Abstract

Elastic light scattering spectroscopy (ELSS) has been proven a powerful method in measuring tissue structures with exquisite nanoscale sensitivity. However, ELSS contrast in the living human retina has been relatively underexplored, primarily due to the lack of imaging tools with a large spectral bandwidth. Here, we report a simple all fiber-based setup to implement dual-channel visible and near infrared (NIR) optical coherence tomography (vnOCT) for human retinal imaging, bridging over a 300nm spectral gap. Remarkably, the fiber components in our vnOCT system support single-mode propagation for both visible and NIR light, both of which maintain excellent interference efficiencies with fringe visibility of 97% and 90%, respectively. The longitudinal chromatic aberration from the eye is corrected by a custom-designed achromatizing lens. The elegant fiber-based design enables simultaneous imaging for both channels and allows comprehensive ELSS analysis on several important anatomical layers, including nerve fiber layer, outer segment of the photoreceptors and retinal pigment epithelium. This vnOCT platform and method of ELSS analysis open new opportunities in understanding structure-function relationship in the human retina and in exploring new biomarkers for retinal diseases.

© 2018 Optical Society of America under the terms of the OSA Open Access Publishing Agreement

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2018 (2)

2017 (8)

S. P. Chong, M. Bernucci, H. Radhakrishnan, and V. J. Srinivasan, “Structural and functional human retinal imaging with a fiber-based visible light OCT ophthalmoscope,” Biomed. Opt. Express 8(1), 323–337 (2017).
[Crossref] [PubMed]

W. Song, L. Zhang, S. Ness, and J. Yi, “Wavelength-dependent optical properties of melanosomes in retinal pigmented epithelium and their changes with melanin bleaching: a numerical study,” Biomed. Opt. Express 8(9), 3966–3980 (2017).
[Crossref] [PubMed]

A. Lichtenegger, D. J. Harper, M. Augustin, P. Eugui, M. Muck, J. Gesperger, C. K. Hitzenberger, A. Woehrer, and B. Baumann, “Spectroscopic imaging with spectral domain visible light optical coherence microscopy in Alzheimer’s disease brain samples,” Biomed. Opt. Express 8(9), 4007–4025 (2017).
[Crossref] [PubMed]

J. Kwon, M. Kim, H. Park, B.-M. Kang, Y. Jo, J.-H. Kim, O. James, S.-H. Yun, S.-G. Kim, M. Suh, and M. Choi, “Label-free nanoscale optical metrology on myelinated axons in vivo,” Nat. Commun. 8(1), 1832 (2017).
[Crossref] [PubMed]

Z. Liu, K. Kurokawa, F. Zhang, J. J. Lee, and D. T. Miller, “Imaging and quantifying ganglion cells and other transparent neurons in the living human retina,” Proc. Natl. Acad. Sci. U.S.A. 114(48), 12803–12808 (2017).
[Crossref] [PubMed]

X. Shu, L. Beckmann, and H. Zhang, “Visible-light optical coherence tomography: a review,” J. Biomed. Opt. 22(12), 1–14 (2017).
[Crossref] [PubMed]

R. Liu, G. Spicer, S. Chen, H. F. Zhang, J. Yi, and V. Backman, “Theoretical model for optical oximetry at the capillary level: exploring hemoglobin oxygen saturation through backscattering of single red blood cells,” J. Biomed. Opt. 22(2), 025002 (2017).
[Crossref] [PubMed]

X.-R. Huang, R. W. Knighton, Y. Z. Spector, J. Qiao, W. Kong, and Q. Zhao, “Reflectance Spectrum and Birefringence of the Retinal Nerve Fiber Layer With Hypertensive Damage of Axonal Cytoskeleton,” Invest. Ophthalmol. Vis. Sci. 58(4), 2118–2129 (2017).
[Crossref] [PubMed]

2016 (3)

J. Yi, Z. Puyang, L. Feng, L. Duan, P. Liang, V. Backman, X. Liu, and H. F. Zhang, “Optical Detection of Early Damage in Retinal Ganglion Cells in a Mouse Model of Partial Optic Nerve Crush Injury,” Invest. Ophthalmol. Vis. Sci. 57(13), 5665–5671 (2016).
[Crossref] [PubMed]

