Abstract

Terahertz (THz) imaging is a nondestructive, label-free, rapid imaging technique which gives the possibility of a real-time tracing of drugs within the skin. We evaluated the feasibility of THz dynamic imaging for visualizing serial changes in the distribution and penetration of a topical agent, dimethyl sulfoxide (DMSO) containing ketoprofen, using excised mouse skins. THz imaging was performed for 6 h after drug application to the skin and was compared with the results obtained using the Franz cell diffusion test, a standard in vitro skin absorption test. THz dynamic reflection imaging showed that the reflection signals decreased rapidly during the early time period, and remained constant through the late time period. The area of drug permeation within the skin layer on THz imaging increased with time. The dynamic pattern of THz reflection signal decrease was similar to that of DMSO absorption analyzed by the Franz cell diffusion test, which indicates that THz imaging mainly reflects the DMSO component. This study demonstrates that THz imaging technique can be used for imaging the spatial distribution and penetration of drug-applied sites.

© 2012 OSA

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  1. J.-H. Son, “Terahertz electromagnetic interactions with biological matter and their applications,” J. Appl. Phys. 105(10), 102033 (2009).
    [CrossRef]
  2. R. M. Woodward, B. E. Cole, V. P. Wallace, R. J. Pye, D. D. Arnone, E. H. Linfield, and M. Pepper, “Terahertz pulse imaging in reflection geometry of human skin cancer and skin tissue,” Phys. Med. Biol. 47(21), 3853–3863 (2002).
    [CrossRef] [PubMed]
  3. A. J. Fitzgerald, V. P. Wallace, M. Jimenez-Linan, L. Bobrow, R. J. Pye, A. D. Purushotham, and D. D. Arnone, “Terahertz pulsed imaging of human breast tumors,” Radiology 239(2), 533–540 (2006).
    [CrossRef] [PubMed]
  4. S. J. Oh, J. Kang, I. Maeng, J. S. Suh, Y. M. Huh, S. Haam, and J.-H. Son, “Nanoparticle-enabled terahertz imaging for cancer diagnosis,” Opt. Express 17(5), 3469–3475 (2009).
    [CrossRef] [PubMed]
  5. S. J. Oh, J. Choi, I. Maeng, J. Y. Park, K. Lee, Y. M. Huh, J. S. Suh, S. Haam, and J.-H. Son, “Molecular imaging with terahertz waves,” Opt. Express 19(5), 4009–4016 (2011).
    [CrossRef] [PubMed]
  6. D. F. Plusquellic, K. Siegrist, E. J. Heilweil, and O. Esenturk, “Applications of terahertz spectroscopy in biosystems,” ChemPhysChem 8(17), 2412–2431 (2007).
    [CrossRef] [PubMed]
  7. Y. Ueno and K. Ajito, “Analytical terahertz spectroscopy,” Anal. Sci. 24(2), 185–192 (2008).
    [CrossRef] [PubMed]
  8. K. W. Kim, H. Kim, J. Park, J. K. Han, and J.-H. Son, ““Terahertz tomographic imaging of transdermal drug delivery,” IEEE Trans. THz,” Sci. Tech. (Paris) 2, 99–106 (2012).
  9. A. Tfayli, O. Piot, F. Pitre, and M. Manfait, “Follow-up of drug permeation through excised human skin with confocal Raman microspectroscopy,” Eur. Biophys. J. 36(8), 1049–1058 (2007).
    [CrossRef] [PubMed]
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    [CrossRef]
  12. M. Rizwan, M. Aqil, S. Talegaonkar, A. Azeem, Y. Sultana, and A. Ali, “Enhanced transdermal drug delivery techniques: an extensive review of patents,” Recent Pat. Drug Deliv. Formul. 3(2), 105–124 (2009).
    [CrossRef] [PubMed]
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    [CrossRef] [PubMed]
  14. T. J. Franz, “The finite dose technique as a valid in vitro model for the study of percutaneous absorption in man,” Curr. Probl. Dermatol. 7, 58–68 (1978).
    [PubMed]
  15. J. Y. Suen, P. Tewari, Z. D. Taylor, W. S. Grundfest, H. Lee, E. R. Brown, M. O. Culjat, and R. S. Singh, “Towards medical terahertz sensing of skin hydration,” Stud. Health Technol. Inform. 142, 364–368 (2009).
    [PubMed]
  16. M. S. Skaf, “Static dielectric properties of a model for liquid DMSO,” Mol. Phys. 90(1), 25–34 (1997).
    [CrossRef]
  17. Y. B. Ji, E. S. Lee, S. H. Kim, J. H. Son, and T. I. Jeon, “A miniaturized fiber-coupled terahertz endoscope system,” Opt. Express 17(19), 17082–17087 (2009).
    [CrossRef] [PubMed]
  18. S. C. Wilkinson, W. J. M. Maas, J. B. Nielsen, L. C. Greaves, J. J. M. van de Sandt, and F. M. Williams, “Interactions of skin thickness and physicochemical properties of test compounds in percutaneous penetration studies,” Int. Arch. Occup. Environ. Health 79(5), 405–413 (2006).
    [CrossRef] [PubMed]
  19. K. König, A. Ehlers, F. Stracke, and I. Riemann, “In vivo drug screening in human skin using femtosecond laser multiphoton tomography,” Skin Pharmacol. Physiol. 19(2), 78–88 (2006).
    [CrossRef] [PubMed]
  20. E. Touitou, V. M. Meidan, and E. Horwitz, “Methods for quantitative determination of drug localized in the skin,” J. Control. Release 56(1-3), 7–21 (1998).
    [CrossRef] [PubMed]
  21. T. Hattori and M. Sakamoto, “Deformation corrected real-time terahertz imaging,” Appl. Phys. Lett. 90(26), 261106 (2007).
    [CrossRef]
  22. S. H. Cho, S. H. Lee, C. Nam-Gung, S. J. Oh, J.-H. Son, H. Park, and C. B. Ahn, “Fast terahertz reflection tomography using block-based compressed sensing,” Opt. Express 19(17), 16401–16409 (2011).
    [CrossRef] [PubMed]
  23. K. Cal, J. Stefanowska, and D. Zakowiecki, “Current tools for skin imaging and analysis,” Int. J. Dermatol. 48(12), 1283–1289 (2009).
    [CrossRef] [PubMed]

