Abstract

Many optical and biomechanical properties of the cornea, specifically the transparency of the stroma and its stiffness, can be traced to the degree of order and direction of the constituent collagen fibers. To measure the degree of order inside the cornea, a new metric, the order coefficient, was introduced to quantify the organization of the collagen fibers from images of the stroma produced with a custom-developed second harmonic generation microscope. The order coefficient method gave a quantitative assessment of the differences in stromal collagen arrangement across the cornea depths and between untreated stroma and cross-linked stroma.

© 2017 Optical Society of America

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References

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2017 (2)

N. Bekesi, P. Gallego-Muñoz, L. Ibarés-Frías, P. Perez-Merino, M. C. Martinez-Garcia, I. E. Kochevar, and S. Marcos, “Biomechanical Changes After In Vivo Collagen Cross-Linking With Rose Bengal-Green Light and Riboflavin-UVA,” Invest. Ophthalmol. Vis. Sci. 58(3), 1612–1620 (2017).
[PubMed]

G. Hall, W. Liang, and X. Li, “Fitting-free algorithm for efficient quantification of collagen fiber alignment in SHG imaging applications,” Biomed. Opt. Express 8(10), 4609–4620 (2017).
[PubMed]

2016 (1)

N. Bekesi, I. E. Kochevar, and S. Marcos, “Corneal Biomechanical Response Following Collagen Cross-Linking With Rose Bengal-Green Light and Riboflavin-UVA,” Invest. Ophthalmol. Vis. Sci. 57(3), 992–1001 (2016).
[PubMed]

2015 (3)

2014 (3)

R. McQuaid, J. Li, A. Cummings, M. Mrochen, and B. Vohnsen, “Second-harmonic reflection imaging of normal and accelerated corneal crosslinking using porcine corneas and the role of intraocular pressure,” Cornea 33(2), 125–130 (2014).
[PubMed]

B. L. Wen, M. A. Brewer, O. Nadiarnykh, J. Hocker, V. Singh, T. R. Mackie, and P. J. Campagnola, “Texture analysis applied to second harmonic generation image data for ovarian cancer classification,” J. Biomed. Opt. 19(9), 096007 (2014).
[PubMed]

J. S. Bredfeldt, Y. Liu, M. W. Conklin, P. J. Keely, T. R. Mackie, and K. W. Eliceiri, “Automated quantification of aligned collagen for human breast carcinoma prognosis,” J. Pathol. Inform. 5(1), 28 (2014).
[PubMed]

2013 (6)

A. Ghazaryan, H. F. Tsai, G. Hayrapetyan, W. L. Chen, Y. F. Chen, M. Y. Jeong, C. S. Kim, S. J. Chen, and C. Y. Dong, “Analysis of collagen fiber domain organization by Fourier second harmonic generation microscopy,” J. Biomed. Opt. 18(3), 31105 (2013).
[PubMed]

M. Winkler, G. Shoa, Y. Xie, S. J. Petsche, P. M. Pinsky, T. Juhasz, D. J. Brown, and J. V. Jester, “Three-dimensional distribution of transverse collagen fibers in the anterior human corneal stroma,” Invest. Ophthalmol. Vis. Sci. 54(12), 7293–7301 (2013).
[PubMed]

S. Hayes, C. S. Kamma-Lorger, C. Boote, R. D. Young, A. J. Quantock, A. Rost, Y. Khatib, J. Harris, N. Yagi, N. Terrill, and K. M. Meek, “The effect of riboflavin/UVA collagen cross-linking therapy on the structure and hydrodynamic behaviour of the ungulate and rabbit corneal stroma,” PLoS One 8(1), e52860 (2013).
[PubMed]

S. Akhtar, T. Almubrad, I. Paladini, and R. Mencucci, “Keratoconus corneal architecture after riboflavin/ultraviolet A cross-linking: ultrastructural studies,” Mol. Vis. 19, 1526–1537 (2013).
[PubMed]

D. Cherfan, E. E. Verter, S. Melki, T. E. Gisel, F. J. Doyle, G. Scarcelli, S. H. Yun, R. W. Redmond, and I. E. Kochevar, “Collagen cross-linking using rose bengal and green light to increase corneal stiffness,” Invest. Ophthalmol. Vis. Sci. 54(5), 3426–3433 (2013).
[PubMed]

J. M. Bueno, R. Palacios, M. K. Chessey, and H. Ginis, “Analysis of spatial lamellar distribution from adaptive-optics second harmonic generation corneal images,” Biomed. Opt. Express 4(7), 1006–1013 (2013).
[PubMed]

2012 (4)

V. Lutz, M. Sattler, S. Gallinat, H. Wenck, R. Poertner, and F. Fischer, “Characterization of fibrillar collagen types using multi-dimensional multiphoton laser scanning microscopy,” Int. J. Cosmet. Sci. 34(2), 209–215 (2012).
[PubMed]

R. Ambekar, M. Chittenden, I. Jasiuk, and K. C. Toussaint., “Quantitative second-harmonic generation microscopy for imaging porcine cortical bone: comparison to SEM and its potential to investigate age-related changes,” Bone 50(3), 643–650 (2012).
[PubMed]

Y. Mega, M. Robitaille, R. Zareian, J. McLean, J. Ruberti, and C. DiMarzio, “Quantification of lamellar orientation in corneal collagen using second harmonic generation images,” Opt. Lett. 37(16), 3312–3314 (2012).
[PubMed]

T. Y. Lau, R. Ambekar, and K. C. Toussaint, “Quantification of collagen fiber organization using three-dimensional Fourier transform-second-harmonic generation imaging,” Opt. Express 20(19), 21821–21832 (2012).
[PubMed]

2011 (1)

J. M. Bueno, E. J. Gualda, and P. Artal, “Analysis of corneal stroma organization with wavefront optimized nonlinear microscopy,” Cornea 30(6), 692–701 (2011).
[PubMed]

2010 (3)

S. Kling, L. Remon, A. Pérez-Escudero, J. Merayo-Lloves, and S. Marcos, “Corneal biomechanical changes after collagen cross-linking from porcine eye inflation experiments,” Invest. Ophthalmol. Vis. Sci. 51(8), 3961–3968 (2010).
[PubMed]

J. V. Jester, M. Winkler, B. E. Jester, C. Nien, D. Chai, and D. J. Brown, “Evaluating corneal collagen organization using high-resolution nonlinear optical macroscopy,” Eye Contact Lens 36(5), 260–264 (2010).
[PubMed]

A. Caporossi, C. Mazzotta, S. Baiocchi, and T. Caporossi, “Long-term results of riboflavin ultraviolet a corneal collagen cross-linking for keratoconus in Italy: the Siena eye cross study,” Am. J. Ophthalmol. 149(4), 585–593 (2010).
[PubMed]

2009 (3)

M. Abahussin, S. Hayes, N. E. Knox Cartwright, C. S. Kamma-Lorger, Y. Khan, J. Marshall, and K. M. Meek, “3D collagen orientation study of the human cornea using X-ray diffraction and femtosecond laser technology,” Invest. Ophthalmol. Vis. Sci. 50(11), 5159–5164 (2009).
[PubMed]

G. Wollensak and E. Iomdina, “Biomechanical and histological changes after corneal crosslinking with and without epithelial debridement,” J. Cataract Refract. Surg. 35(3), 540–546 (2009).
[PubMed]

R. A. Rao, M. R. Mehta, and K. C. Toussaint., “Fourier transform-second-harmonic generation imaging of biological tissues,” Opt. Express 17(17), 14534–14542 (2009).
[PubMed]

2007 (2)

G. Wollensak, H. Aurich, D. T. Pham, and C. Wirbelauer, “Hydration behavior of porcine cornea crosslinked with riboflavin and ultraviolet A,” J. Cataract Refract. Surg. 33(3), 516–521 (2007).
[PubMed]

N. Morishige, A. J. Wahlert, M. C. Kenney, D. J. Brown, K. Kawamoto, T. Chikama, T. Nishida, and J. V. Jester, “Second-harmonic imaging microscopy of normal human and keratoconus cornea,” Invest. Ophthalmol. Vis. Sci. 48(3), 1087–1094 (2007).
[PubMed]

2006 (3)

M. Kohlhaas, E. Spoerl, T. Schilde, G. Unger, C. Wittig, and L. E. Pillunat, “Biomechanical evidence of the distribution of cross-links in corneas treated with riboflavin and ultraviolet A light,” J. Cataract Refract. Surg. 32(2), 279–283 (2006).
[PubMed]

N. Morishige, W. M. Petroll, T. Nishida, M. C. Kenney, and J. V. Jester, “Noninvasive corneal stromal collagen imaging using two-photon-generated second-harmonic signals,” J. Cataract Refract. Surg. 32(11), 1784–1791 (2006).
[PubMed]

T. Seiler and F. Hafezi, “Corneal cross-linking-induced stromal demarcation line,” Cornea 25(9), 1057–1059 (2006).
[PubMed]

2004 (2)

H. Aghamohammadzadeh, R. H. Newton, and K. M. Meek, “X-ray scattering used to map the preferred collagen orientation in the human cornea and limbus,” Structure 12(2), 249–256 (2004).
[PubMed]

G. Wollensak, E. Spoerl, M. Wilsch, and T. Seiler, “Keratocyte apoptosis after corneal collagen cross-linking using riboflavin/UVA treatment,” Cornea 23(1), 43–49 (2004).
[PubMed]

2003 (1)

G. Wollensak, E. Spoerl, and T. Seiler, “Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus,” Am. J. Ophthalmol. 135(5), 620–627 (2003).
[PubMed]

2001 (1)

L. J. Müller, E. Pels, and G. F. Vrensen, “The specific architecture of the anterior stroma accounts for maintenance of corneal curvature,” Br. J. Ophthalmol. 85(4), 437–443 (2001).
[PubMed]

1991 (1)

Y. Komai and T. Ushiki, “The three-dimensional organization of collagen fibrils in the human cornea and sclera,” Invest. Ophthalmol. Vis. Sci. 32(8), 2244–2258 (1991).
[PubMed]

1986 (1)

K. Nakayasu, M. Tanaka, H. Konomi, and T. Hayashi, “Distribution of types I, II, III, IV and V collagen in normal and keratoconus corneas,” Ophthalmic Res. 18(1), 1–10 (1986).
[PubMed]

1979 (1)

S. Roth and I. Freund, “Second harmonic generation in collagen,” J. Chem. Phys. 70, 1637–1643 (1979).

Abahussin, M.

