Abstract

We present a multiphoton microscope designed for mesoscale imaging of human skin. The system is based on two-photon excited fluorescence and second-harmonic generation, and images areas of ~0.8x0.8 mm2 at speeds of 0.8 fps (800x800 pixels; 12 frame averages) for high signal-to-noise ratio, with lateral and axial resolutions of 0.5µm and 3.3µm, respectively. The main novelty of this instrument is the design of the scan head, which includes a fast galvanometric scanner, optimized relay optics, a beam expander and high NA objective lens. Computed aberrations in focus are below the Marechal criterion of 0.07λ rms for diffraction-limited performance. We demonstrate the practical utility of this microscope by ex-vivo imaging of wide areas in normal human skin.

© 2016 Optical Society of America

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2016 (2)

M. Balu, H. Mikami, J. Hou, E. O. Potma, and B. J. Tromberg, “Hou J, Potma EO, Tromberg BJ, “Large field of view multiphoton microscopy of human skin,” Proc. SPIE 9712, 97121F (2016).
[Crossref]

J. N. Stirman, I. T. Smith, M. W. Kudenov, and S. L. Smith, “Wide field-of-view, multi-region, two-photon imaging of neuronal activity in the mammalian brain,” Nat. Biotechnol. 34(8), 857–862 (2016).
[Crossref] [PubMed]

2015 (3)

M. Balu, C. B. Zachary, R. M. Harris, T. B. Krasieva, K. König, B. J. Tromberg, and K. M. Kelly, “In Vivo Multiphoton Microscopy of Basal Cell Carcinoma,” JAMA Dermatol. 151(10), 1068–1074 (2015).
[Crossref] [PubMed]

R. B. Saager, M. Balu, V. Crosignani, A. Sharif, A. J. Durkin, K. M. Kelly, and B. J. Tromberg, “In vivo measurements of cutaneous melanin across spatial scales: using multiphoton microscopy and spatial frequency domain spectroscopy,” J. Biomed. Opt. 20(6), 066005 (2015).
[Crossref] [PubMed]

P. S. Tsai, C. Mateo, J. J. Field, C. B. Schaffer, M. E. Anderson, and D. Kleinfeld, “Ultra-large field-of-view two-photon microscopy,” Opt. Express 23(11), 13833–13847 (2015).
[Crossref] [PubMed]

2014 (3)

2013 (5)

Y. Dancik, A. Favre, C. J. Loy, A. V. Zvyagin, and M. S. Roberts, “Use of multiphoton tomography and fluorescence lifetime imaging to investigate skin pigmentation in vivo,” J. Biomed. Opt. 18(2), 026022 (2013).
[Crossref] [PubMed]

V. R. Leite-Silva, M. Le Lamer, W. Y. Sanchez, D. C. Liu, W. H. Sanchez, I. Morrow, D. Martin, H. D. T. Silva, T. W. Prow, J. E. Grice, and M. S. Roberts, “The effect of formulation on the penetration of coated and uncoated zinc oxide nanoparticles into the viable epidermis of human skin in vivo,” Eur. J. Pharm. Biopharm. 84(2), 297–308 (2013).
[Crossref] [PubMed]

T. Meyer, M. Baumgartl, T. Gottschall, T. Pascher, A. Wuttig, C. Matthäus, B. F. Romeike, B. R. Brehm, J. Limpert, A. Tünnermann, O. Guntinas-Lichius, B. Dietzek, M. Schmitt, and J. Popp, “A compact microscope setup for multimodal nonlinear imaging in clinics and its application to disease diagnostics,” Analyst (Lond.) 138(14), 4048–4057 (2013).
[Crossref] [PubMed]

M. Balu, A. Mazhar, C. K. Hayakawa, R. Mittal, T. B. Krasieva, K. König, V. Venugopalan, and B. J. Tromberg, “In vivo multiphoton NADH fluorescence reveals depth-dependent keratinocyte metabolism in human skin,” Biophys. J. 104(1), 258–267 (2013).
[Crossref] [PubMed]

M. Ulrich, M. Klemp, M. E. Darvin, K. König, J. Lademann, and M. C. Meinke, “In vivo detection of basal cell carcinoma: comparison of a reflectance confocal microscope and a multiphoton tomograph,” J. Biomed. Opt. 18(6), 061229 (2013).
[Crossref] [PubMed]

2012 (3)

J. Lademann, M. C. Meinke, S. Schanzer, H. Richter, M. E. Darvin, S. F. Haag, J. W. Fluhr, H. J. Weigmann, W. Sterry, and A. Patzelt, “In vivo methods for the analysis of the penetration of topically applied substances in and through the skin barrier,” Int. J. Cosmet. Sci. 34(6), 551–559 (2012).
[Crossref] [PubMed]

N. D. Kirkpatrick, E. Chung, D. C. Cook, X. Han, G. Gruionu, S. Liao, L. L. Munn, T. P. Padera, D. Fukumura, and R. K. Jain, “Video-rate resonant scanning multiphoton microscopy: An emerging technique for intravital imaging of the tumor microenvironment,” Intravital 1(1), 60–68 (2012).
[Crossref] [PubMed]

T. B. Krasieva, C. Stringari, F. Liu, C. H. Sun, Y. Kong, M. Balu, F. L. Meyskens, E. Gratton, and B. J. Tromberg, “Two-photon excited fluorescence lifetime imaging and spectroscopy of melanins in vitro and in vivo,” J. Biomed. Opt. 18(3), 031107 (2012).
[Crossref] [PubMed]

2011 (2)

M. J. Koehler, M. Speicher, S. Lange-Asschenfeldt, E. Stockfleth, S. Metz, P. Elsner, M. Kaatz, and K. König, “Clinical application of multiphoton tomography in combination with confocal laser scanning microscopy for in vivo evaluation of skin diseases,” Exp. Dermatol. 20(7), 589–594 (2011).
[Crossref] [PubMed]

A. M. Lee, H. Wang, Y. Yu, S. Tang, J. Zhao, H. Lui, D. I. McLean, and H. Zeng, “In vivo video rate multiphoton microscopy imaging of human skin,” Opt. Lett. 36(15), 2865–2867 (2011).
[Crossref] [PubMed]

2010 (1)

R. Bazin, F. Flament, A. Colonna, R. Le Harzic, R. Bückle, B. Piot, F. Laizé, M. Kaatz, K. König, and J. W. Fluhr, “Clinical study on the effects of a cosmetic product on dermal extracellular matrix components using a high-resolution multiphoton tomograph,” Skin Res. Technol. 16(3), 305–310 (2010).
[PubMed]

2009 (1)

E. Dimitrow, M. Ziemer, M. J. Koehler, J. Norgauer, K. König, P. Elsner, and M. Kaatz, “Sensitivity and specificity of multiphoton laser tomography for in vivo and ex vivo diagnosis of malignant melanoma,” J. Invest. Dermatol. 129(7), 1752–1758 (2009).
[Crossref] [PubMed]

2006 (1)

2005 (1)

C. L. Evans, E. O. Potma, M. Puoris’haag, D. Côté, C. P. Lin, and X. S. Xie, “Chemical imaging of tissue in vivo with video-rate coherent anti-Stokes Raman scattering microscopy,” Proc. Natl. Acad. Sci. U.S.A. 102(46), 16807–16812 (2005).
[Crossref] [PubMed]

1999 (1)

G. Y. Fan, H. Fujisaki, A. Miyawaki, R. K. Tsay, R. Y. Tsien, and M. H. Ellisman, “Video-rate scanning two-photon excitation fluorescence microscopy and ratio imaging with cameleons,” Biophys. J. 76(5), 2412–2420 (1999).
[Crossref] [PubMed]

Anderson, M. E.

Balu, M.

M. Balu, H. Mikami, J. Hou, E. O. Potma, and B. J. Tromberg, “Hou J, Potma EO, Tromberg BJ, “Large field of view multiphoton microscopy of human skin,” Proc. SPIE 9712, 97121F (2016).
[Crossref]

M. Balu, C. B. Zachary, R. M. Harris, T. B. Krasieva, K. König, B. J. Tromberg, and K. M. Kelly, “In Vivo Multiphoton Microscopy of Basal Cell Carcinoma,” JAMA Dermatol. 151(10), 1068–1074 (2015).
[Crossref] [PubMed]

R. B. Saager, M. Balu, V. Crosignani, A. Sharif, A. J. Durkin, K. M. Kelly, and B. J. Tromberg, “In vivo measurements of cutaneous melanin across spatial scales: using multiphoton microscopy and spatial frequency domain spectroscopy,” J. Biomed. Opt. 20(6), 066005 (2015).
[Crossref] [PubMed]

M. Balu, K. M. Kelly, C. B. Zachary, R. M. Harris, T. B. Krasieva, K. König, A. J. Durkin, and B. J. Tromberg, “Distinguishing between benign and malignant melanocytic nevi by in vivo multiphoton microscopy,” Cancer Res. 74(10), 2688–2697 (2014).
[Crossref] [PubMed]

M. Balu, A. Mazhar, C. K. Hayakawa, R. Mittal, T. B. Krasieva, K. König, V. Venugopalan, and B. J. Tromberg, “In vivo multiphoton NADH fluorescence reveals depth-dependent keratinocyte metabolism in human skin,” Biophys. J. 104(1), 258–267 (2013).
[Crossref] [PubMed]

T. B. Krasieva, C. Stringari, F. Liu, C. H. Sun, Y. Kong, M. Balu, F. L. Meyskens, E. Gratton, and B. J. Tromberg, “Two-photon excited fluorescence lifetime imaging and spectroscopy of melanins in vitro and in vivo,” J. Biomed. Opt. 18(3), 031107 (2012).
[Crossref] [PubMed]

Baumgartl, M.

