell monolayer in the terahertz region,” Appl. Phys. Lett. 102(5), 053702 (2013).
[Crossref]

T. L. Cocker, V. Jelic, M. Gupta, S. J. Molesky, J. A. J. Burgess, and G. De Los Reyes, “An ultrafast terahertz scanning tunnelling microscope,” Nat. Photonics 7(8), 620–625 (2013).
[Crossref]

2012 (1)

D. H. M. Dam, J. H. Lee, P. N. Sisco, D. T. Co, and T. W. Odom, “Direct observation of nanoparticle-cancer cell nucleus interactions,” ACS Nano 6(4), 3318–3326 (2012).
[Crossref]

2011 (2)

A. J. L. Adam, “Review of near-field terahertz measurement methods and their applications,” Opt. Commun. 32(8-9), 976–1019 (2011).
[Crossref]

C. Cametti, S. Marchetti, C. M. C. Gambi, and G. Onori, “Dielectric relaxation spectroscopy of lysozyme aqueous solutions: analysis of the δ-dispersion and the contribution of the hydration water,” J. Phys. Chem. B 115(21), 7144–7153 (2011).
[Crossref]

2009 (2)

P. C. Ashworth, E. Pickwell, E. Provenzano, S. E. Pinder, A. D. Purushotham, M. Pepper, and V. P. Wallace, “Terahertz pulsed spectroscopy of freshly excised human breast cancer,” Opt. Express 17(15), 12444–12454 (2009).
[Crossref]

J. Qvist, E. Persson, C. Mattea, and B. Halle, “Time scales of water dynamics at biological interfaces: peptides, proteins and cells,” Faraday Discuss. 141, 131–144 (2009).
[Crossref]

2008 (5)

E. Persson and B. Halle, “Cell water dynamics on multiple time scales,” Proc. Natl. Acad. Sci. U. S. A. 105(17), 6266–6271 (2008).
[Crossref]

H. Yada, M. Nagai, and K. Tanaka, “Origin of the fast relaxation component of water and heavy water revealed by terahertz time-domain attenuated total reflection spectroscopy,” Chem. Phys. Lett. 464(4-6), 166–170 (2008).
[Crossref]

G. Png, J. Choi, B. Ng, S. Mickan, D. Abbott, and X. Zhang, “The impact of hydration changes in fresh bio-tissue on THz spectroscopic measurements,” Phys. Med. Biol. 53(13), 3501–3517 (2008).
[Crossref]

A. J. Huber, F. Keilmann, J. Wittborn, J. Aizpurua, and R. Hillenbrand, “Terahertz near-field nanoscopy of mobile carriers in single semiconductor nanodevices,” Nano Lett. 8(11), 3766–3770 (2008).
[Crossref]

H. G. V. Ribbeck, M. Brehm, D. W. V. D. Weide, S. Winnerl, and F. Keilmann, “Spectroscopic THz near-field microscope,” Opt. Express 16(5), 3430–3438 (2008).
[Crossref]

2007 (1)

L. Hungyen, M. Bernd, S. Fischer, P. Mickan, and A. Derek, “Review of THz near-field methods,” Proc. of SPIE 6414, 64140L (2007).
[Crossref]

2006 (1)

M. Chaplin, “Do we underestimate the importance of water in cell biology?” Nat. Rev. Mol. Cell Biol. 7(11), 861–866 (2006).
[Crossref]

2004 (1)

F. Keilmann and R. Hillenbrand, “Near-field microscopy by elastic light scattering from a tip,” Philos. Trans. R. Soc., A 362(1817), 787–805 (2004).
[Crossref]

2003 (1)

H. T. Chen, R. Kersting, and G. C. Cho, “Terahertz imaging with nanometer resolution,” Appl. Phys. Lett. 83(15), 3009–3011 (2003).
[Crossref]

2002 (3)

B. Ferguson and X. C. Zhang, “Materials for terahertz science and technology,” Nat. Mater. 1(1), 26–33 (2002).
[Crossref]

C. Rønne and S. R. Keiding, “Low frequency spectroscopy of liquid water using THz-time domain spectroscopy,” J. Mol. Liq. 101(1-3), 199–218 (2002).
[Crossref]

M. Papetti and I. M. Herman, “Mechanisms of normal and tumor-derived angiogenesis,” Am. J. Physiol. Cell Physiol. 282(5), C947–C970 (2002).
[Crossref]

2000 (1)

A. G. Markelz, A. Roitberg, and E. J. Heilweil, “Pulsed terahertz spectroscopy of DNA, bovine serum albumin and collagen between 0.1 and 2.0 THz,” Chem. Phys. Lett. 320(1-2), 42–48 (2000).
[Crossref]

1998 (1)

S. Hunsche, M. Koch, I. Brener, and M. C. Nuss, “THz near-field imaging,” Opt. Commun. 150(1-6), 22–26 (1998).
[Crossref]

1997 (2)

D. Smithpeter, A. Welch, and R. K. Richards, “Finite-difference time-domain simulation of light scattering from single cells,” J. Biomed. Opt. 2(3), 262–268 (1997).
[Crossref]

O. M. Ramahi, “Stable FDTD solutions with higher, rder absorbing boundary conditions,” Microwave & Opt. Techn Lett. 15(3), 132–134 (1997).
[Crossref]

1975 (1)

B. M. Fung, D. A. Wassil, D. L. Durham, R. W. Chesnut, N. Durham, and K. D. Berlin, “Water in normal muscle and muscle with tumor,” Biochim. Biophys. Acta, Gen. Subj. 385(2), 180–187 (1975).
[Crossref]

1971 (1)

R. Damadian, “Tumor detection by nuclear magnetic resonance,” Science 171(3976), 1151–1153 (1971).
[Crossref]

1970 (1)

L. M. Matarrese, “Improved coupling toinfrared whisker diodes by use of antenna theory,” Appl. Phys. Lett. 17(1), 8–10 (1970).
[Crossref]

Abbott, D.

