Abstract

Optical microscopy of blood cells in vivo provides a unique opportunity for clinicians and researchers to visualize the morphology and dynamics of circulating cells, but is usually limited by the imaging speed and by the need for exogenous labeling of the cells. Here we present a label-free approach for in vivo flow cytometry of blood using a compact imaging probe that could be adapted for bedside real-time imaging of patients in clinical settings, and demonstrate subcellular resolution imaging of red and white blood cells flowing in the oral mucosa of a human volunteer. By analyzing the large data sets obtained by the system, valuable blood parameters could be extracted and used for direct, reliable assessment of patient physiology.

© 2012 OSA

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    [CrossRef] [PubMed]
  20. S. González, R. Sackstein, R. R. Anderson, and M. Rajadhyaksha, “Real-time evidence of in vivo leukocyte trafficking in human skin by reflectance confocal microscopy,” J. Invest. Dermatol.117(2), 384–386 (2001).
    [CrossRef] [PubMed]
  21. L. Golan and D. Yelin, “Flow cytometry using spectrally encoded confocal microscopy,” Opt. Lett.35(13), 2218–2220 (2010).
    [CrossRef] [PubMed]
  22. G. J. Tearney, R. H. Webb, and B. E. Bouma, “Spectrally encoded confocal microscopy,” Opt. Lett.23(15), 1152–1154 (1998).
    [CrossRef] [PubMed]
  23. D. Yelin, C. Boudoux, B. E. Bouma, and G. J. Tearney, “Large area confocal microscopy,” Opt. Lett.32(9), 1102–1104 (2007).
    [CrossRef] [PubMed]
  24. D. Kang, M. J. Suter, C. Boudoux, H. Yoo, P. S. Yachimski, W. P. Puricelli, N. S. Nishioka, M. Mino-Kenudson, G. Y. Lauwers, B. E. Bouma, and G. J. Tearney, “Comprehensive imaging of gastroesophageal biopsy samples by spectrally encoded confocal microscopy,” Gastrointest. Endosc.71(1), 35–43 (2010).
    [CrossRef] [PubMed]
  25. G. W. Schmid-Schönbein, S. Usami, R. Skalak, and S. Chien, “The interaction of leukocytes and erythrocytes in capillary and postcapillary vessels,” Microvasc. Res.19(1), 45–70 (1980).
    [CrossRef] [PubMed]
  26. J. J. Bishop, P. R. Nance, A. S. Popel, M. Intaglietta, and P. C. Johnson, “Effect of erythrocyte aggregation on velocity profiles in venules,” Am. J. Physiol. Heart Circ. Physiol.280(1), H222–H236 (2001).
    [PubMed]
  27. K. Konstantopoulos, S. Neelamegham, A. R. Burns, E. Hentzen, G. S. Kansas, K. R. Snapp, E. L. Berg, J. D. Hellums, C. W. Smith, L. V. McIntire, and S. I. Simon, “Venous levels of shear support neutrophil-platelet adhesion and neutrophil aggregation in blood via P-selectin and beta2-integrin,” Circulation98(9), 873–882 (1998).
    [PubMed]
  28. M. Rajadhyaksha, R. R. Anderson, and R. H. Webb, “Video-rate confocal scanning laser microscope for imaging human tissues in vivo,” Appl. Opt.38(10), 2105–2115 (1999).
    [CrossRef] [PubMed]
  29. J. Lindert, J. Werner, M. Redlin, H. Kuppe, H. Habazettl, and A. R. Pries, “OPS imaging of human microcirculation: a short technical report,” J. Vasc. Res.39(4), 368–372 (2002).
    [CrossRef] [PubMed]
  30. G. Iddan, G. Meron, A. Glukhovsky, and P. Swain, “Wireless capsule endoscopy,” Nature405(6785), 417 (2000).
    [CrossRef] [PubMed]
  31. C. Liang, K.-B. Sung, R. R. Richards-Kortum, and M. R. Descour, “Design of a high-numerical-aperture miniature microscope objective for an endoscopic fiber confocal reflectance microscope,” Appl. Opt.41(22), 4603–4610 (2002).
    [CrossRef] [PubMed]

2011 (2)

V. V. Tuchin, A. Tárnok, and V. P. Zharov, “In vivo flow cytometry: a horizon of opportunities,” Cytometry A79A(10), 737–745 (2011).
[CrossRef] [PubMed]

E. I. Galanzha and V. P. Zharov, “In vivo photoacoustic and photothermal cytometry for monitoring multiple blood rheology parameters,” Cytometry A79A(10), 746–757 (2011).
[CrossRef] [PubMed]

2010 (2)

D. Kang, M. J. Suter, C. Boudoux, H. Yoo, P. S. Yachimski, W. P. Puricelli, N. S. Nishioka, M. Mino-Kenudson, G. Y. Lauwers, B. E. Bouma, and G. J. Tearney, “Comprehensive imaging of gastroesophageal biopsy samples by spectrally encoded confocal microscopy,” Gastrointest. Endosc.71(1), 35–43 (2010).
[CrossRef] [PubMed]

L. Golan and D. Yelin, “Flow cytometry using spectrally encoded confocal microscopy,” Opt. Lett.35(13), 2218–2220 (2010).
[CrossRef] [PubMed]

2008 (1)

P.-L. Hsiung, J. Hardy, S. Friedland, R. Soetikno, C. B. Du, A. P. Wu, P. Sahbaie, J. M. Crawford, A. W. Lowe, C. H. Contag, and T. D. Wang, “Detection of colonic dysplasia in vivo using a targeted heptapeptide and confocal microendoscopy,” Nat. Med.14(4), 454–458 (2008).
[CrossRef] [PubMed]

2007 (1)

2006 (1)

V. P. Zharov, E. I. Galanzha, Y. Menyaev, and V. V. Tuchin, “In vivo high-speed imaging of individual cells in fast blood flow,” J. Biomed. Opt.11(5), 054034 (2006).
[CrossRef] [PubMed]

2005 (4)

C. Ince, “Sidestream dark field imaging: an improved technique to observe sublingual microcirculation,” Crit. Care9(Suppl 1), P72 (2005).
[CrossRef]

D. A. Sipkins, X. Wei, J. W. Wu, J. M. Runnels, D. Côté, T. K. Means, A. D. Luster, D. T. Scadden, and C. P. Lin, “In vivo imaging of specialized bone marrow endothelial microdomains for tumour engraftment,” Nature435(7044), 969–973 (2005).
[CrossRef] [PubMed]

V. P. Zharov, E. I. Galanzha, and V. V. Tuchin, “Photothermal image flow cytometry in vivo,” Opt. Lett.30(6), 628–630 (2005).
[CrossRef] [PubMed]

I. Y. Petrova, R. O. Esenaliev, Y. Y. Petrov, H.-P. F. Brecht, C. H. Svensen, J. Olsson, D. J. Deyo, and D. S. Prough, “Optoacoustic monitoring of blood hemoglobin concentration: a pilot clinical study,” Opt. Lett.30(13), 1677–1679 (2005).
[CrossRef] [PubMed]

2004 (3)

J. Novak, I. Georgakoudi, X. Wei, A. Prossin, and C. P. Lin, “In vivo flow cytometer for real-time detection and quantification of circulating cells,” Opt. Lett.29(1), 77–79 (2004).
[CrossRef] [PubMed]

R. Kiesslich, J. Burg, M. Vieth, J. Gnaendiger, M. Enders, P. Delaney, A. Polglase, W. McLaren, D. Janell, S. Thomas, B. Nafe, P. R. Galle, and M. F. Neurath, “Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo,” Gastroenterology127(3), 706–713 (2004).
[CrossRef] [PubMed]

I. Georgakoudi, N. Solban, J. Novak, W. L. Rice, X. Wei, T. Hasan, and C. P. Lin, “In vivo flow cytometry: a new method for enumerating circulating cancer cells,” Cancer Res.64(15), 5044–5047 (2004).
[CrossRef] [PubMed]

2003 (1)

W. Secomski, A. Nowicki, F. Guidi, P. Tortoli, and P. A. Lewin, “Noninvasive in vivo measurements of hematocrit,” J. Ultrasound Med.22(4), 375–384 (2003).
[PubMed]

2002 (2)

C. Liang, K.-B. Sung, R. R. Richards-Kortum, and M. R. Descour, “Design of a high-numerical-aperture miniature microscope objective for an endoscopic fiber confocal reflectance microscope,” Appl. Opt.41(22), 4603–4610 (2002).
[CrossRef] [PubMed]