T. Meyer, M. Baumgartl, T. Gottschall, T. Pascher, A. Wuttig, C. Matthäus, B. F. Romeike, B. R. Brehm, J. Limpert, A. Tünnermann, O. Guntinas-Lichius, B. Dietzek, M. Schmitt, and J. Popp, “A compact microscope setup for multimodal nonlinear imaging in clinics and its application to disease diagnostics,” Analyst (Lond.) 138(14), 4048–4057 (2013).
[Crossref] [PubMed]

Bazin, R.

R. Bazin, F. Flament, A. Colonna, R. Le Harzic, R. Bückle, B. Piot, F. Laizé, M. Kaatz, K. König, and J. W. Fluhr, “Clinical study on the effects of a cosmetic product on dermal extracellular matrix components using a high-resolution multiphoton tomograph,” Skin Res. Technol. 16(3), 305–310 (2010).
[PubMed]

Brehm, B. R.

T. Meyer, M. Baumgartl, T. Gottschall, T. Pascher, A. Wuttig, C. Matthäus, B. F. Romeike, B. R. Brehm, J. Limpert, A. Tünnermann, O. Guntinas-Lichius, B. Dietzek, M. Schmitt, and J. Popp, “A compact microscope setup for multimodal nonlinear imaging in clinics and its application to disease diagnostics,” Analyst (Lond.) 138(14), 4048–4057 (2013).
[Crossref] [PubMed]

Bückle, R.

R. Bazin, F. Flament, A. Colonna, R. Le Harzic, R. Bückle, B. Piot, F. Laizé, M. Kaatz, K. König, and J. W. Fluhr, “Clinical study on the effects of a cosmetic product on dermal extracellular matrix components using a high-resolution multiphoton tomograph,” Skin Res. Technol. 16(3), 305–310 (2010).
[PubMed]

M. J. Koehler, K. König, P. Elsner, R. Bückle, and M. Kaatz, “In vivo assessment of human skin aging by multiphoton laser scanning tomography,” Opt. Lett. 31(19), 2879–2881 (2006).
[Crossref] [PubMed]

Chou, S. Y.

Chung, E.

N. D. Kirkpatrick, E. Chung, D. C. Cook, X. Han, G. Gruionu, S. Liao, L. L. Munn, T. P. Padera, D. Fukumura, and R. K. Jain, “Video-rate resonant scanning multiphoton microscopy: An emerging technique for intravital imaging of the tumor microenvironment,” Intravital 1(1), 60–68 (2012).
[Crossref] [PubMed]

Colonna, A.

R. Bazin, F. Flament, A. Colonna, R. Le Harzic, R. Bückle, B. Piot, F. Laizé, M. Kaatz, K. König, and J. W. Fluhr, “Clinical study on the effects of a cosmetic product on dermal extracellular matrix components using a high-resolution multiphoton tomograph,” Skin Res. Technol. 16(3), 305–310 (2010).
[PubMed]

Cook, D. C.

N. D. Kirkpatrick, E. Chung, D. C. Cook, X. Han, G. Gruionu, S. Liao, L. L. Munn, T. P. Padera, D. Fukumura, and R. K. Jain, “Video-rate resonant scanning multiphoton microscopy: An emerging technique for intravital imaging of the tumor microenvironment,” Intravital 1(1), 60–68 (2012).
[Crossref] [PubMed]

Côté, D.

C. L. Evans, E. O. Potma, M. Puoris’haag, D. Côté, C. P. Lin, and X. S. Xie, “Chemical imaging of tissue in vivo with video-rate coherent anti-Stokes Raman scattering microscopy,” Proc. Natl. Acad. Sci. U.S.A. 102(46), 16807–16812 (2005).
[Crossref] [PubMed]

Crosignani, V.

R. B. Saager, M. Balu, V. Crosignani, A. Sharif, A. J. Durkin, K. M. Kelly, and B. J. Tromberg, “In vivo measurements of cutaneous melanin across spatial scales: using multiphoton microscopy and spatial frequency domain spectroscopy,” J. Biomed. Opt. 20(6), 066005 (2015).
[Crossref] [PubMed]

Dancik, Y.

Y. Dancik, A. Favre, C. J. Loy, A. V. Zvyagin, and M. S. Roberts, “Use of multiphoton tomography and fluorescence lifetime imaging to investigate skin pigmentation in vivo,” J. Biomed. Opt. 18(2), 026022 (2013).
[Crossref] [PubMed]

Darvin, M. E.

M. Ulrich, M. Klemp, M. E. Darvin, K. König, J. Lademann, and M. C. Meinke, “In vivo detection of basal cell carcinoma: comparison of a reflectance confocal microscope and a multiphoton tomograph,” J. Biomed. Opt. 18(6), 061229 (2013).
[Crossref] [PubMed]

J. Lademann, M. C. Meinke, S. Schanzer, H. Richter, M. E. Darvin, S. F. Haag, J. W. Fluhr, H. J. Weigmann, W. Sterry, and A. Patzelt, “In vivo methods for the analysis of the penetration of topically applied substances in and through the skin barrier,” Int. J. Cosmet. Sci. 34(6), 551–559 (2012).
[Crossref] [PubMed]

Dietzek, B.

T. Meyer, M. Baumgartl, T. Gottschall, T. Pascher, A. Wuttig, C. Matthäus, B. F. Romeike, B. R. Brehm, J. Limpert, A. Tünnermann, O. Guntinas-Lichius, B. Dietzek, M. Schmitt, and J. Popp, “A compact microscope setup for multimodal nonlinear imaging in clinics and its application to disease diagnostics,” Analyst (Lond.) 138(14), 4048–4057 (2013).
[Crossref] [PubMed]

Dimitrow, E.

E. Dimitrow, M. Ziemer, M. J. Koehler, J. Norgauer, K. König, P. Elsner, and M. Kaatz, “Sensitivity and specificity of multiphoton laser tomography for in vivo and ex vivo diagnosis of malignant melanoma,” J. Invest. Dermatol. 129(7), 1752–1758 (2009).
[Crossref] [PubMed]

Durkin, A. J.

R. B. Saager, M. Balu, V. Crosignani, A. Sharif, A. J. Durkin, K. M. Kelly, and B. J. Tromberg, “In vivo measurements of cutaneous melanin across spatial scales: using multiphoton microscopy and spatial frequency domain spectroscopy,” J. Biomed. Opt. 20(6), 066005 (2015).
[Crossref] [PubMed]

M. Balu, K. M. Kelly, C. B. Zachary, R. M. Harris, T. B. Krasieva, K. König, A. J. Durkin, and B. J. Tromberg, “Distinguishing between benign and malignant melanocytic nevi by in vivo multiphoton microscopy,” Cancer Res. 74(10), 2688–2697 (2014).
[Crossref] [PubMed]

Ellisman, M. H.

G. Y. Fan, H. Fujisaki, A. Miyawaki, R. K. Tsay, R. Y. Tsien, and M. H. Ellisman, “Video-rate scanning two-photon excitation fluorescence microscopy and ratio imaging with cameleons,” Biophys. J. 76(5), 2412–2420 (1999).
[Crossref] [PubMed]

Elsner, P.

M. J. Koehler, M. Speicher, S. Lange-Asschenfeldt, E. Stockfleth, S. Metz, P. Elsner, M. Kaatz, and K. König, “Clinical application of multiphoton tomography in combination with confocal laser scanning microscopy for in vivo evaluation of skin diseases,” Exp. Dermatol. 20(7), 589–594 (2011).
[Crossref] [PubMed]

E. Dimitrow, M. Ziemer, M. J. Koehler, J. Norgauer, K. König, P. Elsner, and M. Kaatz, “Sensitivity and specificity of multiphoton laser tomography for in vivo and ex vivo diagnosis of malignant melanoma,” J. Invest. Dermatol. 129(7), 1752–1758 (2009).
[Crossref] [PubMed]

M. J. Koehler, K. König, P. Elsner, R. Bückle, and M. Kaatz, “In vivo assessment of human skin aging by multiphoton laser scanning tomography,” Opt. Lett. 31(19), 2879–2881 (2006).
[Crossref] [PubMed]

Evans, C. L.

C. L. Evans, E. O. Potma, M. Puoris’haag, D. Côté, C. P. Lin, and X. S. Xie, “Chemical imaging of tissue in vivo with video-rate coherent anti-Stokes Raman scattering microscopy,” Proc. Natl. Acad. Sci. U.S.A. 102(46), 16807–16812 (2005).
[Crossref] [PubMed]

Fan, G. Y.

G. Y. Fan, H. Fujisaki, A. Miyawaki, R. K. Tsay, R. Y. Tsien, and M. H. Ellisman, “Video-rate scanning two-photon excitation fluorescence microscopy and ratio imaging with cameleons,” Biophys. J. 76(5), 2412–2420 (1999).
[Crossref] [PubMed]

Favre, A.

Y. Dancik, A. Favre, C. J. Loy, A. V. Zvyagin, and M. S. Roberts, “Use of multiphoton tomography and fluorescence lifetime imaging to investigate skin pigmentation in vivo,” J. Biomed. Opt. 18(2), 026022 (2013).
[Crossref] [PubMed]

Field, J. J.

Flament, F.

