Abstract

We present a noninvasive method for characterizing the refractive index (RI) and thickness distribution in biological tissues using a combined multiphoton microscopy (MPM) and optical coherence tomography (OCT) system. Tissue layers are distinguished by the MPM and OCT images, and the RI and thickness of each layer are determined by analyzing the co-registered MPM and OCT images. The precision of this method is evaluated on four standard samples which are water, air, immersion oil and cover glass. Precision of within ~1% error compared to reference values is obtained. Biological tissue measurement is demonstrated on fish cornea. Three layers are detected, which are identified as the epithelium and stroma I and II of the cornea. The corresponding RI of each layer is measured to be ~1.446–1.448, 1.345–1.372, and 1.392–1.436, respectively. The difference of RI in the three layers correlates with the tissue compositions including cells in epithelium, large collagen fiber bundles in stroma I, and small collagen fibers in stroma II. The combined MPM/OCT technique is shown to be able to distinguish tissue layers through biochemically specific contrasts and measure RI and thickness of tissue layers at different depths.

© 2012 OSA

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2011 (2)

2010 (1)

2008 (2)

S. Kim, J. Na, M. J. Kim, and B. H. Lee, “Simultaneous measurement of refractive index and thickness by combining low-coherence interferometry and confocal optics,” Opt. Express16(8), 5516–5526 (2008).
[CrossRef] [PubMed]

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[CrossRef] [PubMed]

2007 (2)

W. Choi, C. Fang-Yen, K. Badizadegan, S. Oh, N. Lue, R. R. Dasari, and M. S. Feld, “Tomographic phase microscopy,” Nat. Methods4(9), 717–719 (2007).
[CrossRef] [PubMed]

M. Daimon and A. Masumura, “Measurement of the refractive index of distilled water from the near-infrared region to the ultraviolet region,” Appl. Opt.46(18), 3811–3820 (2007).
[CrossRef] [PubMed]

2006 (1)

E. Borasio, J. Stevens, and G. T. Smith, “Estimation of true corneal power after keratorefractive surgery in eyes requiring cataract surgery: BESSt formula,” J. Cataract Refract. Surg.32(12), 2004–2014 (2006).
[CrossRef] [PubMed]

2005 (3)

2004 (3)

S. Patel, J. L. Alió, and J. J. Pérez-Santonja, “Refractive index change in bovine and human corneal stroma before and after lasik: a study of untreated and re-treated corneas implicating stromal hydration,” Invest. Ophthalmol. Vis. Sci.45(10), 3523–3530 (2004).
[CrossRef] [PubMed]

Y. L. Kim, J. T. Walsh, T. K. Goldstick, and M. R. Glucksberg, “Variation of corneal refractive index with hydration,” Phys. Med. Biol.49(5), 859–868 (2004).
[CrossRef] [PubMed]

R. C. Lin, M. A. Shure, A. M. Rollins, J. A. Izatt, and D. Huang, “Group index of the human cornea at 1.3-microm wavelength obtained in vitro by optical coherence domain reflectometry,” Opt. Lett.29(1), 83–85 (2004).
[CrossRef] [PubMed]

2003 (2)

K. M. Meek, S. Dennis, and S. Khan, “Changes in the refractive index of the stroma and its extrafibrillar matrix when the cornea swells,” Biophys. J.85(4), 2205–2212 (2003).
[CrossRef] [PubMed]

A. Zvyagin, K. K. Silva, S. Alexandrov, T. Hillman, J. Armstrong, T. Tsuzuki, and D. Sampson, “Refractive index tomography of turbid media by bifocal optical coherence refractometry,” Opt. Express11(25), 3503–3517 (2003).
[CrossRef] [PubMed]

2002 (2)

H. Maruyama, S. Inoue, T. Mitsuyama, M. Ohmi, and M. Haruna, “Low-coherence interferometer system for the simultaneous measurement of refractive index and thickness,” Appl. Opt.41(7), 1315–1322 (2002).
[CrossRef] [PubMed]

