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Optics Express

Optics Express

  • Editor: Andrew M. Weiner
  • Vol. 22, Iss. 2 — Jan. 27, 2014
  • pp: 1330–1335
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Stabilization method for signal drifts in terahertz chemical microscopy

Toshihiko Kiwa, Kenji Sakai, and Keiji Tsukada  »View Author Affiliations


Optics Express, Vol. 22, Issue 2, pp. 1330-1335 (2014)
http://dx.doi.org/10.1364/OE.22.001330


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Abstract

A stabilization method for signal drifts in terahertz chemical microscopy (TCM) due to unexpected chemical potential changes in sample solutions was proposed and developed. The sensing plate was separated into two areas: a detection area and a control area. The detection area radiated a THz pulse whose amplitude was related to both the chemical reactions in the sample solutions and unexpected potential changes. The THz pulse from the control area was related only to unexpected potential changes. In the proposed system, the THz pulse from each area was interfered and detected. By adjusting the timing of the positive peak of the THz pulse from the detection area and the negative peak of the THz pulse from the control area, we detected the difference in both peaks as the interference signal. Thus, the signal deviation of 390 when the environmental condition changes in the temperature range of 38 °C and the pH range of 8.33 was stabilized to be the signal deviation of 31. As the result, the TCM with stabilization method could detect the signal shift of 121 when the 275-nmol/L immunoglobulin G was immobilized on the sensing plate.

© 2014 Optical Society of America

1. Introduction

An immunoassay system is a powerful tool for investigating biomaterials, antibody drugs, and cells. The systems that incorporate an enzyme-linked immunosorbent assay (ELISA) technique are conventional and highly sensitive systems [1

1. D. F. Keren, “Enzyme-linked immunosorbent assay for immunoglobulin G and immunoglobulin A antibodies to Shigella Flexneri antigens,” Infect. Immun. 24(2), 441–448 (1979). [PubMed]

,2

2. D. F. Keren, “Parameters affecting an enzyme-linked immunosorbent assay for Igg and Iga antibodies to Shigella-Flexneri antigens,” Fed. Proc. 38, 941 (1979).

]. In the ELISA system, antibodies are initially immobilized on a plate, and antigens with an enzyme are combined with the antibodies. When the substance is added to the plate and illuminated with light of a specific wavelength, fluorescence can be observed. While ELISA results in highly sensitive diagnoses, the assay generally requires several hours for pretreatment and the incubation of reagents. Systems that utilize surface plasmon resonance (SPR) have been developed and successfully used in the field of biology for real-time and label-free sensing [3

3. B. Johnsson, S. Löfås, and G. Lindquist, “Immobilization of proteins to a Carboxymethyldextran-modified gold surface for biospecific interaction analysis in surface plasmon resonance sensors,” Anal. Biochem. 198(2), 268–277 (1991). [CrossRef] [PubMed]

5

5. S. Löfås, M. Malmqvist, I. Ronnberg, E. Stenberg, B. Liedberg, and I. Lundstrom, “Bioanalysis with Surface-Plasmon Resonance,” Sens. Actuators B Chem. 5(1-4), 79–84 (1991). [CrossRef]

]. However, the sensitivity with such systems is reduced in cases where molecular mass of the sample proteins is low. In general, the measurements are limited to sample molecules with molecular masses of at least thousands of daltons (Da). Terahertz technologies are also promising because of their high sensitivity and selectivity to proteins [6

6. M. Tonouchi, “Cutting-edge terahertz technology,” Nat. Photonics 1(2), 97–105 (2007). [CrossRef]

10

10. S. Yoshida, K. Suizu, E. Kato, Y. Nakagomi, Y. Ogawa, and K. Kawase, “A high-sensitivity terahertz sensing method using a metallic mesh with unique transmission properties,” J. Mol. Spectrosc. 256(1), 146–151 (2009). [CrossRef]

].Our group has developed a terahertz chemical microscope (TCM) to visualize the distribution of the chemical potential shift on a Si-based sensing plate [11

11. T. Kiwa, K. Tsukada, M. Suzuki, M. Tonouchi, S. Migitaka, and K. Yokosawa, “Laser terahertz emission system to investigate hydrogen gas sensors,” Appl. Phys. Lett. 86(26), 261102 (2005). [CrossRef]

13

13. T. Kiwa, J. Kondo, S. Oka, I. Kawayama, H. Yamada, M. Tonouchi, and K. Tsukada, “Chemical sensing plate with a laser-terahertz monitoring system,” Appl. Opt. 47(18), 3324–3327 (2008). [CrossRef] [PubMed]