R. Bazin, F. Flament, A. Colonna, R. Le Harzic, R. Bückle, B. Piot, F. Laizé, M. Kaatz, K. König, and J. W. Fluhr, “Clinical study on the effects of a cosmetic product on dermal extracellular matrix components using a high-resolution multiphoton tomograph,” Skin Res. Technol. 16(3), 305–310 (2010).
[PubMed]

Fluhr, J. W.

J. Lademann, M. C. Meinke, S. Schanzer, H. Richter, M. E. Darvin, S. F. Haag, J. W. Fluhr, H. J. Weigmann, W. Sterry, and A. Patzelt, “In vivo methods for the analysis of the penetration of topically applied substances in and through the skin barrier,” Int. J. Cosmet. Sci. 34(6), 551–559 (2012).
[Crossref] [PubMed]

R. Bazin, F. Flament, A. Colonna, R. Le Harzic, R. Bückle, B. Piot, F. Laizé, M. Kaatz, K. König, and J. W. Fluhr, “Clinical study on the effects of a cosmetic product on dermal extracellular matrix components using a high-resolution multiphoton tomograph,” Skin Res. Technol. 16(3), 305–310 (2010).
[PubMed]

Fujisaki, H.

G. Y. Fan, H. Fujisaki, A. Miyawaki, R. K. Tsay, R. Y. Tsien, and M. H. Ellisman, “Video-rate scanning two-photon excitation fluorescence microscopy and ratio imaging with cameleons,” Biophys. J. 76(5), 2412–2420 (1999).
[Crossref] [PubMed]

Fukumura, D.

N. D. Kirkpatrick, E. Chung, D. C. Cook, X. Han, G. Gruionu, S. Liao, L. L. Munn, T. P. Padera, D. Fukumura, and R. K. Jain, “Video-rate resonant scanning multiphoton microscopy: An emerging technique for intravital imaging of the tumor microenvironment,” Intravital 1(1), 60–68 (2012).
[Crossref] [PubMed]

Gottschall, T.

T. Meyer, M. Baumgartl, T. Gottschall, T. Pascher, A. Wuttig, C. Matthäus, B. F. Romeike, B. R. Brehm, J. Limpert, A. Tünnermann, O. Guntinas-Lichius, B. Dietzek, M. Schmitt, and J. Popp, “A compact microscope setup for multimodal nonlinear imaging in clinics and its application to disease diagnostics,” Analyst (Lond.) 138(14), 4048–4057 (2013).
[Crossref] [PubMed]

Gratton, E.

T. B. Krasieva, C. Stringari, F. Liu, C. H. Sun, Y. Kong, M. Balu, F. L. Meyskens, E. Gratton, and B. J. Tromberg, “Two-photon excited fluorescence lifetime imaging and spectroscopy of melanins in vitro and in vivo,” J. Biomed. Opt. 18(3), 031107 (2012).
[Crossref] [PubMed]

Grice, J. E.

V. R. Leite-Silva, M. Le Lamer, W. Y. Sanchez, D. C. Liu, W. H. Sanchez, I. Morrow, D. Martin, H. D. T. Silva, T. W. Prow, J. E. Grice, and M. S. Roberts, “The effect of formulation on the penetration of coated and uncoated zinc oxide nanoparticles into the viable epidermis of human skin in vivo,” Eur. J. Pharm. Biopharm. 84(2), 297–308 (2013).
[Crossref] [PubMed]

Gruionu, G.

N. D. Kirkpatrick, E. Chung, D. C. Cook, X. Han, G. Gruionu, S. Liao, L. L. Munn, T. P. Padera, D. Fukumura, and R. K. Jain, “Video-rate resonant scanning multiphoton microscopy: An emerging technique for intravital imaging of the tumor microenvironment,” Intravital 1(1), 60–68 (2012).
[Crossref] [PubMed]

Guntinas-Lichius, O.

T. Meyer, M. Baumgartl, T. Gottschall, T. Pascher, A. Wuttig, C. Matthäus, B. F. Romeike, B. R. Brehm, J. Limpert, A. Tünnermann, O. Guntinas-Lichius, B. Dietzek, M. Schmitt, and J. Popp, “A compact microscope setup for multimodal nonlinear imaging in clinics and its application to disease diagnostics,” Analyst (Lond.) 138(14), 4048–4057 (2013).
[Crossref] [PubMed]

Haag, S. F.

J. Lademann, M. C. Meinke, S. Schanzer, H. Richter, M. E. Darvin, S. F. Haag, J. W. Fluhr, H. J. Weigmann, W. Sterry, and A. Patzelt, “In vivo methods for the analysis of the penetration of topically applied substances in and through the skin barrier,” Int. J. Cosmet. Sci. 34(6), 551–559 (2012).
[Crossref] [PubMed]

Han, X.

N. D. Kirkpatrick, E. Chung, D. C. Cook, X. Han, G. Gruionu, S. Liao, L. L. Munn, T. P. Padera, D. Fukumura, and R. K. Jain, “Video-rate resonant scanning multiphoton microscopy: An emerging technique for intravital imaging of the tumor microenvironment,” Intravital 1(1), 60–68 (2012).
[Crossref] [PubMed]

Harris, R. M.

M. Balu, C. B. Zachary, R. M. Harris, T. B. Krasieva, K. König, B. J. Tromberg, and K. M. Kelly, “In Vivo Multiphoton Microscopy of Basal Cell Carcinoma,” JAMA Dermatol. 151(10), 1068–1074 (2015).
[Crossref] [PubMed]

M. Balu, K. M. Kelly, C. B. Zachary, R. M. Harris, T. B. Krasieva, K. König, A. J. Durkin, and B. J. Tromberg, “Distinguishing between benign and malignant melanocytic nevi by in vivo multiphoton microscopy,” Cancer Res. 74(10), 2688–2697 (2014).
[Crossref] [PubMed]

Hayakawa, C. K.

M. Balu, A. Mazhar, C. K. Hayakawa, R. Mittal, T. B. Krasieva, K. König, V. Venugopalan, and B. J. Tromberg, “In vivo multiphoton NADH fluorescence reveals depth-dependent keratinocyte metabolism in human skin,” Biophys. J. 104(1), 258–267 (2013).
[Crossref] [PubMed]

Hou, J.

M. Balu, H. Mikami, J. Hou, E. O. Potma, and B. J. Tromberg, “Hou J, Potma EO, Tromberg BJ, “Large field of view multiphoton microscopy of human skin,” Proc. SPIE 9712, 97121F (2016).
[Crossref]

Jain, R. K.

N. D. Kirkpatrick, E. Chung, D. C. Cook, X. Han, G. Gruionu, S. Liao, L. L. Munn, T. P. Padera, D. Fukumura, and R. K. Jain, “Video-rate resonant scanning multiphoton microscopy: An emerging technique for intravital imaging of the tumor microenvironment,” Intravital 1(1), 60–68 (2012).
[Crossref] [PubMed]

Kaatz, M.

M. J. Koehler, M. Speicher, S. Lange-Asschenfeldt, E. Stockfleth, S. Metz, P. Elsner, M. Kaatz, and K. König, “Clinical application of multiphoton tomography in combination with confocal laser scanning microscopy for in vivo evaluation of skin diseases,” Exp. Dermatol. 20(7), 589–594 (2011).
[Crossref] [PubMed]

R. Bazin, F. Flament, A. Colonna, R. Le Harzic, R. Bückle, B. Piot, F. Laizé, M. Kaatz, K. König, and J. W. Fluhr, “Clinical study on the effects of a cosmetic product on dermal extracellular matrix components using a high-resolution multiphoton tomograph,” Skin Res. Technol. 16(3), 305–310 (2010).
[PubMed]

E. Dimitrow, M. Ziemer, M. J. Koehler, J. Norgauer, K. König, P. Elsner, and M. Kaatz, “Sensitivity and specificity of multiphoton laser tomography for in vivo and ex vivo diagnosis of malignant melanoma,” J. Invest. Dermatol. 129(7), 1752–1758 (2009).
[Crossref] [PubMed]

M. J. Koehler, K. König, P. Elsner, R. Bückle, and M. Kaatz, “In vivo assessment of human skin aging by multiphoton laser scanning tomography,” Opt. Lett. 31(19), 2879–2881 (2006).
[Crossref] [PubMed]

Kelly, K. M.

M. Balu, C. B. Zachary, R. M. Harris, T. B. Krasieva, K. König, B. J. Tromberg, and K. M. Kelly, “In Vivo Multiphoton Microscopy of Basal Cell Carcinoma,” JAMA Dermatol. 151(10), 1068–1074 (2015).
[Crossref] [PubMed]

R. B. Saager, M. Balu, V. Crosignani, A. Sharif, A. J. Durkin, K. M. Kelly, and B. J. Tromberg, “In vivo measurements of cutaneous melanin across spatial scales: using multiphoton microscopy and spatial frequency domain spectroscopy,” J. Biomed. Opt. 20(6), 066005 (2015).
[Crossref] [PubMed]

M. Balu, K. M. Kelly, C. B. Zachary, R. M. Harris, T. B. Krasieva, K. König, A. J. Durkin, and B. J. Tromberg, “Distinguishing between benign and malignant melanocytic nevi by in vivo multiphoton microscopy,” Cancer Res. 74(10), 2688–2697 (2014).
[Crossref] [PubMed]

Kirkpatrick, N. D.