X. Y. Wang, C. P. Zhang, L. S. Zhang, L. L. Xue, and J. G. Tian, “Simultaneous refractive index and thickness measurements of bio tissue by optical coherence tomography,” J. Biomed. Opt.7(4), 628–632 (2002).
[CrossRef] [PubMed]

2000 (2)

A. Knüttel and M. Boehlau-Godau, “Spatially confined and temporally resolved refractive index and scattering evaluation in human skin performed with optical coherence tomography,” J. Biomed. Opt.5(1), 83–92 (2000).
[CrossRef] [PubMed]

D. Ganic, X. Gan, and M. Gu, “Reduced effects of spherical aberration on penetration depth under two-photon excitation,” Appl. Opt.39(22), 3945–3947 (2000).
[CrossRef] [PubMed]

1999 (1)

J. M. Schmitt, S. H. Xiang, and K. M. Yung, “Speckle in optical coherence tomography,” J. Biomed. Opt.4(1), 95–105 (1999).
[CrossRef] [PubMed]

1998 (2)

1997 (1)

S. R. Arridge and J. C. Hebden, “Optical imaging in medicine: II. Modelling and reconstruction,” Phys. Med. Biol.42(5), 841–853 (1997).
[CrossRef] [PubMed]

1995 (1)

1991 (1)

B. C. Wilson, “Modeling and measurement of light propagation in tissue for diagnostic and therapeutic applications,” Laser Syst. Photobiol. Photomed.252, 13–27 (1991).
[CrossRef]

1989 (2)

1987 (1)

S. Patel, “Refractive index of the mammalian cornea and its influence during pachometry,” Ophthalmic Physiol. Opt.7(4), 503–506 (1987).
[CrossRef] [PubMed]

1977 (1)

G. K. Klintworth, “The cornea--structure and macromolecules in health and disease. A review,” Am. J. Pathol.89(3), 718–808 (1977).
[PubMed]

Alexandrov, S.

Alió, J. L.

S. Patel, J. L. Alió, and A. Artola, “Changes in the refractive index of the human corneal stroma during laser in situ keratomileusis. Effects of exposure time and method used to create the flap,” J. Cataract Refract. Surg.34(7), 1077–1082 (2008).
[CrossRef] [PubMed]

S. Patel, J. L. Alió, and J. J. Pérez-Santonja, “Refractive index change in bovine and human corneal stroma before and after lasik: a study of untreated and re-treated corneas implicating stromal hydration,” Invest. Ophthalmol. Vis. Sci.45(10), 3523–3530 (2004).
[CrossRef] [PubMed]

Armstrong, J.

Arridge, S. R.

S. R. Arridge and J. C. Hebden, “Optical imaging in medicine: II. Modelling and reconstruction,” Phys. Med. Biol.42(5), 841–853 (1997).
[CrossRef] [PubMed]

Artola, A.

S. Patel, J. L. Alió, and A. Artola, “Changes in the refractive index of the human corneal stroma during laser in situ keratomileusis. Effects of exposure time and method used to create the flap,” J. Cataract Refract. Surg.34(7), 1077–1082 (2008).
[CrossRef] [PubMed]

Badizadegan, K.

W. Choi, C. Fang-Yen, K. Badizadegan, S. Oh, N. Lue, R. R. Dasari, and M. S. Feld, “Tomographic phase microscopy,” Nat. Methods4(9), 717–719 (2007).
[CrossRef] [PubMed]

Balla, A.

Z. Wang, K. Tangella, A. Balla, and G. Popescu, “Tissue refractive index as marker of disease,” J. Biomed. Opt.16(11), 116017 (2011).
[CrossRef] [PubMed]

Boehlau-Godau, M.