M. Abahussin, S. Hayes, N. E. Knox Cartwright, C. S. Kamma-Lorger, Y. Khan, J. Marshall, and K. M. Meek, “3D collagen orientation study of the human cornea using X-ray diffraction and femtosecond laser technology,” Invest. Ophthalmol. Vis. Sci. 50(11), 5159–5164 (2009).
[PubMed]

Aghamohammadzadeh, H.

H. Aghamohammadzadeh, R. H. Newton, and K. M. Meek, “X-ray scattering used to map the preferred collagen orientation in the human cornea and limbus,” Structure 12(2), 249–256 (2004).
[PubMed]

Akhtar, S.

S. Akhtar, T. Almubrad, I. Paladini, and R. Mencucci, “Keratoconus corneal architecture after riboflavin/ultraviolet A cross-linking: ultrastructural studies,” Mol. Vis. 19, 1526–1537 (2013).
[PubMed]

Almubrad, T.

S. Akhtar, T. Almubrad, I. Paladini, and R. Mencucci, “Keratoconus corneal architecture after riboflavin/ultraviolet A cross-linking: ultrastructural studies,” Mol. Vis. 19, 1526–1537 (2013).
[PubMed]

Ambekar, R.

R. Ambekar, M. Chittenden, I. Jasiuk, and K. C. Toussaint., “Quantitative second-harmonic generation microscopy for imaging porcine cortical bone: comparison to SEM and its potential to investigate age-related changes,” Bone 50(3), 643–650 (2012).
[PubMed]

T. Y. Lau, R. Ambekar, and K. C. Toussaint, “Quantification of collagen fiber organization using three-dimensional Fourier transform-second-harmonic generation imaging,” Opt. Express 20(19), 21821–21832 (2012).
[PubMed]

Artal, P.

J. M. Bueno, E. J. Gualda, and P. Artal, “Analysis of corneal stroma organization with wavefront optimized nonlinear microscopy,” Cornea 30(6), 692–701 (2011).
[PubMed]

Aurich, H.

G. Wollensak, H. Aurich, D. T. Pham, and C. Wirbelauer, “Hydration behavior of porcine cornea crosslinked with riboflavin and ultraviolet A,” J. Cataract Refract. Surg. 33(3), 516–521 (2007).
[PubMed]

Ávila, F. J.

Baiocchi, S.

A. Caporossi, C. Mazzotta, S. Baiocchi, and T. Caporossi, “Long-term results of riboflavin ultraviolet a corneal collagen cross-linking for keratoconus in Italy: the Siena eye cross study,” Am. J. Ophthalmol. 149(4), 585–593 (2010).
[PubMed]

Bekesi, N.

N. Bekesi, P. Gallego-Muñoz, L. Ibarés-Frías, P. Perez-Merino, M. C. Martinez-Garcia, I. E. Kochevar, and S. Marcos, “Biomechanical Changes After In Vivo Collagen Cross-Linking With Rose Bengal-Green Light and Riboflavin-UVA,” Invest. Ophthalmol. Vis. Sci. 58(3), 1612–1620 (2017).
[PubMed]

N. Bekesi, I. E. Kochevar, and S. Marcos, “Corneal Biomechanical Response Following Collagen Cross-Linking With Rose Bengal-Green Light and Riboflavin-UVA,” Invest. Ophthalmol. Vis. Sci. 57(3), 992–1001 (2016).
[PubMed]

Boote, C.

S. Hayes, C. S. Kamma-Lorger, C. Boote, R. D. Young, A. J. Quantock, A. Rost, Y. Khatib, J. Harris, N. Yagi, N. Terrill, and K. M. Meek, “The effect of riboflavin/UVA collagen cross-linking therapy on the structure and hydrodynamic behaviour of the ungulate and rabbit corneal stroma,” PLoS One 8(1), e52860 (2013).
[PubMed]

Bredfeldt, J. S.

J. S. Bredfeldt, Y. Liu, M. W. Conklin, P. J. Keely, T. R. Mackie, and K. W. Eliceiri, “Automated quantification of aligned collagen for human breast carcinoma prognosis,” J. Pathol. Inform. 5(1), 28 (2014).
[PubMed]

Brewer, M. A.

B. L. Wen, M. A. Brewer, O. Nadiarnykh, J. Hocker, V. Singh, T. R. Mackie, and P. J. Campagnola, “Texture analysis applied to second harmonic generation image data for ovarian cancer classification,” J. Biomed. Opt. 19(9), 096007 (2014).
[PubMed]

Brown, D. J.

M. Winkler, G. Shoa, Y. Xie, S. J. Petsche, P. M. Pinsky, T. Juhasz, D. J. Brown, and J. V. Jester, “Three-dimensional distribution of transverse collagen fibers in the anterior human corneal stroma,” Invest. Ophthalmol. Vis. Sci. 54(12), 7293–7301 (2013).
[PubMed]

J. V. Jester, M. Winkler, B. E. Jester, C. Nien, D. Chai, and D. J. Brown, “Evaluating corneal collagen organization using high-resolution nonlinear optical macroscopy,” Eye Contact Lens 36(5), 260–264 (2010).
[PubMed]

N. Morishige, A. J. Wahlert, M. C. Kenney, D. J. Brown, K. Kawamoto, T. Chikama, T. Nishida, and J. V. Jester, “Second-harmonic imaging microscopy of normal human and keratoconus cornea,” Invest. Ophthalmol. Vis. Sci. 48(3), 1087–1094 (2007).
[PubMed]

Bueno, J. M.

Campagnola, P. J.

B. L. Wen, M. A. Brewer, O. Nadiarnykh, J. Hocker, V. Singh, T. R. Mackie, and P. J. Campagnola, “Texture analysis applied to second harmonic generation image data for ovarian cancer classification,” J. Biomed. Opt. 19(9), 096007 (2014).
[PubMed]

Caporossi, A.

A. Caporossi, C. Mazzotta, S. Baiocchi, and T. Caporossi, “Long-term results of riboflavin ultraviolet a corneal collagen cross-linking for keratoconus in Italy: the Siena eye cross study,” Am. J. Ophthalmol. 149(4), 585–593 (2010).
[PubMed]

Caporossi, T.

A. Caporossi, C. Mazzotta, S. Baiocchi, and T. Caporossi, “Long-term results of riboflavin ultraviolet a corneal collagen cross-linking for keratoconus in Italy: the Siena eye cross study,” Am. J. Ophthalmol. 149(4), 585–593 (2010).
[PubMed]

Chai, D.

J. V. Jester, M. Winkler, B. E. Jester, C. Nien, D. Chai, and D. J. Brown, “Evaluating corneal collagen organization using high-resolution nonlinear optical macroscopy,” Eye Contact Lens 36(5), 260–264 (2010).
[PubMed]

Chen, S. J.

A. Ghazaryan, H. F. Tsai, G. Hayrapetyan, W. L. Chen, Y. F. Chen, M. Y. Jeong, C. S. Kim, S. J. Chen, and C. Y. Dong, “Analysis of collagen fiber domain organization by Fourier second harmonic generation microscopy,” J. Biomed. Opt. 18(3), 31105 (2013).
[PubMed]

Chen, W. L.

A. Ghazaryan, H. F. Tsai, G. Hayrapetyan, W. L. Chen, Y. F. Chen, M. Y. Jeong, C. S. Kim, S. J. Chen, and C. Y. Dong, “Analysis of collagen fiber domain organization by Fourier second harmonic generation microscopy,” J. Biomed. Opt. 18(3), 31105 (2013).
[PubMed]

Chen, Y. F.

A. Ghazaryan, H. F. Tsai, G. Hayrapetyan, W. L. Chen, Y. F. Chen, M. Y. Jeong, C. S. Kim, S. J. Chen, and C. Y. Dong, “Analysis of collagen fiber domain organization by Fourier second harmonic generation microscopy,” J. Biomed. Opt. 18(3), 31105 (2013).
[PubMed]

Cherfan, D.

D. Cherfan, E. E. Verter, S. Melki, T. E. Gisel, F. J. Doyle, G. Scarcelli, S. H. Yun, R. W. Redmond, and I. E. Kochevar, “Collagen cross-linking using rose bengal and green light to increase corneal stiffness,” Invest. Ophthalmol. Vis. Sci. 54(5), 3426–3433 (2013).
[PubMed]

Chessey, M. K.