N. D. Kirkpatrick, E. Chung, D. C. Cook, X. Han, G. Gruionu, S. Liao, L. L. Munn, T. P. Padera, D. Fukumura, and R. K. Jain, “Video-rate resonant scanning multiphoton microscopy: An emerging technique for intravital imaging of the tumor microenvironment,” Intravital 1(1), 60–68 (2012).
[Crossref] [PubMed]

Kleinfeld, D.

Klemp, M.

M. Ulrich, M. Klemp, M. E. Darvin, K. König, J. Lademann, and M. C. Meinke, “In vivo detection of basal cell carcinoma: comparison of a reflectance confocal microscope and a multiphoton tomograph,” J. Biomed. Opt. 18(6), 061229 (2013).
[Crossref] [PubMed]

Koehler, M. J.

M. J. Koehler, M. Speicher, S. Lange-Asschenfeldt, E. Stockfleth, S. Metz, P. Elsner, M. Kaatz, and K. König, “Clinical application of multiphoton tomography in combination with confocal laser scanning microscopy for in vivo evaluation of skin diseases,” Exp. Dermatol. 20(7), 589–594 (2011).
[Crossref] [PubMed]

E. Dimitrow, M. Ziemer, M. J. Koehler, J. Norgauer, K. König, P. Elsner, and M. Kaatz, “Sensitivity and specificity of multiphoton laser tomography for in vivo and ex vivo diagnosis of malignant melanoma,” J. Invest. Dermatol. 129(7), 1752–1758 (2009).
[Crossref] [PubMed]

M. J. Koehler, K. König, P. Elsner, R. Bückle, and M. Kaatz, “In vivo assessment of human skin aging by multiphoton laser scanning tomography,” Opt. Lett. 31(19), 2879–2881 (2006).
[Crossref] [PubMed]

Kong, Y.

T. B. Krasieva, C. Stringari, F. Liu, C. H. Sun, Y. Kong, M. Balu, F. L. Meyskens, E. Gratton, and B. J. Tromberg, “Two-photon excited fluorescence lifetime imaging and spectroscopy of melanins in vitro and in vivo,” J. Biomed. Opt. 18(3), 031107 (2012).
[Crossref] [PubMed]

König, K.

M. Balu, C. B. Zachary, R. M. Harris, T. B. Krasieva, K. König, B. J. Tromberg, and K. M. Kelly, “In Vivo Multiphoton Microscopy of Basal Cell Carcinoma,” JAMA Dermatol. 151(10), 1068–1074 (2015).
[Crossref] [PubMed]

M. Balu, K. M. Kelly, C. B. Zachary, R. M. Harris, T. B. Krasieva, K. König, A. J. Durkin, and B. J. Tromberg, “Distinguishing between benign and malignant melanocytic nevi by in vivo multiphoton microscopy,” Cancer Res. 74(10), 2688–2697 (2014).
[Crossref] [PubMed]

M. Ulrich, M. Klemp, M. E. Darvin, K. König, J. Lademann, and M. C. Meinke, “In vivo detection of basal cell carcinoma: comparison of a reflectance confocal microscope and a multiphoton tomograph,” J. Biomed. Opt. 18(6), 061229 (2013).
[Crossref] [PubMed]

M. Balu, A. Mazhar, C. K. Hayakawa, R. Mittal, T. B. Krasieva, K. König, V. Venugopalan, and B. J. Tromberg, “In vivo multiphoton NADH fluorescence reveals depth-dependent keratinocyte metabolism in human skin,” Biophys. J. 104(1), 258–267 (2013).
[Crossref] [PubMed]

M. J. Koehler, M. Speicher, S. Lange-Asschenfeldt, E. Stockfleth, S. Metz, P. Elsner, M. Kaatz, and K. König, “Clinical application of multiphoton tomography in combination with confocal laser scanning microscopy for in vivo evaluation of skin diseases,” Exp. Dermatol. 20(7), 589–594 (2011).
[Crossref] [PubMed]

R. Bazin, F. Flament, A. Colonna, R. Le Harzic, R. Bückle, B. Piot, F. Laizé, M. Kaatz, K. König, and J. W. Fluhr, “Clinical study on the effects of a cosmetic product on dermal extracellular matrix components using a high-resolution multiphoton tomograph,” Skin Res. Technol. 16(3), 305–310 (2010).
[PubMed]

E. Dimitrow, M. Ziemer, M. J. Koehler, J. Norgauer, K. König, P. Elsner, and M. Kaatz, “Sensitivity and specificity of multiphoton laser tomography for in vivo and ex vivo diagnosis of malignant melanoma,” J. Invest. Dermatol. 129(7), 1752–1758 (2009).
[Crossref] [PubMed]

M. J. Koehler, K. König, P. Elsner, R. Bückle, and M. Kaatz, “In vivo assessment of human skin aging by multiphoton laser scanning tomography,” Opt. Lett. 31(19), 2879–2881 (2006).
[Crossref] [PubMed]

Krasieva, T. B.

M. Balu, C. B. Zachary, R. M. Harris, T. B. Krasieva, K. König, B. J. Tromberg, and K. M. Kelly, “In Vivo Multiphoton Microscopy of Basal Cell Carcinoma,” JAMA Dermatol. 151(10), 1068–1074 (2015).
[Crossref] [PubMed]

M. Balu, K. M. Kelly, C. B. Zachary, R. M. Harris, T. B. Krasieva, K. König, A. J. Durkin, and B. J. Tromberg, “Distinguishing between benign and malignant melanocytic nevi by in vivo multiphoton microscopy,” Cancer Res. 74(10), 2688–2697 (2014).
[Crossref] [PubMed]

M. Balu, A. Mazhar, C. K. Hayakawa, R. Mittal, T. B. Krasieva, K. König, V. Venugopalan, and B. J. Tromberg, “In vivo multiphoton NADH fluorescence reveals depth-dependent keratinocyte metabolism in human skin,” Biophys. J. 104(1), 258–267 (2013).
[Crossref] [PubMed]

T. B. Krasieva, C. Stringari, F. Liu, C. H. Sun, Y. Kong, M. Balu, F. L. Meyskens, E. Gratton, and B. J. Tromberg, “Two-photon excited fluorescence lifetime imaging and spectroscopy of melanins in vitro and in vivo,” J. Biomed. Opt. 18(3), 031107 (2012).
[Crossref] [PubMed]

Kudenov, M. W.

J. N. Stirman, I. T. Smith, M. W. Kudenov, and S. L. Smith, “Wide field-of-view, multi-region, two-photon imaging of neuronal activity in the mammalian brain,” Nat. Biotechnol. 34(8), 857–862 (2016).
[Crossref] [PubMed]

Kuo, W. C.

Lademann, J.

M. Ulrich, M. Klemp, M. E. Darvin, K. König, J. Lademann, and M. C. Meinke, “In vivo detection of basal cell carcinoma: comparison of a reflectance confocal microscope and a multiphoton tomograph,” J. Biomed. Opt. 18(6), 061229 (2013).
[Crossref] [PubMed]

J. Lademann, M. C. Meinke, S. Schanzer, H. Richter, M. E. Darvin, S. F. Haag, J. W. Fluhr, H. J. Weigmann, W. Sterry, and A. Patzelt, “In vivo methods for the analysis of the penetration of topically applied substances in and through the skin barrier,” Int. J. Cosmet. Sci. 34(6), 551–559 (2012).
[Crossref] [PubMed]

Laizé, F.

R. Bazin, F. Flament, A. Colonna, R. Le Harzic, R. Bückle, B. Piot, F. Laizé, M. Kaatz, K. König, and J. W. Fluhr, “Clinical study on the effects of a cosmetic product on dermal extracellular matrix components using a high-resolution multiphoton tomograph,” Skin Res. Technol. 16(3), 305–310 (2010).
[PubMed]

Lange-Asschenfeldt, S.

M. J. Koehler, M. Speicher, S. Lange-Asschenfeldt, E. Stockfleth, S. Metz, P. Elsner, M. Kaatz, and K. König, “Clinical application of multiphoton tomography in combination with confocal laser scanning microscopy for in vivo evaluation of skin diseases,” Exp. Dermatol. 20(7), 589–594 (2011).
[Crossref] [PubMed]

Le Harzic, R.

R. Bazin, F. Flament, A. Colonna, R. Le Harzic, R. Bückle, B. Piot, F. Laizé, M. Kaatz, K. König, and J. W. Fluhr, “Clinical study on the effects of a cosmetic product on dermal extracellular matrix components using a high-resolution multiphoton tomograph,” Skin Res. Technol. 16(3), 305–310 (2010).
[PubMed]

Le Lamer, M.

V. R. Leite-Silva, M. Le Lamer, W. Y. Sanchez, D. C. Liu, W. H. Sanchez, I. Morrow, D. Martin, H. D. T. Silva, T. W. Prow, J. E. Grice, and M. S. Roberts, “The effect of formulation on the penetration of coated and uncoated zinc oxide nanoparticles into the viable epidermis of human skin in vivo,” Eur. J. Pharm. Biopharm. 84(2), 297–308 (2013).
[Crossref] [PubMed]

Lee, A. M.

Lee, G. G.

Leite-Silva, V. R.

V. R. Leite-Silva, M. Le Lamer, W. Y. Sanchez, D. C. Liu, W. H. Sanchez, I. Morrow, D. Martin, H. D. T. Silva, T. W. Prow, J. E. Grice, and M. S. Roberts, “The effect of formulation on the penetration of coated and uncoated zinc oxide nanoparticles into the viable epidermis of human skin in vivo,” Eur. J. Pharm. Biopharm. 84(2), 297–308 (2013).
[Crossref] [PubMed]

Liao, S.