J. Lindert, J. Werner, M. Redlin, H. Kuppe, H. Habazettl, and A. R. Pries, “OPS imaging of human microcirculation: a short technical report,” J. Vasc. Res.39(4), 368–372 (2002).
[CrossRef] [PubMed]

2001 (2)

J. J. Bishop, P. R. Nance, A. S. Popel, M. Intaglietta, and P. C. Johnson, “Effect of erythrocyte aggregation on velocity profiles in venules,” Am. J. Physiol. Heart Circ. Physiol.280(1), H222–H236 (2001).
[PubMed]

S. González, R. Sackstein, R. R. Anderson, and M. Rajadhyaksha, “Real-time evidence of in vivo leukocyte trafficking in human skin by reflectance confocal microscopy,” J. Invest. Dermatol.117(2), 384–386 (2001).
[CrossRef] [PubMed]

2000 (1)

G. Iddan, G. Meron, A. Glukhovsky, and P. Swain, “Wireless capsule endoscopy,” Nature405(6785), 417 (2000).
[CrossRef] [PubMed]

1999 (3)

M. Rajadhyaksha, R. R. Anderson, and R. H. Webb, “Video-rate confocal scanning laser microscope for imaging human tissues in vivo,” Appl. Opt.38(10), 2105–2115 (1999).
[CrossRef] [PubMed]

W. M. White, M. Rajadhyaksha, S. González, R. L. Fabian, and R. R. Anderson, “Noninvasive imaging of human oral mucosa in vivo by confocal reflectance microscopy,” Laryngoscope109(10), 1709–1717 (1999).
[CrossRef] [PubMed]

W. Groner, J. W. Winkelman, A. G. Harris, C. Ince, G. J. Bouma, K. Messmer, and R. G. Nadeau, “Orthogonal polarization spectral imaging: a new method for study of the microcirculation,” Nat. Med.5(10), 1209–1212 (1999).
[CrossRef] [PubMed]

1998 (2)

G. J. Tearney, R. H. Webb, and B. E. Bouma, “Spectrally encoded confocal microscopy,” Opt. Lett.23(15), 1152–1154 (1998).
[CrossRef] [PubMed]

K. Konstantopoulos, S. Neelamegham, A. R. Burns, E. Hentzen, G. S. Kansas, K. R. Snapp, E. L. Berg, J. D. Hellums, C. W. Smith, L. V. McIntire, and S. I. Simon, “Venous levels of shear support neutrophil-platelet adhesion and neutrophil aggregation in blood via P-selectin and beta2-integrin,” Circulation98(9), 873–882 (1998).
[PubMed]

1995 (1)

M. Rajadhyaksha, M. Grossman, D. Esterowitz, R. H. Webb, and R. R. Anderson, “In vivo confocal scanning laser microscopy of human skin: melanin provides strong contrast,” J. Invest. Dermatol.104(6), 946–952 (1995).
[CrossRef] [PubMed]

1994 (1)

K. Yamakoshi, S. Tanaka, and H. Shimazu, “Electrical admittance cuff for noninvasive and simultaneous measurement of haematocrit, arterial pressure and elasticity using volume-oscillometric method,” Med. Biol. Eng. Comput.32(S1Suppl), S99–S107 (1994).
[CrossRef] [PubMed]

1987 (1)

1982 (1)

I. H. Sarelius and B. R. Duling, “Direct measurement of microvessel hematocrit, red cell flux, velocity, and transit time,” Am. J. Physiol.243(6), H1018–H1026 (1982).
[PubMed]

1980 (1)

G. W. Schmid-Schönbein, S. Usami, R. Skalak, and S. Chien, “The interaction of leukocytes and erythrocytes in capillary and postcapillary vessels,” Microvasc. Res.19(1), 45–70 (1980).
[CrossRef] [PubMed]

Anderson, R. R.

S. González, R. Sackstein, R. R. Anderson, and M. Rajadhyaksha, “Real-time evidence of in vivo leukocyte trafficking in human skin by reflectance confocal microscopy,” J. Invest. Dermatol.117(2), 384–386 (2001).
[CrossRef] [PubMed]

W. M. White, M. Rajadhyaksha, S. González, R. L. Fabian, and R. R. Anderson, “Noninvasive imaging of human oral mucosa in vivo by confocal reflectance microscopy,” Laryngoscope109(10), 1709–1717 (1999).
[CrossRef] [PubMed]

M. Rajadhyaksha, R. R. Anderson, and R. H. Webb, “Video-rate confocal scanning laser microscope for imaging human tissues in vivo,” Appl. Opt.38(10), 2105–2115 (1999).
[CrossRef] [PubMed]

M. Rajadhyaksha, M. Grossman, D. Esterowitz, R. H. Webb, and R. R. Anderson, “In vivo confocal scanning laser microscopy of human skin: melanin provides strong contrast,” J. Invest. Dermatol.104(6), 946–952 (1995).
[CrossRef] [PubMed]

Berg, E. L.

K. Konstantopoulos, S. Neelamegham, A. R. Burns, E. Hentzen, G. S. Kansas, K. R. Snapp, E. L. Berg, J. D. Hellums, C. W. Smith, L. V. McIntire, and S. I. Simon, “Venous levels of shear support neutrophil-platelet adhesion and neutrophil aggregation in blood via P-selectin and beta2-integrin,” Circulation98(9), 873–882 (1998).
[PubMed]

Bishop, J. J.

J. J. Bishop, P. R. Nance, A. S. Popel, M. Intaglietta, and P. C. Johnson, “Effect of erythrocyte aggregation on velocity profiles in venules,” Am. J. Physiol. Heart Circ. Physiol.280(1), H222–H236 (2001).
[PubMed]

Boudoux, C.

D. Kang, M. J. Suter, C. Boudoux, H. Yoo, P. S. Yachimski, W. P. Puricelli, N. S. Nishioka, M. Mino-Kenudson, G. Y. Lauwers, B. E. Bouma, and G. J. Tearney, “Comprehensive imaging of gastroesophageal biopsy samples by spectrally encoded confocal microscopy,” Gastrointest. Endosc.71(1), 35–43 (2010).
[CrossRef] [PubMed]

D. Yelin, C. Boudoux, B. E. Bouma, and G. J. Tearney, “Large area confocal microscopy,” Opt. Lett.32(9), 1102–1104 (2007).
[CrossRef] [PubMed]

Bouma, B. E.

D. Kang, M. J. Suter, C. Boudoux, H. Yoo, P. S. Yachimski, W. P. Puricelli, N. S. Nishioka, M. Mino-Kenudson, G. Y. Lauwers, B. E. Bouma, and G. J. Tearney, “Comprehensive imaging of gastroesophageal biopsy samples by spectrally encoded confocal microscopy,” Gastrointest. Endosc.71(1), 35–43 (2010).
[CrossRef] [PubMed]

D. Yelin, C. Boudoux, B. E. Bouma, and G. J. Tearney, “Large area confocal microscopy,” Opt. Lett.32(9), 1102–1104 (2007).
[CrossRef] [PubMed]

G. J. Tearney, R. H. Webb, and B. E. Bouma, “Spectrally encoded confocal microscopy,” Opt. Lett.23(15), 1152–1154 (1998).
[CrossRef] [PubMed]

Bouma, G. J.

W. Groner, J. W. Winkelman, A. G. Harris, C. Ince, G. J. Bouma, K. Messmer, and R. G. Nadeau, “Orthogonal polarization spectral imaging: a new method for study of the microcirculation,” Nat. Med.5(10), 1209–1212 (1999).
[CrossRef] [PubMed]

Brecht, H.-P. F.

Burg, J.

R. Kiesslich, J. Burg, M. Vieth, J. Gnaendiger, M. Enders, P. Delaney, A. Polglase, W. McLaren, D. Janell, S. Thomas, B. Nafe, P. R. Galle, and M. F. Neurath, “Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo,” Gastroenterology127(3), 706–713 (2004).
[CrossRef] [PubMed]

Burns, A. R.

K. Konstantopoulos, S. Neelamegham, A. R. Burns, E. Hentzen, G. S. Kansas, K. R. Snapp, E. L. Berg, J. D. Hellums, C. W. Smith, L. V. McIntire, and S. I. Simon, “Venous levels of shear support neutrophil-platelet adhesion and neutrophil aggregation in blood via P-selectin and beta2-integrin,” Circulation98(9), 873–882 (1998).
[PubMed]

Chien, S.