]. The sensing plate consists of SiO2/Si thin films on a sapphire substrate. When a femtosecond laser is used to irradiate the Si from the substrate side of the sensing plate, THz pulses are radiated by the local field of the depletion layer in the Si layer. If the chemical potential on the surface of SiO2 shifts in response to chemical reactions and/or the adsorption of proteins, the local field also changes. Consequently, the amplitude of THz pulses changes. Although the TCM has strong potential for investigating immune reactions with greater sensitivity than that provided by the SPR systems [14

14. T. Kiwa, Y. Kondo, Y. Minami, I. Kawayama, M. Tonouchi, and K. Tsukada, “Terahertz chemical microscope for label-free detection of protein complex,” Appl. Phys. Lett. 96(21), 211114 (2010). [CrossRef]

,15

15. T. Kiwa, A. Tenma, S. Takahashi, K. Sakai, and K. Tsukada, “Label free immune assay using terahertz chemical microscope,” Sens. Actuators B 187, 8–11 (2013). [CrossRef]

], the obtained signals tend to drift due to unexpected chemical potential changes. This signal drift generally occurs due to changes in the pH and/or the temperature of the solutions. For example, Fig. 1
Fig. 1 Signal drift when the pH of the sample solutions was changed.
shows the changes in THz amplitude when the pH of the sample solutions was changed. The arrows in the graph indicate the pH of the sample solutions. Phosphate buffer solutions were used as the test sample. The THz amplitude increased when the pH of the solutions was decreased. The potential changes were caused by the shift in the thermal equilibrium state between protons in the solutions and silanol groups formed on the SiO2 surface of the sensing plate [12

12. T. Kiwa, S. Oka, J. Kondo, I. Kawayama, H. Yamada, M. Tonouchi, and K. Tsukada, “A terahertz chemical microscope to visualize chemical concentrations in microftuidic chips,” Jpn. J. Appl. Phys. 2(46), L1052–L1054 (2007). [CrossRef]

]. This signal drift may indicate that the TCM can be used as a highly sensitive pH measurement system. However, pH of the sample solutions must be strictly controlled when protein bindings are measured by TCM. Shifts in the temperature of the solutions also change the local field of the sensing plate and often occur during measurements of biomaterials.

In this investigation, we incorporated a doubled laser path system into our terahertz chemical microscope and demonstrated the stabilization of the signal drifts due to changes in the pH and temperature of the solutions.

2. System setup and stabilization principle

3. Results and discussion

Figures 4(a)
Fig. 4 The THz amplitudes changes when (a) the temperature of the heater mounted on the sensing plate and (b) the pH of the sample solutions were changed.
and 4(b) show the changes in the THz amplitudes that occurred when the temperature of the heater mounted on the sensing plate and the pH of the sample solutionswere changed. The blue line represents the amplitude at 10 ps of the blue line (Fig. 3) (before the stabilization), and the black line represents the amplitude of the interfered waveform (Fig. 3) (after the stabilization). The arrows shown above the graphs in Figs. 4(a) and 4(b) represent the temperature of the heater and the pH of the solutions, respectively. The maximum deviations of the THz amplitude were 390 and 148 for the changes in the temperature and pH, respectively, before the stabilization. The deviation was reduced to 31 and 41 after the stabilization. Figure 5
Fig. 5 The THz amplitude when the temperature of the heater was changed. The red and black curves represent the amplitude before and after the stabilization, respectively. The 275-nmol/L-IgG was immobilized at where the time is around 12 min.
shows the THz amplitude when the temperature of the heater was changed. Mouse immunoglobulin G (IgG) was immobilized by being covalently bound to the detection area of the sensing plate at approximately the 12-min mark. The concentration of IgG was approximately 275 nmol/L. The red and black curves represent the THz amplitudebefore and after the stabilization, respectively. The shift in the THz amplitude due to the immobilization of IgG on the sensing plate was evident in the black curve, whereas the amplitude of the THz before the stabilization showed a large drift due to the change in the temperature, and the shift in the amplitude by the IgG immobilization could not be obtained. The shift in the amplitude was approximately 121 for the 275 nmol/L IgG that is three times larger than the deviation of the stabilized signal during our experiment. This result indicates that the stabilization system using the doubler unit is effective.

Summary

The amplitude drift in TCM due to changes in the temperature and/or the pH were canceled using a doubler unit. The THz pulses from the detection area and the control area of the sensing plate were detected by a single photoconductive antenna. The THz pulses from the two independent areas were adjusted in time-domain and were interfered; thus, the THz pulses were canceled in the amplitude. The maximum deviations of the THz amplitude were reduced to 31 and 41 after the stabilization for the change in the temperature and the pH, respectively. We also demonstrated that the detection of immunoglobulin at a concentration of 275 nmol/L was possible even when the temperature was varied between 25 °C and 63 °C. These results indicate that the double unit is useful for the stabilization of the amplitude drift in TCM measurements.

