Abstract

We demonstrate microfluidic devices for terahertz spectroscopy of biomolecules in aqueous solutions. The devices are fabricated out of a plastic material that is both mechanically rigid and optically transparent with near-zero dispersion in the terahertz frequency range. Using a low-power terahertz time-domain spectrometer, we experimentally measure the absorption spectra of the vibrational modes of bovine serum albumin from 0.5–2.5 THz and find good agreement with previously reported data obtained using large-volume solutions and a high-power free-electron laser. Our results demonstrate the feasibility of performing high sensitivity terahertz spectroscopy of biomolecules in aqueous solutions with detectable molecular quantities as small as 10 picomoles using microfluidic devices.

© 2008 Optical Society of America

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  1. S. Hayward and N. Go, "Collective variable description of native protein dynamics," Annu. Rev. Phys. Chem. 46, 223-250 (1995).
    [CrossRef]
  2. M. C. Chen and R. C. Lord, "Laser-excited Raman spectroscopy of biomolecules: conformational study of bovine serum albumin," J. Am. Chem. Soc. 98, 990-992 (1976).
    [CrossRef] [PubMed]
  3. W. Zhuang, Y. Feng, and E. W. Prohofsky, "Self-consistent calculation of localized DNA vibrational properties at a double-helix-single-strand junction with anharmonic potential," Phys. Rev. A 41, 7033-7042 (1990).
    [CrossRef] [PubMed]
  4. A. G. Markelz, and 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, 42-48 (2000).
    [CrossRef]
  5. T. R. Globus, D. L. Woolard, T. Khromova, T. W. Crowe, M. Bykhovskaia, B. L. Gelmont, J. Hesler, and A. C. Samuels, "THz-spectroscopy of biological molecules," J. Bio. Phys. 29, 89-100 (2003).
    [CrossRef]
  6. T. R. Globus, D. L. Woolard, T. W. Crowe, T. Khromova, M. Bykhovskaia, B. L. Gelmont, and J. Hesler, "Terahertz Fourier transform characterization of biological materials in a liquid phase," J. Phys. D 39, 3405-3413 (2006).
    [CrossRef]
  7. J. Xu, K. W. Plaxco, and S. J. Allen, "Probing the collective vibrational dynamics of a protein in liquid water by terahertz absorption spectroscopy," Prot. Sci. 15, 1175-1181 (2006).
    [CrossRef]
  8. M. Nagai, H. Yada, T. Arikawa, and K. Tanaka, "Terahertz time-domain attenuated total reflection spectroscopy in water and biological solutions," Intl. J. Inf. and Mill. Waves 27, 505-515 (2006).
    [CrossRef]
  9. J. Kitagawa, T. Ohkubo, M. Onuma, and Y. Kadoya, "THz spectroscopic characterization of biomolecule/water systems by compact sensor chips," Appl. Phys. Lett. 89, 041114 (2006).
    [CrossRef]
  10. T. Baras, T. Kleine-Ostmann, and M. Koch, "On-chip THz detection of biomaterials: a numerical study," J. Bio. Phys. 29, 187-194 (2003).
    [CrossRef]
  11. M. Nagel, P. H. Bolivar, M. Brucherseifer, H. Kurz, A. Bosserhoff, and R. Buttner, "Integrated THz technology for label-free genetic diagnostics," Appl. Phys. Lett. 80, 154 (2002).
    [CrossRef]
  12. "Zeonor Production Information Sheet," Zeon Corporation (2004).
  13. T. I. Wallow, A. M. Morales, B. A. Simmons, M. C. Hunter, K. L. Krafcik, L. A. Domeier, S. M. Sickafoose, K. D. Patel, and A. Gardea, "Low-distortion, high-strength bonding of thermoplastic microfluidic devices employing case-II diffusion-mediated permeant activation," Lab on a Chip 7, 1825-1831 (2007).
    [CrossRef] [PubMed]
  14. B. G. Hawkins, A. E. Smith, Y. A. Syed, and B. J. Kirby, "Continuous-flow particle separation by 3D insulative dielectrophoresis using coherently shaped, dc-biased, ac electric fields," Anal. Chem. 79, 7291-7300(2007).
    [CrossRef] [PubMed]
  15. "Bovine serum albumin product information sheet," (Sigma-Aldrich, 2000).
  16. R. D. Levine, Molecular Reaction Dynamics, (Cambridge Univeristy Press, 2005).
    [CrossRef]

2007 (2)