Chikama, T.

N. Morishige, A. J. Wahlert, M. C. Kenney, D. J. Brown, K. Kawamoto, T. Chikama, T. Nishida, and J. V. Jester, “Second-harmonic imaging microscopy of normal human and keratoconus cornea,” Invest. Ophthalmol. Vis. Sci. 48(3), 1087–1094 (2007).
[PubMed]

Chittenden, M.

R. Ambekar, M. Chittenden, I. Jasiuk, and K. C. Toussaint., “Quantitative second-harmonic generation microscopy for imaging porcine cortical bone: comparison to SEM and its potential to investigate age-related changes,” Bone 50(3), 643–650 (2012).
[PubMed]

Conklin, M. W.

J. S. Bredfeldt, Y. Liu, M. W. Conklin, P. J. Keely, T. R. Mackie, and K. W. Eliceiri, “Automated quantification of aligned collagen for human breast carcinoma prognosis,” J. Pathol. Inform. 5(1), 28 (2014).
[PubMed]

Cummings, A.

R. McQuaid, J. Li, A. Cummings, M. Mrochen, and B. Vohnsen, “Second-harmonic reflection imaging of normal and accelerated corneal crosslinking using porcine corneas and the role of intraocular pressure,” Cornea 33(2), 125–130 (2014).
[PubMed]

DiMarzio, C.

Dong, C. Y.

A. Ghazaryan, H. F. Tsai, G. Hayrapetyan, W. L. Chen, Y. F. Chen, M. Y. Jeong, C. S. Kim, S. J. Chen, and C. Y. Dong, “Analysis of collagen fiber domain organization by Fourier second harmonic generation microscopy,” J. Biomed. Opt. 18(3), 31105 (2013).
[PubMed]

Doyle, F. J.

D. Cherfan, E. E. Verter, S. Melki, T. E. Gisel, F. J. Doyle, G. Scarcelli, S. H. Yun, R. W. Redmond, and I. E. Kochevar, “Collagen cross-linking using rose bengal and green light to increase corneal stiffness,” Invest. Ophthalmol. Vis. Sci. 54(5), 3426–3433 (2013).
[PubMed]

Eliceiri, K. W.

J. S. Bredfeldt, Y. Liu, M. W. Conklin, P. J. Keely, T. R. Mackie, and K. W. Eliceiri, “Automated quantification of aligned collagen for human breast carcinoma prognosis,” J. Pathol. Inform. 5(1), 28 (2014).
[PubMed]

Fischer, F.

V. Lutz, M. Sattler, S. Gallinat, H. Wenck, R. Poertner, and F. Fischer, “Characterization of fibrillar collagen types using multi-dimensional multiphoton laser scanning microscopy,” Int. J. Cosmet. Sci. 34(2), 209–215 (2012).
[PubMed]

Freund, I.

S. Roth and I. Freund, “Second harmonic generation in collagen,” J. Chem. Phys. 70, 1637–1643 (1979).

Gallego-Muñoz, P.

N. Bekesi, P. Gallego-Muñoz, L. Ibarés-Frías, P. Perez-Merino, M. C. Martinez-Garcia, I. E. Kochevar, and S. Marcos, “Biomechanical Changes After In Vivo Collagen Cross-Linking With Rose Bengal-Green Light and Riboflavin-UVA,” Invest. Ophthalmol. Vis. Sci. 58(3), 1612–1620 (2017).
[PubMed]

Gallinat, S.

V. Lutz, M. Sattler, S. Gallinat, H. Wenck, R. Poertner, and F. Fischer, “Characterization of fibrillar collagen types using multi-dimensional multiphoton laser scanning microscopy,” Int. J. Cosmet. Sci. 34(2), 209–215 (2012).
[PubMed]

Ghazaryan, A.

A. Ghazaryan, H. F. Tsai, G. Hayrapetyan, W. L. Chen, Y. F. Chen, M. Y. Jeong, C. S. Kim, S. J. Chen, and C. Y. Dong, “Analysis of collagen fiber domain organization by Fourier second harmonic generation microscopy,” J. Biomed. Opt. 18(3), 31105 (2013).
[PubMed]

Ginis, H.

Gisel, T. E.

D. Cherfan, E. E. Verter, S. Melki, T. E. Gisel, F. J. Doyle, G. Scarcelli, S. H. Yun, R. W. Redmond, and I. E. Kochevar, “Collagen cross-linking using rose bengal and green light to increase corneal stiffness,” Invest. Ophthalmol. Vis. Sci. 54(5), 3426–3433 (2013).
[PubMed]

Gualda, E. J.

J. M. Bueno, E. J. Gualda, and P. Artal, “Analysis of corneal stroma organization with wavefront optimized nonlinear microscopy,” Cornea 30(6), 692–701 (2011).
[PubMed]

Hafezi, F.

T. Seiler and F. Hafezi, “Corneal cross-linking-induced stromal demarcation line,” Cornea 25(9), 1057–1059 (2006).
[PubMed]

Hall, G.

Harris, J.

S. Hayes, C. S. Kamma-Lorger, C. Boote, R. D. Young, A. J. Quantock, A. Rost, Y. Khatib, J. Harris, N. Yagi, N. Terrill, and K. M. Meek, “The effect of riboflavin/UVA collagen cross-linking therapy on the structure and hydrodynamic behaviour of the ungulate and rabbit corneal stroma,” PLoS One 8(1), e52860 (2013).
[PubMed]

Hayashi, T.

K. Nakayasu, M. Tanaka, H. Konomi, and T. Hayashi, “Distribution of types I, II, III, IV and V collagen in normal and keratoconus corneas,” Ophthalmic Res. 18(1), 1–10 (1986).
[PubMed]

Hayes, S.

S. Hayes, C. S. Kamma-Lorger, C. Boote, R. D. Young, A. J. Quantock, A. Rost, Y. Khatib, J. Harris, N. Yagi, N. Terrill, and K. M. Meek, “The effect of riboflavin/UVA collagen cross-linking therapy on the structure and hydrodynamic behaviour of the ungulate and rabbit corneal stroma,” PLoS One 8(1), e52860 (2013).
[PubMed]

M. Abahussin, S. Hayes, N. E. Knox Cartwright, C. S. Kamma-Lorger, Y. Khan, J. Marshall, and K. M. Meek, “3D collagen orientation study of the human cornea using X-ray diffraction and femtosecond laser technology,” Invest. Ophthalmol. Vis. Sci. 50(11), 5159–5164 (2009).
[PubMed]

Hayrapetyan, G.

A. Ghazaryan, H. F. Tsai, G. Hayrapetyan, W. L. Chen, Y. F. Chen, M. Y. Jeong, C. S. Kim, S. J. Chen, and C. Y. Dong, “Analysis of collagen fiber domain organization by Fourier second harmonic generation microscopy,” J. Biomed. Opt. 18(3), 31105 (2013).
[PubMed]

Hocker, J.

B. L. Wen, M. A. Brewer, O. Nadiarnykh, J. Hocker, V. Singh, T. R. Mackie, and P. J. Campagnola, “Texture analysis applied to second harmonic generation image data for ovarian cancer classification,” J. Biomed. Opt. 19(9), 096007 (2014).
[PubMed]

Ibarés-Frías, L.

N. Bekesi, P. Gallego-Muñoz, L. Ibarés-Frías, P. Perez-Merino, M. C. Martinez-Garcia, I. E. Kochevar, and S. Marcos, “Biomechanical Changes After In Vivo Collagen Cross-Linking With Rose Bengal-Green Light and Riboflavin-UVA,” Invest. Ophthalmol. Vis. Sci. 58(3), 1612–1620 (2017).
[PubMed]

Iomdina, E.

G. Wollensak and E. Iomdina, “Biomechanical and histological changes after corneal crosslinking with and without epithelial debridement,” J. Cataract Refract. Surg. 35(3), 540–546 (2009).
[PubMed]

Jasiuk, I.

R. Ambekar, M. Chittenden, I. Jasiuk, and K. C. Toussaint., “Quantitative second-harmonic generation microscopy for imaging porcine cortical bone: comparison to SEM and its potential to investigate age-related changes,” Bone 50(3), 643–650 (2012).
[PubMed]

Jeong, M. Y.

A. Ghazaryan, H. F. Tsai, G. Hayrapetyan, W. L. Chen, Y. F. Chen, M. Y. Jeong, C. S. Kim, S. J. Chen, and C. Y. Dong, “Analysis of collagen fiber domain organization by Fourier second harmonic generation microscopy,” J. Biomed. Opt. 18(3), 31105 (2013).
[PubMed]

Jester, B. E.

J. V. Jester, M. Winkler, B. E. Jester, C. Nien, D. Chai, and D. J. Brown, “Evaluating corneal collagen organization using high-resolution nonlinear optical macroscopy,” Eye Contact Lens 36(5), 260–264 (2010).
[PubMed]

Jester, J. V.