A. Knüttel and M. Boehlau-Godau, “Spatially confined and temporally resolved refractive index and scattering evaluation in human skin performed with optical coherence tomography,” J. Biomed. Opt.5(1), 83–92 (2000).
[CrossRef] [PubMed]

Bolin, F. P.

Borasio, E.

E. Borasio, J. Stevens, and G. T. Smith, “Estimation of true corneal power after keratorefractive surgery in eyes requiring cataract surgery: BESSt formula,” J. Cataract Refract. Surg.32(12), 2004–2014 (2006).
[CrossRef] [PubMed]

Bouma, B. E.

Brezinski, M. E.

Chan, K. K. H.

Choi, W.

W. Choi, C. Fang-Yen, K. Badizadegan, S. Oh, N. Lue, R. R. Dasari, and M. S. Feld, “Tomographic phase microscopy,” Nat. Methods4(9), 717–719 (2007).
[CrossRef] [PubMed]

Daimon, M.

Dasari, R. R.

W. Choi, C. Fang-Yen, K. Badizadegan, S. Oh, N. Lue, R. R. Dasari, and M. S. Feld, “Tomographic phase microscopy,” Nat. Methods4(9), 717–719 (2007).
[CrossRef] [PubMed]

Decraemer, W. F.

J. J. Dirckx, L. C. Kuypers, and W. F. Decraemer, “Refractive index of tissue measured with confocal microscopy,” J. Biomed. Opt.10(4), 044014 (2005).
[CrossRef] [PubMed]

Dennis, S.

K. M. Meek, S. Dennis, and S. Khan, “Changes in the refractive index of the stroma and its extrafibrillar matrix when the cornea swells,” Biophys. J.85(4), 2205–2212 (2003).
[CrossRef] [PubMed]

Ding, H. F.

Dirckx, J. J.

J. J. Dirckx, L. C. Kuypers, and W. F. Decraemer, “Refractive index of tissue measured with confocal microscopy,” J. Biomed. Opt.10(4), 044014 (2005).
[CrossRef] [PubMed]

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. Methods4(9), 717–719 (2007).
[CrossRef] [PubMed]

Feld, M. S.

W. Choi, C. Fang-Yen, K. Badizadegan, S. Oh, N. Lue, R. R. Dasari, and M. S. Feld, “Tomographic phase microscopy,” Nat. Methods4(9), 717–719 (2007).
[CrossRef] [PubMed]

Ference, R. J.

Fujimoto, J. G.

Gan, X.

Ganic, D.

Glucksberg, M. R.

Y. L. Kim, J. T. Walsh, T. K. Goldstick, and M. R. Glucksberg, “Variation of corneal refractive index with hydration,” Phys. Med. Biol.49(5), 859–868 (2004).
[CrossRef] [PubMed]

Goldstick, T. K.

Y. L. Kim, J. T. Walsh, T. K. Goldstick, and M. R. Glucksberg, “Variation of corneal refractive index with hydration,” Phys. Med. Biol.49(5), 859–868 (2004).
[CrossRef] [PubMed]

Gu, M.

Güell, J. L.

C. P. Lohmann and J. L. Güell, “Regression after LASIK for the treatment of myopia: the role of the corneal epithelium,” Semin. Ophthalmol.13(2), 79–82 (1998).
[CrossRef] [PubMed]

Haruna, M.

Hashimoto, M.

He, A.

Hebden, J. C.

S. R. Arridge and J. C. Hebden, “Optical imaging in medicine: II. Modelling and reconstruction,” Phys. Med. Biol.42(5), 841–853 (1997).
[CrossRef] [PubMed]

Hee, M. R.

Hillman, T.

Hu, X. H.

Huang, D.

Inoue, S.

Izatt, J. A.

Jacobs, K. M.

Khan, S.

K. M. Meek, S. Dennis, and S. Khan, “Changes in the refractive index of the stroma and its extrafibrillar matrix when the cornea swells,” Biophys. J.85(4), 2205–2212 (2003).
[CrossRef] [PubMed]

Kim, M. J.

