Abstract

Refractive index properties, especially at the nanoscale, have shown great potential in cancer diagnosis and screening. Due to the intrinsic complexity and weak refractive index fluctuation, the reconstruction of internal structures of a biological cell has been challenging. In this paper, we propose a simple and practical approach to derive the statistical properties of internal refractive index fluctuations within a biological cell with a new optical microscopy method – Low-coherence Statistical Amplitude Microscopy (SAM). We validated the capability of SAM to characterize the statistical properties of cell internal structures, which is described by numerical models of one-dimensional Gaussian random field. We demonstrated the potential of SAM in cancer detection with an animal model of intestinal carcinogenesis – multiple intestinal neoplasia mouse model. We showed that SAM-derived statistical properties of cell nuclear structures could detect the subtle changes that are otherwise undetectable by conventional cytopathology.

© 2010 OSA

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  1. H. Subramanian, H. K. Roy, P. Pradhan, M. J. Goldberg, J. Muldoon, R. E. Brand, C. Sturgis, T. Hensing, D. Ray, A. Bogojevic, J. Mohammed, J. S. Chang, and V. Backman, “Nanoscale cellular changes in field carcinogenesis detected by partial wave spectroscopy,” Cancer Res. 69(13), 5357–5363 (2009).
    [CrossRef] [PubMed]
  2. P. Wang, R. Bista, R. Bhargava, R. E. Brand, and Y. Liu, “Spatial-domain low-coherence quantitative phase microscopy for cancer diagnosis,” Opt. Lett. 35(17), 2840–2842 (2010).
    [CrossRef] [PubMed]
  3. G. Popescu, L. P. Deflores, J. C. Vaughan, K. Badizadegan, H. Iwai, R. R. Dasari, and M. S. Feld, “Fourier phase microscopy for investigation of biological structures and dynamics,” Opt. Lett. 29(21), 2503–2505 (2004).
    [CrossRef] [PubMed]
  4. N. T. Shaked, M. T. Rinehart, and A. Wax, “Dual-interference-channel quantitative-phase microscopy of live cell dynamics,” Opt. Lett. 34(6), 767–769 (2009).
    [CrossRef] [PubMed]
  5. P. Marquet, B. Rappaz, P. J. Magistretti, E. Cuche, Y. Emery, T. Colomb, and C. Depeursinge, “Digital holographic microscopy: a noninvasive contrast imaging technique allowing quantitative visualization of living cells with subwavelength axial accuracy,” Opt. Lett. 30(5), 468–470 (2005).
    [CrossRef] [PubMed]
  6. G. Popescu, T. Ikeda, R. R. Dasari, and M. S. Feld, “Diffraction phase microscopy for quantifying cell structure and dynamics,” Opt. Lett. 31(6), 775–777 (2006).
    [CrossRef] [PubMed]
  7. O. P. Bruno and J. Chaubell, “Inverse scattering problem for optical coherence tomography,” Opt. Lett. 28(21), 2049–2051 (2003).
    [CrossRef] [PubMed]
  8. W. Choi, C. Fang-Yen, K. Badizadegan, S. Oh, N. Lue, R. R. Dasari, and M. S. Feld, “Tomographic phase microscopy,” Nat. Methods 4(9), 717–719 (2007).
    [CrossRef] [PubMed]
  9. F. Charrière, A. Marian, F. Montfort, J. Kuehn, T. Colomb, E. Cuche, P. Marquet, and C. Depeursinge, “Cell refractive index tomography by digital holographic microscopy,” Opt. Lett. 31(2), 178–180 (2006).
    [CrossRef] [PubMed]
  10. C. Joo, T. Akkin, B. Cense, B. H. Park, and J. F. de Boer, “Spectral-domain optical coherence phase microscopy for quantitative phase-contrast imaging,” Opt. Lett. 30(16), 2131–2133 (2005).
    [CrossRef] [PubMed]
  11. M. V. Sarunic, S. Weinberg, and J. A. Izatt, “Full-field swept-source phase microscopy,” Opt. Lett. 31(10), 1462–1464 (2006).
    [CrossRef] [PubMed]
  12. R. J. Adler, The geometry of random fields (J. Wiley, Chichester Eng., New York, 1981).
  13. U. S. Inan, and A. S. Inan, Electromagnetic waves (Prentice Hall, Upper Saddle River, N.J., 2000).
  14. Y. Liu, X. Li, Y. L. Kim, and V. Backman, “Elastic backscattering spectroscopic microscopy,” Opt. Lett. 30(18), 2445–2447 (2005).
    [CrossRef] [PubMed]