M. Winkler, G. Shoa, Y. Xie, S. J. Petsche, P. M. Pinsky, T. Juhasz, D. J. Brown, and J. V. Jester, “Three-dimensional distribution of transverse collagen fibers in the anterior human corneal stroma,” Invest. Ophthalmol. Vis. Sci. 54(12), 7293–7301 (2013).
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J. V. Jester, M. Winkler, B. E. Jester, C. Nien, D. Chai, and D. J. Brown, “Evaluating corneal collagen organization using high-resolution nonlinear optical macroscopy,” Eye Contact Lens 36(5), 260–264 (2010).
[PubMed]

N. Morishige, A. J. Wahlert, M. C. Kenney, D. J. Brown, K. Kawamoto, T. Chikama, T. Nishida, and J. V. Jester, “Second-harmonic imaging microscopy of normal human and keratoconus cornea,” Invest. Ophthalmol. Vis. Sci. 48(3), 1087–1094 (2007).
[PubMed]

N. Morishige, W. M. Petroll, T. Nishida, M. C. Kenney, and J. V. Jester, “Noninvasive corneal stromal collagen imaging using two-photon-generated second-harmonic signals,” J. Cataract Refract. Surg. 32(11), 1784–1791 (2006).
[PubMed]

Juhasz, T.

M. Winkler, G. Shoa, Y. Xie, S. J. Petsche, P. M. Pinsky, T. Juhasz, D. J. Brown, and J. V. Jester, “Three-dimensional distribution of transverse collagen fibers in the anterior human corneal stroma,” Invest. Ophthalmol. Vis. Sci. 54(12), 7293–7301 (2013).
[PubMed]

Kamma-Lorger, C. S.

S. Hayes, C. S. Kamma-Lorger, C. Boote, R. D. Young, A. J. Quantock, A. Rost, Y. Khatib, J. Harris, N. Yagi, N. Terrill, and K. M. Meek, “The effect of riboflavin/UVA collagen cross-linking therapy on the structure and hydrodynamic behaviour of the ungulate and rabbit corneal stroma,” PLoS One 8(1), e52860 (2013).
[PubMed]

M. Abahussin, S. Hayes, N. E. Knox Cartwright, C. S. Kamma-Lorger, Y. Khan, J. Marshall, and K. M. Meek, “3D collagen orientation study of the human cornea using X-ray diffraction and femtosecond laser technology,” Invest. Ophthalmol. Vis. Sci. 50(11), 5159–5164 (2009).
[PubMed]

Kawamoto, K.

N. Morishige, A. J. Wahlert, M. C. Kenney, D. J. Brown, K. Kawamoto, T. Chikama, T. Nishida, and J. V. Jester, “Second-harmonic imaging microscopy of normal human and keratoconus cornea,” Invest. Ophthalmol. Vis. Sci. 48(3), 1087–1094 (2007).
[PubMed]

Keely, P. J.

J. S. Bredfeldt, Y. Liu, M. W. Conklin, P. J. Keely, T. R. Mackie, and K. W. Eliceiri, “Automated quantification of aligned collagen for human breast carcinoma prognosis,” J. Pathol. Inform. 5(1), 28 (2014).
[PubMed]

Kenney, M. C.

N. Morishige, A. J. Wahlert, M. C. Kenney, D. J. Brown, K. Kawamoto, T. Chikama, T. Nishida, and J. V. Jester, “Second-harmonic imaging microscopy of normal human and keratoconus cornea,” Invest. Ophthalmol. Vis. Sci. 48(3), 1087–1094 (2007).
[PubMed]

N. Morishige, W. M. Petroll, T. Nishida, M. C. Kenney, and J. V. Jester, “Noninvasive corneal stromal collagen imaging using two-photon-generated second-harmonic signals,” J. Cataract Refract. Surg. 32(11), 1784–1791 (2006).
[PubMed]

Khan, Y.

M. Abahussin, S. Hayes, N. E. Knox Cartwright, C. S. Kamma-Lorger, Y. Khan, J. Marshall, and K. M. Meek, “3D collagen orientation study of the human cornea using X-ray diffraction and femtosecond laser technology,” Invest. Ophthalmol. Vis. Sci. 50(11), 5159–5164 (2009).
[PubMed]

Khatib, Y.

S. Hayes, C. S. Kamma-Lorger, C. Boote, R. D. Young, A. J. Quantock, A. Rost, Y. Khatib, J. Harris, N. Yagi, N. Terrill, and K. M. Meek, “The effect of riboflavin/UVA collagen cross-linking therapy on the structure and hydrodynamic behaviour of the ungulate and rabbit corneal stroma,” PLoS One 8(1), e52860 (2013).
[PubMed]

Kim, C. S.

A. Ghazaryan, H. F. Tsai, G. Hayrapetyan, W. L. Chen, Y. F. Chen, M. Y. Jeong, C. S. Kim, S. J. Chen, and C. Y. Dong, “Analysis of collagen fiber domain organization by Fourier second harmonic generation microscopy,” J. Biomed. Opt. 18(3), 31105 (2013).
[PubMed]

Kling, S.

S. Kling, L. Remon, A. Pérez-Escudero, J. Merayo-Lloves, and S. Marcos, “Corneal biomechanical changes after collagen cross-linking from porcine eye inflation experiments,” Invest. Ophthalmol. Vis. Sci. 51(8), 3961–3968 (2010).
[PubMed]

Knox Cartwright, N. E.

M. Abahussin, S. Hayes, N. E. Knox Cartwright, C. S. Kamma-Lorger, Y. Khan, J. Marshall, and K. M. Meek, “3D collagen orientation study of the human cornea using X-ray diffraction and femtosecond laser technology,” Invest. Ophthalmol. Vis. Sci. 50(11), 5159–5164 (2009).
[PubMed]

Knupp, C.

K. M. Meek and C. Knupp, “Corneal structure and transparency,” Prog. Retin. Eye Res. 49, 1–16 (2015).
[PubMed]

Kochevar, I. E.

N. Bekesi, P. Gallego-Muñoz, L. Ibarés-Frías, P. Perez-Merino, M. C. Martinez-Garcia, I. E. Kochevar, and S. Marcos, “Biomechanical Changes After In Vivo Collagen Cross-Linking With Rose Bengal-Green Light and Riboflavin-UVA,” Invest. Ophthalmol. Vis. Sci. 58(3), 1612–1620 (2017).
[PubMed]

N. Bekesi, I. E. Kochevar, and S. Marcos, “Corneal Biomechanical Response Following Collagen Cross-Linking With Rose Bengal-Green Light and Riboflavin-UVA,” Invest. Ophthalmol. Vis. Sci. 57(3), 992–1001 (2016).
[PubMed]

D. Cherfan, E. E. Verter, S. Melki, T. E. Gisel, F. J. Doyle, G. Scarcelli, S. H. Yun, R. W. Redmond, and I. E. Kochevar, “Collagen cross-linking using rose bengal and green light to increase corneal stiffness,” Invest. Ophthalmol. Vis. Sci. 54(5), 3426–3433 (2013).
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Kohlhaas, M.

M. Kohlhaas, E. Spoerl, T. Schilde, G. Unger, C. Wittig, and L. E. Pillunat, “Biomechanical evidence of the distribution of cross-links in corneas treated with riboflavin and ultraviolet A light,” J. Cataract Refract. Surg. 32(2), 279–283 (2006).
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Komai, Y.

Y. Komai and T. Ushiki, “The three-dimensional organization of collagen fibrils in the human cornea and sclera,” Invest. Ophthalmol. Vis. Sci. 32(8), 2244–2258 (1991).
[PubMed]

Konomi, H.

K. Nakayasu, M. Tanaka, H. Konomi, and T. Hayashi, “Distribution of types I, II, III, IV and V collagen in normal and keratoconus corneas,” Ophthalmic Res. 18(1), 1–10 (1986).
[PubMed]

Lau, T. Y.

Li, J.

R. McQuaid, J. Li, A. Cummings, M. Mrochen, and B. Vohnsen, “Second-harmonic reflection imaging of normal and accelerated corneal crosslinking using porcine corneas and the role of intraocular pressure,” Cornea 33(2), 125–130 (2014).
[PubMed]

Li, X.

Liang, W.

Liu, Y.

J. S. Bredfeldt, Y. Liu, M. W. Conklin, P. J. Keely, T. R. Mackie, and K. W. Eliceiri, “Automated quantification of aligned collagen for human breast carcinoma prognosis,” J. Pathol. Inform. 5(1), 28 (2014).
[PubMed]

Lombardo, G.

Lombardo, M.

Loza-Alvarez, P.

Lutz, V.

V. Lutz, M. Sattler, S. Gallinat, H. Wenck, R. Poertner, and F. Fischer, “Characterization of fibrillar collagen types using multi-dimensional multiphoton laser scanning microscopy,” Int. J. Cosmet. Sci. 34(2), 209–215 (2012).
[PubMed]

Mackie, T. R.

J. S. Bredfeldt, Y. Liu, M. W. Conklin, P. J. Keely, T. R. Mackie, and K. W. Eliceiri, “Automated quantification of aligned collagen for human breast carcinoma prognosis,” J. Pathol. Inform. 5(1), 28 (2014).
[PubMed]

B. L. Wen, M. A. Brewer, O. Nadiarnykh, J. Hocker, V. Singh, T. R. Mackie, and P. J. Campagnola, “Texture analysis applied to second harmonic generation image data for ovarian cancer classification,” J. Biomed. Opt. 19(9), 096007 (2014).
[PubMed]

Marcos, S.