G. W. Schmid-Schönbein, S. Usami, R. Skalak, and S. Chien, “The interaction of leukocytes and erythrocytes in capillary and postcapillary vessels,” Microvasc. Res.19(1), 45–70 (1980).
[CrossRef] [PubMed]

Contag, C. H.

P.-L. Hsiung, J. Hardy, S. Friedland, R. Soetikno, C. B. Du, A. P. Wu, P. Sahbaie, J. M. Crawford, A. W. Lowe, C. H. Contag, and T. D. Wang, “Detection of colonic dysplasia in vivo using a targeted heptapeptide and confocal microendoscopy,” Nat. Med.14(4), 454–458 (2008).
[CrossRef] [PubMed]

Côté, D.

D. A. Sipkins, X. Wei, J. W. Wu, J. M. Runnels, D. Côté, T. K. Means, A. D. Luster, D. T. Scadden, and C. P. Lin, “In vivo imaging of specialized bone marrow endothelial microdomains for tumour engraftment,” Nature435(7044), 969–973 (2005).
[CrossRef] [PubMed]

Crawford, J. M.

P.-L. Hsiung, J. Hardy, S. Friedland, R. Soetikno, C. B. Du, A. P. Wu, P. Sahbaie, J. M. Crawford, A. W. Lowe, C. H. Contag, and T. D. Wang, “Detection of colonic dysplasia in vivo using a targeted heptapeptide and confocal microendoscopy,” Nat. Med.14(4), 454–458 (2008).
[CrossRef] [PubMed]

Delaney, P.

R. Kiesslich, J. Burg, M. Vieth, J. Gnaendiger, M. Enders, P. Delaney, A. Polglase, W. McLaren, D. Janell, S. Thomas, B. Nafe, P. R. Galle, and M. F. Neurath, “Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo,” Gastroenterology127(3), 706–713 (2004).
[CrossRef] [PubMed]

Delori, F. C.

Descour, M. R.

Deyo, D. J.

Du, C. B.

P.-L. Hsiung, J. Hardy, S. Friedland, R. Soetikno, C. B. Du, A. P. Wu, P. Sahbaie, J. M. Crawford, A. W. Lowe, C. H. Contag, and T. D. Wang, “Detection of colonic dysplasia in vivo using a targeted heptapeptide and confocal microendoscopy,” Nat. Med.14(4), 454–458 (2008).
[CrossRef] [PubMed]

Duling, B. R.

I. H. Sarelius and B. R. Duling, “Direct measurement of microvessel hematocrit, red cell flux, velocity, and transit time,” Am. J. Physiol.243(6), H1018–H1026 (1982).
[PubMed]

Enders, M.

R. Kiesslich, J. Burg, M. Vieth, J. Gnaendiger, M. Enders, P. Delaney, A. Polglase, W. McLaren, D. Janell, S. Thomas, B. Nafe, P. R. Galle, and M. F. Neurath, “Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo,” Gastroenterology127(3), 706–713 (2004).
[CrossRef] [PubMed]

Esenaliev, R. O.

Esterowitz, D.

M. Rajadhyaksha, M. Grossman, D. Esterowitz, R. H. Webb, and R. R. Anderson, “In vivo confocal scanning laser microscopy of human skin: melanin provides strong contrast,” J. Invest. Dermatol.104(6), 946–952 (1995).
[CrossRef] [PubMed]

Fabian, R. L.

W. M. White, M. Rajadhyaksha, S. González, R. L. Fabian, and R. R. Anderson, “Noninvasive imaging of human oral mucosa in vivo by confocal reflectance microscopy,” Laryngoscope109(10), 1709–1717 (1999).
[CrossRef] [PubMed]

Friedland, S.

P.-L. Hsiung, J. Hardy, S. Friedland, R. Soetikno, C. B. Du, A. P. Wu, P. Sahbaie, J. M. Crawford, A. W. Lowe, C. H. Contag, and T. D. Wang, “Detection of colonic dysplasia in vivo using a targeted heptapeptide and confocal microendoscopy,” Nat. Med.14(4), 454–458 (2008).
[CrossRef] [PubMed]

Galanzha, E. I.

E. I. Galanzha and V. P. Zharov, “In vivo photoacoustic and photothermal cytometry for monitoring multiple blood rheology parameters,” Cytometry A79A(10), 746–757 (2011).
[CrossRef] [PubMed]

V. P. Zharov, E. I. Galanzha, Y. Menyaev, and V. V. Tuchin, “In vivo high-speed imaging of individual cells in fast blood flow,” J. Biomed. Opt.11(5), 054034 (2006).
[CrossRef] [PubMed]

V. P. Zharov, E. I. Galanzha, and V. V. Tuchin, “Photothermal image flow cytometry in vivo,” Opt. Lett.30(6), 628–630 (2005).
[CrossRef] [PubMed]

Galle, P. R.

R. Kiesslich, J. Burg, M. Vieth, J. Gnaendiger, M. Enders, P. Delaney, A. Polglase, W. McLaren, D. Janell, S. Thomas, B. Nafe, P. R. Galle, and M. F. Neurath, “Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo,” Gastroenterology127(3), 706–713 (2004).
[CrossRef] [PubMed]

Georgakoudi, I.

I. Georgakoudi, N. Solban, J. Novak, W. L. Rice, X. Wei, T. Hasan, and C. P. Lin, “In vivo flow cytometry: a new method for enumerating circulating cancer cells,” Cancer Res.64(15), 5044–5047 (2004).
[CrossRef] [PubMed]

J. Novak, I. Georgakoudi, X. Wei, A. Prossin, and C. P. Lin, “In vivo flow cytometer for real-time detection and quantification of circulating cells,” Opt. Lett.29(1), 77–79 (2004).
[CrossRef] [PubMed]

Glukhovsky, A.

G. Iddan, G. Meron, A. Glukhovsky, and P. Swain, “Wireless capsule endoscopy,” Nature405(6785), 417 (2000).
[CrossRef] [PubMed]

Gnaendiger, J.

R. Kiesslich, J. Burg, M. Vieth, J. Gnaendiger, M. Enders, P. Delaney, A. Polglase, W. McLaren, D. Janell, S. Thomas, B. Nafe, P. R. Galle, and M. F. Neurath, “Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo,” Gastroenterology127(3), 706–713 (2004).
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Golan, L.

González, S.

S. González, R. Sackstein, R. R. Anderson, and M. Rajadhyaksha, “Real-time evidence of in vivo leukocyte trafficking in human skin by reflectance confocal microscopy,” J. Invest. Dermatol.117(2), 384–386 (2001).
[CrossRef] [PubMed]

W. M. White, M. Rajadhyaksha, S. González, R. L. Fabian, and R. R. Anderson, “Noninvasive imaging of human oral mucosa in vivo by confocal reflectance microscopy,” Laryngoscope109(10), 1709–1717 (1999).
[CrossRef] [PubMed]

Groner, W.

W. Groner, J. W. Winkelman, A. G. Harris, C. Ince, G. J. Bouma, K. Messmer, and R. G. Nadeau, “Orthogonal polarization spectral imaging: a new method for study of the microcirculation,” Nat. Med.5(10), 1209–1212 (1999).
[CrossRef] [PubMed]

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M. Rajadhyaksha, M. Grossman, D. Esterowitz, R. H. Webb, and R. R. Anderson, “In vivo confocal scanning laser microscopy of human skin: melanin provides strong contrast,” J. Invest. Dermatol.104(6), 946–952 (1995).
[CrossRef] [PubMed]

Guidi, F.

W. Secomski, A. Nowicki, F. Guidi, P. Tortoli, and P. A. Lewin, “Noninvasive in vivo measurements of hematocrit,” J. Ultrasound Med.22(4), 375–384 (2003).
[PubMed]

Habazettl, H.

J. Lindert, J. Werner, M. Redlin, H. Kuppe, H. Habazettl, and A. R. Pries, “OPS imaging of human microcirculation: a short technical report,” J. Vasc. Res.39(4), 368–372 (2002).
[CrossRef] [PubMed]

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P.-L. Hsiung, J. Hardy, S. Friedland, R. Soetikno, C. B. Du, A. P. Wu, P. Sahbaie, J. M. Crawford, A. W. Lowe, C. H. Contag, and T. D. Wang, “Detection of colonic dysplasia in vivo using a targeted heptapeptide and confocal microendoscopy,” Nat. Med.14(4), 454–458 (2008).
[CrossRef] [PubMed]

Harris, A. G.