G. Png, J. Choi, B. Ng, S. Mickan, D. Abbott, and X. Zhang, “The impact of hydration changes in fresh bio-tissue on THz spectroscopic measurements,” Phys. Med. Biol. 53(13), 3501–3517 (2008).
[Crossref]

Adam, A. J. L.

A. J. L. Adam, “Review of near-field terahertz measurement methods and their applications,” Opt. Commun. 32(8-9), 976–1019 (2011).
[Crossref]

Aizpurua, J.

A. J. Huber, F. Keilmann, J. Wittborn, J. Aizpurua, and R. Hillenbrand, “Terahertz near-field nanoscopy of mobile carriers in single semiconductor nanodevices,” Nano Lett. 8(11), 3766–3770 (2008).
[Crossref]

Ashworth, P. C.

Bechtel, H.

X. Chen, X. Liu, X. Guo, S. Chen, H. Hu, E. Nikulina, X. Ye, Z. Yao, H. Bechtel, M. Martin, G. Carr, Q. Dai, S. Zhuang, Q. Hu, Y. Zhu, R. Hillenbrand, M. Liu, and G. You, “THz near-field imaging of extreme subwavelength metal structures,” ACS Photonics 7(3), 687–694 (2020).
[Crossref]

Berenger, J. P.

J. P. Berenger, “A perfectly matched layer for the absorption of electromagnetic waves,” Appl. Spectrosc. Rev. 53(10), 806–835 (2018).
[Crossref]

Berlin, K. D.

B. M. Fung, D. A. Wassil, D. L. Durham, R. W. Chesnut, N. Durham, and K. D. Berlin, “Water in normal muscle and muscle with tumor,” Biochim. Biophys. Acta, Gen. Subj. 385(2), 180–187 (1975).
[Crossref]

Bernd, M.

L. Hungyen, M. Bernd, S. Fischer, P. Mickan, and A. Derek, “Review of THz near-field methods,” Proc. of SPIE 6414, 64140L (2007).
[Crossref]

Brehm, M.

Brener, I.

S. Hunsche, M. Koch, I. Brener, and M. C. Nuss, “THz near-field imaging,” Opt. Commun. 150(1-6), 22–26 (1998).
[Crossref]

Burgess, J. A. J.

T. L. Cocker, V. Jelic, M. Gupta, S. J. Molesky, J. A. J. Burgess, and G. De Los Reyes, “An ultrafast terahertz scanning tunnelling microscope,” Nat. Photonics 7(8), 620–625 (2013).
[Crossref]

Cametti, C.

C. Cametti, S. Marchetti, C. M. C. Gambi, and G. Onori, “Dielectric relaxation spectroscopy of lysozyme aqueous solutions: analysis of the δ-dispersion and the contribution of the hydration water,” J. Phys. Chem. B 115(21), 7144–7153 (2011).
[Crossref]

Carr, G.

X. Chen, X. Liu, X. Guo, S. Chen, H. Hu, E. Nikulina, X. Ye, Z. Yao, H. Bechtel, M. Martin, G. Carr, Q. Dai, S. Zhuang, Q. Hu, Y. Zhu, R. Hillenbrand, M. Liu, and G. You, “THz near-field imaging of extreme subwavelength metal structures,” ACS Photonics 7(3), 687–694 (2020).
[Crossref]

Chan, C.

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Supplementary Material (1)

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Figures (6)

Fig. 1.
Fig. 1. Schematic of the coupled tip–cell model system.
Fig. 2.
Fig. 2. Simulated THz near-field signal of a cell with various intracellular water states. Inset graph shows the trend of signal strength with increasing refractive index of cytoplasm, and the curve is obtained by fitting the scatter point of near field signal strength at X=0.
Fig. 3.
Fig. 3. Simulated THz near-field signal of a cell with various nucleocytoplasmic ratio. Inset graph shows the trend of signal strength with increasing cellular nucleocytoplasmic ratio, and the curve is obtained by fitting the scatter point of near field signal strength at X=0.
Fig. 4.
Fig. 4. Simulated THz near-field signal of two cells in extreme physiological states.
Fig. 5.
Fig. 5. Simulated THz near-field signals of cells in different physiological states and interior inhomogeneities.
Fig. 6.
Fig. 6. Simulated THz near-field signal of a cell, while moving the tip from the center of the cell to its edge, eventually on to the substrate. Inset: Electric field strength when the tip apex is at different positions. Note: cell edge is at X = 5 µm.

Tables (1)

Tables Icon

Table 1. Parameters of four cellular models