S. Chen, X. Shu, J. Yi, A. Fawzi, and H. F. Zhang, “Dual-band optical coherence tomography using a single supercontinuum laser source,” J. Biomed. Opt. 21(6), 066013 (2016).
[Crossref] [PubMed]

F. LaRocca, D. Nankivil, T. DuBose, C. A. Toth, S. Farsiu, and J. A. Izatt, “In vivo cellular-resolution retinal imaging in infants and children using an ultracompact handheld probe,” Nat. Photonics 10(9), 580–584 (2016).
[Crossref] [PubMed]

2015 (2)

S. Chen, J. Yi, W. Liu, V. Backman, and H. F. Zhang, “Monte Carlo Investigation of Optical Coherence Tomography Retinal Oximetry,” IEEE Trans. Biomed. Eng. 62(9), 2308–2315 (2015).
[Crossref] [PubMed]

J. Yi, S. Chen, X. Shu, A. A. Fawzi, and H. F. Zhang, “Human retinal imaging using visible-light optical coherence tomography guided by scanning laser ophthalmoscopy,” Biomed. Opt. Express 6(10), 3701–3713 (2015).
[Crossref] [PubMed]

2014 (6)

2013 (5)

L. Cherkezyan, I. Çapoğlu, H. Subramanian, J. D. Rogers, D. Damania, A. Taflove, and V. Backman, “Interferometric Spectroscopy of Scattered Light Can Quantify the Statistics of Subdiffractional Refractive-Index Fluctuations,” Phys. Rev. Lett. 111(3), 033903 (2013).
[Crossref] [PubMed]

J. D. Rogers, A. J. Radosevich, J. Yi, and V. Backman, “Modeling Light Scattering in Tissue as Continuous Random Media Using a Versatile Refractive Index Correlation Function,” IEEE J. Sel. Top. Quantum Electron. 20(2), 7000514 (2013).
[PubMed]

J. Yi, A. J. Radosevich, J. D. Rogers, S. C. P. Norris, İ. R. Çapoğlu, A. Taflove, and V. Backman, “Can OCT be sensitive to nanoscale structural alterations in biological tissue?” Opt. Express 21(7), 9043–9059 (2013).
[Crossref] [PubMed]

J. Yi, Q. Wei, W. Liu, V. Backman, and H. F. Zhang, “Visible-light optical coherence tomography for retinal oximetry,” Opt. Lett. 38(11), 1796–1798 (2013).
[Crossref] [PubMed]

C. P. Fleming, J. Eckert, E. F. Halpern, J. A. Gardecki, and G. J. Tearney, “Depth resolved detection of lipid using spectroscopic optical coherence tomography,” Biomed. Opt. Express 4(8), 1269–1284 (2013).
[Crossref] [PubMed]

2012 (5)

2011 (6)

X.-R. Huang, Y. Zhou, W. Kong, and R. W. Knighton, “Reflectance Decreases before Thickness Changes in the Retinal Nerve Fiber Layer in Glaucomatous Retinas,” Invest. Ophthalmol. Vis. Sci. 52(9), 6737–6742 (2011).
[Crossref] [PubMed]

N. G. Terry, Y. Zhu, M. T. Rinehart, W. J. Brown, S. C. Gebhart, S. Bright, E. Carretta, C. G. Ziefle, M. Panjehpour, J. Galanko, R. D. Madanick, E. S. Dellon, D. Trembath, A. Bennett, J. R. Goldblum, B. F. Overholt, J. T. Woosley, N. J. Shaheen, and A. Wax, “Detection of Dysplasia in Barrett’s Esophagus With In Vivo Depth-Resolved Nuclear Morphology Measurements,” Gastroenterology 140(1), 42–50 (2011).
[Crossref] [PubMed]

F. E. Robles, C. Wilson, G. Grant, and A. Wax, “Molecular imaging true-colour spectroscopic optical coherence tomography,” Nat. Photonics 5(12), 744–747 (2011).
[Crossref] [PubMed]