W. Groner, J. W. Winkelman, A. G. Harris, C. Ince, G. J. Bouma, K. Messmer, and R. G. Nadeau, “Orthogonal polarization spectral imaging: a new method for study of the microcirculation,” Nat. Med.5(10), 1209–1212 (1999).
[CrossRef] [PubMed]

Hasan, T.

I. Georgakoudi, N. Solban, J. Novak, W. L. Rice, X. Wei, T. Hasan, and C. P. Lin, “In vivo flow cytometry: a new method for enumerating circulating cancer cells,” Cancer Res.64(15), 5044–5047 (2004).
[CrossRef] [PubMed]

Hellums, J. D.

K. Konstantopoulos, S. Neelamegham, A. R. Burns, E. Hentzen, G. S. Kansas, K. R. Snapp, E. L. Berg, J. D. Hellums, C. W. Smith, L. V. McIntire, and S. I. Simon, “Venous levels of shear support neutrophil-platelet adhesion and neutrophil aggregation in blood via P-selectin and beta2-integrin,” Circulation98(9), 873–882 (1998).
[PubMed]

Hentzen, E.

K. Konstantopoulos, S. Neelamegham, A. R. Burns, E. Hentzen, G. S. Kansas, K. R. Snapp, E. L. Berg, J. D. Hellums, C. W. Smith, L. V. McIntire, and S. I. Simon, “Venous levels of shear support neutrophil-platelet adhesion and neutrophil aggregation in blood via P-selectin and beta2-integrin,” Circulation98(9), 873–882 (1998).
[PubMed]

Hsiung, P.-L.

P.-L. Hsiung, J. Hardy, S. Friedland, R. Soetikno, C. B. Du, A. P. Wu, P. Sahbaie, J. M. Crawford, A. W. Lowe, C. H. Contag, and T. D. Wang, “Detection of colonic dysplasia in vivo using a targeted heptapeptide and confocal microendoscopy,” Nat. Med.14(4), 454–458 (2008).
[CrossRef] [PubMed]

Hughes, G. W.

Iddan, G.

G. Iddan, G. Meron, A. Glukhovsky, and P. Swain, “Wireless capsule endoscopy,” Nature405(6785), 417 (2000).
[CrossRef] [PubMed]

Ince, C.

C. Ince, “Sidestream dark field imaging: an improved technique to observe sublingual microcirculation,” Crit. Care9(Suppl 1), P72 (2005).
[CrossRef]

W. Groner, J. W. Winkelman, A. G. Harris, C. Ince, G. J. Bouma, K. Messmer, and R. G. Nadeau, “Orthogonal polarization spectral imaging: a new method for study of the microcirculation,” Nat. Med.5(10), 1209–1212 (1999).
[CrossRef] [PubMed]

Intaglietta, M.

J. J. Bishop, P. R. Nance, A. S. Popel, M. Intaglietta, and P. C. Johnson, “Effect of erythrocyte aggregation on velocity profiles in venules,” Am. J. Physiol. Heart Circ. Physiol.280(1), H222–H236 (2001).
[PubMed]

Janell, D.

R. Kiesslich, J. Burg, M. Vieth, J. Gnaendiger, M. Enders, P. Delaney, A. Polglase, W. McLaren, D. Janell, S. Thomas, B. Nafe, P. R. Galle, and M. F. Neurath, “Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo,” Gastroenterology127(3), 706–713 (2004).
[CrossRef] [PubMed]

Johnson, P. C.

J. J. Bishop, P. R. Nance, A. S. Popel, M. Intaglietta, and P. C. Johnson, “Effect of erythrocyte aggregation on velocity profiles in venules,” Am. J. Physiol. Heart Circ. Physiol.280(1), H222–H236 (2001).
[PubMed]

Kang, D.

D. Kang, M. J. Suter, C. Boudoux, H. Yoo, P. S. Yachimski, W. P. Puricelli, N. S. Nishioka, M. Mino-Kenudson, G. Y. Lauwers, B. E. Bouma, and G. J. Tearney, “Comprehensive imaging of gastroesophageal biopsy samples by spectrally encoded confocal microscopy,” Gastrointest. Endosc.71(1), 35–43 (2010).
[CrossRef] [PubMed]

Kansas, G. S.

K. Konstantopoulos, S. Neelamegham, A. R. Burns, E. Hentzen, G. S. Kansas, K. R. Snapp, E. L. Berg, J. D. Hellums, C. W. Smith, L. V. McIntire, and S. I. Simon, “Venous levels of shear support neutrophil-platelet adhesion and neutrophil aggregation in blood via P-selectin and beta2-integrin,” Circulation98(9), 873–882 (1998).
[PubMed]

Kiesslich, R.

R. Kiesslich, J. Burg, M. Vieth, J. Gnaendiger, M. Enders, P. Delaney, A. Polglase, W. McLaren, D. Janell, S. Thomas, B. Nafe, P. R. Galle, and M. F. Neurath, “Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo,” Gastroenterology127(3), 706–713 (2004).
[CrossRef] [PubMed]

Konstantopoulos, K.

K. Konstantopoulos, S. Neelamegham, A. R. Burns, E. Hentzen, G. S. Kansas, K. R. Snapp, E. L. Berg, J. D. Hellums, C. W. Smith, L. V. McIntire, and S. I. Simon, “Venous levels of shear support neutrophil-platelet adhesion and neutrophil aggregation in blood via P-selectin and beta2-integrin,” Circulation98(9), 873–882 (1998).
[PubMed]

Kuppe, H.

J. Lindert, J. Werner, M. Redlin, H. Kuppe, H. Habazettl, and A. R. Pries, “OPS imaging of human microcirculation: a short technical report,” J. Vasc. Res.39(4), 368–372 (2002).
[CrossRef] [PubMed]

Lauwers, G. Y.

D. Kang, M. J. Suter, C. Boudoux, H. Yoo, P. S. Yachimski, W. P. Puricelli, N. S. Nishioka, M. Mino-Kenudson, G. Y. Lauwers, B. E. Bouma, and G. J. Tearney, “Comprehensive imaging of gastroesophageal biopsy samples by spectrally encoded confocal microscopy,” Gastrointest. Endosc.71(1), 35–43 (2010).
[CrossRef] [PubMed]

Lewin, P. A.

W. Secomski, A. Nowicki, F. Guidi, P. Tortoli, and P. A. Lewin, “Noninvasive in vivo measurements of hematocrit,” J. Ultrasound Med.22(4), 375–384 (2003).
[PubMed]

Liang, C.

Lin, C. P.

D. A. Sipkins, X. Wei, J. W. Wu, J. M. Runnels, D. Côté, T. K. Means, A. D. Luster, D. T. Scadden, and C. P. Lin, “In vivo imaging of specialized bone marrow endothelial microdomains for tumour engraftment,” Nature435(7044), 969–973 (2005).
[CrossRef] [PubMed]

I. Georgakoudi, N. Solban, J. Novak, W. L. Rice, X. Wei, T. Hasan, and C. P. Lin, “In vivo flow cytometry: a new method for enumerating circulating cancer cells,” Cancer Res.64(15), 5044–5047 (2004).
[CrossRef] [PubMed]

J. Novak, I. Georgakoudi, X. Wei, A. Prossin, and C. P. Lin, “In vivo flow cytometer for real-time detection and quantification of circulating cells,” Opt. Lett.29(1), 77–79 (2004).
[CrossRef] [PubMed]

Lindert, J.

J. Lindert, J. Werner, M. Redlin, H. Kuppe, H. Habazettl, and A. R. Pries, “OPS imaging of human microcirculation: a short technical report,” J. Vasc. Res.39(4), 368–372 (2002).
[CrossRef] [PubMed]

Lowe, A. W.

P.-L. Hsiung, J. Hardy, S. Friedland, R. Soetikno, C. B. Du, A. P. Wu, P. Sahbaie, J. M. Crawford, A. W. Lowe, C. H. Contag, and T. D. Wang, “Detection of colonic dysplasia in vivo using a targeted heptapeptide and confocal microendoscopy,” Nat. Med.14(4), 454–458 (2008).
[CrossRef] [PubMed]

Luster, A. D.