2012 (1)

K. W. Kim, H. Kim, J. Park, J. K. Han, and J.-H. Son, ““Terahertz tomographic imaging of transdermal drug delivery,” IEEE Trans. THz,” Sci. Tech. (Paris) 2, 99–106 (2012).

2011 (3)

2009 (6)

K. Cal, J. Stefanowska, and D. Zakowiecki, “Current tools for skin imaging and analysis,” Int. J. Dermatol. 48(12), 1283–1289 (2009).
[CrossRef] [PubMed]

S. J. Oh, J. Kang, I. Maeng, J. S. Suh, Y. M. Huh, S. Haam, and J.-H. Son, “Nanoparticle-enabled terahertz imaging for cancer diagnosis,” Opt. Express 17(5), 3469–3475 (2009).
[CrossRef] [PubMed]

Y. B. Ji, E. S. Lee, S. H. Kim, J. H. Son, and T. I. Jeon, “A miniaturized fiber-coupled terahertz endoscope system,” Opt. Express 17(19), 17082–17087 (2009).
[CrossRef] [PubMed]

M. Rizwan, M. Aqil, S. Talegaonkar, A. Azeem, Y. Sultana, and A. Ali, “Enhanced transdermal drug delivery techniques: an extensive review of patents,” Recent Pat. Drug Deliv. Formul. 3(2), 105–124 (2009).
[CrossRef] [PubMed]

J. Y. Suen, P. Tewari, Z. D. Taylor, W. S. Grundfest, H. Lee, E. R. Brown, M. O. Culjat, and R. S. Singh, “Towards medical terahertz sensing of skin hydration,” Stud. Health Technol. Inform. 142, 364–368 (2009).
[PubMed]

J.-H. Son, “Terahertz electromagnetic interactions with biological matter and their applications,” J. Appl. Phys. 105(10), 102033 (2009).
[CrossRef]

2008 (1)

Y. Ueno and K. Ajito, “Analytical terahertz spectroscopy,” Anal. Sci. 24(2), 185–192 (2008).
[CrossRef] [PubMed]

2007 (3)

D. F. Plusquellic, K. Siegrist, E. J. Heilweil, and O. Esenturk, “Applications of terahertz spectroscopy in biosystems,” ChemPhysChem 8(17), 2412–2431 (2007).
[CrossRef] [PubMed]

A. Tfayli, O. Piot, F. Pitre, and M. Manfait, “Follow-up of drug permeation through excised human skin with confocal Raman microspectroscopy,” Eur. Biophys. J. 36(8), 1049–1058 (2007).
[CrossRef] [PubMed]

T. Hattori and M. Sakamoto, “Deformation corrected real-time terahertz imaging,” Appl. Phys. Lett. 90(26), 261106 (2007).
[CrossRef]

2006 (3)

A. J. Fitzgerald, V. P. Wallace, M. Jimenez-Linan, L. Bobrow, R. J. Pye, A. D. Purushotham, and D. D. Arnone, “Terahertz pulsed imaging of human breast tumors,” Radiology 239(2), 533–540 (2006).
[CrossRef] [PubMed]

S. C. Wilkinson, W. J. M. Maas, J. B. Nielsen, L. C. Greaves, J. J. M. van de Sandt, and F. M. Williams, “Interactions of skin thickness and physicochemical properties of test compounds in percutaneous penetration studies,” Int. Arch. Occup. Environ. Health 79(5), 405–413 (2006).
[CrossRef] [PubMed]

K. König, A. Ehlers, F. Stracke, and I. Riemann, “In vivo drug screening in human skin using femtosecond laser multiphoton tomography,” Skin Pharmacol. Physiol. 19(2), 78–88 (2006).
[CrossRef] [PubMed]

2002 (1)

R. M. Woodward, B. E. Cole, V. P. Wallace, R. J. Pye, D. D. Arnone, E. H. Linfield, and M. Pepper, “Terahertz pulse imaging in reflection geometry of human skin cancer and skin tissue,” Phys. Med. Biol. 47(21), 3853–3863 (2002).
[CrossRef] [PubMed]