Kim, S.

Kim, Y. L.

Y. L. Kim, J. T. Walsh, T. K. Goldstick, and M. R. Glucksberg, “Variation of corneal refractive index with hydration,” Phys. Med. Biol.49(5), 859–868 (2004).
[CrossRef] [PubMed]

Klintworth, G. K.

G. K. Klintworth, “The cornea--structure and macromolecules in health and disease. A review,” Am. J. Pathol.89(3), 718–808 (1977).
[PubMed]

Knüttel, A.

A. Knüttel and M. Boehlau-Godau, “Spatially confined and temporally resolved refractive index and scattering evaluation in human skin performed with optical coherence tomography,” J. Biomed. Opt.5(1), 83–92 (2000).
[CrossRef] [PubMed]

Kuypers, L. C.

J. J. Dirckx, L. C. Kuypers, and W. F. Decraemer, “Refractive index of tissue measured with confocal microscopy,” J. Biomed. Opt.10(4), 044014 (2005).
[CrossRef] [PubMed]

Lai, J. C.

Lai, T.

Lecarpentier, G.

Lee, B. H.

Li, Z. H.

Lin, R. C.

Lohmann, C. P.

C. P. Lohmann and J. L. Güell, “Regression after LASIK for the treatment of myopia: the role of the corneal epithelium,” Semin. Ophthalmol.13(2), 79–82 (1998).
[CrossRef] [PubMed]

Lu, J. Q.

Lue, N.

W. Choi, C. Fang-Yen, K. Badizadegan, S. Oh, N. Lue, R. R. Dasari, and M. S. Feld, “Tomographic phase microscopy,” Nat. Methods4(9), 717–719 (2007).
[CrossRef] [PubMed]

Maruyama, H.

Masumura, A.

Meek, K. M.

K. M. Meek, S. Dennis, and S. Khan, “Changes in the refractive index of the stroma and its extrafibrillar matrix when the cornea swells,” Biophys. J.85(4), 2205–2212 (2003).
[CrossRef] [PubMed]

Mitsuyama, T.

Motamedi, M.

Na, J.

Oh, S.

W. Choi, C. Fang-Yen, K. Badizadegan, S. Oh, N. Lue, R. R. Dasari, and M. S. Feld, “Tomographic phase microscopy,” Nat. Methods4(9), 717–719 (2007).
[CrossRef] [PubMed]

Ohmi, M.

Patel, S.

S. Patel, J. L. Alió, and A. Artola, “Changes in the refractive index of the human corneal stroma during laser in situ keratomileusis. Effects of exposure time and method used to create the flap,” J. Cataract Refract. Surg.34(7), 1077–1082 (2008).
[CrossRef] [PubMed]

S. Patel, J. L. Alió, and J. J. Pérez-Santonja, “Refractive index change in bovine and human corneal stroma before and after lasik: a study of untreated and re-treated corneas implicating stromal hydration,” Invest. Ophthalmol. Vis. Sci.45(10), 3523–3530 (2004).
[CrossRef] [PubMed]

S. Patel, “Refractive index of the mammalian cornea and its influence during pachometry,” Ophthalmic Physiol. Opt.7(4), 503–506 (1987).
[CrossRef] [PubMed]

Pérez-Santonja, J. J.

S. Patel, J. L. Alió, and J. J. Pérez-Santonja, “Refractive index change in bovine and human corneal stroma before and after lasik: a study of untreated and re-treated corneas implicating stromal hydration,” Invest. Ophthalmol. Vis. Sci.45(10), 3523–3530 (2004).
[CrossRef] [PubMed]

Popescu, G.

Z. Wang, K. Tangella, A. Balla, and G. Popescu, “Tissue refractive index as marker of disease,” J. Biomed. Opt.16(11), 116017 (2011).
[CrossRef] [PubMed]

Preuss, L. E.

Rastegar, S.