D. A. Sipkins, X. Wei, J. W. Wu, J. M. Runnels, D. Côté, T. K. Means, A. D. Luster, D. T. Scadden, and C. P. Lin, “In vivo imaging of specialized bone marrow endothelial microdomains for tumour engraftment,” Nature435(7044), 969–973 (2005).
[CrossRef] [PubMed]

McIntire, L. V.

K. Konstantopoulos, S. Neelamegham, A. R. Burns, E. Hentzen, G. S. Kansas, K. R. Snapp, E. L. Berg, J. D. Hellums, C. W. Smith, L. V. McIntire, and S. I. Simon, “Venous levels of shear support neutrophil-platelet adhesion and neutrophil aggregation in blood via P-selectin and beta2-integrin,” Circulation98(9), 873–882 (1998).
[PubMed]

McLaren, W.

R. Kiesslich, J. Burg, M. Vieth, J. Gnaendiger, M. Enders, P. Delaney, A. Polglase, W. McLaren, D. Janell, S. Thomas, B. Nafe, P. R. Galle, and M. F. Neurath, “Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo,” Gastroenterology127(3), 706–713 (2004).
[CrossRef] [PubMed]

Means, T. K.

D. A. Sipkins, X. Wei, J. W. Wu, J. M. Runnels, D. Côté, T. K. Means, A. D. Luster, D. T. Scadden, and C. P. Lin, “In vivo imaging of specialized bone marrow endothelial microdomains for tumour engraftment,” Nature435(7044), 969–973 (2005).
[CrossRef] [PubMed]

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V. P. Zharov, E. I. Galanzha, Y. Menyaev, and V. V. Tuchin, “In vivo high-speed imaging of individual cells in fast blood flow,” J. Biomed. Opt.11(5), 054034 (2006).
[CrossRef] [PubMed]

Meron, G.

G. Iddan, G. Meron, A. Glukhovsky, and P. Swain, “Wireless capsule endoscopy,” Nature405(6785), 417 (2000).
[CrossRef] [PubMed]

Messmer, K.

W. Groner, J. W. Winkelman, A. G. Harris, C. Ince, G. J. Bouma, K. Messmer, and R. G. Nadeau, “Orthogonal polarization spectral imaging: a new method for study of the microcirculation,” Nat. Med.5(10), 1209–1212 (1999).
[CrossRef] [PubMed]

Mino-Kenudson, M.

D. Kang, M. J. Suter, C. Boudoux, H. Yoo, P. S. Yachimski, W. P. Puricelli, N. S. Nishioka, M. Mino-Kenudson, G. Y. Lauwers, B. E. Bouma, and G. J. Tearney, “Comprehensive imaging of gastroesophageal biopsy samples by spectrally encoded confocal microscopy,” Gastrointest. Endosc.71(1), 35–43 (2010).
[CrossRef] [PubMed]

Nadeau, R. G.

W. Groner, J. W. Winkelman, A. G. Harris, C. Ince, G. J. Bouma, K. Messmer, and R. G. Nadeau, “Orthogonal polarization spectral imaging: a new method for study of the microcirculation,” Nat. Med.5(10), 1209–1212 (1999).
[CrossRef] [PubMed]

Nafe, B.

R. Kiesslich, J. Burg, M. Vieth, J. Gnaendiger, M. Enders, P. Delaney, A. Polglase, W. McLaren, D. Janell, S. Thomas, B. Nafe, P. R. Galle, and M. F. Neurath, “Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo,” Gastroenterology127(3), 706–713 (2004).
[CrossRef] [PubMed]

Nance, P. R.

J. J. Bishop, P. R. Nance, A. S. Popel, M. Intaglietta, and P. C. Johnson, “Effect of erythrocyte aggregation on velocity profiles in venules,” Am. J. Physiol. Heart Circ. Physiol.280(1), H222–H236 (2001).
[PubMed]

Neelamegham, S.

K. Konstantopoulos, S. Neelamegham, A. R. Burns, E. Hentzen, G. S. Kansas, K. R. Snapp, E. L. Berg, J. D. Hellums, C. W. Smith, L. V. McIntire, and S. I. Simon, “Venous levels of shear support neutrophil-platelet adhesion and neutrophil aggregation in blood via P-selectin and beta2-integrin,” Circulation98(9), 873–882 (1998).
[PubMed]

Neurath, M. F.

R. Kiesslich, J. Burg, M. Vieth, J. Gnaendiger, M. Enders, P. Delaney, A. Polglase, W. McLaren, D. Janell, S. Thomas, B. Nafe, P. R. Galle, and M. F. Neurath, “Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo,” Gastroenterology127(3), 706–713 (2004).
[CrossRef] [PubMed]

Nishioka, N. S.

D. Kang, M. J. Suter, C. Boudoux, H. Yoo, P. S. Yachimski, W. P. Puricelli, N. S. Nishioka, M. Mino-Kenudson, G. Y. Lauwers, B. E. Bouma, and G. J. Tearney, “Comprehensive imaging of gastroesophageal biopsy samples by spectrally encoded confocal microscopy,” Gastrointest. Endosc.71(1), 35–43 (2010).
[CrossRef] [PubMed]

Novak, J.

I. Georgakoudi, N. Solban, J. Novak, W. L. Rice, X. Wei, T. Hasan, and C. P. Lin, “In vivo flow cytometry: a new method for enumerating circulating cancer cells,” Cancer Res.64(15), 5044–5047 (2004).
[CrossRef] [PubMed]

J. Novak, I. Georgakoudi, X. Wei, A. Prossin, and C. P. Lin, “In vivo flow cytometer for real-time detection and quantification of circulating cells,” Opt. Lett.29(1), 77–79 (2004).
[CrossRef] [PubMed]

Nowicki, A.

W. Secomski, A. Nowicki, F. Guidi, P. Tortoli, and P. A. Lewin, “Noninvasive in vivo measurements of hematocrit,” J. Ultrasound Med.22(4), 375–384 (2003).
[PubMed]

Olsson, J.

Petrov, Y. Y.

Petrova, I. Y.

Polglase, A.

R. Kiesslich, J. Burg, M. Vieth, J. Gnaendiger, M. Enders, P. Delaney, A. Polglase, W. McLaren, D. Janell, S. Thomas, B. Nafe, P. R. Galle, and M. F. Neurath, “Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo,” Gastroenterology127(3), 706–713 (2004).
[CrossRef] [PubMed]

Popel, A. S.

J. J. Bishop, P. R. Nance, A. S. Popel, M. Intaglietta, and P. C. Johnson, “Effect of erythrocyte aggregation on velocity profiles in venules,” Am. J. Physiol. Heart Circ. Physiol.280(1), H222–H236 (2001).
[PubMed]

Pries, A. R.

J. Lindert, J. Werner, M. Redlin, H. Kuppe, H. Habazettl, and A. R. Pries, “OPS imaging of human microcirculation: a short technical report,” J. Vasc. Res.39(4), 368–372 (2002).
[CrossRef] [PubMed]

Prossin, A.

Prough, D. S.

Puricelli, W. P.

D. Kang, M. J. Suter, C. Boudoux, H. Yoo, P. S. Yachimski, W. P. Puricelli, N. S. Nishioka, M. Mino-Kenudson, G. Y. Lauwers, B. E. Bouma, and G. J. Tearney, “Comprehensive imaging of gastroesophageal biopsy samples by spectrally encoded confocal microscopy,” Gastrointest. Endosc.71(1), 35–43 (2010).
[CrossRef] [PubMed]

Rajadhyaksha, M.

S. González, R. Sackstein, R. R. Anderson, and M. Rajadhyaksha, “Real-time evidence of in vivo leukocyte trafficking in human skin by reflectance confocal microscopy,” J. Invest. Dermatol.117(2), 384–386 (2001).
[CrossRef] [PubMed]

W. M. White, M. Rajadhyaksha, S. González, R. L. Fabian, and R. R. Anderson, “Noninvasive imaging of human oral mucosa in vivo by confocal reflectance microscopy,” Laryngoscope109(10), 1709–1717 (1999).
[CrossRef] [PubMed]

M. Rajadhyaksha, R. R. Anderson, and R. H. Webb, “Video-rate confocal scanning laser microscope for imaging human tissues in vivo,” Appl. Opt.38(10), 2105–2115 (1999).
[CrossRef] [PubMed]

M. Rajadhyaksha, M. Grossman, D. Esterowitz, R. H. Webb, and R. R. Anderson, “In vivo confocal scanning laser microscopy of human skin: melanin provides strong contrast,” J. Invest. Dermatol.104(6), 946–952 (1995).
[CrossRef] [PubMed]

Redlin, M.