1998 (1)

E. Touitou, V. M. Meidan, and E. Horwitz, “Methods for quantitative determination of drug localized in the skin,” J. Control. Release 56(1-3), 7–21 (1998).
[CrossRef] [PubMed]

1997 (1)

M. S. Skaf, “Static dielectric properties of a model for liquid DMSO,” Mol. Phys. 90(1), 25–34 (1997).
[CrossRef]

1978 (1)

T. J. Franz, “The finite dose technique as a valid in vitro model for the study of percutaneous absorption in man,” Curr. Probl. Dermatol. 7, 58–68 (1978).
[PubMed]

1975 (1)

T. J. Franz, “Percutaneous absorption on the relevance of in vitro data,” J. Invest. Dermatol. 64(3), 190–195 (1975).
[CrossRef] [PubMed]

Ahn, C. B.

Ajito, K.

Y. Ueno and K. Ajito, “Analytical terahertz spectroscopy,” Anal. Sci. 24(2), 185–192 (2008).
[CrossRef] [PubMed]

Ali, A.

M. Rizwan, M. Aqil, S. Talegaonkar, A. Azeem, Y. Sultana, and A. Ali, “Enhanced transdermal drug delivery techniques: an extensive review of patents,” Recent Pat. Drug Deliv. Formul. 3(2), 105–124 (2009).
[CrossRef] [PubMed]

Aqil, M.

M. Rizwan, M. Aqil, S. Talegaonkar, A. Azeem, Y. Sultana, and A. Ali, “Enhanced transdermal drug delivery techniques: an extensive review of patents,” Recent Pat. Drug Deliv. Formul. 3(2), 105–124 (2009).
[CrossRef] [PubMed]

Arnone, D. D.

A. J. Fitzgerald, V. P. Wallace, M. Jimenez-Linan, L. Bobrow, R. J. Pye, A. D. Purushotham, and D. D. Arnone, “Terahertz pulsed imaging of human breast tumors,” Radiology 239(2), 533–540 (2006).
[CrossRef] [PubMed]

R. M. Woodward, B. E. Cole, V. P. Wallace, R. J. Pye, D. D. Arnone, E. H. Linfield, and M. Pepper, “Terahertz pulse imaging in reflection geometry of human skin cancer and skin tissue,” Phys. Med. Biol. 47(21), 3853–3863 (2002).
[CrossRef] [PubMed]

Azeem, A.

M. Rizwan, M. Aqil, S. Talegaonkar, A. Azeem, Y. Sultana, and A. Ali, “Enhanced transdermal drug delivery techniques: an extensive review of patents,” Recent Pat. Drug Deliv. Formul. 3(2), 105–124 (2009).
[CrossRef] [PubMed]

Bobrow, L.

A. J. Fitzgerald, V. P. Wallace, M. Jimenez-Linan, L. Bobrow, R. J. Pye, A. D. Purushotham, and D. D. Arnone, “Terahertz pulsed imaging of human breast tumors,” Radiology 239(2), 533–540 (2006).
[CrossRef] [PubMed]

Brown, E. R.

J. Y. Suen, P. Tewari, Z. D. Taylor, W. S. Grundfest, H. Lee, E. R. Brown, M. O. Culjat, and R. S. Singh, “Towards medical terahertz sensing of skin hydration,” Stud. Health Technol. Inform. 142, 364–368 (2009).
[PubMed]

Cal, K.

K. Cal, J. Stefanowska, and D. Zakowiecki, “Current tools for skin imaging and analysis,” Int. J. Dermatol. 48(12), 1283–1289 (2009).
[CrossRef] [PubMed]

Cho, K.-S.

J. Y. Park, H. J. Choi, K.-S. Cho, K.-R. Kim, and J.-H. Son, “Terahertz spectroscopic imaging of a rabbit VX2 hepatoma model,” J. Appl. Phys. 109(6), 064704 (2011).
[CrossRef]

Cho, S. H.

Choi, H. J.

J. Y. Park, H. J. Choi, K.-S. Cho, K.-R. Kim, and J.-H. Son, “Terahertz spectroscopic imaging of a rabbit VX2 hepatoma model,” J. Appl. Phys. 109(6), 064704 (2011).
[CrossRef]

Choi, J.

Cole, B. E.

R. M. Woodward, B. E. Cole, V. P. Wallace, R. J. Pye, D. D. Arnone, E. H. Linfield, and M. Pepper, “Terahertz pulse imaging in reflection geometry of human skin cancer and skin tissue,” Phys. Med. Biol. 47(21), 3853–3863 (2002).
[CrossRef] [PubMed]

Culjat, M. O.

J. Y. Suen, P. Tewari, Z. D. Taylor, W. S. Grundfest, H. Lee, E. R. Brown, M. O. Culjat, and R. S. Singh, “Towards medical terahertz sensing of skin hydration,” Stud. Health Technol. Inform. 142, 364–368 (2009).
[PubMed]

Ehlers, A.