N. D. Kirkpatrick, E. Chung, D. C. Cook, X. Han, G. Gruionu, S. Liao, L. L. Munn, T. P. Padera, D. Fukumura, and R. K. Jain, “Video-rate resonant scanning multiphoton microscopy: An emerging technique for intravital imaging of the tumor microenvironment,” Intravital 1(1), 60–68 (2012).
[Crossref] [PubMed]

Liao, Y. H.

Limpert, J.

T. Meyer, M. Baumgartl, T. Gottschall, T. Pascher, A. Wuttig, C. Matthäus, B. F. Romeike, B. R. Brehm, J. Limpert, A. Tünnermann, O. Guntinas-Lichius, B. Dietzek, M. Schmitt, and J. Popp, “A compact microscope setup for multimodal nonlinear imaging in clinics and its application to disease diagnostics,” Analyst (Lond.) 138(14), 4048–4057 (2013).
[Crossref] [PubMed]

Lin, C. P.

C. L. Evans, E. O. Potma, M. Puoris’haag, D. Côté, C. P. Lin, and X. S. Xie, “Chemical imaging of tissue in vivo with video-rate coherent anti-Stokes Raman scattering microscopy,” Proc. Natl. Acad. Sci. U.S.A. 102(46), 16807–16812 (2005).
[Crossref] [PubMed]

Lin, G. L.

Liu, D. C.

V. R. Leite-Silva, M. Le Lamer, W. Y. Sanchez, D. C. Liu, W. H. Sanchez, I. Morrow, D. Martin, H. D. T. Silva, T. W. Prow, J. E. Grice, and M. S. Roberts, “The effect of formulation on the penetration of coated and uncoated zinc oxide nanoparticles into the viable epidermis of human skin in vivo,” Eur. J. Pharm. Biopharm. 84(2), 297–308 (2013).
[Crossref] [PubMed]

Liu, F.

T. B. Krasieva, C. Stringari, F. Liu, C. H. Sun, Y. Kong, M. Balu, F. L. Meyskens, E. Gratton, and B. J. Tromberg, “Two-photon excited fluorescence lifetime imaging and spectroscopy of melanins in vitro and in vivo,” J. Biomed. Opt. 18(3), 031107 (2012).
[Crossref] [PubMed]

Loy, C. J.

Y. Dancik, A. Favre, C. J. Loy, A. V. Zvyagin, and M. S. Roberts, “Use of multiphoton tomography and fluorescence lifetime imaging to investigate skin pigmentation in vivo,” J. Biomed. Opt. 18(2), 026022 (2013).
[Crossref] [PubMed]

Lui, H.

Mansvelder, H. D.

Martin, D.

V. R. Leite-Silva, M. Le Lamer, W. Y. Sanchez, D. C. Liu, W. H. Sanchez, I. Morrow, D. Martin, H. D. T. Silva, T. W. Prow, J. E. Grice, and M. S. Roberts, “The effect of formulation on the penetration of coated and uncoated zinc oxide nanoparticles into the viable epidermis of human skin in vivo,” Eur. J. Pharm. Biopharm. 84(2), 297–308 (2013).
[Crossref] [PubMed]

Mateo, C.

Matthäus, C.

T. Meyer, M. Baumgartl, T. Gottschall, T. Pascher, A. Wuttig, C. Matthäus, B. F. Romeike, B. R. Brehm, J. Limpert, A. Tünnermann, O. Guntinas-Lichius, B. Dietzek, M. Schmitt, and J. Popp, “A compact microscope setup for multimodal nonlinear imaging in clinics and its application to disease diagnostics,” Analyst (Lond.) 138(14), 4048–4057 (2013).
[Crossref] [PubMed]

Mazhar, A.

M. Balu, A. Mazhar, C. K. Hayakawa, R. Mittal, T. B. Krasieva, K. König, V. Venugopalan, and B. J. Tromberg, “In vivo multiphoton NADH fluorescence reveals depth-dependent keratinocyte metabolism in human skin,” Biophys. J. 104(1), 258–267 (2013).
[Crossref] [PubMed]

McLean, D. I.

Meinke, M. C.

M. Ulrich, M. Klemp, M. E. Darvin, K. König, J. Lademann, and M. C. Meinke, “In vivo detection of basal cell carcinoma: comparison of a reflectance confocal microscope and a multiphoton tomograph,” J. Biomed. Opt. 18(6), 061229 (2013).
[Crossref] [PubMed]

J. Lademann, M. C. Meinke, S. Schanzer, H. Richter, M. E. Darvin, S. F. Haag, J. W. Fluhr, H. J. Weigmann, W. Sterry, and A. Patzelt, “In vivo methods for the analysis of the penetration of topically applied substances in and through the skin barrier,” Int. J. Cosmet. Sci. 34(6), 551–559 (2012).
[Crossref] [PubMed]

Metz, S.

M. J. Koehler, M. Speicher, S. Lange-Asschenfeldt, E. Stockfleth, S. Metz, P. Elsner, M. Kaatz, and K. König, “Clinical application of multiphoton tomography in combination with confocal laser scanning microscopy for in vivo evaluation of skin diseases,” Exp. Dermatol. 20(7), 589–594 (2011).
[Crossref] [PubMed]

Meyer, T.

T. Meyer, M. Baumgartl, T. Gottschall, T. Pascher, A. Wuttig, C. Matthäus, B. F. Romeike, B. R. Brehm, J. Limpert, A. Tünnermann, O. Guntinas-Lichius, B. Dietzek, M. Schmitt, and J. Popp, “A compact microscope setup for multimodal nonlinear imaging in clinics and its application to disease diagnostics,” Analyst (Lond.) 138(14), 4048–4057 (2013).
[Crossref] [PubMed]

Meyskens, F. L.

T. B. Krasieva, C. Stringari, F. Liu, C. H. Sun, Y. Kong, M. Balu, F. L. Meyskens, E. Gratton, and B. J. Tromberg, “Two-photon excited fluorescence lifetime imaging and spectroscopy of melanins in vitro and in vivo,” J. Biomed. Opt. 18(3), 031107 (2012).
[Crossref] [PubMed]

Mikami, H.

M. Balu, H. Mikami, J. Hou, E. O. Potma, and B. J. Tromberg, “Hou J, Potma EO, Tromberg BJ, “Large field of view multiphoton microscopy of human skin,” Proc. SPIE 9712, 97121F (2016).
[Crossref]

Mittal, R.

M. Balu, A. Mazhar, C. K. Hayakawa, R. Mittal, T. B. Krasieva, K. König, V. Venugopalan, and B. J. Tromberg, “In vivo multiphoton NADH fluorescence reveals depth-dependent keratinocyte metabolism in human skin,” Biophys. J. 104(1), 258–267 (2013).
[Crossref] [PubMed]

Miyawaki, A.

G. Y. Fan, H. Fujisaki, A. Miyawaki, R. K. Tsay, R. Y. Tsien, and M. H. Ellisman, “Video-rate scanning two-photon excitation fluorescence microscopy and ratio imaging with cameleons,” Biophys. J. 76(5), 2412–2420 (1999).
[Crossref] [PubMed]

Morrow, I.

V. R. Leite-Silva, M. Le Lamer, W. Y. Sanchez, D. C. Liu, W. H. Sanchez, I. Morrow, D. Martin, H. D. T. Silva, T. W. Prow, J. E. Grice, and M. S. Roberts, “The effect of formulation on the penetration of coated and uncoated zinc oxide nanoparticles into the viable epidermis of human skin in vivo,” Eur. J. Pharm. Biopharm. 84(2), 297–308 (2013).
[Crossref] [PubMed]

Munn, L. L.

N. D. Kirkpatrick, E. Chung, D. C. Cook, X. Han, G. Gruionu, S. Liao, L. L. Munn, T. P. Padera, D. Fukumura, and R. K. Jain, “Video-rate resonant scanning multiphoton microscopy: An emerging technique for intravital imaging of the tumor microenvironment,” Intravital 1(1), 60–68 (2012).
[Crossref] [PubMed]

Negrean, A.

Norgauer, J.

E. Dimitrow, M. Ziemer, M. J. Koehler, J. Norgauer, K. König, P. Elsner, and M. Kaatz, “Sensitivity and specificity of multiphoton laser tomography for in vivo and ex vivo diagnosis of malignant melanoma,” J. Invest. Dermatol. 129(7), 1752–1758 (2009).
[Crossref] [PubMed]

Padera, T. P.

N. D. Kirkpatrick, E. Chung, D. C. Cook, X. Han, G. Gruionu, S. Liao, L. L. Munn, T. P. Padera, D. Fukumura, and R. K. Jain, “Video-rate resonant scanning multiphoton microscopy: An emerging technique for intravital imaging of the tumor microenvironment,” Intravital 1(1), 60–68 (2012).
[Crossref] [PubMed]

Pascher, T.

T. Meyer, M. Baumgartl, T. Gottschall, T. Pascher, A. Wuttig, C. Matthäus, B. F. Romeike, B. R. Brehm, J. Limpert, A. Tünnermann, O. Guntinas-Lichius, B. Dietzek, M. Schmitt, and J. Popp, “A compact microscope setup for multimodal nonlinear imaging in clinics and its application to disease diagnostics,” Analyst (Lond.) 138(14), 4048–4057 (2013).
[Crossref] [PubMed]

Patzelt, A.