2010 (1)

2009 (2)

N. T. Shaked, M. T. Rinehart, and A. Wax, “Dual-interference-channel quantitative-phase microscopy of live cell dynamics,” Opt. Lett. 34(6), 767–769 (2009).
[CrossRef] [PubMed]

H. Subramanian, H. K. Roy, P. Pradhan, M. J. Goldberg, J. Muldoon, R. E. Brand, C. Sturgis, T. Hensing, D. Ray, A. Bogojevic, J. Mohammed, J. S. Chang, and V. Backman, “Nanoscale cellular changes in field carcinogenesis detected by partial wave spectroscopy,” Cancer Res. 69(13), 5357–5363 (2009).
[CrossRef] [PubMed]

2007 (1)

W. Choi, C. Fang-Yen, K. Badizadegan, S. Oh, N. Lue, R. R. Dasari, and M. S. Feld, “Tomographic phase microscopy,” Nat. Methods 4(9), 717–719 (2007).
[CrossRef] [PubMed]

2006 (3)

2005 (3)

2004 (1)

2003 (1)

Akkin, T.

Backman, V.

H. Subramanian, H. K. Roy, P. Pradhan, M. J. Goldberg, J. Muldoon, R. E. Brand, C. Sturgis, T. Hensing, D. Ray, A. Bogojevic, J. Mohammed, J. S. Chang, and V. Backman, “Nanoscale cellular changes in field carcinogenesis detected by partial wave spectroscopy,” Cancer Res. 69(13), 5357–5363 (2009).
[CrossRef] [PubMed]

Y. Liu, X. Li, Y. L. Kim, and V. Backman, “Elastic backscattering spectroscopic microscopy,” Opt. Lett. 30(18), 2445–2447 (2005).
[CrossRef] [PubMed]

Badizadegan, K.

Bhargava, R.

Bista, R.

Bogojevic, A.

H. Subramanian, H. K. Roy, P. Pradhan, M. J. Goldberg, J. Muldoon, R. E. Brand, C. Sturgis, T. Hensing, D. Ray, A. Bogojevic, J. Mohammed, J. S. Chang, and V. Backman, “Nanoscale cellular changes in field carcinogenesis detected by partial wave spectroscopy,” Cancer Res. 69(13), 5357–5363 (2009).
[CrossRef] [PubMed]

Brand, R. E.

P. Wang, R. Bista, R. Bhargava, R. E. Brand, and Y. Liu, “Spatial-domain low-coherence quantitative phase microscopy for cancer diagnosis,” Opt. Lett. 35(17), 2840–2842 (2010).
[CrossRef] [PubMed]

H. Subramanian, H. K. Roy, P. Pradhan, M. J. Goldberg, J. Muldoon, R. E. Brand, C. Sturgis, T. Hensing, D. Ray, A. Bogojevic, J. Mohammed, J. S. Chang, and V. Backman, “Nanoscale cellular changes in field carcinogenesis detected by partial wave spectroscopy,” Cancer Res. 69(13), 5357–5363 (2009).
[CrossRef] [PubMed]

Bruno, O. P.

Cense, B.

Chang, J. S.