K. König, A. Ehlers, F. Stracke, and I. Riemann, “In vivo drug screening in human skin using femtosecond laser multiphoton tomography,” Skin Pharmacol. Physiol. 19(2), 78–88 (2006).
[CrossRef] [PubMed]

Esenturk, O.

D. F. Plusquellic, K. Siegrist, E. J. Heilweil, and O. Esenturk, “Applications of terahertz spectroscopy in biosystems,” ChemPhysChem 8(17), 2412–2431 (2007).
[CrossRef] [PubMed]

Fitzgerald, A. J.

A. J. Fitzgerald, V. P. Wallace, M. Jimenez-Linan, L. Bobrow, R. J. Pye, A. D. Purushotham, and D. D. Arnone, “Terahertz pulsed imaging of human breast tumors,” Radiology 239(2), 533–540 (2006).
[CrossRef] [PubMed]

Franz, T. J.

T. J. Franz, “The finite dose technique as a valid in vitro model for the study of percutaneous absorption in man,” Curr. Probl. Dermatol. 7, 58–68 (1978).
[PubMed]

T. J. Franz, “Percutaneous absorption on the relevance of in vitro data,” J. Invest. Dermatol. 64(3), 190–195 (1975).
[CrossRef] [PubMed]

Greaves, L. C.

S. C. Wilkinson, W. J. M. Maas, J. B. Nielsen, L. C. Greaves, J. J. M. van de Sandt, and F. M. Williams, “Interactions of skin thickness and physicochemical properties of test compounds in percutaneous penetration studies,” Int. Arch. Occup. Environ. Health 79(5), 405–413 (2006).
[CrossRef] [PubMed]

Grundfest, W. S.

J. Y. Suen, P. Tewari, Z. D. Taylor, W. S. Grundfest, H. Lee, E. R. Brown, M. O. Culjat, and R. S. Singh, “Towards medical terahertz sensing of skin hydration,” Stud. Health Technol. Inform. 142, 364–368 (2009).
[PubMed]

Haam, S.

Han, J. K.

K. W. Kim, H. Kim, J. Park, J. K. Han, and J.-H. Son, ““Terahertz tomographic imaging of transdermal drug delivery,” IEEE Trans. THz,” Sci. Tech. (Paris) 2, 99–106 (2012).

Hattori, T.

T. Hattori and M. Sakamoto, “Deformation corrected real-time terahertz imaging,” Appl. Phys. Lett. 90(26), 261106 (2007).
[CrossRef]

Heilweil, E. J.

D. F. Plusquellic, K. Siegrist, E. J. Heilweil, and O. Esenturk, “Applications of terahertz spectroscopy in biosystems,” ChemPhysChem 8(17), 2412–2431 (2007).
[CrossRef] [PubMed]

Horwitz, E.

E. Touitou, V. M. Meidan, and E. Horwitz, “Methods for quantitative determination of drug localized in the skin,” J. Control. Release 56(1-3), 7–21 (1998).
[CrossRef] [PubMed]

Huh, Y. M.

Jeon, T. I.

Ji, Y. B.

Jimenez-Linan, M.

A. J. Fitzgerald, V. P. Wallace, M. Jimenez-Linan, L. Bobrow, R. J. Pye, A. D. Purushotham, and D. D. Arnone, “Terahertz pulsed imaging of human breast tumors,” Radiology 239(2), 533–540 (2006).
[CrossRef] [PubMed]

Kang, J.

Kim, H.

K. W. Kim, H. Kim, J. Park, J. K. Han, and J.-H. Son, ““Terahertz tomographic imaging of transdermal drug delivery,” IEEE Trans. THz,” Sci. Tech. (Paris) 2, 99–106 (2012).

Kim, K. W.

K. W. Kim, H. Kim, J. Park, J. K. Han, and J.-H. Son, ““Terahertz tomographic imaging of transdermal drug delivery,” IEEE Trans. THz,” Sci. Tech. (Paris) 2, 99–106 (2012).

Kim, K.-R.

J. Y. Park, H. J. Choi, K.-S. Cho, K.-R. Kim, and J.-H. Son, “Terahertz spectroscopic imaging of a rabbit VX2 hepatoma model,” J. Appl. Phys. 109(6), 064704 (2011).
[CrossRef]

Kim, S. H.

König, K.

K. König, A. Ehlers, F. Stracke, and I. Riemann, “In vivo drug screening in human skin using femtosecond laser multiphoton tomography,” Skin Pharmacol. Physiol. 19(2), 78–88 (2006).
[CrossRef] [PubMed]

Lee, E. S.

Lee, H.

J. Y. Suen, P. Tewari, Z. D. Taylor, W. S. Grundfest, H. Lee, E. R. Brown, M. O. Culjat, and R. S. Singh, “Towards medical terahertz sensing of skin hydration,” Stud. Health Technol. Inform. 142, 364–368 (2009).
[PubMed]

Lee, K.

Lee, S. H.

Linfield, E. H.

R. M. Woodward, B. E. Cole, V. P. Wallace, R. J. Pye, D. D. Arnone, E. H. Linfield, and M. Pepper, “Terahertz pulse imaging in reflection geometry of human skin cancer and skin tissue,” Phys. Med. Biol. 47(21), 3853–3863 (2002).
[CrossRef] [PubMed]

Maas, W. J. M.

