Abstract

We have combined hyperspectral imaging with spectral domain optical coherence tomography (SDOCT) to noninvasively image changes in hemoglobin saturation, blood flow, microvessel morphology, and sheer rate on the vessel wall with tumor growth. Changes in these hemodynamic variables were measured over 24h in dorsal skin fold window chamber tumors. There was a strong correlation between volumetric flow and hemoglobin saturation (ρ=0.89, p=9×106, N=15) and a moderate correlation between shear rate on the vessel wall and hemoglobin saturation (ρ=0.56, p=0.03, N=15).

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  1. J. Lanzen, R. D. Braun, B. Klitzman, D. Brizel, T. W. Secomb, and M. W. Dewhirst, Cancer Res. 66, 4 (2006).
    [CrossRef]
  2. A. Mariampillai, B. A. Standish, E. H. Moriyama, M. Khurana, N. R. Munce, M. K. Leung, J. Jiang, A. Cable, B. C. Wilson, I. A. Vitkin, and V. X. Yang, Opt. Lett. 33, 13 (2008).
    [CrossRef]
  3. R. D. Braun, J. L. Lanzen, and M. W. Dewhirst, Am. J. Physiol. 277, 2 (1999).
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    [CrossRef]
  5. Y. Tsuzuki, D. Fukumura, B. Oosthuyse, C. Koike, P. Carmeliet, and R. K. Jain, Cancer Res. 60, 22 (2000).
  6. V. X. Yang, S. J. Tang, M. L. Gordon, B. Qi, G. Gardiner, M. Cirocco, P. Kortan, G. B. Haber, G. Kandel, I. A. Vitkin, B. C. Wilson, and N. E. Marcon, Gastrointest. Endosc. 61, 7 (2005).
  7. B. S. Sorg, B. J. Moeller, O. Donovan, Y. Cao, and M. W. Dewhirst, J. Biomed. Opt. 10, 4 (2005).
    [CrossRef]
  8. T. G. van Leeuwen, M. D. Kulkarni, S. Yazdanfar, A. M. Rollins, and J. A. Izatt, Opt. Lett. 24, 22 (1999).
    [CrossRef]
  9. M. W. Dewhirst, E. T. Ong, G. L. Rosner, S. W. Rehmus, S. Shan, R. D. Braun, D. M. Brizel, and T. W. Secomb, Br. J. Cancer Suppl. 27, S241 (1996).
    [PubMed]
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  11. M. W. Dewhirst, R. Oliver, C. Y. Tso, C. Gustafson, T. Secomb, and J. F. Gross, Int. J. Radiat. Oncol. Biol. Phys. 18, 3 (1990).
    [CrossRef]

2008

2006

J. Lanzen, R. D. Braun, B. Klitzman, D. Brizel, T. W. Secomb, and M. W. Dewhirst, Cancer Res. 66, 4 (2006).
[CrossRef]

2005

V. X. Yang, S. J. Tang, M. L. Gordon, B. Qi, G. Gardiner, M. Cirocco, P. Kortan, G. B. Haber, G. Kandel, I. A. Vitkin, B. C. Wilson, and N. E. Marcon, Gastrointest. Endosc. 61, 7 (2005).

B. S. Sorg, B. J. Moeller, O. Donovan, Y. Cao, and M. W. Dewhirst, J. Biomed. Opt. 10, 4 (2005).
[CrossRef]

2000

Y. Tsuzuki, D. Fukumura, B. Oosthuyse, C. Koike, P. Carmeliet, and R. K. Jain, Cancer Res. 60, 22 (2000).

1999

R. D. Braun, J. L. Lanzen, and M. W. Dewhirst, Am. J. Physiol. 277, 2 (1999).

T. G. van Leeuwen, M. D. Kulkarni, S. Yazdanfar, A. M. Rollins, and J. A. Izatt, Opt. Lett. 24, 22 (1999).
[CrossRef]

1997

G. Helmlinger, F. Yuan, M. Dellian, and R. K. Jain, Nat. Med. 3, 2 (1997).
[CrossRef]

1996

M. W. Dewhirst, E. T. Ong, G. L. Rosner, S. W. Rehmus, S. Shan, R. D. Braun, D. M. Brizel, and T. W. Secomb, Br. J. Cancer Suppl. 27, S241 (1996).
[PubMed]

1990

M. W. Dewhirst, R. Oliver, C. Y. Tso, C. Gustafson, T. Secomb, and J. F. Gross, Int. J. Radiat. Oncol. Biol. Phys. 18, 3 (1990).
[CrossRef]

1970

B. R. Duling and R. M. Berne, Circ. Res. 27, 5 (1970).

Berne, R. M.