N. Bekesi, P. Gallego-Muñoz, L. Ibarés-Frías, P. Perez-Merino, M. C. Martinez-Garcia, I. E. Kochevar, and S. Marcos, “Biomechanical Changes After In Vivo Collagen Cross-Linking With Rose Bengal-Green Light and Riboflavin-UVA,” Invest. Ophthalmol. Vis. Sci. 58(3), 1612–1620 (2017).
[PubMed]

N. Bekesi, I. E. Kochevar, and S. Marcos, “Corneal Biomechanical Response Following Collagen Cross-Linking With Rose Bengal-Green Light and Riboflavin-UVA,” Invest. Ophthalmol. Vis. Sci. 57(3), 992–1001 (2016).
[PubMed]

S. Kling, L. Remon, A. Pérez-Escudero, J. Merayo-Lloves, and S. Marcos, “Corneal biomechanical changes after collagen cross-linking from porcine eye inflation experiments,” Invest. Ophthalmol. Vis. Sci. 51(8), 3961–3968 (2010).
[PubMed]

Marshall, J.

M. Abahussin, S. Hayes, N. E. Knox Cartwright, C. S. Kamma-Lorger, Y. Khan, J. Marshall, and K. M. Meek, “3D collagen orientation study of the human cornea using X-ray diffraction and femtosecond laser technology,” Invest. Ophthalmol. Vis. Sci. 50(11), 5159–5164 (2009).
[PubMed]

Martinez-Garcia, M. C.

N. Bekesi, P. Gallego-Muñoz, L. Ibarés-Frías, P. Perez-Merino, M. C. Martinez-Garcia, I. E. Kochevar, and S. Marcos, “Biomechanical Changes After In Vivo Collagen Cross-Linking With Rose Bengal-Green Light and Riboflavin-UVA,” Invest. Ophthalmol. Vis. Sci. 58(3), 1612–1620 (2017).
[PubMed]

Mazzotta, C.

A. Caporossi, C. Mazzotta, S. Baiocchi, and T. Caporossi, “Long-term results of riboflavin ultraviolet a corneal collagen cross-linking for keratoconus in Italy: the Siena eye cross study,” Am. J. Ophthalmol. 149(4), 585–593 (2010).
[PubMed]

McLean, J.

McQuaid, R.

R. McQuaid, J. Li, A. Cummings, M. Mrochen, and B. Vohnsen, “Second-harmonic reflection imaging of normal and accelerated corneal crosslinking using porcine corneas and the role of intraocular pressure,” Cornea 33(2), 125–130 (2014).
[PubMed]

Meek, K. M.

K. M. Meek and C. Knupp, “Corneal structure and transparency,” Prog. Retin. Eye Res. 49, 1–16 (2015).
[PubMed]

S. Hayes, C. S. Kamma-Lorger, C. Boote, R. D. Young, A. J. Quantock, A. Rost, Y. Khatib, J. Harris, N. Yagi, N. Terrill, and K. M. Meek, “The effect of riboflavin/UVA collagen cross-linking therapy on the structure and hydrodynamic behaviour of the ungulate and rabbit corneal stroma,” PLoS One 8(1), e52860 (2013).
[PubMed]

M. Abahussin, S. Hayes, N. E. Knox Cartwright, C. S. Kamma-Lorger, Y. Khan, J. Marshall, and K. M. Meek, “3D collagen orientation study of the human cornea using X-ray diffraction and femtosecond laser technology,” Invest. Ophthalmol. Vis. Sci. 50(11), 5159–5164 (2009).
[PubMed]

H. Aghamohammadzadeh, R. H. Newton, and K. M. Meek, “X-ray scattering used to map the preferred collagen orientation in the human cornea and limbus,” Structure 12(2), 249–256 (2004).
[PubMed]

Mega, Y.

Mehta, M. R.

Melki, S.

D. Cherfan, E. E. Verter, S. Melki, T. E. Gisel, F. J. Doyle, G. Scarcelli, S. H. Yun, R. W. Redmond, and I. E. Kochevar, “Collagen cross-linking using rose bengal and green light to increase corneal stiffness,” Invest. Ophthalmol. Vis. Sci. 54(5), 3426–3433 (2013).
[PubMed]

Mencucci, R.

S. Akhtar, T. Almubrad, I. Paladini, and R. Mencucci, “Keratoconus corneal architecture after riboflavin/ultraviolet A cross-linking: ultrastructural studies,” Mol. Vis. 19, 1526–1537 (2013).
[PubMed]

Merayo-Lloves, J.

S. Kling, L. Remon, A. Pérez-Escudero, J. Merayo-Lloves, and S. Marcos, “Corneal biomechanical changes after collagen cross-linking from porcine eye inflation experiments,” Invest. Ophthalmol. Vis. Sci. 51(8), 3961–3968 (2010).
[PubMed]

Merino, D.

Morishige, N.

N. Morishige, A. J. Wahlert, M. C. Kenney, D. J. Brown, K. Kawamoto, T. Chikama, T. Nishida, and J. V. Jester, “Second-harmonic imaging microscopy of normal human and keratoconus cornea,” Invest. Ophthalmol. Vis. Sci. 48(3), 1087–1094 (2007).
[PubMed]

N. Morishige, W. M. Petroll, T. Nishida, M. C. Kenney, and J. V. Jester, “Noninvasive corneal stromal collagen imaging using two-photon-generated second-harmonic signals,” J. Cataract Refract. Surg. 32(11), 1784–1791 (2006).
[PubMed]

Mrochen, M.

R. McQuaid, J. Li, A. Cummings, M. Mrochen, and B. Vohnsen, “Second-harmonic reflection imaging of normal and accelerated corneal crosslinking using porcine corneas and the role of intraocular pressure,” Cornea 33(2), 125–130 (2014).
[PubMed]

Müller, L. J.

L. J. Müller, E. Pels, and G. F. Vrensen, “The specific architecture of the anterior stroma accounts for maintenance of corneal curvature,” Br. J. Ophthalmol. 85(4), 437–443 (2001).
[PubMed]

Nadiarnykh, O.

B. L. Wen, M. A. Brewer, O. Nadiarnykh, J. Hocker, V. Singh, T. R. Mackie, and P. J. Campagnola, “Texture analysis applied to second harmonic generation image data for ovarian cancer classification,” J. Biomed. Opt. 19(9), 096007 (2014).
[PubMed]

Nakayasu, K.

K. Nakayasu, M. Tanaka, H. Konomi, and T. Hayashi, “Distribution of types I, II, III, IV and V collagen in normal and keratoconus corneas,” Ophthalmic Res. 18(1), 1–10 (1986).
[PubMed]

Newton, R. H.

H. Aghamohammadzadeh, R. H. Newton, and K. M. Meek, “X-ray scattering used to map the preferred collagen orientation in the human cornea and limbus,” Structure 12(2), 249–256 (2004).
[PubMed]

Nien, C.

J. V. Jester, M. Winkler, B. E. Jester, C. Nien, D. Chai, and D. J. Brown, “Evaluating corneal collagen organization using high-resolution nonlinear optical macroscopy,” Eye Contact Lens 36(5), 260–264 (2010).
[PubMed]

Nishida, T.

N. Morishige, A. J. Wahlert, M. C. Kenney, D. J. Brown, K. Kawamoto, T. Chikama, T. Nishida, and J. V. Jester, “Second-harmonic imaging microscopy of normal human and keratoconus cornea,” Invest. Ophthalmol. Vis. Sci. 48(3), 1087–1094 (2007).
[PubMed]

N. Morishige, W. M. Petroll, T. Nishida, M. C. Kenney, and J. V. Jester, “Noninvasive corneal stromal collagen imaging using two-photon-generated second-harmonic signals,” J. Cataract Refract. Surg. 32(11), 1784–1791 (2006).
[PubMed]

Palacios, R.

Paladini, I.

S. Akhtar, T. Almubrad, I. Paladini, and R. Mencucci, “Keratoconus corneal architecture after riboflavin/ultraviolet A cross-linking: ultrastructural studies,” Mol. Vis. 19, 1526–1537 (2013).
[PubMed]

Pels, E.

L. J. Müller, E. Pels, and G. F. Vrensen, “The specific architecture of the anterior stroma accounts for maintenance of corneal curvature,” Br. J. Ophthalmol. 85(4), 437–443 (2001).
[PubMed]

Pérez-Escudero, A.

S. Kling, L. Remon, A. Pérez-Escudero, J. Merayo-Lloves, and S. Marcos, “Corneal biomechanical changes after collagen cross-linking from porcine eye inflation experiments,” Invest. Ophthalmol. Vis. Sci. 51(8), 3961–3968 (2010).
[PubMed]

Perez-Merino, P.

N. Bekesi, P. Gallego-Muñoz, L. Ibarés-Frías, P. Perez-Merino, M. C. Martinez-Garcia, I. E. Kochevar, and S. Marcos, “Biomechanical Changes After In Vivo Collagen Cross-Linking With Rose Bengal-Green Light and Riboflavin-UVA,” Invest. Ophthalmol. Vis. Sci. 58(3), 1612–1620 (2017).
[PubMed]

Petroll, W. M.

N. Morishige, W. M. Petroll, T. Nishida, M. C. Kenney, and J. V. Jester, “Noninvasive corneal stromal collagen imaging using two-photon-generated second-harmonic signals,” J. Cataract Refract. Surg. 32(11), 1784–1791 (2006).
[PubMed]

Petsche, S. J.

M. Winkler, G. Shoa, Y. Xie, S. J. Petsche, P. M. Pinsky, T. Juhasz, D. J. Brown, and J. V. Jester, “Three-dimensional distribution of transverse collagen fibers in the anterior human corneal stroma,” Invest. Ophthalmol. Vis. Sci. 54(12), 7293–7301 (2013).
[PubMed]

Pham, D. T.