S. C. Wilkinson, W. J. M. Maas, J. B. Nielsen, L. C. Greaves, J. J. M. van de Sandt, and F. M. Williams, “Interactions of skin thickness and physicochemical properties of test compounds in percutaneous penetration studies,” Int. Arch. Occup. Environ. Health 79(5), 405–413 (2006).
[CrossRef] [PubMed]

Maeng, I.

Manfait, M.

A. Tfayli, O. Piot, F. Pitre, and M. Manfait, “Follow-up of drug permeation through excised human skin with confocal Raman microspectroscopy,” Eur. Biophys. J. 36(8), 1049–1058 (2007).
[CrossRef] [PubMed]

Meidan, V. M.

E. Touitou, V. M. Meidan, and E. Horwitz, “Methods for quantitative determination of drug localized in the skin,” J. Control. Release 56(1-3), 7–21 (1998).
[CrossRef] [PubMed]

Nam-Gung, C.

Nielsen, J. B.

S. C. Wilkinson, W. J. M. Maas, J. B. Nielsen, L. C. Greaves, J. J. M. van de Sandt, and F. M. Williams, “Interactions of skin thickness and physicochemical properties of test compounds in percutaneous penetration studies,” Int. Arch. Occup. Environ. Health 79(5), 405–413 (2006).
[CrossRef] [PubMed]

Oh, S. J.

Park, H.

Park, J.

K. W. Kim, H. Kim, J. Park, J. K. Han, and J.-H. Son, ““Terahertz tomographic imaging of transdermal drug delivery,” IEEE Trans. THz,” Sci. Tech. (Paris) 2, 99–106 (2012).

Park, J. Y.

J. Y. Park, H. J. Choi, K.-S. Cho, K.-R. Kim, and J.-H. Son, “Terahertz spectroscopic imaging of a rabbit VX2 hepatoma model,” J. Appl. Phys. 109(6), 064704 (2011).
[CrossRef]

S. J. Oh, J. Choi, I. Maeng, J. Y. Park, K. Lee, Y. M. Huh, J. S. Suh, S. Haam, and J.-H. Son, “Molecular imaging with terahertz waves,” Opt. Express 19(5), 4009–4016 (2011).
[CrossRef] [PubMed]

Pepper, M.

R. M. Woodward, B. E. Cole, V. P. Wallace, R. J. Pye, D. D. Arnone, E. H. Linfield, and M. Pepper, “Terahertz pulse imaging in reflection geometry of human skin cancer and skin tissue,” Phys. Med. Biol. 47(21), 3853–3863 (2002).
[CrossRef] [PubMed]

Piot, O.

A. Tfayli, O. Piot, F. Pitre, and M. Manfait, “Follow-up of drug permeation through excised human skin with confocal Raman microspectroscopy,” Eur. Biophys. J. 36(8), 1049–1058 (2007).
[CrossRef] [PubMed]

Pitre, F.

A. Tfayli, O. Piot, F. Pitre, and M. Manfait, “Follow-up of drug permeation through excised human skin with confocal Raman microspectroscopy,” Eur. Biophys. J. 36(8), 1049–1058 (2007).
[CrossRef] [PubMed]

Plusquellic, D. F.

D. F. Plusquellic, K. Siegrist, E. J. Heilweil, and O. Esenturk, “Applications of terahertz spectroscopy in biosystems,” ChemPhysChem 8(17), 2412–2431 (2007).
[CrossRef] [PubMed]

Purushotham, A. D.

A. J. Fitzgerald, V. P. Wallace, M. Jimenez-Linan, L. Bobrow, R. J. Pye, A. D. Purushotham, and D. D. Arnone, “Terahertz pulsed imaging of human breast tumors,” Radiology 239(2), 533–540 (2006).
[CrossRef] [PubMed]

Pye, R. J.

A. J. Fitzgerald, V. P. Wallace, M. Jimenez-Linan, L. Bobrow, R. J. Pye, A. D. Purushotham, and D. D. Arnone, “Terahertz pulsed imaging of human breast tumors,” Radiology 239(2), 533–540 (2006).
[CrossRef] [PubMed]

R. M. Woodward, B. E. Cole, V. P. Wallace, R. J. Pye, D. D. Arnone, E. H. Linfield, and M. Pepper, “Terahertz pulse imaging in reflection geometry of human skin cancer and skin tissue,” Phys. Med. Biol. 47(21), 3853–3863 (2002).
[CrossRef] [PubMed]

Riemann, I.

K. König, A. Ehlers, F. Stracke, and I. Riemann, “In vivo drug screening in human skin using femtosecond laser multiphoton tomography,” Skin Pharmacol. Physiol. 19(2), 78–88 (2006).
[CrossRef] [PubMed]

Rizwan, M.

M. Rizwan, M. Aqil, S. Talegaonkar, A. Azeem, Y. Sultana, and A. Ali, “Enhanced transdermal drug delivery techniques: an extensive review of patents,” Recent Pat. Drug Deliv. Formul. 3(2), 105–124 (2009).
[CrossRef] [PubMed]

Sakamoto, M.