A. Dubra and Y. Sulai, “Reflective afocal broadband adaptive optics scanning ophthalmoscope,” Biomed. Opt. Express 2(6), 1757–1768 (2011).
[Crossref] [PubMed]

A. Dubra, Y. Sulai, J. L. Norris, R. F. Cooper, A. M. Dubis, D. R. Williams, and J. Carroll, “Noninvasive imaging of the human rod photoreceptor mosaic using a confocal adaptive optics scanning ophthalmoscope,” Biomed. Opt. Express 2(7), 1864–1876 (2011).
[Crossref] [PubMed]

X. Zhang, J. Hu, R. W. Knighton, X.-R. Huang, C. A. Puliafito, and S. Jiao, “Dual-band spectral-domain optical coherence tomography for in vivo imaging the spectral contrasts of the retinal nerve fiber layer,” Opt. Express 19(20), 19653–19659 (2011).
[Crossref] [PubMed]

2010 (3)

S. J. Chiu, X. T. Li, P. Nicholas, C. A. Toth, J. A. Izatt, and S. Farsiu, “Automatic segmentation of seven retinal layers in SDOCT images congruent with expert manual segmentation,” Opt. Express 18(18), 19413–19428 (2010).
[Crossref] [PubMed]

L. Qiu, D. K. Pleskow, R. Chuttani, E. Vitkin, J. Leyden, N. Ozden, S. Itani, L. Guo, A. Sacks, J. D. Goldsmith, M. D. Modell, E. B. Hanlon, I. Itzkan, and L. T. Perelman, “Multispectral scanning during endoscopy guides biopsy of dysplasia in Barrett’s esophagus,” Nat. Med. 16(5), 603–606 (2010).
[Crossref] [PubMed]

N. N. Boustany, S. A. Boppart, and V. Backman, “Microscopic Imaging and Spectroscopy with Scattered Light,” Annu. Rev. Biomed. Eng. 12(1), 285–314 (2010).
[Crossref] [PubMed]

2009 (3)

Y. Zhu, T. Fearn, G. Mackenzie, I. J. Bigio, S. G. Bown, L. B. Lovat, B. Clark, and J. M. Dunn, “Elastic scattering spectroscopy for detection of cancer risk in Barrett’s esophagus: experimental and clinical validation of error removal by orthogonal subtraction for increasing accuracy,” J. Biomed. Opt. 14, 044022 (2009).

M. K. Garvin, M. D. Abràmoff, X. Wu, S. R. Russell, T. L. Burns, and M. Sonka, “Automated 3-D Intraretinal Layer Segmentation of Macular Spectral-Domain Optical Coherence Tomography Images,” IEEE Trans. Med. Imaging 28(9), 1436–1447 (2009).
[Crossref] [PubMed]

A. Mishra, A. Wong, K. Bizheva, and D. A. Clausi, “Intra-retinal layer segmentation in optical coherence tomography images,” Opt. Express 17(26), 23719–23728 (2009).
[Crossref] [PubMed]

2008 (3)

R. J. Zawadzki, B. Cense, Y. Zhang, S. S. Choi, D. T. Miller, and J. S. Werner, “Ultrahigh-resolution optical coherence tomography with monochromatic and chromatic aberration correction,” Opt. Express 16(11), 8126–8143 (2008).
[Crossref] [PubMed]

A. Hajiaboli and M. Popovic, “FDTD Analysis of Light Propagation in the Human Photoreceptor Cells,” IEEE Trans. Magn. 44(6), 1430–1433 (2008).
[Crossref]

A. Hajiaboli and M. Popovic, “Human Retinal Photoreceptors: Electrodynamic Model of Optical Microfilters,” IEEE J. Sel. Top. Quantum Electron. 14, 126–130 (2008).
[Crossref]

2007 (2)