B. R. Duling and R. M. Berne, Circ. Res. 27, 5 (1970).

Braun, R. D.

J. Lanzen, R. D. Braun, B. Klitzman, D. Brizel, T. W. Secomb, and M. W. Dewhirst, Cancer Res. 66, 4 (2006).
[CrossRef]

R. D. Braun, J. L. Lanzen, and M. W. Dewhirst, Am. J. Physiol. 277, 2 (1999).

M. W. Dewhirst, E. T. Ong, G. L. Rosner, S. W. Rehmus, S. Shan, R. D. Braun, D. M. Brizel, and T. W. Secomb, Br. J. Cancer Suppl. 27, S241 (1996).
[PubMed]

Brizel, D.

J. Lanzen, R. D. Braun, B. Klitzman, D. Brizel, T. W. Secomb, and M. W. Dewhirst, Cancer Res. 66, 4 (2006).
[CrossRef]

Brizel, D. M.

M. W. Dewhirst, E. T. Ong, G. L. Rosner, S. W. Rehmus, S. Shan, R. D. Braun, D. M. Brizel, and T. W. Secomb, Br. J. Cancer Suppl. 27, S241 (1996).
[PubMed]

Cable, A.

Cao, Y.

B. S. Sorg, B. J. Moeller, O. Donovan, Y. Cao, and M. W. Dewhirst, J. Biomed. Opt. 10, 4 (2005).
[CrossRef]

Carmeliet, P.

Y. Tsuzuki, D. Fukumura, B. Oosthuyse, C. Koike, P. Carmeliet, and R. K. Jain, Cancer Res. 60, 22 (2000).

Cirocco, M.

V. X. Yang, S. J. Tang, M. L. Gordon, B. Qi, G. Gardiner, M. Cirocco, P. Kortan, G. B. Haber, G. Kandel, I. A. Vitkin, B. C. Wilson, and N. E. Marcon, Gastrointest. Endosc. 61, 7 (2005).

Dellian, M.

G. Helmlinger, F. Yuan, M. Dellian, and R. K. Jain, Nat. Med. 3, 2 (1997).
[CrossRef]

Dewhirst, M. W.

J. Lanzen, R. D. Braun, B. Klitzman, D. Brizel, T. W. Secomb, and M. W. Dewhirst, Cancer Res. 66, 4 (2006).
[CrossRef]

B. S. Sorg, B. J. Moeller, O. Donovan, Y. Cao, and M. W. Dewhirst, J. Biomed. Opt. 10, 4 (2005).
[CrossRef]

R. D. Braun, J. L. Lanzen, and M. W. Dewhirst, Am. J. Physiol. 277, 2 (1999).

M. W. Dewhirst, E. T. Ong, G. L. Rosner, S. W. Rehmus, S. Shan, R. D. Braun, D. M. Brizel, and T. W. Secomb, Br. J. Cancer Suppl. 27, S241 (1996).
[PubMed]

M. W. Dewhirst, R. Oliver, C. Y. Tso, C. Gustafson, T. Secomb, and J. F. Gross, Int. J. Radiat. Oncol. Biol. Phys. 18, 3 (1990).
[CrossRef]

Donovan, O.

B. S. Sorg, B. J. Moeller, O. Donovan, Y. Cao, and M. W. Dewhirst, J. Biomed. Opt. 10, 4 (2005).
[CrossRef]

Duling, B. R.

B. R. Duling and R. M. Berne, Circ. Res. 27, 5 (1970).

Fukumura, D.

Y. Tsuzuki, D. Fukumura, B. Oosthuyse, C. Koike, P. Carmeliet, and R. K. Jain, Cancer Res. 60, 22 (2000).

Gardiner, G.

V. X. Yang, S. J. Tang, M. L. Gordon, B. Qi, G. Gardiner, M. Cirocco, P. Kortan, G. B. Haber, G. Kandel, I. A. Vitkin, B. C. Wilson, and N. E. Marcon, Gastrointest. Endosc. 61, 7 (2005).

Gordon, M. L.

V. X. Yang, S. J. Tang, M. L. Gordon, B. Qi, G. Gardiner, M. Cirocco, P. Kortan, G. B. Haber, G. Kandel, I. A. Vitkin, B. C. Wilson, and N. E. Marcon, Gastrointest. Endosc. 61, 7 (2005).

Gross, J. F.

M. W. Dewhirst, R. Oliver, C. Y. Tso, C. Gustafson, T. Secomb, and J. F. Gross, Int. J. Radiat. Oncol. Biol. Phys. 18, 3 (1990).
[CrossRef]

Gustafson, C.