J. Lindert, J. Werner, M. Redlin, H. Kuppe, H. Habazettl, and A. R. Pries, “OPS imaging of human microcirculation: a short technical report,” J. Vasc. Res.39(4), 368–372 (2002).
[CrossRef] [PubMed]

Rice, W. L.

I. Georgakoudi, N. Solban, J. Novak, W. L. Rice, X. Wei, T. Hasan, and C. P. Lin, “In vivo flow cytometry: a new method for enumerating circulating cancer cells,” Cancer Res.64(15), 5044–5047 (2004).
[CrossRef] [PubMed]

Richards-Kortum, R. R.

Runnels, J. M.

D. A. Sipkins, X. Wei, J. W. Wu, J. M. Runnels, D. Côté, T. K. Means, A. D. Luster, D. T. Scadden, and C. P. Lin, “In vivo imaging of specialized bone marrow endothelial microdomains for tumour engraftment,” Nature435(7044), 969–973 (2005).
[CrossRef] [PubMed]

Sackstein, R.

S. González, R. Sackstein, R. R. Anderson, and M. Rajadhyaksha, “Real-time evidence of in vivo leukocyte trafficking in human skin by reflectance confocal microscopy,” J. Invest. Dermatol.117(2), 384–386 (2001).
[CrossRef] [PubMed]

Sahbaie, P.

P.-L. Hsiung, J. Hardy, S. Friedland, R. Soetikno, C. B. Du, A. P. Wu, P. Sahbaie, J. M. Crawford, A. W. Lowe, C. H. Contag, and T. D. Wang, “Detection of colonic dysplasia in vivo using a targeted heptapeptide and confocal microendoscopy,” Nat. Med.14(4), 454–458 (2008).
[CrossRef] [PubMed]

Sarelius, I. H.

I. H. Sarelius and B. R. Duling, “Direct measurement of microvessel hematocrit, red cell flux, velocity, and transit time,” Am. J. Physiol.243(6), H1018–H1026 (1982).
[PubMed]

Scadden, D. T.

D. A. Sipkins, X. Wei, J. W. Wu, J. M. Runnels, D. Côté, T. K. Means, A. D. Luster, D. T. Scadden, and C. P. Lin, “In vivo imaging of specialized bone marrow endothelial microdomains for tumour engraftment,” Nature435(7044), 969–973 (2005).
[CrossRef] [PubMed]

Schmid-Schönbein, G. W.

G. W. Schmid-Schönbein, S. Usami, R. Skalak, and S. Chien, “The interaction of leukocytes and erythrocytes in capillary and postcapillary vessels,” Microvasc. Res.19(1), 45–70 (1980).
[CrossRef] [PubMed]

Secomski, W.

W. Secomski, A. Nowicki, F. Guidi, P. Tortoli, and P. A. Lewin, “Noninvasive in vivo measurements of hematocrit,” J. Ultrasound Med.22(4), 375–384 (2003).
[PubMed]

Shimazu, H.

K. Yamakoshi, S. Tanaka, and H. Shimazu, “Electrical admittance cuff for noninvasive and simultaneous measurement of haematocrit, arterial pressure and elasticity using volume-oscillometric method,” Med. Biol. Eng. Comput.32(S1Suppl), S99–S107 (1994).
[CrossRef] [PubMed]

Simon, S. I.

K. Konstantopoulos, S. Neelamegham, A. R. Burns, E. Hentzen, G. S. Kansas, K. R. Snapp, E. L. Berg, J. D. Hellums, C. W. Smith, L. V. McIntire, and S. I. Simon, “Venous levels of shear support neutrophil-platelet adhesion and neutrophil aggregation in blood via P-selectin and beta2-integrin,” Circulation98(9), 873–882 (1998).
[PubMed]

Sipkins, D. A.

D. A. Sipkins, X. Wei, J. W. Wu, J. M. Runnels, D. Côté, T. K. Means, A. D. Luster, D. T. Scadden, and C. P. Lin, “In vivo imaging of specialized bone marrow endothelial microdomains for tumour engraftment,” Nature435(7044), 969–973 (2005).
[CrossRef] [PubMed]

Skalak, R.

G. W. Schmid-Schönbein, S. Usami, R. Skalak, and S. Chien, “The interaction of leukocytes and erythrocytes in capillary and postcapillary vessels,” Microvasc. Res.19(1), 45–70 (1980).
[CrossRef] [PubMed]

Smith, C. W.

K. Konstantopoulos, S. Neelamegham, A. R. Burns, E. Hentzen, G. S. Kansas, K. R. Snapp, E. L. Berg, J. D. Hellums, C. W. Smith, L. V. McIntire, and S. I. Simon, “Venous levels of shear support neutrophil-platelet adhesion and neutrophil aggregation in blood via P-selectin and beta2-integrin,” Circulation98(9), 873–882 (1998).
[PubMed]

Snapp, K. R.

K. Konstantopoulos, S. Neelamegham, A. R. Burns, E. Hentzen, G. S. Kansas, K. R. Snapp, E. L. Berg, J. D. Hellums, C. W. Smith, L. V. McIntire, and S. I. Simon, “Venous levels of shear support neutrophil-platelet adhesion and neutrophil aggregation in blood via P-selectin and beta2-integrin,” Circulation98(9), 873–882 (1998).
[PubMed]

Soetikno, R.

P.-L. Hsiung, J. Hardy, S. Friedland, R. Soetikno, C. B. Du, A. P. Wu, P. Sahbaie, J. M. Crawford, A. W. Lowe, C. H. Contag, and T. D. Wang, “Detection of colonic dysplasia in vivo using a targeted heptapeptide and confocal microendoscopy,” Nat. Med.14(4), 454–458 (2008).
[CrossRef] [PubMed]

Solban, N.

I. Georgakoudi, N. Solban, J. Novak, W. L. Rice, X. Wei, T. Hasan, and C. P. Lin, “In vivo flow cytometry: a new method for enumerating circulating cancer cells,” Cancer Res.64(15), 5044–5047 (2004).
[CrossRef] [PubMed]

Sung, K.-B.

Suter, M. J.

D. Kang, M. J. Suter, C. Boudoux, H. Yoo, P. S. Yachimski, W. P. Puricelli, N. S. Nishioka, M. Mino-Kenudson, G. Y. Lauwers, B. E. Bouma, and G. J. Tearney, “Comprehensive imaging of gastroesophageal biopsy samples by spectrally encoded confocal microscopy,” Gastrointest. Endosc.71(1), 35–43 (2010).
[CrossRef] [PubMed]

Svensen, C. H.

Swain, P.

G. Iddan, G. Meron, A. Glukhovsky, and P. Swain, “Wireless capsule endoscopy,” Nature405(6785), 417 (2000).
[CrossRef] [PubMed]

Tanaka, S.

K. Yamakoshi, S. Tanaka, and H. Shimazu, “Electrical admittance cuff for noninvasive and simultaneous measurement of haematocrit, arterial pressure and elasticity using volume-oscillometric method,” Med. Biol. Eng. Comput.32(S1Suppl), S99–S107 (1994).
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V. V. Tuchin, A. Tárnok, and V. P. Zharov, “In vivo flow cytometry: a horizon of opportunities,” Cytometry A79A(10), 737–745 (2011).
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D. Kang, M. J. Suter, C. Boudoux, H. Yoo, P. S. Yachimski, W. P. Puricelli, N. S. Nishioka, M. Mino-Kenudson, G. Y. Lauwers, B. E. Bouma, and G. J. Tearney, “Comprehensive imaging of gastroesophageal biopsy samples by spectrally encoded confocal microscopy,” Gastrointest. Endosc.71(1), 35–43 (2010).
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D. Yelin, C. Boudoux, B. E. Bouma, and G. J. Tearney, “Large area confocal microscopy,” Opt. Lett.32(9), 1102–1104 (2007).
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G. J. Tearney, R. H. Webb, and B. E. Bouma, “Spectrally encoded confocal microscopy,” Opt. Lett.23(15), 1152–1154 (1998).
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Thomas, S.