I. Itzkan, L. Qiu, H. Fang, M. M. Zaman, E. Vitkin, I. C. Ghiran, S. Salahuddin, M. Modell, C. Andersson, L. M. Kimerer, P. B. Cipolloni, K.-H. Lim, S. D. Freedman, I. Bigio, B. P. Sachs, E. B. Hanlon, and L. T. Perelman, “Confocal light absorption and scattering spectroscopic microscopy monitors organelles in live cells with no exogenous labels,” Proc. Natl. Acad. Sci. U.S.A. 104(44), 17255–17260 (2007).
[Crossref] [PubMed]

F. C. Delori, R. H. Webb, D. H. Sliney, and American National Standards Institute, “Maximum permissible exposures for ocular safety (ANSI 2000), with emphasis on ophthalmic devices,” J. Opt. Soc. Am. A 24(5), 1250–1265 (2007).
[Crossref] [PubMed]

2006 (3)

M. Hunter, V. Backman, G. Popescu, M. Kalashnikov, C. W. Boone, A. Wax, V. Gopal, K. Badizadegan, G. D. Stoner, and M. S. Feld, “Tissue Self-Affinity and Polarized Light Scattering in the Born Approximation: A New Model for Precancer Detection,” Phys. Rev. Lett. 97(13), 138102 (2006).
[Crossref] [PubMed]

C. N. Keilhauer and F. C. Delori, “Near-Infrared Autofluorescence Imaging of the Fundus: Visualization of Ocular Melanin,” Invest. Ophthalmol. Vis. Sci. 47(8), 3556–3564 (2006).
[Crossref] [PubMed]

X.-R. Huang, R. W. Knighton, and L. N. Cavuoto, “Microtubule Contribution to the Reflectance of the Retinal Nerve Fiber Layer,” Invest. Ophthalmol. Vis. Sci. 47(12), 5363–5367 (2006).
[Crossref] [PubMed]

2004 (1)

D. J. Faber, M. C. G. Aalders, E. G. Mik, B. A. Hooper, M. J. C. van Gemert, and T. G. van Leeuwen, “Oxygen Saturation-Dependent Absorption and Scattering of Blood,” Phys. Rev. Lett. 93(2), 028102 (2004).
[Crossref] [PubMed]

2002 (2)

Q. V. Hoang, R. A. Linsenmeier, C. K. Chung, and C. A. Curcio, “Photoreceptor inner segments in monkey and human retina: mitochondrial density, optics, and regional variation,” Vis. Neurosci. 19(4), 395–407 (2002).
[Crossref] [PubMed]

Y. N. Mirabal, S. K. Chang, E. N. Atkinson, A. Malpica, M. Follen, and R. Richards-Kortum, “Reflectance spectroscopy for in vivo detection of cervical precancer,” J. Biomed. Opt. 7(4), 587–594 (2002).
[Crossref] [PubMed]

2000 (1)

1991 (1)

D. Huang, E. A. Swanson, C. P. Lin, J. S. Schuman, W. G. Stinson, W. Chang, M. R. Hee, T. Flotte, K. Gregory, C. A. Puliafito, and et, “Optical coherence tomography,” Science 254(5035), 1178–1181 (1991).
[Crossref] [PubMed]

1979 (1)

N. Otsu, “A threshold selection method from gray-level histograms,” IEEE Trans. Syst. Man Cybern. 9(1), 62–66 (1979).
[Crossref]

1954 (2)

R. Barer and S. Tkaczyk, “Refractive Index of Concentrated Protein Solutions,” Nature 173(4409), 821–822 (1954).
[Crossref] [PubMed]

H. G. Davies, M. H. F. Wilkins, J. Chayen, and L. F. La Cour, “The Use of the Interference Microscope to Determine Dry Mass in Living Cells and as a Quantitative Cytochemical Method,” Quarterly Journal of Microscopical Science s3–95, 271– 304 (1954).

Aalders, M. C. G.

D. J. Faber, M. C. G. Aalders, E. G. Mik, B. A. Hooper, M. J. C. van Gemert, and T. G. van Leeuwen, “Oxygen Saturation-Dependent Absorption and Scattering of Blood,” Phys. Rev. Lett. 93(2), 028102 (2004).
[Crossref] [PubMed]

Abràmoff, M. D.