H. Subramanian, H. K. Roy, P. Pradhan, M. J. Goldberg, J. Muldoon, R. E. Brand, C. Sturgis, T. Hensing, D. Ray, A. Bogojevic, J. Mohammed, J. S. Chang, and V. Backman, “Nanoscale cellular changes in field carcinogenesis detected by partial wave spectroscopy,” Cancer Res. 69(13), 5357–5363 (2009).
[CrossRef] [PubMed]

Charrière, F.

Chaubell, J.

Choi, W.

W. Choi, C. Fang-Yen, K. Badizadegan, S. Oh, N. Lue, R. R. Dasari, and M. S. Feld, “Tomographic phase microscopy,” Nat. Methods 4(9), 717–719 (2007).
[CrossRef] [PubMed]

Colomb, T.

Cuche, E.

Dasari, R. R.

de Boer, J. F.

Deflores, L. P.

Depeursinge, C.

Emery, Y.

Fang-Yen, C.

W. Choi, C. Fang-Yen, K. Badizadegan, S. Oh, N. Lue, R. R. Dasari, and M. S. Feld, “Tomographic phase microscopy,” Nat. Methods 4(9), 717–719 (2007).
[CrossRef] [PubMed]

Feld, M. S.

Goldberg, M. J.

H. Subramanian, H. K. Roy, P. Pradhan, M. J. Goldberg, J. Muldoon, R. E. Brand, C. Sturgis, T. Hensing, D. Ray, A. Bogojevic, J. Mohammed, J. S. Chang, and V. Backman, “Nanoscale cellular changes in field carcinogenesis detected by partial wave spectroscopy,” Cancer Res. 69(13), 5357–5363 (2009).
[CrossRef] [PubMed]

Hensing, T.

H. Subramanian, H. K. Roy, P. Pradhan, M. J. Goldberg, J. Muldoon, R. E. Brand, C. Sturgis, T. Hensing, D. Ray, A. Bogojevic, J. Mohammed, J. S. Chang, and V. Backman, “Nanoscale cellular changes in field carcinogenesis detected by partial wave spectroscopy,” Cancer Res. 69(13), 5357–5363 (2009).
[CrossRef] [PubMed]

Ikeda, T.

Iwai, H.

Izatt, J. A.

Joo, C.

Kim, Y. L.

Kuehn, J.

Li, X.

Liu, Y.

Lue, N.

W. Choi, C. Fang-Yen, K. Badizadegan, S. Oh, N. Lue, R. R. Dasari, and M. S. Feld, “Tomographic phase microscopy,” Nat. Methods 4(9), 717–719 (2007).
[CrossRef] [PubMed]

Magistretti, P. J.

Marian, A.

Marquet, P.

Mohammed, J.

H. Subramanian, H. K. Roy, P. Pradhan, M. J. Goldberg, J. Muldoon, R. E. Brand, C. Sturgis, T. Hensing, D. Ray, A. Bogojevic, J. Mohammed, J. S. Chang, and V. Backman, “Nanoscale cellular changes in field carcinogenesis detected by partial wave spectroscopy,” Cancer Res. 69(13), 5357–5363 (2009).
[CrossRef] [PubMed]

Montfort, F.

Muldoon, J.

H. Subramanian, H. K. Roy, P. Pradhan, M. J. Goldberg, J. Muldoon, R. E. Brand, C. Sturgis, T. Hensing, D. Ray, A. Bogojevic, J. Mohammed, J. S. Chang, and V. Backman, “Nanoscale cellular changes in field carcinogenesis detected by partial wave spectroscopy,” Cancer Res. 69(13), 5357–5363 (2009).
[CrossRef] [PubMed]

Oh, S.

W. Choi, C. Fang-Yen, K. Badizadegan, S. Oh, N. Lue, R. R. Dasari, and M. S. Feld, “Tomographic phase microscopy,” Nat. Methods 4(9), 717–719 (2007).
[CrossRef] [PubMed]

Park, B. H.

Popescu, G.

Pradhan, P.