T. Hattori and M. Sakamoto, “Deformation corrected real-time terahertz imaging,” Appl. Phys. Lett. 90(26), 261106 (2007).
[CrossRef]

Siegrist, K.

D. F. Plusquellic, K. Siegrist, E. J. Heilweil, and O. Esenturk, “Applications of terahertz spectroscopy in biosystems,” ChemPhysChem 8(17), 2412–2431 (2007).
[CrossRef] [PubMed]

Singh, R. S.

J. Y. Suen, P. Tewari, Z. D. Taylor, W. S. Grundfest, H. Lee, E. R. Brown, M. O. Culjat, and R. S. Singh, “Towards medical terahertz sensing of skin hydration,” Stud. Health Technol. Inform. 142, 364–368 (2009).
[PubMed]

Skaf, M. S.

M. S. Skaf, “Static dielectric properties of a model for liquid DMSO,” Mol. Phys. 90(1), 25–34 (1997).
[CrossRef]

Son, J. H.

Son, J.-H.

K. W. Kim, H. Kim, J. Park, J. K. Han, and J.-H. Son, ““Terahertz tomographic imaging of transdermal drug delivery,” IEEE Trans. THz,” Sci. Tech. (Paris) 2, 99–106 (2012).

J. Y. Park, H. J. Choi, K.-S. Cho, K.-R. Kim, and J.-H. Son, “Terahertz spectroscopic imaging of a rabbit VX2 hepatoma model,” J. Appl. Phys. 109(6), 064704 (2011).
[CrossRef]

S. J. Oh, J. Choi, I. Maeng, J. Y. Park, K. Lee, Y. M. Huh, J. S. Suh, S. Haam, and J.-H. Son, “Molecular imaging with terahertz waves,” Opt. Express 19(5), 4009–4016 (2011).
[CrossRef] [PubMed]

S. H. Cho, S. H. Lee, C. Nam-Gung, S. J. Oh, J.-H. Son, H. Park, and C. B. Ahn, “Fast terahertz reflection tomography using block-based compressed sensing,” Opt. Express 19(17), 16401–16409 (2011).
[CrossRef] [PubMed]

S. J. Oh, J. Kang, I. Maeng, J. S. Suh, Y. M. Huh, S. Haam, and J.-H. Son, “Nanoparticle-enabled terahertz imaging for cancer diagnosis,” Opt. Express 17(5), 3469–3475 (2009).
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J.-H. Son, “Terahertz electromagnetic interactions with biological matter and their applications,” J. Appl. Phys. 105(10), 102033 (2009).
[CrossRef]

Stefanowska, J.

K. Cal, J. Stefanowska, and D. Zakowiecki, “Current tools for skin imaging and analysis,” Int. J. Dermatol. 48(12), 1283–1289 (2009).
[CrossRef] [PubMed]

Stracke, F.

K. König, A. Ehlers, F. Stracke, and I. Riemann, “In vivo drug screening in human skin using femtosecond laser multiphoton tomography,” Skin Pharmacol. Physiol. 19(2), 78–88 (2006).
[CrossRef] [PubMed]

Suen, J. Y.

J. Y. Suen, P. Tewari, Z. D. Taylor, W. S. Grundfest, H. Lee, E. R. Brown, M. O. Culjat, and R. S. Singh, “Towards medical terahertz sensing of skin hydration,” Stud. Health Technol. Inform. 142, 364–368 (2009).
[PubMed]

Suh, J. S.

Sultana, Y.

M. Rizwan, M. Aqil, S. Talegaonkar, A. Azeem, Y. Sultana, and A. Ali, “Enhanced transdermal drug delivery techniques: an extensive review of patents,” Recent Pat. Drug Deliv. Formul. 3(2), 105–124 (2009).
[CrossRef] [PubMed]

Talegaonkar, S.

M. Rizwan, M. Aqil, S. Talegaonkar, A. Azeem, Y. Sultana, and A. Ali, “Enhanced transdermal drug delivery techniques: an extensive review of patents,” Recent Pat. Drug Deliv. Formul. 3(2), 105–124 (2009).
[CrossRef] [PubMed]

Taylor, Z. D.

J. Y. Suen, P. Tewari, Z. D. Taylor, W. S. Grundfest, H. Lee, E. R. Brown, M. O. Culjat, and R. S. Singh, “Towards medical terahertz sensing of skin hydration,” Stud. Health Technol. Inform. 142, 364–368 (2009).
[PubMed]

Tewari, P.