G. Wollensak, H. Aurich, D. T. Pham, and C. Wirbelauer, “Hydration behavior of porcine cornea crosslinked with riboflavin and ultraviolet A,” J. Cataract Refract. Surg. 33(3), 516–521 (2007).
[PubMed]

Pillunat, L. E.

M. Kohlhaas, E. Spoerl, T. Schilde, G. Unger, C. Wittig, and L. E. Pillunat, “Biomechanical evidence of the distribution of cross-links in corneas treated with riboflavin and ultraviolet A light,” J. Cataract Refract. Surg. 32(2), 279–283 (2006).
[PubMed]

Pinsky, P. M.

M. Winkler, G. Shoa, Y. Xie, S. J. Petsche, P. M. Pinsky, T. Juhasz, D. J. Brown, and J. V. Jester, “Three-dimensional distribution of transverse collagen fibers in the anterior human corneal stroma,” Invest. Ophthalmol. Vis. Sci. 54(12), 7293–7301 (2013).
[PubMed]

Poertner, R.

V. Lutz, M. Sattler, S. Gallinat, H. Wenck, R. Poertner, and F. Fischer, “Characterization of fibrillar collagen types using multi-dimensional multiphoton laser scanning microscopy,” Int. J. Cosmet. Sci. 34(2), 209–215 (2012).
[PubMed]

Quantock, A. J.

S. Hayes, C. S. Kamma-Lorger, C. Boote, R. D. Young, A. J. Quantock, A. Rost, Y. Khatib, J. Harris, N. Yagi, N. Terrill, and K. M. Meek, “The effect of riboflavin/UVA collagen cross-linking therapy on the structure and hydrodynamic behaviour of the ungulate and rabbit corneal stroma,” PLoS One 8(1), e52860 (2013).
[PubMed]

Rao, R. A.

Redmond, R. W.

D. Cherfan, E. E. Verter, S. Melki, T. E. Gisel, F. J. Doyle, G. Scarcelli, S. H. Yun, R. W. Redmond, and I. E. Kochevar, “Collagen cross-linking using rose bengal and green light to increase corneal stiffness,” Invest. Ophthalmol. Vis. Sci. 54(5), 3426–3433 (2013).
[PubMed]

Remon, L.

S. Kling, L. Remon, A. Pérez-Escudero, J. Merayo-Lloves, and S. Marcos, “Corneal biomechanical changes after collagen cross-linking from porcine eye inflation experiments,” Invest. Ophthalmol. Vis. Sci. 51(8), 3961–3968 (2010).
[PubMed]

Robitaille, M.

Rost, A.

S. Hayes, C. S. Kamma-Lorger, C. Boote, R. D. Young, A. J. Quantock, A. Rost, Y. Khatib, J. Harris, N. Yagi, N. Terrill, and K. M. Meek, “The effect of riboflavin/UVA collagen cross-linking therapy on the structure and hydrodynamic behaviour of the ungulate and rabbit corneal stroma,” PLoS One 8(1), e52860 (2013).
[PubMed]

Roth, S.

S. Roth and I. Freund, “Second harmonic generation in collagen,” J. Chem. Phys. 70, 1637–1643 (1979).

Ruberti, J.

Sattler, M.

V. Lutz, M. Sattler, S. Gallinat, H. Wenck, R. Poertner, and F. Fischer, “Characterization of fibrillar collagen types using multi-dimensional multiphoton laser scanning microscopy,” Int. J. Cosmet. Sci. 34(2), 209–215 (2012).
[PubMed]

Scarcelli, G.

D. Cherfan, E. E. Verter, S. Melki, T. E. Gisel, F. J. Doyle, G. Scarcelli, S. H. Yun, R. W. Redmond, and I. E. Kochevar, “Collagen cross-linking using rose bengal and green light to increase corneal stiffness,” Invest. Ophthalmol. Vis. Sci. 54(5), 3426–3433 (2013).
[PubMed]

Schilde, T.

M. Kohlhaas, E. Spoerl, T. Schilde, G. Unger, C. Wittig, and L. E. Pillunat, “Biomechanical evidence of the distribution of cross-links in corneas treated with riboflavin and ultraviolet A light,” J. Cataract Refract. Surg. 32(2), 279–283 (2006).
[PubMed]

Seiler, T.

T. Seiler and F. Hafezi, “Corneal cross-linking-induced stromal demarcation line,” Cornea 25(9), 1057–1059 (2006).
[PubMed]

G. Wollensak, E. Spoerl, M. Wilsch, and T. Seiler, “Keratocyte apoptosis after corneal collagen cross-linking using riboflavin/UVA treatment,” Cornea 23(1), 43–49 (2004).
[PubMed]

G. Wollensak, E. Spoerl, and T. Seiler, “Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus,” Am. J. Ophthalmol. 135(5), 620–627 (2003).
[PubMed]

Shoa, G.

M. Winkler, G. Shoa, Y. Xie, S. J. Petsche, P. M. Pinsky, T. Juhasz, D. J. Brown, and J. V. Jester, “Three-dimensional distribution of transverse collagen fibers in the anterior human corneal stroma,” Invest. Ophthalmol. Vis. Sci. 54(12), 7293–7301 (2013).
[PubMed]

Singh, V.

B. L. Wen, M. A. Brewer, O. Nadiarnykh, J. Hocker, V. Singh, T. R. Mackie, and P. J. Campagnola, “Texture analysis applied to second harmonic generation image data for ovarian cancer classification,” J. Biomed. Opt. 19(9), 096007 (2014).
[PubMed]

Spoerl, E.

M. Kohlhaas, E. Spoerl, T. Schilde, G. Unger, C. Wittig, and L. E. Pillunat, “Biomechanical evidence of the distribution of cross-links in corneas treated with riboflavin and ultraviolet A light,” J. Cataract Refract. Surg. 32(2), 279–283 (2006).
[PubMed]

G. Wollensak, E. Spoerl, M. Wilsch, and T. Seiler, “Keratocyte apoptosis after corneal collagen cross-linking using riboflavin/UVA treatment,” Cornea 23(1), 43–49 (2004).
[PubMed]

G. Wollensak, E. Spoerl, and T. Seiler, “Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus,” Am. J. Ophthalmol. 135(5), 620–627 (2003).
[PubMed]

Tanaka, M.

K. Nakayasu, M. Tanaka, H. Konomi, and T. Hayashi, “Distribution of types I, II, III, IV and V collagen in normal and keratoconus corneas,” Ophthalmic Res. 18(1), 1–10 (1986).
[PubMed]

Terrill, N.

S. Hayes, C. S. Kamma-Lorger, C. Boote, R. D. Young, A. J. Quantock, A. Rost, Y. Khatib, J. Harris, N. Yagi, N. Terrill, and K. M. Meek, “The effect of riboflavin/UVA collagen cross-linking therapy on the structure and hydrodynamic behaviour of the ungulate and rabbit corneal stroma,” PLoS One 8(1), e52860 (2013).
[PubMed]

Toussaint, K. C.

Tsai, H. F.

A. Ghazaryan, H. F. Tsai, G. Hayrapetyan, W. L. Chen, Y. F. Chen, M. Y. Jeong, C. S. Kim, S. J. Chen, and C. Y. Dong, “Analysis of collagen fiber domain organization by Fourier second harmonic generation microscopy,” J. Biomed. Opt. 18(3), 31105 (2013).
[PubMed]

Unger, G.

M. Kohlhaas, E. Spoerl, T. Schilde, G. Unger, C. Wittig, and L. E. Pillunat, “Biomechanical evidence of the distribution of cross-links in corneas treated with riboflavin and ultraviolet A light,” J. Cataract Refract. Surg. 32(2), 279–283 (2006).
[PubMed]

Ushiki, T.

Y. Komai and T. Ushiki, “The three-dimensional organization of collagen fibrils in the human cornea and sclera,” Invest. Ophthalmol. Vis. Sci. 32(8), 2244–2258 (1991).
[PubMed]

Verter, E. E.

D. Cherfan, E. E. Verter, S. Melki, T. E. Gisel, F. J. Doyle, G. Scarcelli, S. H. Yun, R. W. Redmond, and I. E. Kochevar, “Collagen cross-linking using rose bengal and green light to increase corneal stiffness,” Invest. Ophthalmol. Vis. Sci. 54(5), 3426–3433 (2013).
[PubMed]

Vohnsen, B.

R. McQuaid, J. Li, A. Cummings, M. Mrochen, and B. Vohnsen, “Second-harmonic reflection imaging of normal and accelerated corneal crosslinking using porcine corneas and the role of intraocular pressure,” Cornea 33(2), 125–130 (2014).
[PubMed]

Vrensen, G. F.

L. J. Müller, E. Pels, and G. F. Vrensen, “The specific architecture of the anterior stroma accounts for maintenance of corneal curvature,” Br. J. Ophthalmol. 85(4), 437–443 (2001).
[PubMed]

Wahlert, A. J.

N. Morishige, A. J. Wahlert, M. C. Kenney, D. J. Brown, K. Kawamoto, T. Chikama, T. Nishida, and J. V. Jester, “Second-harmonic imaging microscopy of normal human and keratoconus cornea,” Invest. Ophthalmol. Vis. Sci. 48(3), 1087–1094 (2007).
[PubMed]

Wen, B. L.