M. K. Garvin, M. D. Abràmoff, X. Wu, S. R. Russell, T. L. Burns, and M. Sonka, “Automated 3-D Intraretinal Layer Segmentation of Macular Spectral-Domain Optical Coherence Tomography Images,” IEEE Trans. Med. Imaging 28(9), 1436–1447 (2009).
[Crossref] [PubMed]

Akif Çiftçioglu, M.

M. Canpolat, A. Akman-Karakaş, G. A. Gökhan-Ocak, İ. C. Başsorgun, M. Akif Çiftçioğlu, and E. Alpsoy, “Diagnosis and Demarcation of Skin Malignancy Using Elastic Light Single-Scattering Spectroscopy: A Pilot Study,” Dermatol. Surg. 38(2), 215–223 (2012).
[Crossref] [PubMed]

Akman-Karakas, A.

M. Canpolat, A. Akman-Karakaş, G. A. Gökhan-Ocak, İ. C. Başsorgun, M. Akif Çiftçioğlu, and E. Alpsoy, “Diagnosis and Demarcation of Skin Malignancy Using Elastic Light Single-Scattering Spectroscopy: A Pilot Study,” Dermatol. Surg. 38(2), 215–223 (2012).
[Crossref] [PubMed]

Alpsoy, E.

M. Canpolat, A. Akman-Karakaş, G. A. Gökhan-Ocak, İ. C. Başsorgun, M. Akif Çiftçioğlu, and E. Alpsoy, “Diagnosis and Demarcation of Skin Malignancy Using Elastic Light Single-Scattering Spectroscopy: A Pilot Study,” Dermatol. Surg. 38(2), 215–223 (2012).
[Crossref] [PubMed]

Andersson, C.

I. Itzkan, L. Qiu, H. Fang, M. M. Zaman, E. Vitkin, I. C. Ghiran, S. Salahuddin, M. Modell, C. Andersson, L. M. Kimerer, P. B. Cipolloni, K.-H. Lim, S. D. Freedman, I. Bigio, B. P. Sachs, E. B. Hanlon, and L. T. Perelman, “Confocal light absorption and scattering spectroscopic microscopy monitors organelles in live cells with no exogenous labels,” Proc. Natl. Acad. Sci. U.S.A. 104(44), 17255–17260 (2007).
[Crossref] [PubMed]

Atkinson, E. N.

Y. N. Mirabal, S. K. Chang, E. N. Atkinson, A. Malpica, M. Follen, and R. Richards-Kortum, “Reflectance spectroscopy for in vivo detection of cervical precancer,” J. Biomed. Opt. 7(4), 587–594 (2002).
[Crossref] [PubMed]

Augustin, M.

Backman, V.

R. Liu, G. Spicer, S. Chen, H. F. Zhang, J. Yi, and V. Backman, “Theoretical model for optical oximetry at the capillary level: exploring hemoglobin oxygen saturation through backscattering of single red blood cells,” J. Biomed. Opt. 22(2), 025002 (2017).
[Crossref] [PubMed]

J. Yi, Z. Puyang, L. Feng, L. Duan, P. Liang, V. Backman, X. Liu, and H. F. Zhang, “Optical Detection of Early Damage in Retinal Ganglion Cells in a Mouse Model of Partial Optic Nerve Crush Injury,” Invest. Ophthalmol. Vis. Sci. 57(13), 5665–5671 (2016).
[Crossref] [PubMed]

S. Chen, J. Yi, W. Liu, V. Backman, and H. F. Zhang, “Monte Carlo Investigation of Optical Coherence Tomography Retinal Oximetry,” IEEE Trans. Biomed. Eng. 62(9), 2308–2315 (2015).
[Crossref] [PubMed]

L. Cherkezyan, H. Subramanian, and V. Backman, “What structural length scales can be detected by the spectral variance of a microscope image?” Opt. Lett. 39(15), 4290–4293 (2014).
[Crossref] [PubMed]

J. Yi, Q. Wei, W. Liu, V. Backman, and H. F. Zhang, “Visible-light optical coherence tomography for retinal oximetry,” Opt. Lett. 38(11), 1796–1798 (2013).
[Crossref] [PubMed]