R. Kiesslich, J. Burg, M. Vieth, J. Gnaendiger, M. Enders, P. Delaney, A. Polglase, W. McLaren, D. Janell, S. Thomas, B. Nafe, P. R. Galle, and M. F. Neurath, “Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo,” Gastroenterology127(3), 706–713 (2004).
[CrossRef] [PubMed]

Tortoli, P.

W. Secomski, A. Nowicki, F. Guidi, P. Tortoli, and P. A. Lewin, “Noninvasive in vivo measurements of hematocrit,” J. Ultrasound Med.22(4), 375–384 (2003).
[PubMed]

Tuchin, V. V.

V. V. Tuchin, A. Tárnok, and V. P. Zharov, “In vivo flow cytometry: a horizon of opportunities,” Cytometry A79A(10), 737–745 (2011).
[CrossRef] [PubMed]

V. P. Zharov, E. I. Galanzha, Y. Menyaev, and V. V. Tuchin, “In vivo high-speed imaging of individual cells in fast blood flow,” J. Biomed. Opt.11(5), 054034 (2006).
[CrossRef] [PubMed]

V. P. Zharov, E. I. Galanzha, and V. V. Tuchin, “Photothermal image flow cytometry in vivo,” Opt. Lett.30(6), 628–630 (2005).
[CrossRef] [PubMed]

Usami, S.

G. W. Schmid-Schönbein, S. Usami, R. Skalak, and S. Chien, “The interaction of leukocytes and erythrocytes in capillary and postcapillary vessels,” Microvasc. Res.19(1), 45–70 (1980).
[CrossRef] [PubMed]

Vieth, M.

R. Kiesslich, J. Burg, M. Vieth, J. Gnaendiger, M. Enders, P. Delaney, A. Polglase, W. McLaren, D. Janell, S. Thomas, B. Nafe, P. R. Galle, and M. F. Neurath, “Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo,” Gastroenterology127(3), 706–713 (2004).
[CrossRef] [PubMed]

Wang, T. D.

P.-L. Hsiung, J. Hardy, S. Friedland, R. Soetikno, C. B. Du, A. P. Wu, P. Sahbaie, J. M. Crawford, A. W. Lowe, C. H. Contag, and T. D. Wang, “Detection of colonic dysplasia in vivo using a targeted heptapeptide and confocal microendoscopy,” Nat. Med.14(4), 454–458 (2008).
[CrossRef] [PubMed]

Webb, R. H.

Wei, X.

D. A. Sipkins, X. Wei, J. W. Wu, J. M. Runnels, D. Côté, T. K. Means, A. D. Luster, D. T. Scadden, and C. P. Lin, “In vivo imaging of specialized bone marrow endothelial microdomains for tumour engraftment,” Nature435(7044), 969–973 (2005).
[CrossRef] [PubMed]

I. Georgakoudi, N. Solban, J. Novak, W. L. Rice, X. Wei, T. Hasan, and C. P. Lin, “In vivo flow cytometry: a new method for enumerating circulating cancer cells,” Cancer Res.64(15), 5044–5047 (2004).
[CrossRef] [PubMed]

J. Novak, I. Georgakoudi, X. Wei, A. Prossin, and C. P. Lin, “In vivo flow cytometer for real-time detection and quantification of circulating cells,” Opt. Lett.29(1), 77–79 (2004).
[CrossRef] [PubMed]

Werner, J.

J. Lindert, J. Werner, M. Redlin, H. Kuppe, H. Habazettl, and A. R. Pries, “OPS imaging of human microcirculation: a short technical report,” J. Vasc. Res.39(4), 368–372 (2002).
[CrossRef] [PubMed]

White, W. M.

W. M. White, M. Rajadhyaksha, S. González, R. L. Fabian, and R. R. Anderson, “Noninvasive imaging of human oral mucosa in vivo by confocal reflectance microscopy,” Laryngoscope109(10), 1709–1717 (1999).
[CrossRef] [PubMed]

Winkelman, J. W.

W. Groner, J. W. Winkelman, A. G. Harris, C. Ince, G. J. Bouma, K. Messmer, and R. G. Nadeau, “Orthogonal polarization spectral imaging: a new method for study of the microcirculation,” Nat. Med.5(10), 1209–1212 (1999).
[CrossRef] [PubMed]

Wu, A. P.

P.-L. Hsiung, J. Hardy, S. Friedland, R. Soetikno, C. B. Du, A. P. Wu, P. Sahbaie, J. M. Crawford, A. W. Lowe, C. H. Contag, and T. D. Wang, “Detection of colonic dysplasia in vivo using a targeted heptapeptide and confocal microendoscopy,” Nat. Med.14(4), 454–458 (2008).
[CrossRef] [PubMed]

Wu, J. W.

D. A. Sipkins, X. Wei, J. W. Wu, J. M. Runnels, D. Côté, T. K. Means, A. D. Luster, D. T. Scadden, and C. P. Lin, “In vivo imaging of specialized bone marrow endothelial microdomains for tumour engraftment,” Nature435(7044), 969–973 (2005).
[CrossRef] [PubMed]

Yachimski, P. S.

D. Kang, M. J. Suter, C. Boudoux, H. Yoo, P. S. Yachimski, W. P. Puricelli, N. S. Nishioka, M. Mino-Kenudson, G. Y. Lauwers, B. E. Bouma, and G. J. Tearney, “Comprehensive imaging of gastroesophageal biopsy samples by spectrally encoded confocal microscopy,” Gastrointest. Endosc.71(1), 35–43 (2010).
[CrossRef] [PubMed]

Yamakoshi, K.

K. Yamakoshi, S. Tanaka, and H. Shimazu, “Electrical admittance cuff for noninvasive and simultaneous measurement of haematocrit, arterial pressure and elasticity using volume-oscillometric method,” Med. Biol. Eng. Comput.32(S1Suppl), S99–S107 (1994).
[CrossRef] [PubMed]

Yelin, D.

Yoo, H.

D. Kang, M. J. Suter, C. Boudoux, H. Yoo, P. S. Yachimski, W. P. Puricelli, N. S. Nishioka, M. Mino-Kenudson, G. Y. Lauwers, B. E. Bouma, and G. J. Tearney, “Comprehensive imaging of gastroesophageal biopsy samples by spectrally encoded confocal microscopy,” Gastrointest. Endosc.71(1), 35–43 (2010).
[CrossRef] [PubMed]

Zharov, V. P.

E. I. Galanzha and V. P. Zharov, “In vivo photoacoustic and photothermal cytometry for monitoring multiple blood rheology parameters,” Cytometry A79A(10), 746–757 (2011).
[CrossRef] [PubMed]

V. V. Tuchin, A. Tárnok, and V. P. Zharov, “In vivo flow cytometry: a horizon of opportunities,” Cytometry A79A(10), 737–745 (2011).
[CrossRef] [PubMed]

V. P. Zharov, E. I. Galanzha, Y. Menyaev, and V. V. Tuchin, “In vivo high-speed imaging of individual cells in fast blood flow,” J. Biomed. Opt.11(5), 054034 (2006).
[CrossRef] [PubMed]

V. P. Zharov, E. I. Galanzha, and V. V. Tuchin, “Photothermal image flow cytometry in vivo,” Opt. Lett.30(6), 628–630 (2005).
[CrossRef] [PubMed]

Am. J. Physiol. (1)

I. H. Sarelius and B. R. Duling, “Direct measurement of microvessel hematocrit, red cell flux, velocity, and transit time,” Am. J. Physiol.243(6), H1018–H1026 (1982).
[PubMed]

Am. J. Physiol. Heart Circ. Physiol. (1)

J. J. Bishop, P. R. Nance, A. S. Popel, M. Intaglietta, and P. C. Johnson, “Effect of erythrocyte aggregation on velocity profiles in venules,” Am. J. Physiol. Heart Circ. Physiol.280(1), H222–H236 (2001).
[PubMed]

Appl. Opt. (3)

Cancer Res. (1)

I. Georgakoudi, N. Solban, J. Novak, W. L. Rice, X. Wei, T. Hasan, and C. P. Lin, “In vivo flow cytometry: a new method for enumerating circulating cancer cells,” Cancer Res.64(15), 5044–5047 (2004).
[CrossRef] [PubMed]

Circulation (1)

K. Konstantopoulos, S. Neelamegham, A. R. Burns, E. Hentzen, G. S. Kansas, K. R. Snapp, E. L. Berg, J. D. Hellums, C. W. Smith, L. V. McIntire, and S. I. Simon, “Venous levels of shear support neutrophil-platelet adhesion and neutrophil aggregation in blood via P-selectin and beta2-integrin,” Circulation98(9), 873–882 (1998).
[PubMed]