B. L. Wen, M. A. Brewer, O. Nadiarnykh, J. Hocker, V. Singh, T. R. Mackie, and P. J. Campagnola, “Texture analysis applied to second harmonic generation image data for ovarian cancer classification,” J. Biomed. Opt. 19(9), 096007 (2014).
[PubMed]

Wenck, H.

V. Lutz, M. Sattler, S. Gallinat, H. Wenck, R. Poertner, and F. Fischer, “Characterization of fibrillar collagen types using multi-dimensional multiphoton laser scanning microscopy,” Int. J. Cosmet. Sci. 34(2), 209–215 (2012).
[PubMed]

Wilsch, M.

G. Wollensak, E. Spoerl, M. Wilsch, and T. Seiler, “Keratocyte apoptosis after corneal collagen cross-linking using riboflavin/UVA treatment,” Cornea 23(1), 43–49 (2004).
[PubMed]

Winkler, M.

M. Winkler, G. Shoa, Y. Xie, S. J. Petsche, P. M. Pinsky, T. Juhasz, D. J. Brown, and J. V. Jester, “Three-dimensional distribution of transverse collagen fibers in the anterior human corneal stroma,” Invest. Ophthalmol. Vis. Sci. 54(12), 7293–7301 (2013).
[PubMed]

J. V. Jester, M. Winkler, B. E. Jester, C. Nien, D. Chai, and D. J. Brown, “Evaluating corneal collagen organization using high-resolution nonlinear optical macroscopy,” Eye Contact Lens 36(5), 260–264 (2010).
[PubMed]

Wirbelauer, C.

G. Wollensak, H. Aurich, D. T. Pham, and C. Wirbelauer, “Hydration behavior of porcine cornea crosslinked with riboflavin and ultraviolet A,” J. Cataract Refract. Surg. 33(3), 516–521 (2007).
[PubMed]

Wittig, C.

M. Kohlhaas, E. Spoerl, T. Schilde, G. Unger, C. Wittig, and L. E. Pillunat, “Biomechanical evidence of the distribution of cross-links in corneas treated with riboflavin and ultraviolet A light,” J. Cataract Refract. Surg. 32(2), 279–283 (2006).
[PubMed]

Wollensak, G.

G. Wollensak and E. Iomdina, “Biomechanical and histological changes after corneal crosslinking with and without epithelial debridement,” J. Cataract Refract. Surg. 35(3), 540–546 (2009).
[PubMed]

G. Wollensak, H. Aurich, D. T. Pham, and C. Wirbelauer, “Hydration behavior of porcine cornea crosslinked with riboflavin and ultraviolet A,” J. Cataract Refract. Surg. 33(3), 516–521 (2007).
[PubMed]

G. Wollensak, E. Spoerl, M. Wilsch, and T. Seiler, “Keratocyte apoptosis after corneal collagen cross-linking using riboflavin/UVA treatment,” Cornea 23(1), 43–49 (2004).
[PubMed]

G. Wollensak, E. Spoerl, and T. Seiler, “Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus,” Am. J. Ophthalmol. 135(5), 620–627 (2003).
[PubMed]

Xie, Y.

M. Winkler, G. Shoa, Y. Xie, S. J. Petsche, P. M. Pinsky, T. Juhasz, D. J. Brown, and J. V. Jester, “Three-dimensional distribution of transverse collagen fibers in the anterior human corneal stroma,” Invest. Ophthalmol. Vis. Sci. 54(12), 7293–7301 (2013).
[PubMed]

Yagi, N.

S. Hayes, C. S. Kamma-Lorger, C. Boote, R. D. Young, A. J. Quantock, A. Rost, Y. Khatib, J. Harris, N. Yagi, N. Terrill, and K. M. Meek, “The effect of riboflavin/UVA collagen cross-linking therapy on the structure and hydrodynamic behaviour of the ungulate and rabbit corneal stroma,” PLoS One 8(1), e52860 (2013).
[PubMed]

Young, R. D.

S. Hayes, C. S. Kamma-Lorger, C. Boote, R. D. Young, A. J. Quantock, A. Rost, Y. Khatib, J. Harris, N. Yagi, N. Terrill, and K. M. Meek, “The effect of riboflavin/UVA collagen cross-linking therapy on the structure and hydrodynamic behaviour of the ungulate and rabbit corneal stroma,” PLoS One 8(1), e52860 (2013).
[PubMed]

Yun, S. H.

D. Cherfan, E. E. Verter, S. Melki, T. E. Gisel, F. J. Doyle, G. Scarcelli, S. H. Yun, R. W. Redmond, and I. E. Kochevar, “Collagen cross-linking using rose bengal and green light to increase corneal stiffness,” Invest. Ophthalmol. Vis. Sci. 54(5), 3426–3433 (2013).
[PubMed]

Zareian, R.

Am. J. Ophthalmol. (2)

A. Caporossi, C. Mazzotta, S. Baiocchi, and T. Caporossi, “Long-term results of riboflavin ultraviolet a corneal collagen cross-linking for keratoconus in Italy: the Siena eye cross study,” Am. J. Ophthalmol. 149(4), 585–593 (2010).
[PubMed]

G. Wollensak, E. Spoerl, and T. Seiler, “Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus,” Am. J. Ophthalmol. 135(5), 620–627 (2003).
[PubMed]

Appl. Opt. (1)

Biomed. Opt. Express (3)

Bone (1)

R. Ambekar, M. Chittenden, I. Jasiuk, and K. C. Toussaint., “Quantitative second-harmonic generation microscopy for imaging porcine cortical bone: comparison to SEM and its potential to investigate age-related changes,” Bone 50(3), 643–650 (2012).
[PubMed]

Br. J. Ophthalmol. (1)

L. J. Müller, E. Pels, and G. F. Vrensen, “The specific architecture of the anterior stroma accounts for maintenance of corneal curvature,” Br. J. Ophthalmol. 85(4), 437–443 (2001).
[PubMed]

Cornea (4)

R. McQuaid, J. Li, A. Cummings, M. Mrochen, and B. Vohnsen, “Second-harmonic reflection imaging of normal and accelerated corneal crosslinking using porcine corneas and the role of intraocular pressure,” Cornea 33(2), 125–130 (2014).
[PubMed]

J. M. Bueno, E. J. Gualda, and P. Artal, “Analysis of corneal stroma organization with wavefront optimized nonlinear microscopy,” Cornea 30(6), 692–701 (2011).
[PubMed]

T. Seiler and F. Hafezi, “Corneal cross-linking-induced stromal demarcation line,” Cornea 25(9), 1057–1059 (2006).
[PubMed]

G. Wollensak, E. Spoerl, M. Wilsch, and T. Seiler, “Keratocyte apoptosis after corneal collagen cross-linking using riboflavin/UVA treatment,” Cornea 23(1), 43–49 (2004).
[PubMed]

Eye Contact Lens (1)

J. V. Jester, M. Winkler, B. E. Jester, C. Nien, D. Chai, and D. J. Brown, “Evaluating corneal collagen organization using high-resolution nonlinear optical macroscopy,” Eye Contact Lens 36(5), 260–264 (2010).
[PubMed]

Int. J. Cosmet. Sci. (1)

V. Lutz, M. Sattler, S. Gallinat, H. Wenck, R. Poertner, and F. Fischer, “Characterization of fibrillar collagen types using multi-dimensional multiphoton laser scanning microscopy,” Int. J. Cosmet. Sci. 34(2), 209–215 (2012).
[PubMed]

Invest. Ophthalmol. Vis. Sci. (8)

S. Kling, L. Remon, A. Pérez-Escudero, J. Merayo-Lloves, and S. Marcos, “Corneal biomechanical changes after collagen cross-linking from porcine eye inflation experiments,” Invest. Ophthalmol. Vis. Sci. 51(8), 3961–3968 (2010).
[PubMed]

N. Bekesi, P. Gallego-Muñoz, L. Ibarés-Frías, P. Perez-Merino, M. C. Martinez-Garcia, I. E. Kochevar, and S. Marcos, “Biomechanical Changes After In Vivo Collagen Cross-Linking With Rose Bengal-Green Light and Riboflavin-UVA,” Invest. Ophthalmol. Vis. Sci. 58(3), 1612–1620 (2017).
[PubMed]

D. Cherfan, E. E. Verter, S. Melki, T. E. Gisel, F. J. Doyle, G. Scarcelli, S. H. Yun, R. W. Redmond, and I. E. Kochevar, “Collagen cross-linking using rose bengal and green light to increase corneal stiffness,” Invest. Ophthalmol. Vis. Sci. 54(5), 3426–3433 (2013).
[PubMed]

N. Bekesi, I. E. Kochevar, and S. Marcos, “Corneal Biomechanical Response Following Collagen Cross-Linking With Rose Bengal-Green Light and Riboflavin-UVA,” Invest. Ophthalmol. Vis. Sci. 57(3), 992–1001 (2016).
[PubMed]

N. Morishige, A. J. Wahlert, M. C. Kenney, D. J. Brown, K. Kawamoto, T. Chikama, T. Nishida, and J. V. Jester, “Second-harmonic imaging microscopy of normal human and keratoconus cornea,” Invest. Ophthalmol. Vis. Sci. 48(3), 1087–1094 (2007).
[PubMed]

Y. Komai and T. Ushiki, “The three-dimensional organization of collagen fibrils in the human cornea and sclera,” Invest. Ophthalmol. Vis. Sci. 32(8), 2244–2258 (1991).
[PubMed]