H. Subramanian, H. K. Roy, P. Pradhan, M. J. Goldberg, J. Muldoon, R. E. Brand, C. Sturgis, T. Hensing, D. Ray, A. Bogojevic, J. Mohammed, J. S. Chang, and V. Backman, “Nanoscale cellular changes in field carcinogenesis detected by partial wave spectroscopy,” Cancer Res. 69(13), 5357–5363 (2009).
[CrossRef] [PubMed]

Rappaz, B.

Ray, D.

H. Subramanian, H. K. Roy, P. Pradhan, M. J. Goldberg, J. Muldoon, R. E. Brand, C. Sturgis, T. Hensing, D. Ray, A. Bogojevic, J. Mohammed, J. S. Chang, and V. Backman, “Nanoscale cellular changes in field carcinogenesis detected by partial wave spectroscopy,” Cancer Res. 69(13), 5357–5363 (2009).
[CrossRef] [PubMed]

Rinehart, M. T.

Roy, H. K.

H. Subramanian, H. K. Roy, P. Pradhan, M. J. Goldberg, J. Muldoon, R. E. Brand, C. Sturgis, T. Hensing, D. Ray, A. Bogojevic, J. Mohammed, J. S. Chang, and V. Backman, “Nanoscale cellular changes in field carcinogenesis detected by partial wave spectroscopy,” Cancer Res. 69(13), 5357–5363 (2009).
[CrossRef] [PubMed]

Sarunic, M. V.

Shaked, N. T.

Sturgis, C.

H. Subramanian, H. K. Roy, P. Pradhan, M. J. Goldberg, J. Muldoon, R. E. Brand, C. Sturgis, T. Hensing, D. Ray, A. Bogojevic, J. Mohammed, J. S. Chang, and V. Backman, “Nanoscale cellular changes in field carcinogenesis detected by partial wave spectroscopy,” Cancer Res. 69(13), 5357–5363 (2009).
[CrossRef] [PubMed]

Subramanian, H.

H. Subramanian, H. K. Roy, P. Pradhan, M. J. Goldberg, J. Muldoon, R. E. Brand, C. Sturgis, T. Hensing, D. Ray, A. Bogojevic, J. Mohammed, J. S. Chang, and V. Backman, “Nanoscale cellular changes in field carcinogenesis detected by partial wave spectroscopy,” Cancer Res. 69(13), 5357–5363 (2009).
[CrossRef] [PubMed]

Vaughan, J. C.

Wang, P.

Wax, A.

Weinberg, S.

Cancer Res. (1)

H. Subramanian, H. K. Roy, P. Pradhan, M. J. Goldberg, J. Muldoon, R. E. Brand, C. Sturgis, T. Hensing, D. Ray, A. Bogojevic, J. Mohammed, J. S. Chang, and V. Backman, “Nanoscale cellular changes in field carcinogenesis detected by partial wave spectroscopy,” Cancer Res. 69(13), 5357–5363 (2009).
[CrossRef] [PubMed]

Nat. Methods (1)

W. Choi, C. Fang-Yen, K. Badizadegan, S. Oh, N. Lue, R. R. Dasari, and M. S. Feld, “Tomographic phase microscopy,” Nat. Methods 4(9), 717–719 (2007).
[CrossRef] [PubMed]

Opt. Lett. (10)

F. Charrière, A. Marian, F. Montfort, J. Kuehn, T. Colomb, E. Cuche, P. Marquet, and C. Depeursinge, “Cell refractive index tomography by digital holographic microscopy,” Opt. Lett. 31(2), 178–180 (2006).
[CrossRef] [PubMed]

C. Joo, T. Akkin, B. Cense, B. H. Park, and J. F. de Boer, “Spectral-domain optical coherence phase microscopy for quantitative phase-contrast imaging,” Opt. Lett. 30(16), 2131–2133 (2005).
[CrossRef] [PubMed]

M. V. Sarunic, S. Weinberg, and J. A. Izatt, “Full-field swept-source phase microscopy,” Opt. Lett. 31(10), 1462–1464 (2006).
[CrossRef] [PubMed]