Rollins, A. M.

Sampson, D.

Schmitt, J. M.

J. M. Schmitt, S. H. Xiang, and K. M. Yung, “Speckle in optical coherence tomography,” J. Biomed. Opt.4(1), 95–105 (1999).
[CrossRef] [PubMed]

Shure, M. A.

Silva, K. K.

Smith, G. T.

E. Borasio, J. Stevens, and G. T. Smith, “Estimation of true corneal power after keratorefractive surgery in eyes requiring cataract surgery: BESSt formula,” J. Cataract Refract. Surg.32(12), 2004–2014 (2006).
[CrossRef] [PubMed]

Southern, J. F.

Stevens, J.

E. Borasio, J. Stevens, and G. T. Smith, “Estimation of true corneal power after keratorefractive surgery in eyes requiring cataract surgery: BESSt formula,” J. Cataract Refract. Surg.32(12), 2004–2014 (2006).
[CrossRef] [PubMed]

Tajiri, H.

Tang, S.

Tangella, K.

Z. Wang, K. Tangella, A. Balla, and G. Popescu, “Tissue refractive index as marker of disease,” J. Biomed. Opt.16(11), 116017 (2011).
[CrossRef] [PubMed]

Taylor, R. C.

Tearney, G. J.

Tian, J. G.

X. Y. Wang, C. P. Zhang, L. S. Zhang, L. L. Xue, and J. G. Tian, “Simultaneous refractive index and thickness measurements of bio tissue by optical coherence tomography,” J. Biomed. Opt.7(4), 628–632 (2002).
[CrossRef] [PubMed]

Tsuzuki, T.

Walsh, J. T.

Y. L. Kim, J. T. Walsh, T. K. Goldstick, and M. R. Glucksberg, “Variation of corneal refractive index with hydration,” Phys. Med. Biol.49(5), 859–868 (2004).
[CrossRef] [PubMed]

Wang, C. Y.

Wang, X. Y.

X. Y. Wang, C. P. Zhang, L. S. Zhang, L. L. Xue, and J. G. Tian, “Simultaneous refractive index and thickness measurements of bio tissue by optical coherence tomography,” J. Biomed. Opt.7(4), 628–632 (2002).
[CrossRef] [PubMed]

Wang, Z.

Z. Wang, K. Tangella, A. Balla, and G. Popescu, “Tissue refractive index as marker of disease,” J. Biomed. Opt.16(11), 116017 (2011).
[CrossRef] [PubMed]

Welch, A. J.

Wilson, B. C.

B. C. Wilson, “Modeling and measurement of light propagation in tissue for diagnostic and therapeutic applications,” Laser Syst. Photobiol. Photomed.252, 13–27 (1991).
[CrossRef]

Xiang, S. H.

J. M. Schmitt, S. H. Xiang, and K. M. Yung, “Speckle in optical coherence tomography,” J. Biomed. Opt.4(1), 95–105 (1999).
[CrossRef] [PubMed]

Xue, L. L.

X. Y. Wang, C. P. Zhang, L. S. Zhang, L. L. Xue, and J. G. Tian, “Simultaneous refractive index and thickness measurements of bio tissue by optical coherence tomography,” J. Biomed. Opt.7(4), 628–632 (2002).
[CrossRef] [PubMed]

Yung, K. M.

J. M. Schmitt, S. H. Xiang, and K. M. Yung, “Speckle in optical coherence tomography,” J. Biomed. Opt.4(1), 95–105 (1999).
[CrossRef] [PubMed]

Zhang, C. P.

X. Y. Wang, C. P. Zhang, L. S. Zhang, L. L. Xue, and J. G. Tian, “Simultaneous refractive index and thickness measurements of bio tissue by optical coherence tomography,” J. Biomed. Opt.7(4), 628–632 (2002).
[CrossRef] [PubMed]

Zhang, L. S.