T. I. Wallow, A. M. Morales, B. A. Simmons, M. C. Hunter, K. L. Krafcik, L. A. Domeier, S. M. Sickafoose, K. D. Patel, and A. Gardea, "Low-distortion, high-strength bonding of thermoplastic microfluidic devices employing case-II diffusion-mediated permeant activation," Lab on a Chip 7, 1825-1831 (2007).
[CrossRef] [PubMed]

B. G. Hawkins, A. E. Smith, Y. A. Syed, and B. J. Kirby, "Continuous-flow particle separation by 3D insulative dielectrophoresis using coherently shaped, dc-biased, ac electric fields," Anal. Chem. 79, 7291-7300(2007).
[CrossRef] [PubMed]

2006 (4)

T. R. Globus, D. L. Woolard, T. W. Crowe, T. Khromova, M. Bykhovskaia, B. L. Gelmont, and J. Hesler, "Terahertz Fourier transform characterization of biological materials in a liquid phase," J. Phys. D 39, 3405-3413 (2006).
[CrossRef]

J. Xu, K. W. Plaxco, and S. J. Allen, "Probing the collective vibrational dynamics of a protein in liquid water by terahertz absorption spectroscopy," Prot. Sci. 15, 1175-1181 (2006).
[CrossRef]

M. Nagai, H. Yada, T. Arikawa, and K. Tanaka, "Terahertz time-domain attenuated total reflection spectroscopy in water and biological solutions," Intl. J. Inf. and Mill. Waves 27, 505-515 (2006).
[CrossRef]

J. Kitagawa, T. Ohkubo, M. Onuma, and Y. Kadoya, "THz spectroscopic characterization of biomolecule/water systems by compact sensor chips," Appl. Phys. Lett. 89, 041114 (2006).
[CrossRef]

2003 (2)

T. Baras, T. Kleine-Ostmann, and M. Koch, "On-chip THz detection of biomaterials: a numerical study," J. Bio. Phys. 29, 187-194 (2003).
[CrossRef]

T. R. Globus, D. L. Woolard, T. Khromova, T. W. Crowe, M. Bykhovskaia, B. L. Gelmont, J. Hesler, and A. C. Samuels, "THz-spectroscopy of biological molecules," J. Bio. Phys. 29, 89-100 (2003).
[CrossRef]

2002 (1)

M. Nagel, P. H. Bolivar, M. Brucherseifer, H. Kurz, A. Bosserhoff, and R. Buttner, "Integrated THz technology for label-free genetic diagnostics," Appl. Phys. Lett. 80, 154 (2002).
[CrossRef]

2000 (1)

A. G. Markelz, and 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, 42-48 (2000).
[CrossRef]

1995 (1)

S. Hayward and N. Go, "Collective variable description of native protein dynamics," Annu. Rev. Phys. Chem. 46, 223-250 (1995).
[CrossRef]

1990 (1)

W. Zhuang, Y. Feng, and E. W. Prohofsky, "Self-consistent calculation of localized DNA vibrational properties at a double-helix-single-strand junction with anharmonic potential," Phys. Rev. A 41, 7033-7042 (1990).
[CrossRef] [PubMed]

1976 (1)

M. C. Chen and R. C. Lord, "Laser-excited Raman spectroscopy of biomolecules: conformational study of bovine serum albumin," J. Am. Chem. Soc. 98, 990-992 (1976).
[CrossRef] [PubMed]

Anal. Chem. (1)

B. G. Hawkins, A. E. Smith, Y. A. Syed, and B. J. Kirby, "Continuous-flow particle separation by 3D insulative dielectrophoresis using coherently shaped, dc-biased, ac electric fields," Anal. Chem. 79, 7291-7300(2007).
[CrossRef] [PubMed]

Annu. Rev. Phys. Chem. (1)

S. Hayward and N. Go, "Collective variable description of native protein dynamics," Annu. Rev. Phys. Chem. 46, 223-250 (1995).
[CrossRef]

Appl. Phys. Lett. (2)

J. Kitagawa, T. Ohkubo, M. Onuma, and Y. Kadoya, "THz spectroscopic characterization of biomolecule/water systems by compact sensor chips," Appl. Phys. Lett. 89, 041114 (2006).
[CrossRef]

M. Nagel, P. H. Bolivar, M. Brucherseifer, H. Kurz, A. Bosserhoff, and R. Buttner, "Integrated THz technology for label-free genetic diagnostics," Appl. Phys. Lett. 80, 154 (2002).
[CrossRef]

Chem. Phys. Lett. (1)

A. G. Markelz, and 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, 42-48 (2000).
[CrossRef]

Intl. J. Inf. and Mill. Waves (1)