J. Lademann, M. C. Meinke, S. Schanzer, H. Richter, M. E. Darvin, S. F. Haag, J. W. Fluhr, H. J. Weigmann, W. Sterry, and A. Patzelt, “In vivo methods for the analysis of the penetration of topically applied substances in and through the skin barrier,” Int. J. Cosmet. Sci. 34(6), 551–559 (2012).
[Crossref] [PubMed]

Piot, B.

R. Bazin, F. Flament, A. Colonna, R. Le Harzic, R. Bückle, B. Piot, F. Laizé, M. Kaatz, K. König, and J. W. Fluhr, “Clinical study on the effects of a cosmetic product on dermal extracellular matrix components using a high-resolution multiphoton tomograph,” Skin Res. Technol. 16(3), 305–310 (2010).
[PubMed]

Popp, J.

T. Meyer, M. Baumgartl, T. Gottschall, T. Pascher, A. Wuttig, C. Matthäus, B. F. Romeike, B. R. Brehm, J. Limpert, A. Tünnermann, O. Guntinas-Lichius, B. Dietzek, M. Schmitt, and J. Popp, “A compact microscope setup for multimodal nonlinear imaging in clinics and its application to disease diagnostics,” Analyst (Lond.) 138(14), 4048–4057 (2013).
[Crossref] [PubMed]

Potma, E. O.

M. Balu, H. Mikami, J. Hou, E. O. Potma, and B. J. Tromberg, “Hou J, Potma EO, Tromberg BJ, “Large field of view multiphoton microscopy of human skin,” Proc. SPIE 9712, 97121F (2016).
[Crossref]

C. L. Evans, E. O. Potma, M. Puoris’haag, D. Côté, C. P. Lin, and X. S. Xie, “Chemical imaging of tissue in vivo with video-rate coherent anti-Stokes Raman scattering microscopy,” Proc. Natl. Acad. Sci. U.S.A. 102(46), 16807–16812 (2005).
[Crossref] [PubMed]

Prow, T. W.

V. R. Leite-Silva, M. Le Lamer, W. Y. Sanchez, D. C. Liu, W. H. Sanchez, I. Morrow, D. Martin, H. D. T. Silva, T. W. Prow, J. E. Grice, and M. S. Roberts, “The effect of formulation on the penetration of coated and uncoated zinc oxide nanoparticles into the viable epidermis of human skin in vivo,” Eur. J. Pharm. Biopharm. 84(2), 297–308 (2013).
[Crossref] [PubMed]

Puoris’haag, M.

C. L. Evans, E. O. Potma, M. Puoris’haag, D. Côté, C. P. Lin, and X. S. Xie, “Chemical imaging of tissue in vivo with video-rate coherent anti-Stokes Raman scattering microscopy,” Proc. Natl. Acad. Sci. U.S.A. 102(46), 16807–16812 (2005).
[Crossref] [PubMed]

Richter, H.

J. Lademann, M. C. Meinke, S. Schanzer, H. Richter, M. E. Darvin, S. F. Haag, J. W. Fluhr, H. J. Weigmann, W. Sterry, and A. Patzelt, “In vivo methods for the analysis of the penetration of topically applied substances in and through the skin barrier,” Int. J. Cosmet. Sci. 34(6), 551–559 (2012).
[Crossref] [PubMed]

Roberts, M. S.

V. R. Leite-Silva, M. Le Lamer, W. Y. Sanchez, D. C. Liu, W. H. Sanchez, I. Morrow, D. Martin, H. D. T. Silva, T. W. Prow, J. E. Grice, and M. S. Roberts, “The effect of formulation on the penetration of coated and uncoated zinc oxide nanoparticles into the viable epidermis of human skin in vivo,” Eur. J. Pharm. Biopharm. 84(2), 297–308 (2013).
[Crossref] [PubMed]

Y. Dancik, A. Favre, C. J. Loy, A. V. Zvyagin, and M. S. Roberts, “Use of multiphoton tomography and fluorescence lifetime imaging to investigate skin pigmentation in vivo,” J. Biomed. Opt. 18(2), 026022 (2013).
[Crossref] [PubMed]

Romeike, B. F.

T. Meyer, M. Baumgartl, T. Gottschall, T. Pascher, A. Wuttig, C. Matthäus, B. F. Romeike, B. R. Brehm, J. Limpert, A. Tünnermann, O. Guntinas-Lichius, B. Dietzek, M. Schmitt, and J. Popp, “A compact microscope setup for multimodal nonlinear imaging in clinics and its application to disease diagnostics,” Analyst (Lond.) 138(14), 4048–4057 (2013).
[Crossref] [PubMed]

Saager, R. B.

R. B. Saager, M. Balu, V. Crosignani, A. Sharif, A. J. Durkin, K. M. Kelly, and B. J. Tromberg, “In vivo measurements of cutaneous melanin across spatial scales: using multiphoton microscopy and spatial frequency domain spectroscopy,” J. Biomed. Opt. 20(6), 066005 (2015).
[Crossref] [PubMed]

Sanchez, W. H.

V. R. Leite-Silva, M. Le Lamer, W. Y. Sanchez, D. C. Liu, W. H. Sanchez, I. Morrow, D. Martin, H. D. T. Silva, T. W. Prow, J. E. Grice, and M. S. Roberts, “The effect of formulation on the penetration of coated and uncoated zinc oxide nanoparticles into the viable epidermis of human skin in vivo,” Eur. J. Pharm. Biopharm. 84(2), 297–308 (2013).
[Crossref] [PubMed]

Sanchez, W. Y.

V. R. Leite-Silva, M. Le Lamer, W. Y. Sanchez, D. C. Liu, W. H. Sanchez, I. Morrow, D. Martin, H. D. T. Silva, T. W. Prow, J. E. Grice, and M. S. Roberts, “The effect of formulation on the penetration of coated and uncoated zinc oxide nanoparticles into the viable epidermis of human skin in vivo,” Eur. J. Pharm. Biopharm. 84(2), 297–308 (2013).
[Crossref] [PubMed]

Schaffer, C. B.

Schanzer, S.

J. Lademann, M. C. Meinke, S. Schanzer, H. Richter, M. E. Darvin, S. F. Haag, J. W. Fluhr, H. J. Weigmann, W. Sterry, and A. Patzelt, “In vivo methods for the analysis of the penetration of topically applied substances in and through the skin barrier,” Int. J. Cosmet. Sci. 34(6), 551–559 (2012).
[Crossref] [PubMed]

Schmitt, M.

T. Meyer, M. Baumgartl, T. Gottschall, T. Pascher, A. Wuttig, C. Matthäus, B. F. Romeike, B. R. Brehm, J. Limpert, A. Tünnermann, O. Guntinas-Lichius, B. Dietzek, M. Schmitt, and J. Popp, “A compact microscope setup for multimodal nonlinear imaging in clinics and its application to disease diagnostics,” Analyst (Lond.) 138(14), 4048–4057 (2013).
[Crossref] [PubMed]

Sharif, A.

R. B. Saager, M. Balu, V. Crosignani, A. Sharif, A. J. Durkin, K. M. Kelly, and B. J. Tromberg, “In vivo measurements of cutaneous melanin across spatial scales: using multiphoton microscopy and spatial frequency domain spectroscopy,” J. Biomed. Opt. 20(6), 066005 (2015).
[Crossref] [PubMed]

Shih, Y. T.

Silva, H. D. T.

V. R. Leite-Silva, M. Le Lamer, W. Y. Sanchez, D. C. Liu, W. H. Sanchez, I. Morrow, D. Martin, H. D. T. Silva, T. W. Prow, J. E. Grice, and M. S. Roberts, “The effect of formulation on the penetration of coated and uncoated zinc oxide nanoparticles into the viable epidermis of human skin in vivo,” Eur. J. Pharm. Biopharm. 84(2), 297–308 (2013).
[Crossref] [PubMed]

Smith, I. T.

J. N. Stirman, I. T. Smith, M. W. Kudenov, and S. L. Smith, “Wide field-of-view, multi-region, two-photon imaging of neuronal activity in the mammalian brain,” Nat. Biotechnol. 34(8), 857–862 (2016).
[Crossref] [PubMed]

Smith, S. L.

J. N. Stirman, I. T. Smith, M. W. Kudenov, and S. L. Smith, “Wide field-of-view, multi-region, two-photon imaging of neuronal activity in the mammalian brain,” Nat. Biotechnol. 34(8), 857–862 (2016).
[Crossref] [PubMed]

Speicher, M.

M. J. Koehler, M. Speicher, S. Lange-Asschenfeldt, E. Stockfleth, S. Metz, P. Elsner, M. Kaatz, and K. König, “Clinical application of multiphoton tomography in combination with confocal laser scanning microscopy for in vivo evaluation of skin diseases,” Exp. Dermatol. 20(7), 589–594 (2011).
[Crossref] [PubMed]

Sterry, W.

J. Lademann, M. C. Meinke, S. Schanzer, H. Richter, M. E. Darvin, S. F. Haag, J. W. Fluhr, H. J. Weigmann, W. Sterry, and A. Patzelt, “In vivo methods for the analysis of the penetration of topically applied substances in and through the skin barrier,” Int. J. Cosmet. Sci. 34(6), 551–559 (2012).
[Crossref] [PubMed]

Stirman, J. N.

J. N. Stirman, I. T. Smith, M. W. Kudenov, and S. L. Smith, “Wide field-of-view, multi-region, two-photon imaging of neuronal activity in the mammalian brain,” Nat. Biotechnol. 34(8), 857–862 (2016).
[Crossref] [PubMed]

Stockfleth, E.