Acknowledgment

This study was partly supported by Industry-Academia Collaborative R&D from Japan Science and Technology Agency (JST).

References and links

1.

D. F. Keren, “Enzyme-linked immunosorbent assay for immunoglobulin G and immunoglobulin A antibodies to Shigella Flexneri antigens,” Infect. Immun. 24(2), 441–448 (1979). [PubMed]

2.

D. F. Keren, “Parameters affecting an enzyme-linked immunosorbent assay for Igg and Iga antibodies to Shigella-Flexneri antigens,” Fed. Proc. 38, 941 (1979).

3.

B. Johnsson, S. Löfås, and G. Lindquist, “Immobilization of proteins to a Carboxymethyldextran-modified gold surface for biospecific interaction analysis in surface plasmon resonance sensors,” Anal. Biochem. 198(2), 268–277 (1991). [CrossRef] [PubMed]

4.

U. Jönsson, L. Fägerstam, B. Ivarsson, B. Johnsson, R. Karlsson, K. Lundh, S. Löfås, B. Persson, H. Roos, I. Rönnberg, S. Sjolander, E. Stenberg, R. Stahlberg, C. Urbaniczky, H. Ostlin, and M. Malmqvist, “Real-time biospecific interaction analysis using surface plasmon resonance and a sensor chip technology,” Biotechniques 11(5), 620–627 (1991). [PubMed]

5.

S. Löfås, M. Malmqvist, I. Ronnberg, E. Stenberg, B. Liedberg, and I. Lundstrom, “Bioanalysis with Surface-Plasmon Resonance,” Sens. Actuators B Chem. 5(1-4), 79–84 (1991). [CrossRef]

6.

M. Tonouchi, “Cutting-edge terahertz technology,” Nat. Photonics 1(2), 97–105 (2007). [CrossRef]

7.

K. Kawase, Y. Ogawa, Y. Watanabe, and H. Inoue, “Non-destructive terahertz imaging of illicit drugs using spectral fingerprints,” Opt. Express 11(20), 2549–2554 (2003). [CrossRef] [PubMed]

8.

H. Yoshida, Y. Ogawa, Y. Kawai, S. Hayashi, A. Hayashi, C. Otani, E. Kato, F. Miyamaru, and K. Kawase, “Terahertz sensing method for protein detection using a thin metallic mesh,” Appl. Phys. Lett. 91(25), 253901 (2007). [CrossRef]

9.

Y. Ogawa, S. Hayashi, M. Oikawa, C. Otani, and K. Kawase, “Interference terahertz label-free imaging for protein detection on a membrane,” Opt. Express 16(26), 22083–22089 (2008). [CrossRef] [PubMed]

10.

S. Yoshida, K. Suizu, E. Kato, Y. Nakagomi, Y. Ogawa, and K. Kawase, “A high-sensitivity terahertz sensing method using a metallic mesh with unique transmission properties,” J. Mol. Spectrosc. 256(1), 146–151 (2009). [CrossRef]

11.

T. Kiwa, K. Tsukada, M. Suzuki, M. Tonouchi, S. Migitaka, and K. Yokosawa, “Laser terahertz emission system to investigate hydrogen gas sensors,” Appl. Phys. Lett. 86(26), 261102 (2005). [CrossRef]

12.

T. Kiwa, S. Oka, J. Kondo, I. Kawayama, H. Yamada, M. Tonouchi, and K. Tsukada, “A terahertz chemical microscope to visualize chemical concentrations in microftuidic chips,” Jpn. J. Appl. Phys. 2(46), L1052–L1054 (2007). [CrossRef]

13.

T. Kiwa, J. Kondo, S. Oka, I. Kawayama, H. Yamada, M. Tonouchi, and K. Tsukada, “Chemical sensing plate with a laser-terahertz monitoring system,” Appl. Opt. 47(18), 3324–3327 (2008). [CrossRef] [PubMed]

14.

T. Kiwa, Y. Kondo, Y. Minami, I. Kawayama, M. Tonouchi, and K. Tsukada, “Terahertz chemical microscope for label-free detection of protein complex,” Appl. Phys. Lett. 96(21), 211114 (2010). [CrossRef]

15.