M. W. Dewhirst, R. Oliver, C. Y. Tso, C. Gustafson, T. Secomb, and J. F. Gross, Int. J. Radiat. Oncol. Biol. Phys. 18, 3 (1990).
[CrossRef]

Haber, G. B.

V. X. Yang, S. J. Tang, M. L. Gordon, B. Qi, G. Gardiner, M. Cirocco, P. Kortan, G. B. Haber, G. Kandel, I. A. Vitkin, B. C. Wilson, and N. E. Marcon, Gastrointest. Endosc. 61, 7 (2005).

Helmlinger, G.

G. Helmlinger, F. Yuan, M. Dellian, and R. K. Jain, Nat. Med. 3, 2 (1997).
[CrossRef]

Izatt, J. A.

Jain, R. K.

Y. Tsuzuki, D. Fukumura, B. Oosthuyse, C. Koike, P. Carmeliet, and R. K. Jain, Cancer Res. 60, 22 (2000).

G. Helmlinger, F. Yuan, M. Dellian, and R. K. Jain, Nat. Med. 3, 2 (1997).
[CrossRef]

Jiang, J.

Kandel, G.

V. X. Yang, S. J. Tang, M. L. Gordon, B. Qi, G. Gardiner, M. Cirocco, P. Kortan, G. B. Haber, G. Kandel, I. A. Vitkin, B. C. Wilson, and N. E. Marcon, Gastrointest. Endosc. 61, 7 (2005).

Khurana, M.

Klitzman, B.

J. Lanzen, R. D. Braun, B. Klitzman, D. Brizel, T. W. Secomb, and M. W. Dewhirst, Cancer Res. 66, 4 (2006).
[CrossRef]

Koike, C.

Y. Tsuzuki, D. Fukumura, B. Oosthuyse, C. Koike, P. Carmeliet, and R. K. Jain, Cancer Res. 60, 22 (2000).

Kortan, P.

V. X. Yang, S. J. Tang, M. L. Gordon, B. Qi, G. Gardiner, M. Cirocco, P. Kortan, G. B. Haber, G. Kandel, I. A. Vitkin, B. C. Wilson, and N. E. Marcon, Gastrointest. Endosc. 61, 7 (2005).

Kulkarni, M. D.

Lanzen, J.

J. Lanzen, R. D. Braun, B. Klitzman, D. Brizel, T. W. Secomb, and M. W. Dewhirst, Cancer Res. 66, 4 (2006).
[CrossRef]

Lanzen, J. L.

R. D. Braun, J. L. Lanzen, and M. W. Dewhirst, Am. J. Physiol. 277, 2 (1999).

Leung, M. K.

Marcon, N. E.

V. X. Yang, S. J. Tang, M. L. Gordon, B. Qi, G. Gardiner, M. Cirocco, P. Kortan, G. B. Haber, G. Kandel, I. A. Vitkin, B. C. Wilson, and N. E. Marcon, Gastrointest. Endosc. 61, 7 (2005).

Mariampillai, A.

Moeller, B. J.

B. S. Sorg, B. J. Moeller, O. Donovan, Y. Cao, and M. W. Dewhirst, J. Biomed. Opt. 10, 4 (2005).
[CrossRef]

Moriyama, E. H.

Munce, N. R.

Oliver, R.

M. W. Dewhirst, R. Oliver, C. Y. Tso, C. Gustafson, T. Secomb, and J. F. Gross, Int. J. Radiat. Oncol. Biol. Phys. 18, 3 (1990).
[CrossRef]

Ong, E. T.

M. W. Dewhirst, E. T. Ong, G. L. Rosner, S. W. Rehmus, S. Shan, R. D. Braun, D. M. Brizel, and T. W. Secomb, Br. J. Cancer Suppl. 27, S241 (1996).
[PubMed]

Oosthuyse, B.

Y. Tsuzuki, D. Fukumura, B. Oosthuyse, C. Koike, P. Carmeliet, and R. K. Jain, Cancer Res. 60, 22 (2000).

Qi, B.

V. X. Yang, S. J. Tang, M. L. Gordon, B. Qi, G. Gardiner, M. Cirocco, P. Kortan, G. B. Haber, G. Kandel, I. A. Vitkin, B. C. Wilson, and N. E. Marcon, Gastrointest. Endosc. 61, 7 (2005).

Rehmus, S. W.

M. W. Dewhirst, E. T. Ong, G. L. Rosner, S. W. Rehmus, S. Shan, R. D. Braun, D. M. Brizel, and T. W. Secomb, Br. J. Cancer Suppl. 27, S241 (1996).
[PubMed]

Rollins, A. M.