M. J. Koehler, M. Speicher, S. Lange-Asschenfeldt, E. Stockfleth, S. Metz, P. Elsner, M. Kaatz, and K. König, “Clinical application of multiphoton tomography in combination with confocal laser scanning microscopy for in vivo evaluation of skin diseases,” Exp. Dermatol. 20(7), 589–594 (2011).
[Crossref] [PubMed]

Stringari, C.

T. B. Krasieva, C. Stringari, F. Liu, C. H. Sun, Y. Kong, M. Balu, F. L. Meyskens, E. Gratton, and B. J. Tromberg, “Two-photon excited fluorescence lifetime imaging and spectroscopy of melanins in vitro and in vivo,” J. Biomed. Opt. 18(3), 031107 (2012).
[Crossref] [PubMed]

Sun, C. H.

T. B. Krasieva, C. Stringari, F. Liu, C. H. Sun, Y. Kong, M. Balu, F. L. Meyskens, E. Gratton, and B. J. Tromberg, “Two-photon excited fluorescence lifetime imaging and spectroscopy of melanins in vitro and in vivo,” J. Biomed. Opt. 18(3), 031107 (2012).
[Crossref] [PubMed]

Sun, C. K.

Tang, S.

Tromberg, B. J.

M. Balu, H. Mikami, J. Hou, E. O. Potma, and B. J. Tromberg, “Hou J, Potma EO, Tromberg BJ, “Large field of view multiphoton microscopy of human skin,” Proc. SPIE 9712, 97121F (2016).
[Crossref]

M. Balu, C. B. Zachary, R. M. Harris, T. B. Krasieva, K. König, B. J. Tromberg, and K. M. Kelly, “In Vivo Multiphoton Microscopy of Basal Cell Carcinoma,” JAMA Dermatol. 151(10), 1068–1074 (2015).
[Crossref] [PubMed]

R. B. Saager, M. Balu, V. Crosignani, A. Sharif, A. J. Durkin, K. M. Kelly, and B. J. Tromberg, “In vivo measurements of cutaneous melanin across spatial scales: using multiphoton microscopy and spatial frequency domain spectroscopy,” J. Biomed. Opt. 20(6), 066005 (2015).
[Crossref] [PubMed]

M. Balu, K. M. Kelly, C. B. Zachary, R. M. Harris, T. B. Krasieva, K. König, A. J. Durkin, and B. J. Tromberg, “Distinguishing between benign and malignant melanocytic nevi by in vivo multiphoton microscopy,” Cancer Res. 74(10), 2688–2697 (2014).
[Crossref] [PubMed]

M. Balu, A. Mazhar, C. K. Hayakawa, R. Mittal, T. B. Krasieva, K. König, V. Venugopalan, and B. J. Tromberg, “In vivo multiphoton NADH fluorescence reveals depth-dependent keratinocyte metabolism in human skin,” Biophys. J. 104(1), 258–267 (2013).
[Crossref] [PubMed]

T. B. Krasieva, C. Stringari, F. Liu, C. H. Sun, Y. Kong, M. Balu, F. L. Meyskens, E. Gratton, and B. J. Tromberg, “Two-photon excited fluorescence lifetime imaging and spectroscopy of melanins in vitro and in vivo,” J. Biomed. Opt. 18(3), 031107 (2012).
[Crossref] [PubMed]

Tsai, C. S.

Tsai, M. R.

Tsai, P. S.

Tsay, R. K.

G. Y. Fan, H. Fujisaki, A. Miyawaki, R. K. Tsay, R. Y. Tsien, and M. H. Ellisman, “Video-rate scanning two-photon excitation fluorescence microscopy and ratio imaging with cameleons,” Biophys. J. 76(5), 2412–2420 (1999).
[Crossref] [PubMed]

Tsien, R. Y.

G. Y. Fan, H. Fujisaki, A. Miyawaki, R. K. Tsay, R. Y. Tsien, and M. H. Ellisman, “Video-rate scanning two-photon excitation fluorescence microscopy and ratio imaging with cameleons,” Biophys. J. 76(5), 2412–2420 (1999).
[Crossref] [PubMed]

Tünnermann, A.

T. Meyer, M. Baumgartl, T. Gottschall, T. Pascher, A. Wuttig, C. Matthäus, B. F. Romeike, B. R. Brehm, J. Limpert, A. Tünnermann, O. Guntinas-Lichius, B. Dietzek, M. Schmitt, and J. Popp, “A compact microscope setup for multimodal nonlinear imaging in clinics and its application to disease diagnostics,” Analyst (Lond.) 138(14), 4048–4057 (2013).
[Crossref] [PubMed]

Ulrich, M.

M. Ulrich, M. Klemp, M. E. Darvin, K. König, J. Lademann, and M. C. Meinke, “In vivo detection of basal cell carcinoma: comparison of a reflectance confocal microscope and a multiphoton tomograph,” J. Biomed. Opt. 18(6), 061229 (2013).
[Crossref] [PubMed]

Venugopalan, V.

M. Balu, A. Mazhar, C. K. Hayakawa, R. Mittal, T. B. Krasieva, K. König, V. Venugopalan, and B. J. Tromberg, “In vivo multiphoton NADH fluorescence reveals depth-dependent keratinocyte metabolism in human skin,” Biophys. J. 104(1), 258–267 (2013).
[Crossref] [PubMed]

Wang, H.

Weigmann, H. J.

J. Lademann, M. C. Meinke, S. Schanzer, H. Richter, M. E. Darvin, S. F. Haag, J. W. Fluhr, H. J. Weigmann, W. Sterry, and A. Patzelt, “In vivo methods for the analysis of the penetration of topically applied substances in and through the skin barrier,” Int. J. Cosmet. Sci. 34(6), 551–559 (2012).
[Crossref] [PubMed]

Wuttig, A.

T. Meyer, M. Baumgartl, T. Gottschall, T. Pascher, A. Wuttig, C. Matthäus, B. F. Romeike, B. R. Brehm, J. Limpert, A. Tünnermann, O. Guntinas-Lichius, B. Dietzek, M. Schmitt, and J. Popp, “A compact microscope setup for multimodal nonlinear imaging in clinics and its application to disease diagnostics,” Analyst (Lond.) 138(14), 4048–4057 (2013).
[Crossref] [PubMed]

Xie, X. S.

C. L. Evans, E. O. Potma, M. Puoris’haag, D. Côté, C. P. Lin, and X. S. Xie, “Chemical imaging of tissue in vivo with video-rate coherent anti-Stokes Raman scattering microscopy,” Proc. Natl. Acad. Sci. U.S.A. 102(46), 16807–16812 (2005).
[Crossref] [PubMed]

Yu, Y.

Zachary, C. B.

M. Balu, C. B. Zachary, R. M. Harris, T. B. Krasieva, K. König, B. J. Tromberg, and K. M. Kelly, “In Vivo Multiphoton Microscopy of Basal Cell Carcinoma,” JAMA Dermatol. 151(10), 1068–1074 (2015).
[Crossref] [PubMed]

M. Balu, K. M. Kelly, C. B. Zachary, R. M. Harris, T. B. Krasieva, K. König, A. J. Durkin, and B. J. Tromberg, “Distinguishing between benign and malignant melanocytic nevi by in vivo multiphoton microscopy,” Cancer Res. 74(10), 2688–2697 (2014).
[Crossref] [PubMed]

Zeng, H.

Zhao, J.

Ziemer, M.

E. Dimitrow, M. Ziemer, M. J. Koehler, J. Norgauer, K. König, P. Elsner, and M. Kaatz, “Sensitivity and specificity of multiphoton laser tomography for in vivo and ex vivo diagnosis of malignant melanoma,” J. Invest. Dermatol. 129(7), 1752–1758 (2009).
[Crossref] [PubMed]

Zvyagin, A. V.

Y. Dancik, A. Favre, C. J. Loy, A. V. Zvyagin, and M. S. Roberts, “Use of multiphoton tomography and fluorescence lifetime imaging to investigate skin pigmentation in vivo,” J. Biomed. Opt. 18(2), 026022 (2013).
[Crossref] [PubMed]

Analyst (Lond.) (1)

T. Meyer, M. Baumgartl, T. Gottschall, T. Pascher, A. Wuttig, C. Matthäus, B. F. Romeike, B. R. Brehm, J. Limpert, A. Tünnermann, O. Guntinas-Lichius, B. Dietzek, M. Schmitt, and J. Popp, “A compact microscope setup for multimodal nonlinear imaging in clinics and its application to disease diagnostics,” Analyst (Lond.) 138(14), 4048–4057 (2013).
[Crossref] [PubMed]

Biomed. Opt. Express (2)

Biophys. J. (2)

G. Y. Fan, H. Fujisaki, A. Miyawaki, R. K. Tsay, R. Y. Tsien, and M. H. Ellisman, “Video-rate scanning two-photon excitation fluorescence microscopy and ratio imaging with cameleons,” Biophys. J. 76(5), 2412–2420 (1999).
[Crossref] [PubMed]

M. Balu, A. Mazhar, C. K. Hayakawa, R. Mittal, T. B. Krasieva, K. König, V. Venugopalan, and B. J. Tromberg, “In vivo multiphoton NADH fluorescence reveals depth-dependent keratinocyte metabolism in human skin,” Biophys. J. 104(1), 258–267 (2013).
[Crossref] [PubMed]

Cancer Res. (1)

M. Balu, K. M. Kelly, C. B. Zachary, R. M. Harris, T. B. Krasieva, K. König, A. J. Durkin, and B. J. Tromberg, “Distinguishing between benign and malignant melanocytic nevi by in vivo multiphoton microscopy,” Cancer Res. 74(10), 2688–2697 (2014).
[Crossref] [PubMed]