M. Nagai, H. Yada, T. Arikawa, and K. Tanaka, "Terahertz time-domain attenuated total reflection spectroscopy in water and biological solutions," Intl. J. Inf. and Mill. Waves 27, 505-515 (2006).
[CrossRef]

J. Am. Chem. Soc. (1)

M. C. Chen and R. C. Lord, "Laser-excited Raman spectroscopy of biomolecules: conformational study of bovine serum albumin," J. Am. Chem. Soc. 98, 990-992 (1976).
[CrossRef] [PubMed]

J. Bio. Phys. (2)

T. Baras, T. Kleine-Ostmann, and M. Koch, "On-chip THz detection of biomaterials: a numerical study," J. Bio. Phys. 29, 187-194 (2003).
[CrossRef]

T. R. Globus, D. L. Woolard, T. Khromova, T. W. Crowe, M. Bykhovskaia, B. L. Gelmont, J. Hesler, and A. C. Samuels, "THz-spectroscopy of biological molecules," J. Bio. Phys. 29, 89-100 (2003).
[CrossRef]

J. Phys. D (1)

T. R. Globus, D. L. Woolard, T. W. Crowe, T. Khromova, M. Bykhovskaia, B. L. Gelmont, and J. Hesler, "Terahertz Fourier transform characterization of biological materials in a liquid phase," J. Phys. D 39, 3405-3413 (2006).
[CrossRef]

Lab on a Chip (1)

T. I. Wallow, A. M. Morales, B. A. Simmons, M. C. Hunter, K. L. Krafcik, L. A. Domeier, S. M. Sickafoose, K. D. Patel, and A. Gardea, "Low-distortion, high-strength bonding of thermoplastic microfluidic devices employing case-II diffusion-mediated permeant activation," Lab on a Chip 7, 1825-1831 (2007).
[CrossRef] [PubMed]

Phys. Rev. A (1)

W. Zhuang, Y. Feng, and E. W. Prohofsky, "Self-consistent calculation of localized DNA vibrational properties at a double-helix-single-strand junction with anharmonic potential," Phys. Rev. A 41, 7033-7042 (1990).
[CrossRef] [PubMed]

Prot. Sci. (1)

J. Xu, K. W. Plaxco, and S. J. Allen, "Probing the collective vibrational dynamics of a protein in liquid water by terahertz absorption spectroscopy," Prot. Sci. 15, 1175-1181 (2006).
[CrossRef]

Other (3)

"Zeonor Production Information Sheet," Zeon Corporation (2004).

"Bovine serum albumin product information sheet," (Sigma-Aldrich, 2000).

R. D. Levine, Molecular Reaction Dynamics, (Cambridge Univeristy Press, 2005).
[CrossRef]

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Figures (5)

Fig. 1.
Fig. 1.

A system for on-chip THz sensing. The device contains sample and reagent inputs, a reaction chamber, and a detection chamber for THz as well as optical and IR spectroscopy.

Fig. 2.
Fig. 2.

The measured absorption coefficient of Zeonor 1020R and PDMS. Zeonor has a nearly constant index of 1.518 (not shown) and an absorption coefficient <1 cm-1 at THz frequencies, which is 10-20 times smaller than that of PDMS.

Fig. 3.
Fig. 3.

Fabrication of the microfluidic devices used in this work. (a) A slab of Zeonor 1020R was first embossed using a Si template. (b) The embossed slab was then bonded to another piece of Zeonor 1020R. The final channel depth was 95 µm.

Fig. 4.
Fig. 4.

The absorption coefficient of the phosphate buffer and BSA solutions measured by THz-TDS using microfluidic devices. Values are extracted using Eq. 2.

Fig. 5.
Fig. 5.

(a) The measured molecular absorption coefficient of hydrated BSA molecules. In agreement with Beer’s Law, the absorption coefficient does not depend on solution concentration. (b) The molar extinction of BSA measured using microfluidic channels compared to the results in [7]. The excellent agreement demonstrates the feasibility of performing THz spectroscopy of biomolecules in microfluidic channels using low-power THz sources.

Equations (4)

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t = E m ( ω ) E r ( ω ) = 4 n ( 1 + n ) 2 e i ω c ( n 1 ) d
t = E s ( ω ) E a ( ω ) = n s e i ω c ( n s 1 ) d c [ ( n z + 1 ) 2 ( n z 1 ) 2 e 2 i ω c d c ( n z + n s ) 2 ( n z n s ) 2 e 2 i ω c n s d c ]
α s = α bsa V bsa V bsa + V pb + α pb V pb V bsa + V pb
α mbsa = α bsa N A V mbsa

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