Rosner, G. L.

M. W. Dewhirst, E. T. Ong, G. L. Rosner, S. W. Rehmus, S. Shan, R. D. Braun, D. M. Brizel, and T. W. Secomb, Br. J. Cancer Suppl. 27, S241 (1996).
[PubMed]

Secomb, T.

M. W. Dewhirst, R. Oliver, C. Y. Tso, C. Gustafson, T. Secomb, and J. F. Gross, Int. J. Radiat. Oncol. Biol. Phys. 18, 3 (1990).
[CrossRef]

Secomb, T. W.

J. Lanzen, R. D. Braun, B. Klitzman, D. Brizel, T. W. Secomb, and M. W. Dewhirst, Cancer Res. 66, 4 (2006).
[CrossRef]

M. W. Dewhirst, E. T. Ong, G. L. Rosner, S. W. Rehmus, S. Shan, R. D. Braun, D. M. Brizel, and T. W. Secomb, Br. J. Cancer Suppl. 27, S241 (1996).
[PubMed]

Shan, S.

M. W. Dewhirst, E. T. Ong, G. L. Rosner, S. W. Rehmus, S. Shan, R. D. Braun, D. M. Brizel, and T. W. Secomb, Br. J. Cancer Suppl. 27, S241 (1996).
[PubMed]

Sorg, B. S.

B. S. Sorg, B. J. Moeller, O. Donovan, Y. Cao, and M. W. Dewhirst, J. Biomed. Opt. 10, 4 (2005).
[CrossRef]

Standish, B. A.

Tang, S. J.

V. X. Yang, S. J. Tang, M. L. Gordon, B. Qi, G. Gardiner, M. Cirocco, P. Kortan, G. B. Haber, G. Kandel, I. A. Vitkin, B. C. Wilson, and N. E. Marcon, Gastrointest. Endosc. 61, 7 (2005).

Tso, C. Y.

M. W. Dewhirst, R. Oliver, C. Y. Tso, C. Gustafson, T. Secomb, and J. F. Gross, Int. J. Radiat. Oncol. Biol. Phys. 18, 3 (1990).
[CrossRef]

Tsuzuki, Y.

Y. Tsuzuki, D. Fukumura, B. Oosthuyse, C. Koike, P. Carmeliet, and R. K. Jain, Cancer Res. 60, 22 (2000).

van Leeuwen, T. G.

Vitkin, I. A.

A. Mariampillai, B. A. Standish, E. H. Moriyama, M. Khurana, N. R. Munce, M. K. Leung, J. Jiang, A. Cable, B. C. Wilson, I. A. Vitkin, and V. X. Yang, Opt. Lett. 33, 13 (2008).
[CrossRef]

V. X. Yang, S. J. Tang, M. L. Gordon, B. Qi, G. Gardiner, M. Cirocco, P. Kortan, G. B. Haber, G. Kandel, I. A. Vitkin, B. C. Wilson, and N. E. Marcon, Gastrointest. Endosc. 61, 7 (2005).

Wilson, B. C.

A. Mariampillai, B. A. Standish, E. H. Moriyama, M. Khurana, N. R. Munce, M. K. Leung, J. Jiang, A. Cable, B. C. Wilson, I. A. Vitkin, and V. X. Yang, Opt. Lett. 33, 13 (2008).
[CrossRef]

V. X. Yang, S. J. Tang, M. L. Gordon, B. Qi, G. Gardiner, M. Cirocco, P. Kortan, G. B. Haber, G. Kandel, I. A. Vitkin, B. C. Wilson, and N. E. Marcon, Gastrointest. Endosc. 61, 7 (2005).

Yang, V. X.

A. Mariampillai, B. A. Standish, E. H. Moriyama, M. Khurana, N. R. Munce, M. K. Leung, J. Jiang, A. Cable, B. C. Wilson, I. A. Vitkin, and V. X. Yang, Opt. Lett. 33, 13 (2008).
[CrossRef]

V. X. Yang, S. J. Tang, M. L. Gordon, B. Qi, G. Gardiner, M. Cirocco, P. Kortan, G. B. Haber, G. Kandel, I. A. Vitkin, B. C. Wilson, and N. E. Marcon, Gastrointest. Endosc. 61, 7 (2005).

Yazdanfar, S.

Yuan, F.

G. Helmlinger, F. Yuan, M. Dellian, and R. K. Jain, Nat. Med. 3, 2 (1997).
[CrossRef]

Am. J. Physiol.