Eur. J. Pharm. Biopharm. (1)

V. R. Leite-Silva, M. Le Lamer, W. Y. Sanchez, D. C. Liu, W. H. Sanchez, I. Morrow, D. Martin, H. D. T. Silva, T. W. Prow, J. E. Grice, and M. S. Roberts, “The effect of formulation on the penetration of coated and uncoated zinc oxide nanoparticles into the viable epidermis of human skin in vivo,” Eur. J. Pharm. Biopharm. 84(2), 297–308 (2013).
[Crossref] [PubMed]

Exp. Dermatol. (1)

M. J. Koehler, M. Speicher, S. Lange-Asschenfeldt, E. Stockfleth, S. Metz, P. Elsner, M. Kaatz, and K. König, “Clinical application of multiphoton tomography in combination with confocal laser scanning microscopy for in vivo evaluation of skin diseases,” Exp. Dermatol. 20(7), 589–594 (2011).
[Crossref] [PubMed]

Int. J. Cosmet. Sci. (1)

J. Lademann, M. C. Meinke, S. Schanzer, H. Richter, M. E. Darvin, S. F. Haag, J. W. Fluhr, H. J. Weigmann, W. Sterry, and A. Patzelt, “In vivo methods for the analysis of the penetration of topically applied substances in and through the skin barrier,” Int. J. Cosmet. Sci. 34(6), 551–559 (2012).
[Crossref] [PubMed]

Intravital (1)

N. D. Kirkpatrick, E. Chung, D. C. Cook, X. Han, G. Gruionu, S. Liao, L. L. Munn, T. P. Padera, D. Fukumura, and R. K. Jain, “Video-rate resonant scanning multiphoton microscopy: An emerging technique for intravital imaging of the tumor microenvironment,” Intravital 1(1), 60–68 (2012).
[Crossref] [PubMed]

J. Biomed. Opt. (4)

M. Ulrich, M. Klemp, M. E. Darvin, K. König, J. Lademann, and M. C. Meinke, “In vivo detection of basal cell carcinoma: comparison of a reflectance confocal microscope and a multiphoton tomograph,” J. Biomed. Opt. 18(6), 061229 (2013).
[Crossref] [PubMed]

Y. Dancik, A. Favre, C. J. Loy, A. V. Zvyagin, and M. S. Roberts, “Use of multiphoton tomography and fluorescence lifetime imaging to investigate skin pigmentation in vivo,” J. Biomed. Opt. 18(2), 026022 (2013).
[Crossref] [PubMed]

T. B. Krasieva, C. Stringari, F. Liu, C. H. Sun, Y. Kong, M. Balu, F. L. Meyskens, E. Gratton, and B. J. Tromberg, “Two-photon excited fluorescence lifetime imaging and spectroscopy of melanins in vitro and in vivo,” J. Biomed. Opt. 18(3), 031107 (2012).
[Crossref] [PubMed]

R. B. Saager, M. Balu, V. Crosignani, A. Sharif, A. J. Durkin, K. M. Kelly, and B. J. Tromberg, “In vivo measurements of cutaneous melanin across spatial scales: using multiphoton microscopy and spatial frequency domain spectroscopy,” J. Biomed. Opt. 20(6), 066005 (2015).
[Crossref] [PubMed]

J. Invest. Dermatol. (1)

E. Dimitrow, M. Ziemer, M. J. Koehler, J. Norgauer, K. König, P. Elsner, and M. Kaatz, “Sensitivity and specificity of multiphoton laser tomography for in vivo and ex vivo diagnosis of malignant melanoma,” J. Invest. Dermatol. 129(7), 1752–1758 (2009).
[Crossref] [PubMed]

JAMA Dermatol. (1)

M. Balu, C. B. Zachary, R. M. Harris, T. B. Krasieva, K. König, B. J. Tromberg, and K. M. Kelly, “In Vivo Multiphoton Microscopy of Basal Cell Carcinoma,” JAMA Dermatol. 151(10), 1068–1074 (2015).
[Crossref] [PubMed]

Nat. Biotechnol. (1)

J. N. Stirman, I. T. Smith, M. W. Kudenov, and S. L. Smith, “Wide field-of-view, multi-region, two-photon imaging of neuronal activity in the mammalian brain,” Nat. Biotechnol. 34(8), 857–862 (2016).
[Crossref] [PubMed]

Opt. Express (1)

Opt. Lett. (2)

Proc. Natl. Acad. Sci. U.S.A. (1)

C. L. Evans, E. O. Potma, M. Puoris’haag, D. Côté, C. P. Lin, and X. S. Xie, “Chemical imaging of tissue in vivo with video-rate coherent anti-Stokes Raman scattering microscopy,” Proc. Natl. Acad. Sci. U.S.A. 102(46), 16807–16812 (2005).
[Crossref] [PubMed]

Proc. SPIE (1)

M. Balu, H. Mikami, J. Hou, E. O. Potma, and B. J. Tromberg, “Hou J, Potma EO, Tromberg BJ, “Large field of view multiphoton microscopy of human skin,” Proc. SPIE 9712, 97121F (2016).
[Crossref]

Skin Res. Technol. (1)

R. Bazin, F. Flament, A. Colonna, R. Le Harzic, R. Bückle, B. Piot, F. Laizé, M. Kaatz, K. König, and J. W. Fluhr, “Clinical study on the effects of a cosmetic product on dermal extracellular matrix components using a high-resolution multiphoton tomograph,” Skin Res. Technol. 16(3), 305–310 (2010).
[PubMed]

Other (1)

P. S. Tsai, N. Nishimura, E. J. Yoder, G. A. White, E. M. Dolnik, and D. Kleinfeld, “Principles, design and construction of a two photon scanning microscope for in vitro and in vivo brain imaging,” in In Vivo Optical Imaging of Brain Function, R. Frostig, ed. (CRC Press, 2002), pp. 113–171.

Supplementary Material (2)

NameDescription
» Visualization 1: AVI (7579 KB)      stack1-FOV820x820um2
» Visualization 2: AVI (10230 KB)      stack2-FOV410x410um2

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Figures (8)

Fig. 1
Fig. 1 Schematic and overview of the main elements of the scan head.
Fig. 2
Fig. 2 Relay system-layout and RMS wavefront error. a) optical layout; arrow indicates the image surface at which the aberrations were calculated b) The RMS wavefront error as a function of incidence angle with respect to the diffraction limited value (horizontal line)
Fig. 3
Fig. 3 Beam expander-layout and RMS wavefront error. a) optical layout with the vertical line indicating the surface at which the aberrations are reported b) The RMS wavefront error as a function of incidence angle with respect to the diffraction limited value (horizontal line)
Fig. 4
Fig. 4 Schematic for efficient collection of signals in the epi-direction. Diameter and focal length of the lenses were optimized in ZEMAX for maximum collection of photons. Dichroic mirrors (DM) separate the signal into TPEF and SHG components. Sensitive photomuliplier tubes (PMT) are used.
Fig. 5
Fig. 5 MPM imaging system resolution. Point spread function representing (a) lateral resolution - FWHM = 0.5 µm and (b) axial resolution - FWHM = 3.3 µm. Data were acquired at 800 nm excitation wavelength and represent the fluorescence average of 15 beads. The error bars represent the standard deviation of the fifteen measurements.
Fig. 6
Fig. 6 Ex-vivo human skin imaging-comparison of home-built MPM-based imaging platform with a commercial system using the same objective. (a) Dermo-epidermal junction (DEJ) imaged with the home-built microscope by SHG (blue) and TPEF (green). TPEF signal originates from keratin in the epidermal keratinocytes and from elastin fibers (arrows) in the superficial papillary dermis, while SHG highlights the collagen fibers. (b) A similar location of the DEJ in the skin sample acquired with a commercial Olympus microscope over an area of 370 x 370 µm2 by using the same objective as in the home-built microscope. (c) MPM image of the DEJ acquired with the home-built microscope over an area of 370 x 370 µm2 for comparison with the image in (b) acquired with the Olympus microscope. The image in (c) corresponds to the inset in (a). (d) MPM image of the DEJ corresponding to the inset in (c) showing keratinocytes (full line arrows), elastin fibers (arrow heads) and collagen fibers (dashed line arrows). Images were acquired at 50µm depth in the sample. Scale bar is 100 µm.
Fig. 7
Fig. 7 Ex vivo MPM imaging of human skin at different depths. MPM horizontal sections show images of (a) epidermis (z = 15µm); (b-e) basal cells (green) surrounding dermal papilla (blue) at the dermo-epidermal junction (z = 35µm, 60 µm, 80 µm, 110 µm); arrows indicate hair follicle (c, d); (f) collagen (blue) and elastin (green) fibers in the papillary dermis (z = 135µm). Scale bar is 200 µm.
Fig. 8
Fig. 8 Ex vivo MPM mesoscale imaging of human skin. MPM image of the DEJ in human skin showing keratin in skin folds (green) and fibrilar structure of dermal papilla (collagen fibers-blue; elastin fibers-green). The wide area image (3.1 x 2.5 mm2) includes a mosaic of 20 frames and was acquired in 2 minutes. The image shown as inset was acquired as single frame in 2.4 s. Scale bar is 0.25 mm.

Tables (1)

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Table 1 Basic imaging properties of the scan head

Equations (1)

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FOV| = 2 x f obj x Φ ,

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