X. Y. Wang, C. P. Zhang, L. S. Zhang, L. L. Xue, and J. G. Tian, “Simultaneous refractive index and thickness measurements of bio tissue by optical coherence tomography,” J. Biomed. Opt.7(4), 628–632 (2002).
[CrossRef] [PubMed]

Zhou, Y. F.

Zvyagin, A.

Am. J. Pathol. (1)

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Figures (6)

Fig. 1
Fig. 1

Illustration of the OCT/MPM image acquisition procedure. (a) The solid rectangle denotes the OCT cross-sectional image which is reconstructed from 512 A-lines. (b) MPM en face image. (c) A stack of MPM en face images. (d) The reconstructed MPM 3D matrix from the MPM stack. (e) MPM cross-sectional image (solid rectangle) is sectioned from the MPM 3D matrix.

Fig. 2
Fig. 2

Schematic of the optical phantom for validation. t and n are the physical thickness and RI of the sample, no is the RI of the immersion medium.

Fig. 3
Fig. 3

The multilayer refraction of laser beam in sample arm. t and n are the physical thickness and RI of the sample. no is the RI of the immersion medium (water), n1 is the RI of the glass plate, θ1 is the incident angle, θ2 and θ3 are the refractive angles. Lo is the distance of the objective lens moved during imaging.

Fig. 4
Fig. 4

Schematics of the combined MPM/OCT system. BS: beam splitter; F: filter; Obj: Objective; PMT: photomultiplier tube [25].

Fig. 5
Fig. 5

MPM/OCT images of the phantom. (a) Cross-sectional view of OCT. (b) The intensity profile along the central line of OCT cross-sectional image. (c) Reconstructed cross-sectional view of MPM. (d) The intensity profile along the central line of MPM cross-sectional image. Scale bars are 50 μm.

Fig. 6
Fig. 6

MPM/OCT images of fish cornea. (a) Cross-sectional view of OCT. (b) Reconstructed cross-sectional view of MPM. (c)-(g) MPM en face view at depths 80, 200, 316, 370 and 387 µm, respectively. TPEF is in red and SHG in green. Scale bars are 50 μm.

Tables (2)

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Table 1 The measurement of RI of standard samplesa

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Table 2 RI and thickness of fish cornea

Equations (18)

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

L p =t×n
n o sin θ 1 = n 1 sin θ 2 =nsin θ 3
L o =t× n 0 2 n 0 2 sin 2 θ 1 n 2 n 0 2 sin 2 θ 1 .
n o sin θ 1 =NA
L o =t× n o 2 ( NA ) 2 n 2 ( NA ) 2
n= ( NA ) 2 + ( NA ) 4 +4[ n o 2 ( NA ) 2 ] L p 2 / L o 2 2
t= 2 L p ( NA ) 2 + ( NA ) 4 +4[ n o 2 ( NA ) 2 ] L p 2 / L o 2
n=f( L p , L o )= ( NA ) 2 + ( NA ) 4 +4[ n o 2 ( NA ) 2 ] L p 2 / L o 2 2
Δn | n ¯ | = Δf | f ¯ | =| lnf L p ¯ |×Δ L p +| lnf L o ¯ |×Δ L o
Δn | n ¯ | Δ L p 2 L p + Δ L o 2 L o
tan θ 1 tan θ 2 = ac/cf ac/ch = ch cf
tan θ 1 tan θ 2 = bc/cd bc/ce = ce cd
tan θ 1 tan θ 2 = ch cf = ce cd = chce cfcd = eh df
tan θ 2 tan θ 3 = eg eh
tan θ 1 tan θ 3 = eg df = t L o
tan θ 1 = sin θ 1 cos θ 1 = sin θ 1 1 sin 2 θ 1
tan θ 3 = sin θ 3 cos θ 3 = sin θ 3 1 sin 2 θ 3
L o =t× n 0 2 n 0 2 sin 2 θ 1 n 2 n 0 2 sin 2 θ 1

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