R. D. Braun, J. L. Lanzen, and M. W. Dewhirst, Am. J. Physiol. 277, 2 (1999).

Br. J. Cancer Suppl.

M. W. Dewhirst, E. T. Ong, G. L. Rosner, S. W. Rehmus, S. Shan, R. D. Braun, D. M. Brizel, and T. W. Secomb, Br. J. Cancer Suppl. 27, S241 (1996).
[PubMed]

Cancer Res.

Y. Tsuzuki, D. Fukumura, B. Oosthuyse, C. Koike, P. Carmeliet, and R. K. Jain, Cancer Res. 60, 22 (2000).

J. Lanzen, R. D. Braun, B. Klitzman, D. Brizel, T. W. Secomb, and M. W. Dewhirst, Cancer Res. 66, 4 (2006).
[CrossRef]

Circ. Res.

B. R. Duling and R. M. Berne, Circ. Res. 27, 5 (1970).

Gastrointest. Endosc.

V. X. Yang, S. J. Tang, M. L. Gordon, B. Qi, G. Gardiner, M. Cirocco, P. Kortan, G. B. Haber, G. Kandel, I. A. Vitkin, B. C. Wilson, and N. E. Marcon, Gastrointest. Endosc. 61, 7 (2005).

Int. J. Radiat. Oncol. Biol. Phys.

M. W. Dewhirst, R. Oliver, C. Y. Tso, C. Gustafson, T. Secomb, and J. F. Gross, Int. J. Radiat. Oncol. Biol. Phys. 18, 3 (1990).
[CrossRef]

J. Biomed. Opt.

B. S. Sorg, B. J. Moeller, O. Donovan, Y. Cao, and M. W. Dewhirst, J. Biomed. Opt. 10, 4 (2005).
[CrossRef]

Nat. Med.

G. Helmlinger, F. Yuan, M. Dellian, and R. K. Jain, Nat. Med. 3, 2 (1997).
[CrossRef]

Opt. Lett.

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Figures (4)

Fig. 1
Fig. 1

Schematic of the combined hyperspectral–SDOCT microscope. L1–L4, lenses 1–4; TL, tube lens; BS, beam splitter; LCTF, liquid-crystal tunable filter.

Fig. 2
Fig. 2

Multidimensional functional imaging of 4T1 tumor vasculature in the dorsal skin fold mouse window chamber. Transmission image of the window chamber taken with the liquid crystal tunable filter set at 500 nm , with a portion of the tumor visible (arrow, A). Scale bar is 200 μ m . B, Speckle variance OCT image of vessel morphology shown as an en face average intensity projection over 1 mm depth. C, Hyperspectral image of percent hemoglobin oxygen saturation, thresholded for the R-squared value of the linear fit and total absorption value at each pixel (background pixels are black). D, Doppler OCT image of vessel blood flow direction shown as an en face maximum intensity projection over depth, with red vessels (1) flowing toward the top of the image and blue vessels (2) flowing toward the bottom of the image. The flow profiles at points 1 (E) and 2 (F) were fit to a second-order polynomial and corrected for the angle of incidence to provide velocity in millimeters per second.

Fig. 3
Fig. 3

Time series data taken from a 4T1 window chamber tumor using the combined hyperspectral–OCT microscope. The transmission image (A) is 3 mm (height) × 2 mm (width) and delineates the three VOIs for which maximum blood velocity (B), diameter (C), and hemoglobin saturation (D) are plotted (open circles, VOI 1; open triangles, VOI 2; open squares, VOI 3).

Fig. 4
Fig. 4

Scatter plots of maximum velocity vs. hemoglobin saturation (○) and diameter vs. hemoglobin saturation (▲) for VOI 1 (A), VOI 2 (B), and VOI 3 (C). There was a strong correlation (B) between the maximum velocity and hemoglobin saturation for VOI 2 ( ρ = 0.94 , p = 0.018 , N = 5 ), and no correlation for any other VOI ( p > 0.05 ) . However, when all VOI (○, VOI 1; ▲, VOI 2; ◻, VOI 3) and time points were grouped together (D), there was a strong correlation between maximum velocity and hemoglobin saturation ( ρ = 0.78 , p = 0.0006 , N = 15 ). There was also a strong correlation (E) between flow (vessel cross sectional area times 1 2 maximum velocity) and hemoglobin saturation ( ρ = 0.89 , p = 9 × 10 6 , N = 15 ) and a moderate correlation (F) between shear rate on the vessel wall and hemoglobin saturation ( ρ = 0.56 , p = 0.03 , N = 15 ) when all VOI and time points were grouped together.

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