J. D. Rogers, A. J. Radosevich, J. Yi, and V. Backman, “Modeling Light Scattering in Tissue as Continuous Random Media Using a Versatile Refractive Index Correlation Function,” IEEE J. Sel. Top. Quantum Electron. 20(2), 7000514 (2013).
[PubMed]

J. Yi, A. J. Radosevich, J. D. Rogers, S. C. P. Norris, İ. R. Çapoğlu, A. Taflove, and V. Backman, “Can OCT be sensitive to nanoscale structural alterations in biological tissue?” Opt. Express 21(7), 9043–9059 (2013).
[Crossref] [PubMed]

L. Cherkezyan, I. Çapoğlu, H. Subramanian, J. D. Rogers, D. Damania, A. Taflove, and V. Backman, “Interferometric Spectroscopy of Scattered Light Can Quantify the Statistics of Subdiffractional Refractive-Index Fluctuations,” Phys. Rev. Lett. 111(3), 033903 (2013).
[Crossref] [PubMed]

J. Yi and V. Backman, “Imaging a full set of optical scattering properties of biological tissue by inverse spectroscopic optical coherence tomography,” Opt. Lett. 37(21), 4443–4445 (2012).
[Crossref] [PubMed]

A. J. Radosevich, J. Yi, J. D. Rogers, and V. Backman, “Structural length-scale sensitivities of reflectance measurements in continuous random media under the Born approximation,” Opt. Lett. 37(24), 5220–5222 (2012).
[Crossref] [PubMed]

N. N. Boustany, S. A. Boppart, and V. Backman, “Microscopic Imaging and Spectroscopy with Scattered Light,” Annu. Rev. Biomed. Eng. 12(1), 285–314 (2010).
[Crossref] [PubMed]

M. Hunter, V. Backman, G. Popescu, M. Kalashnikov, C. W. Boone, A. Wax, V. Gopal, K. Badizadegan, G. D. Stoner, and M. S. Feld, “Tissue Self-Affinity and Polarized Light Scattering in the Born Approximation: A New Model for Precancer Detection,” Phys. Rev. Lett. 97(13), 138102 (2006).
[Crossref] [PubMed]

Badizadegan, K.

M. Hunter, V. Backman, G. Popescu, M. Kalashnikov, C. W. Boone, A. Wax, V. Gopal, K. Badizadegan, G. D. Stoner, and M. S. Feld, “Tissue Self-Affinity and Polarized Light Scattering in the Born Approximation: A New Model for Precancer Detection,” Phys. Rev. Lett. 97(13), 138102 (2006).
[Crossref] [PubMed]

Barer, R.

R. Barer and S. Tkaczyk, “Refractive Index of Concentrated Protein Solutions,” Nature 173(4409), 821–822 (1954).
[Crossref] [PubMed]

Bassorgun, I. C.

M. Canpolat, A. Akman-Karakaş, G. A. Gökhan-Ocak, İ. C. Başsorgun, M. Akif Çiftçioğlu, and E. Alpsoy, “Diagnosis and Demarcation of Skin Malignancy Using Elastic Light Single-Scattering Spectroscopy: A Pilot Study,” Dermatol. Surg. 38(2), 215–223 (2012).
[Crossref] [PubMed]

Baumann, B.

Beckmann, L.

X. Shu, L. Beckmann, and H. Zhang, “Visible-light optical coherence tomography: a review,” J. Biomed. Opt. 22(12), 1–14 (2017).
[Crossref] [PubMed]

Bennett, A.

N. G. Terry, Y. Zhu, M. T. Rinehart, W. J. Brown, S. C. Gebhart, S. Bright, E. Carretta, C. G. Ziefle, M. Panjehpour, J. Galanko, R. D. Madanick, E. S. Dellon, D. Trembath, A. Bennett, J. R. Goldblum, B. F. Overholt, J. T. Woosley, N. J. Shaheen, and A. Wax, “Detection of Dysplasia in Barrett’s Esophagus With In Vivo Depth-Resolved Nuclear Morphology Measurements,” Gastroenterology 140(1), 42–50 (2011).
[Crossref] [PubMed]

Bernucci, M.