J. Y. Suen, P. Tewari, Z. D. Taylor, W. S. Grundfest, H. Lee, E. R. Brown, M. O. Culjat, and R. S. Singh, “Towards medical terahertz sensing of skin hydration,” Stud. Health Technol. Inform. 142, 364–368 (2009).
[PubMed]

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A. Tfayli, O. Piot, F. Pitre, and M. Manfait, “Follow-up of drug permeation through excised human skin with confocal Raman microspectroscopy,” Eur. Biophys. J. 36(8), 1049–1058 (2007).
[CrossRef] [PubMed]

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E. Touitou, V. M. Meidan, and E. Horwitz, “Methods for quantitative determination of drug localized in the skin,” J. Control. Release 56(1-3), 7–21 (1998).
[CrossRef] [PubMed]

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Y. Ueno and K. Ajito, “Analytical terahertz spectroscopy,” Anal. Sci. 24(2), 185–192 (2008).
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S. C. Wilkinson, W. J. M. Maas, J. B. Nielsen, L. C. Greaves, J. J. M. van de Sandt, and F. M. Williams, “Interactions of skin thickness and physicochemical properties of test compounds in percutaneous penetration studies,” Int. Arch. Occup. Environ. Health 79(5), 405–413 (2006).
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A. J. Fitzgerald, V. P. Wallace, M. Jimenez-Linan, L. Bobrow, R. J. Pye, A. D. Purushotham, and D. D. Arnone, “Terahertz pulsed imaging of human breast tumors,” Radiology 239(2), 533–540 (2006).
[CrossRef] [PubMed]

R. M. Woodward, B. E. Cole, V. P. Wallace, R. J. Pye, D. D. Arnone, E. H. Linfield, and M. Pepper, “Terahertz pulse imaging in reflection geometry of human skin cancer and skin tissue,” Phys. Med. Biol. 47(21), 3853–3863 (2002).
[CrossRef] [PubMed]

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S. C. Wilkinson, W. J. M. Maas, J. B. Nielsen, L. C. Greaves, J. J. M. van de Sandt, and F. M. Williams, “Interactions of skin thickness and physicochemical properties of test compounds in percutaneous penetration studies,” Int. Arch. Occup. Environ. Health 79(5), 405–413 (2006).
[CrossRef] [PubMed]

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S. C. Wilkinson, W. J. M. Maas, J. B. Nielsen, L. C. Greaves, J. J. M. van de Sandt, and F. M. Williams, “Interactions of skin thickness and physicochemical properties of test compounds in percutaneous penetration studies,” Int. Arch. Occup. Environ. Health 79(5), 405–413 (2006).
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R. M. Woodward, B. E. Cole, V. P. Wallace, R. J. Pye, D. D. Arnone, E. H. Linfield, and M. Pepper, “Terahertz pulse imaging in reflection geometry of human skin cancer and skin tissue,” Phys. Med. Biol. 47(21), 3853–3863 (2002).
[CrossRef] [PubMed]

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K. Cal, J. Stefanowska, and D. Zakowiecki, “Current tools for skin imaging and analysis,” Int. J. Dermatol. 48(12), 1283–1289 (2009).
[CrossRef] [PubMed]

Anal. Sci. (1)

Y. Ueno and K. Ajito, “Analytical terahertz spectroscopy,” Anal. Sci. 24(2), 185–192 (2008).
[CrossRef] [PubMed]

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T. Hattori and M. Sakamoto, “Deformation corrected real-time terahertz imaging,” Appl. Phys. Lett. 90(26), 261106 (2007).
[CrossRef]

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D. F. Plusquellic, K. Siegrist, E. J. Heilweil, and O. Esenturk, “Applications of terahertz spectroscopy in biosystems,” ChemPhysChem 8(17), 2412–2431 (2007).
[CrossRef] [PubMed]

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T. J. Franz, “The finite dose technique as a valid in vitro model for the study of percutaneous absorption in man,” Curr. Probl. Dermatol. 7, 58–68 (1978).
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Eur. Biophys. J. (1)

A. Tfayli, O. Piot, F. Pitre, and M. Manfait, “Follow-up of drug permeation through excised human skin with confocal Raman microspectroscopy,” Eur. Biophys. J. 36(8), 1049–1058 (2007).
[CrossRef] [PubMed]

Int. Arch. Occup. Environ. Health (1)

S. C. Wilkinson, W. J. M. Maas, J. B. Nielsen, L. C. Greaves, J. J. M. van de Sandt, and F. M. Williams, “Interactions of skin thickness and physicochemical properties of test compounds in percutaneous penetration studies,” Int. Arch. Occup. Environ. Health 79(5), 405–413 (2006).
[CrossRef] [PubMed]

Int. J. Dermatol. (1)

K. Cal, J. Stefanowska, and D. Zakowiecki, “Current tools for skin imaging and analysis,” Int. J. Dermatol. 48(12), 1283–1289 (2009).
[CrossRef] [PubMed]

J. Appl. Phys. (2)

J.-H. Son, “Terahertz electromagnetic interactions with biological matter and their applications,” J. Appl. Phys. 105(10), 102033 (2009).
[CrossRef]

J. Y. Park, H. J. Choi, K.-S. Cho, K.-R. Kim, and J.-H. Son, “Terahertz spectroscopic imaging of a rabbit VX2 hepatoma model,” J. Appl. Phys. 109(6), 064704 (2011).
[CrossRef]

J. Control. Release (1)

E. Touitou, V. M. Meidan, and E. Horwitz, “Methods for quantitative determination of drug localized in the skin,” J. Control. Release 56(1-3), 7–21 (1998).
[CrossRef] [PubMed]