M. Abahussin, S. Hayes, N. E. Knox Cartwright, C. S. Kamma-Lorger, Y. Khan, J. Marshall, and K. M. Meek, “3D collagen orientation study of the human cornea using X-ray diffraction and femtosecond laser technology,” Invest. Ophthalmol. Vis. Sci. 50(11), 5159–5164 (2009).
[PubMed]

M. Winkler, G. Shoa, Y. Xie, S. J. Petsche, P. M. Pinsky, T. Juhasz, D. J. Brown, and J. V. Jester, “Three-dimensional distribution of transverse collagen fibers in the anterior human corneal stroma,” Invest. Ophthalmol. Vis. Sci. 54(12), 7293–7301 (2013).
[PubMed]

J. Biomed. Opt. (2)

B. L. Wen, M. A. Brewer, O. Nadiarnykh, J. Hocker, V. Singh, T. R. Mackie, and P. J. Campagnola, “Texture analysis applied to second harmonic generation image data for ovarian cancer classification,” J. Biomed. Opt. 19(9), 096007 (2014).
[PubMed]

A. Ghazaryan, H. F. Tsai, G. Hayrapetyan, W. L. Chen, Y. F. Chen, M. Y. Jeong, C. S. Kim, S. J. Chen, and C. Y. Dong, “Analysis of collagen fiber domain organization by Fourier second harmonic generation microscopy,” J. Biomed. Opt. 18(3), 31105 (2013).
[PubMed]

J. Cataract Refract. Surg. (4)

N. Morishige, W. M. Petroll, T. Nishida, M. C. Kenney, and J. V. Jester, “Noninvasive corneal stromal collagen imaging using two-photon-generated second-harmonic signals,” J. Cataract Refract. Surg. 32(11), 1784–1791 (2006).
[PubMed]

M. Kohlhaas, E. Spoerl, T. Schilde, G. Unger, C. Wittig, and L. E. Pillunat, “Biomechanical evidence of the distribution of cross-links in corneas treated with riboflavin and ultraviolet A light,” J. Cataract Refract. Surg. 32(2), 279–283 (2006).
[PubMed]

G. Wollensak and E. Iomdina, “Biomechanical and histological changes after corneal crosslinking with and without epithelial debridement,” J. Cataract Refract. Surg. 35(3), 540–546 (2009).
[PubMed]

G. Wollensak, H. Aurich, D. T. Pham, and C. Wirbelauer, “Hydration behavior of porcine cornea crosslinked with riboflavin and ultraviolet A,” J. Cataract Refract. Surg. 33(3), 516–521 (2007).
[PubMed]

J. Chem. Phys. (1)

S. Roth and I. Freund, “Second harmonic generation in collagen,” J. Chem. Phys. 70, 1637–1643 (1979).

J. Pathol. Inform. (1)

J. S. Bredfeldt, Y. Liu, M. W. Conklin, P. J. Keely, T. R. Mackie, and K. W. Eliceiri, “Automated quantification of aligned collagen for human breast carcinoma prognosis,” J. Pathol. Inform. 5(1), 28 (2014).
[PubMed]

Mol. Vis. (1)

S. Akhtar, T. Almubrad, I. Paladini, and R. Mencucci, “Keratoconus corneal architecture after riboflavin/ultraviolet A cross-linking: ultrastructural studies,” Mol. Vis. 19, 1526–1537 (2013).
[PubMed]

Ophthalmic Res. (1)

K. Nakayasu, M. Tanaka, H. Konomi, and T. Hayashi, “Distribution of types I, II, III, IV and V collagen in normal and keratoconus corneas,” Ophthalmic Res. 18(1), 1–10 (1986).
[PubMed]

Opt. Express (2)

Opt. Lett. (1)

PLoS One (1)

S. Hayes, C. S. Kamma-Lorger, C. Boote, R. D. Young, A. J. Quantock, A. Rost, Y. Khatib, J. Harris, N. Yagi, N. Terrill, and K. M. Meek, “The effect of riboflavin/UVA collagen cross-linking therapy on the structure and hydrodynamic behaviour of the ungulate and rabbit corneal stroma,” PLoS One 8(1), e52860 (2013).
[PubMed]

Prog. Retin. Eye Res. (1)

K. M. Meek and C. Knupp, “Corneal structure and transparency,” Prog. Retin. Eye Res. 49, 1–16 (2015).
[PubMed]

Structure (1)

H. Aghamohammadzadeh, R. H. Newton, and K. M. Meek, “X-ray scattering used to map the preferred collagen orientation in the human cornea and limbus,” Structure 12(2), 249–256 (2004).
[PubMed]

Other (1)

R. C. Gonzalez and R. E. Woods, Digital Image Processing (Prentice Hall, 2002).

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Figures (10)

Fig. 1
Fig. 1 Sketch of two-photon microscope setup. The pulsed source was a MaiTai Ti-Sapphire femtosecond laser. The beam position and angle were controlled by a pair of scanning galvanometer mirrors (SGM), and the beam passed through a pair of lenses (L) before entering the focusing objective (F. Obj.) in order to overfill the entrance pupil of the objective. SHG was collected in the forward direction by a collection objective (C.Obj.) and was separated from the excitation wavelength by a pair of dichroic filters (F). SHG signal was single photon counted with a photomultiplier tube (PMT), and a National Instruments PCI card (NI-PCI). The SGM were also controlled with the same PCI card. A beam block (BB) was employed to absorb excess excitation light filtered from the SHG signal.
Fig. 2
Fig. 2 Image Processing Procedure. The edges of the collagen fibers in the raw images (a) were sharpened (b) and a Hanning window (c) was applied to the image to produce a windowed image (d), which concentrates analysis on the central fibers. The windowed image was Fourier transformed in two dimensions (e) and the resulting transformed image was translated to a polar representation (f), where anti-biasing windows were applied (points within 90° ± 2.8° and 270° ± 2.8° on the polar plot were excluded). The polar plot was then divided into 10° windows (g) (30° shown in (g) for easier visibility to the reader) and the points in each window were used to calculate the order coefficient (h). The white bars in (a), (b), and (d) represent a distance of 60 μm.
Fig. 3
Fig. 3 Order coefficient vs depth for four z-stacks in the paraformaldehyde treated cornea.
Fig. 4
Fig. 4 Anterior-to-posterior and posterior-to-anterior order coefficient averages of untreated eyes (n = 3). Averages were taken over 100 μm depth slices (number of images averaged per point n = 150) and the same samples were used for the anterior-posterior and posterior-anterior image stacks. Error bars here represent the variance of the average order coefficient value at each point.
Fig. 5
Fig. 5 Images of collagen from the anterior ((a) and (b)), intermediate (c), and posterior (d) of a de-epithelialized eye. The anterior images were collected at 10 μm and 140 μm below that anterior stromal surface, the intermediate 740 μm, and the posterior 1015 μm. White bars represent 50 μm. All images presented here are from an anterior to posterior z-scan and the contrast was artificially increased for the images presented here to increase fiber visibility for the reader.
Fig. 6
Fig. 6 SHG images of stromal collagen fibers ((a), (c), and (e)) with different treatments and corresponding Fourier transforms ((b), (d), and (f)). The untreated ((a) and (b)) and riboflavin only ((c) and (d)) treatments showed more fibers with crimps and the Fourier transform was spread across more windows than the UVX case ((e) and (f)). The order coefficient values of the individual images were; 0.357 for the untreated, 0.369 for the riboflavin only, and 0.791 for the UVX cornea. Images have been rotated by 90° and contrast has been enhanced so the reader can more clearly see the collagen fibers. All three images were taken 108 μm below the anterior surface of the stroma. The white bars represent a distance of 50 μm.
Fig. 7
Fig. 7 Average order coefficient vs. depth. Order coefficient values are averaged over 20 μm sections across all eyes of the same treatment type, untreated (n = 8), riboflavin only (n = 8), and UVX (n = 8) eyes. Error bars represent the variance in order coefficient over the 20 μm sections.
Fig. 8
Fig. 8 Distribution of the order coefficient across the anterior, intermediate, and posterior section of the stroma across all eyes of the same treatment type, for de-epithelized (n = 8), riboflavin only (n = 8), and UVX (n = 8) eyes. The total number of images used in each graph is listed in Table 1. Fits of the normal distribution are displayed (red line) and the mean value and variance are displayed in Fig. 9. The mean value for each range ((a), (b), and (c), first 100 μm; (d), (e), and (f), 100-400 μm range; (g), (h), and (i), 400-700 μm range) and treatment ((a), (d), and (g), untreated; (b), (e), and (h), Riboflavin only; (c), (f), and (i), UVX) is marked with a dashed black line.
Fig. 9
Fig. 9 Order coefficient averages of corneal treatments. The number of images used to compute each average in the separate depths regions and treatments (averages computed across all samples in each treatment, untreated n = 8, riboflavin only n = 8, UVX n = 8) is listed in Table 1. Black bars represent the variance.
Fig. 10
Fig. 10 Ideal examples of order and disorder with Fourier transforms.

Tables (1)

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Table 1 Total number of images used for each treatment type and depth range.

Equations (1)

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OrderCoefficient= i=1 N windows ( M i M total 1 N windows ) 2 2 ( 1 2 1 N windows ) 2 +( N windows 2 ) ( 1 N windows ) 2 .

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