P. Wang, R. Bista, R. Bhargava, R. E. Brand, and Y. Liu, “Spatial-domain low-coherence quantitative phase microscopy for cancer diagnosis,” Opt. Lett. 35(17), 2840–2842 (2010).
[CrossRef] [PubMed]

G. Popescu, L. P. Deflores, J. C. Vaughan, K. Badizadegan, H. Iwai, R. R. Dasari, and M. S. Feld, “Fourier phase microscopy for investigation of biological structures and dynamics,” Opt. Lett. 29(21), 2503–2505 (2004).
[CrossRef] [PubMed]

N. T. Shaked, M. T. Rinehart, and A. Wax, “Dual-interference-channel quantitative-phase microscopy of live cell dynamics,” Opt. Lett. 34(6), 767–769 (2009).
[CrossRef] [PubMed]

P. Marquet, B. Rappaz, P. J. Magistretti, E. Cuche, Y. Emery, T. Colomb, and C. Depeursinge, “Digital holographic microscopy: a noninvasive contrast imaging technique allowing quantitative visualization of living cells with subwavelength axial accuracy,” Opt. Lett. 30(5), 468–470 (2005).
[CrossRef] [PubMed]

G. Popescu, T. Ikeda, R. R. Dasari, and M. S. Feld, “Diffraction phase microscopy for quantifying cell structure and dynamics,” Opt. Lett. 31(6), 775–777 (2006).
[CrossRef] [PubMed]

O. P. Bruno and J. Chaubell, “Inverse scattering problem for optical coherence tomography,” Opt. Lett. 28(21), 2049–2051 (2003).
[CrossRef] [PubMed]

Y. Liu, X. Li, Y. L. Kim, and V. Backman, “Elastic backscattering spectroscopic microscopy,” Opt. Lett. 30(18), 2445–2447 (2005).
[CrossRef] [PubMed]

Other (2)

R. J. Adler, The geometry of random fields (J. Wiley, Chichester Eng., New York, 1981).

U. S. Inan, and A. S. Inan, Electromagnetic waves (Prentice Hall, Upper Saddle River, N.J., 2000).

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Figures (5)

Fig. 1
Fig. 1

Illustrative refractive index profile of internal structures of a biological cell.

Fig. 2
Fig. 2

The representative refractive index profiles n ( z ) modeled with GRF (a) with fixed n 0 = 1.4 and < Δ n > = 0.02 , but different correlation length L c , and (b) with fixed n 0 = 1.4 and L c = 140 n m and different average magnitude of refractive index variation < Δ n > .

Fig. 3
Fig. 3

The dependence of statistical amplitude parameters – < A > , σ A and Ron the (a) average refractive index n 0 , (b) standard deviation of refractive index < Δ n > and (c) thickness L.

Fig. 4
Fig. 4

Representative (A) cytological images and (B) the corresponding amplitude maps of cell nuclei (as shown in circles) of intestinal epithelial cells from the wild-type and the Min mice. Scale bars in the image indicate 5μm.

Fig. 5
Fig. 5

Statistical analysis of (a) A , (b) σ A and (c) Rin cytologically normal-appearing cell nuclei from wild-type and Min mice. The error bar represents the standard errors.

Equations (5)

Equations on this page are rendered with MathJax. Learn more.

C n ( z ) = < [ n ( z = 0 ) n 0 ] [ n ( z ) n 0 ] >
A ( z ) | ( x , y ) = | F ( z ) | | ( x , y )
I ( k ) | ( x , y ) = S ( k ) { R r + R s + 2 R r R s cos ( 2 k ( p 0 + Δ p ) ) } | ( x , y )
F ( z ) = S R r R s ( z ) exp ( j 2 k 0 Δ p ( z ) )
A ( z ) | ( x , y ) = | F ( z ) | | ( x , y ) = S ( R r R s ( z ) )

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