Bernucci, M. T.

Bigio, I.

I. Itzkan, L. Qiu, H. Fang, M. M. Zaman, E. Vitkin, I. C. Ghiran, S. Salahuddin, M. Modell, C. Andersson, L. M. Kimerer, P. B. Cipolloni, K.-H. Lim, S. D. Freedman, I. Bigio, B. P. Sachs, E. B. Hanlon, and L. T. Perelman, “Confocal light absorption and scattering spectroscopic microscopy monitors organelles in live cells with no exogenous labels,” Proc. Natl. Acad. Sci. U.S.A. 104(44), 17255–17260 (2007).
[Crossref] [PubMed]

Bigio, I. J.

Y. Zhu, T. Fearn, G. Mackenzie, I. J. Bigio, S. G. Bown, L. B. Lovat, B. Clark, and J. M. Dunn, “Elastic scattering spectroscopy for detection of cancer risk in Barrett’s esophagus: experimental and clinical validation of error removal by orthogonal subtraction for increasing accuracy,” J. Biomed. Opt. 14, 044022 (2009).

Bizheva, K.

Boone, C. W.

M. Hunter, V. Backman, G. Popescu, M. Kalashnikov, C. W. Boone, A. Wax, V. Gopal, K. Badizadegan, G. D. Stoner, and M. S. Feld, “Tissue Self-Affinity and Polarized Light Scattering in the Born Approximation: A New Model for Precancer Detection,” Phys. Rev. Lett. 97(13), 138102 (2006).
[Crossref] [PubMed]

Boppart, S. A.

N. N. Boustany, S. A. Boppart, and V. Backman, “Microscopic Imaging and Spectroscopy with Scattered Light,” Annu. Rev. Biomed. Eng. 12(1), 285–314 (2010).
[Crossref] [PubMed]

Boustany, N. N.

N. N. Boustany, S. A. Boppart, and V. Backman, “Microscopic Imaging and Spectroscopy with Scattered Light,” Annu. Rev. Biomed. Eng. 12(1), 285–314 (2010).
[Crossref] [PubMed]

Bown, S. G.

Y. Zhu, T. Fearn, G. Mackenzie, I. J. Bigio, S. G. Bown, L. B. Lovat, B. Clark, and J. M. Dunn, “Elastic scattering spectroscopy for detection of cancer risk in Barrett’s esophagus: experimental and clinical validation of error removal by orthogonal subtraction for increasing accuracy,” J. Biomed. Opt. 14, 044022 (2009).

Bright, S.

N. G. Terry, Y. Zhu, M. T. Rinehart, W. J. Brown, S. C. Gebhart, S. Bright, E. Carretta, C. G. Ziefle, M. Panjehpour, J. Galanko, R. D. Madanick, E. S. Dellon, D. Trembath, A. Bennett, J. R. Goldblum, B. F. Overholt, J. T. Woosley, N. J. Shaheen, and A. Wax, “Detection of Dysplasia in Barrett’s Esophagus With In Vivo Depth-Resolved Nuclear Morphology Measurements,” Gastroenterology 140(1), 42–50 (2011).
[Crossref] [PubMed]

Brown, W. J.

J. R. Maher, V. Jaedicke, M. Medina, H. Levinson, M. A. Selim, W. J. Brown, and A. Wax, “In vivo analysis of burns in a mouse model using spectroscopic optical coherence tomography,” Opt. Lett. 39(19), 5594–5597 (2014).
[Crossref] [PubMed]

N. G. Terry, Y. Zhu, M. T. Rinehart, W. J. Brown, S. C. Gebhart, S. Bright, E. Carretta, C. G. Ziefle, M. Panjehpour, J. Galanko, R. D. Madanick, E. S. Dellon, D. Trembath, A. Bennett, J. R. Goldblum, B. F. Overholt, J. T. Woosley, N. J. Shaheen, and A. Wax, “Detection of Dysplasia in Barrett’s Esophagus With In Vivo Depth-Resolved Nuclear Morphology Measurements,” Gastroenterology 140(1), 42–50 (2011).
[Crossref] [PubMed]

Burns, T. L.