Crit. Care (1)

C. Ince, “Sidestream dark field imaging: an improved technique to observe sublingual microcirculation,” Crit. Care9(Suppl 1), P72 (2005).
[CrossRef]

Cytometry A (2)

V. V. Tuchin, A. Tárnok, and V. P. Zharov, “In vivo flow cytometry: a horizon of opportunities,” Cytometry A79A(10), 737–745 (2011).
[CrossRef] [PubMed]

E. I. Galanzha and V. P. Zharov, “In vivo photoacoustic and photothermal cytometry for monitoring multiple blood rheology parameters,” Cytometry A79A(10), 746–757 (2011).
[CrossRef] [PubMed]

Gastroenterology (1)

R. Kiesslich, J. Burg, M. Vieth, J. Gnaendiger, M. Enders, P. Delaney, A. Polglase, W. McLaren, D. Janell, S. Thomas, B. Nafe, P. R. Galle, and M. F. Neurath, “Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo,” Gastroenterology127(3), 706–713 (2004).
[CrossRef] [PubMed]

Gastrointest. Endosc. (1)

D. Kang, M. J. Suter, C. Boudoux, H. Yoo, P. S. Yachimski, W. P. Puricelli, N. S. Nishioka, M. Mino-Kenudson, G. Y. Lauwers, B. E. Bouma, and G. J. Tearney, “Comprehensive imaging of gastroesophageal biopsy samples by spectrally encoded confocal microscopy,” Gastrointest. Endosc.71(1), 35–43 (2010).
[CrossRef] [PubMed]

J. Biomed. Opt. (1)

V. P. Zharov, E. I. Galanzha, Y. Menyaev, and V. V. Tuchin, “In vivo high-speed imaging of individual cells in fast blood flow,” J. Biomed. Opt.11(5), 054034 (2006).
[CrossRef] [PubMed]

J. Invest. Dermatol. (2)

M. Rajadhyaksha, M. Grossman, D. Esterowitz, R. H. Webb, and R. R. Anderson, “In vivo confocal scanning laser microscopy of human skin: melanin provides strong contrast,” J. Invest. Dermatol.104(6), 946–952 (1995).
[CrossRef] [PubMed]

S. González, R. Sackstein, R. R. Anderson, and M. Rajadhyaksha, “Real-time evidence of in vivo leukocyte trafficking in human skin by reflectance confocal microscopy,” J. Invest. Dermatol.117(2), 384–386 (2001).
[CrossRef] [PubMed]

J. Ultrasound Med. (1)

W. Secomski, A. Nowicki, F. Guidi, P. Tortoli, and P. A. Lewin, “Noninvasive in vivo measurements of hematocrit,” J. Ultrasound Med.22(4), 375–384 (2003).
[PubMed]

J. Vasc. Res. (1)

J. Lindert, J. Werner, M. Redlin, H. Kuppe, H. Habazettl, and A. R. Pries, “OPS imaging of human microcirculation: a short technical report,” J. Vasc. Res.39(4), 368–372 (2002).
[CrossRef] [PubMed]

Laryngoscope (1)

W. M. White, M. Rajadhyaksha, S. González, R. L. Fabian, and R. R. Anderson, “Noninvasive imaging of human oral mucosa in vivo by confocal reflectance microscopy,” Laryngoscope109(10), 1709–1717 (1999).
[CrossRef] [PubMed]

Med. Biol. Eng. Comput. (1)

K. Yamakoshi, S. Tanaka, and H. Shimazu, “Electrical admittance cuff for noninvasive and simultaneous measurement of haematocrit, arterial pressure and elasticity using volume-oscillometric method,” Med. Biol. Eng. Comput.32(S1Suppl), S99–S107 (1994).
[CrossRef] [PubMed]

Microvasc. Res. (1)

G. W. Schmid-Schönbein, S. Usami, R. Skalak, and S. Chien, “The interaction of leukocytes and erythrocytes in capillary and postcapillary vessels,” Microvasc. Res.19(1), 45–70 (1980).
[CrossRef] [PubMed]

Nat. Med. (2)

W. Groner, J. W. Winkelman, A. G. Harris, C. Ince, G. J. Bouma, K. Messmer, and R. G. Nadeau, “Orthogonal polarization spectral imaging: a new method for study of the microcirculation,” Nat. Med.5(10), 1209–1212 (1999).
[CrossRef] [PubMed]

P.-L. Hsiung, J. Hardy, S. Friedland, R. Soetikno, C. B. Du, A. P. Wu, P. Sahbaie, J. M. Crawford, A. W. Lowe, C. H. Contag, and T. D. Wang, “Detection of colonic dysplasia in vivo using a targeted heptapeptide and confocal microendoscopy,” Nat. Med.14(4), 454–458 (2008).
[CrossRef] [PubMed]

Nature (2)

D. A. Sipkins, X. Wei, J. W. Wu, J. M. Runnels, D. Côté, T. K. Means, A. D. Luster, D. T. Scadden, and C. P. Lin, “In vivo imaging of specialized bone marrow endothelial microdomains for tumour engraftment,” Nature435(7044), 969–973 (2005).
[CrossRef] [PubMed]

G. Iddan, G. Meron, A. Glukhovsky, and P. Swain, “Wireless capsule endoscopy,” Nature405(6785), 417 (2000).
[CrossRef] [PubMed]

Opt. Lett. (6)

Other (1)

V. Hoffbrand, P. Moss, and J. Pettit, Essential Hematology, 5th ed. (Blackwell, Malden, Mass., 2006), pp. 320–365.

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Figures (6)

Fig. 1
Fig. 1

Image acquisition in SEFC. (a) A single line within a blood vessel is imaged with multiple colors of light that encode lateral positions. (b) A single cell crossing the spectral line produces a two-dimensional image with one axis encoded by wavelength and the other by time.

Fig. 2
Fig. 2

Schematic illustration of the SEFC system.

Fig. 3
Fig. 3

In vitro imaging of flowing blood cells. (a) SEFC raw image of diluted whole blood. Right insets, four individual RBCs of different orientations in space whose location in the raw image is marked by arrows. (b) Typical SEFC images of live granulocytes and lymphocytes separated from whole blood compared to standard fluorescence microscopy. Cells' nuclei were stained blue (Hoechst). The lymphocyte SEFC image was brightened (3×) to allow visual comparison. (c) Diameter histograms of granulocytes and lymphocytes, with corresponding mean ± S.D values. (d) Scatter plot of WBC as function of size and integrated brightness allows good statistical separation of lymphocytes from granulocytes.

Fig. 4
Fig. 4

In vivo noninvasive imaging of blood flow in a single vessel. (a) Raw image acquired during 4 seconds of flow. (b) Crop of the raw data acquired during the period marked by the dashed rectangle in a. (c) Crop of the raw data acquired during the period marked by the dashed rectangle in b. (d) Crop of the raw data marked by the dashed rectangle in c. Inset, an image of the blood vessel as seen through the auxiliary green channel. Dashed red line indicates the transverse location of the spectrally encoded line.

Fig. 5
Fig. 5

In vivo imaging in microvessels. (a) RBC flow in a vessel which was slightly deformed by applying external pressure. (b) A histogram showing distribution of RBC diameters. (c) Extracting the fractional area occupied by RBCs in a vessel using manual segmentation for assessing hematocrit levels. Red regions correspond to areas occupied by RBCs. (d) Individual RBCs flowing in a small-diameter capillary.

Fig. 6
Fig. 6

In vivo imaging of WBCs. (a) Imaging close to the wall of a post capillary venule allows forming a plot of the total intensity across the image as a function of time. Good correlation between the appearances of WBCs (magnified cell images below the plot) and intensity peaks was obtained. (b) Averaged flux of WBCs for different vessel diameters. (c) Diameter histogram of the imaged WBCs. (d) A single rolling WBC (outlined by a dashed blue line) near a vessel wall, characterized by an elongated shape which indicates its low relative velocity (approximately 0.18 mm/s) in contrast to the nearby fast RBC flow (approximately 1.1 mm/s). (e) Two attached WBCs flowing in a capillary. (f) A single WBC flowing in a small capillary with a downstream plasma gap (RBC depleted region).

Equations (2)

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v av = d av / t av ,
C WBC =N/( π R 2 v av T ),

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