T. Kiwa, A. Tenma, S. Takahashi, K. Sakai, and K. Tsukada, “Label free immune assay using terahertz chemical microscope,” Sens. Actuators B 187, 8–11 (2013). [CrossRef]

OCIS Codes
(180.5810) Microscopy : Scanning microscopy
(320.7160) Ultrafast optics : Ultrafast technology
(170.6795) Medical optics and biotechnology : Terahertz imaging

ToC Category:
Terahertz optics

History
Original Manuscript: September 13, 2013
Revised Manuscript: November 24, 2013
Manuscript Accepted: December 2, 2013
Published: January 14, 2014

Virtual Issues
Vol. 9, Iss. 3 Virtual Journal for Biomedical Optics

Citation
Toshihiko Kiwa, Kenji Sakai, and Keiji Tsukada, "Stabilization method for signal drifts in terahertz chemical microscopy," Opt. Express 22, 1330-1335 (2014)
http://www.opticsinfobase.org/oe/abstract.cfm?URI=oe-22-2-1330


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References

  1. D. F. Keren, “Enzyme-linked immunosorbent assay for immunoglobulin G and immunoglobulin A antibodies to Shigella Flexneri antigens,” Infect. Immun. 24(2), 441–448 (1979). [PubMed]
  2. D. F. Keren, “Parameters affecting an enzyme-linked immunosorbent assay for Igg and Iga antibodies to Shigella-Flexneri antigens,” Fed. Proc. 38, 941 (1979).
  3. B. Johnsson, S. Löfås, G. Lindquist, “Immobilization of proteins to a Carboxymethyldextran-modified gold surface for biospecific interaction analysis in surface plasmon resonance sensors,” Anal. Biochem. 198(2), 268–277 (1991). [CrossRef] [PubMed]
  4. U. Jönsson, L. Fägerstam, B. Ivarsson, B. Johnsson, R. Karlsson, K. Lundh, S. Löfås, B. Persson, H. Roos, I. Rönnberg, S. Sjolander, E. Stenberg, R. Stahlberg, C. Urbaniczky, H. Ostlin, M. Malmqvist, “Real-time biospecific interaction analysis using surface plasmon resonance and a sensor chip technology,” Biotechniques 11(5), 620–627 (1991). [PubMed]
  5. S. Löfås, M. Malmqvist, I. Ronnberg, E. Stenberg, B. Liedberg, I. Lundstrom, “Bioanalysis with Surface-Plasmon Resonance,” Sens. Actuators B Chem. 5(1-4), 79–84 (1991). [CrossRef]
  6. M. Tonouchi, “Cutting-edge terahertz technology,” Nat. Photonics 1(2), 97–105 (2007). [CrossRef]
  7. K. Kawase, Y. Ogawa, Y. Watanabe, H. Inoue, “Non-destructive terahertz imaging of illicit drugs using spectral fingerprints,” Opt. Express 11(20), 2549–2554 (2003). [CrossRef] [PubMed]
  8. H. Yoshida, Y. Ogawa, Y. Kawai, S. Hayashi, A. Hayashi, C. Otani, E. Kato, F. Miyamaru, K. Kawase, “Terahertz sensing method for protein detection using a thin metallic mesh,” Appl. Phys. Lett. 91(25), 253901 (2007). [CrossRef]
  9. Y. Ogawa, S. Hayashi, M. Oikawa, C. Otani, K. Kawase, “Interference terahertz label-free imaging for protein detection on a membrane,” Opt. Express 16(26), 22083–22089 (2008). [CrossRef] [PubMed]
  10. S. Yoshida, K. Suizu, E. Kato, Y. Nakagomi, Y. Ogawa, K. Kawase, “A high-sensitivity terahertz sensing method using a metallic mesh with unique transmission properties,” J. Mol. Spectrosc. 256(1), 146–151 (2009). [CrossRef]
  11. T. Kiwa, K. Tsukada, M. Suzuki, M. Tonouchi, S. Migitaka, K. Yokosawa, “Laser terahertz emission system to investigate hydrogen gas sensors,” Appl. Phys. Lett. 86(26), 261102 (2005). [CrossRef]
  12. T. Kiwa, S. Oka, J. Kondo, I. Kawayama, H. Yamada, M. Tonouchi, K. Tsukada, “A terahertz chemical microscope to visualize chemical concentrations in microftuidic chips,” Jpn. J. Appl. Phys. 2(46), L1052–L1054 (2007). [CrossRef]
  13. T. Kiwa, J. Kondo, S. Oka, I. Kawayama, H. Yamada, M. Tonouchi, K. Tsukada, “Chemical sensing plate with a laser-terahertz monitoring system,” Appl. Opt. 47(18), 3324–3327 (2008). [CrossRef] [PubMed]
  14. T. Kiwa, Y. Kondo, Y. Minami, I. Kawayama, M. Tonouchi, K. Tsukada, “Terahertz chemical microscope for label-free detection of protein complex,” Appl. Phys. Lett. 96(21), 211114 (2010). [CrossRef]
  15. T. Kiwa, A. Tenma, S. Takahashi, K. Sakai, K. Tsukada, “Label free immune assay using terahertz chemical microscope,” Sens. Actuators B 187, 8–11 (2013). [CrossRef]

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