J. Invest. Dermatol. (1)

T. J. Franz, “Percutaneous absorption on the relevance of in vitro data,” J. Invest. Dermatol. 64(3), 190–195 (1975).
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M. S. Skaf, “Static dielectric properties of a model for liquid DMSO,” Mol. Phys. 90(1), 25–34 (1997).
[CrossRef]

Opt. Express (4)

Phys. Med. Biol. (1)

R. M. Woodward, B. E. Cole, V. P. Wallace, R. J. Pye, D. D. Arnone, E. H. Linfield, and M. Pepper, “Terahertz pulse imaging in reflection geometry of human skin cancer and skin tissue,” Phys. Med. Biol. 47(21), 3853–3863 (2002).
[CrossRef] [PubMed]

Radiology (1)

A. J. Fitzgerald, V. P. Wallace, M. Jimenez-Linan, L. Bobrow, R. J. Pye, A. D. Purushotham, and D. D. Arnone, “Terahertz pulsed imaging of human breast tumors,” Radiology 239(2), 533–540 (2006).
[CrossRef] [PubMed]

Recent Pat. Drug Deliv. Formul. (1)

M. Rizwan, M. Aqil, S. Talegaonkar, A. Azeem, Y. Sultana, and A. Ali, “Enhanced transdermal drug delivery techniques: an extensive review of patents,” Recent Pat. Drug Deliv. Formul. 3(2), 105–124 (2009).
[CrossRef] [PubMed]

Sci. Tech. (Paris) (1)

K. W. Kim, H. Kim, J. Park, J. K. Han, and J.-H. Son, ““Terahertz tomographic imaging of transdermal drug delivery,” IEEE Trans. THz,” Sci. Tech. (Paris) 2, 99–106 (2012).

Skin Pharmacol. Physiol. (1)

K. König, A. Ehlers, F. Stracke, and I. Riemann, “In vivo drug screening in human skin using femtosecond laser multiphoton tomography,” Skin Pharmacol. Physiol. 19(2), 78–88 (2006).
[CrossRef] [PubMed]

Stud. Health Technol. Inform. (1)

J. Y. Suen, P. Tewari, Z. D. Taylor, W. S. Grundfest, H. Lee, E. R. Brown, M. O. Culjat, and R. S. Singh, “Towards medical terahertz sensing of skin hydration,” Stud. Health Technol. Inform. 142, 364–368 (2009).
[PubMed]

Other (1)

OECD, “Test Guideline 428. Skin absorption: in vitro method” (OECD, Paris, 2004).

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Figures (6)

Fig. 1
Fig. 1

THz imaging experimental setup.

Fig. 2
Fig. 2

Schematic drawing of excised skin mounted in the Franz cell diffusion system. The donor chamber (1) above the skin contains the applied topical agent. The chamber below the skin is the receptor chamber (2) from which samples are taken through the sampling port. The receptor chamber is surrounded by a water jacket (3) maintained at 32 °C. A magnetic stirrer and stirring helix are magnetically rotated at the bottom of the receptor chamber. The topical drug, which is applied to the stratum corneum side of the skin, permeates into the dermis side and then crosses the skin.

Fig. 3
Fig. 3

Serial THz reflection images of the drug-applied site. On the image obtained 8 min after drug application, the drug-applied site appeared as a dark shaded area with a low reflection signal; the intensity of darkness gradually increased for 1 h. The area of the dark shade increased with time, which may indicate diffusion and distribution changes of the topical drug in the skin. The scan time was 8 min for each image series.

Fig. 4
Fig. 4

Time-domain waveforms and B-scan images of a drug-applied site. (a) Serial time-domain waveforms obtained before (Ref), and 15 min, 30 min, and 60 min after the drug application show the MA of the main peak (arrowheads) at the drug-applied sites (at the red dot in the THz reflection image on the upper right) gradually decreased with time. (b) THz B-scan images of the drug-applied site show the reconstructed perpendicular images (at the red dotted line in the THz reflection image on the upper right) as the vertical axis represents the optical delay, and the gray-scale represents the THz amplitude. These data indicate that the signal and optical time width of the quartz-dermis interface (arrows) decreased with time, which corresponds to the main peak on the time-domain waveforms [arrowheads in (a)]. The signal of the layer (white curved-arrows) just above the quartz plate-dermis interface, which corresponds to the small peak on the time-domain waveforms [black curved-arrows in (a)], increased with time.

Fig. 5
Fig. 5

A diagram showing the time course of the MAD (%) difference on THz reflection imaging. In all experimental sessions of serial THz reflection imaging of the drug-applied site (2 sessions, followed up for 6 h; 2 sessions, followed up for 2 h), the measured MAD (%) increased rapidly in the early time period until approximately 1 h, and then, remained constant.

Fig. 6
Fig. 6

Profiles of the cumulative permeated drug amount obtained using the Franz cell diffusion test. Two conditions were tested: applying 50-μL and 100-μL doses of the topical agent. (a) Permeation profiles of all drug components for 24 h. (b) Permeation profiles of all drug components for 6 h.

Equations (1)

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MAD (%)= MA (ref)MA (time after application) MA (ref) ×100

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