M. K. Garvin, M. D. Abràmoff, X. Wu, S. R. Russell, T. L. Burns, and M. Sonka, “Automated 3-D Intraretinal Layer Segmentation of Macular Spectral-Domain Optical Coherence Tomography Images,” IEEE Trans. Med. Imaging 28(9), 1436–1447 (2009).
[Crossref] [PubMed]

Canpolat, M.

M. Canpolat, A. Akman-Karakaş, G. A. Gökhan-Ocak, İ. C. Başsorgun, M. Akif Çiftçioğlu, and E. Alpsoy, “Diagnosis and Demarcation of Skin Malignancy Using Elastic Light Single-Scattering Spectroscopy: A Pilot Study,” Dermatol. Surg. 38(2), 215–223 (2012).
[Crossref] [PubMed]

Çapoglu, I.

L. Cherkezyan, I. Çapoğlu, H. Subramanian, J. D. Rogers, D. Damania, A. Taflove, and V. Backman, “Interferometric Spectroscopy of Scattered Light Can Quantify the Statistics of Subdiffractional Refractive-Index Fluctuations,” Phys. Rev. Lett. 111(3), 033903 (2013).
[Crossref] [PubMed]

Çapoglu, I. R.

Carretta, E.

N. G. Terry, Y. Zhu, M. T. Rinehart, W. J. Brown, S. C. Gebhart, S. Bright, E. Carretta, C. G. Ziefle, M. Panjehpour, J. Galanko, R. D. Madanick, E. S. Dellon, D. Trembath, A. Bennett, J. R. Goldblum, B. F. Overholt, J. T. Woosley, N. J. Shaheen, and A. Wax, “Detection of Dysplasia in Barrett’s Esophagus With In Vivo Depth-Resolved Nuclear Morphology Measurements,” Gastroenterology 140(1), 42–50 (2011).
[Crossref] [PubMed]

Carroll, J.

Cavuoto, L. N.

X.-R. Huang, R. W. Knighton, and L. N. Cavuoto, “Microtubule Contribution to the Reflectance of the Retinal Nerve Fiber Layer,” Invest. Ophthalmol. Vis. Sci. 47(12), 5363–5367 (2006).
[Crossref] [PubMed]

Cense, B.

Chang, S. K.

Y. N. Mirabal, S. K. Chang, E. N. Atkinson, A. Malpica, M. Follen, and R. Richards-Kortum, “Reflectance spectroscopy for in vivo detection of cervical precancer,” J. Biomed. Opt. 7(4), 587–594 (2002).
[Crossref] [PubMed]

Chang, W.

D. Huang, E. A. Swanson, C. P. Lin, J. S. Schuman, W. G. Stinson, W. Chang, M. R. Hee, T. Flotte, K. Gregory, C. A. Puliafito, and et, “Optical coherence tomography,” Science 254(5035), 1178–1181 (1991).
[Crossref] [PubMed]

Chayen, J.

H. G. Davies, M. H. F. Wilkins, J. Chayen, and L. F. La Cour, “The Use of the Interference Microscope to Determine Dry Mass in Living Cells and as a Quantitative Cytochemical Method,” Quarterly Journal of Microscopical Science s3–95, 271– 304 (1954).

Chen, S.

R. Liu, G. Spicer, S. Chen, H. F. Zhang, J. Yi, and V. Backman, “Theoretical model for optical oximetry at the capillary level: exploring hemoglobin oxygen saturation through backscattering of single red blood cells,” J. Biomed. Opt. 22(2), 025002 (2017).
[Crossref] [PubMed]

S. Chen, X. Shu, J. Yi, A. Fawzi, and H. F. Zhang, “Dual-band optical coherence tomography using a single supercontinuum laser source,” J. Biomed. Opt. 21(6), 066013 (2016).
[Crossref] [PubMed]

S. Chen, J. Yi, W. Liu, V. Backman, and H. F. Zhang, “Monte Carlo Investigation of Optical Coherence Tomography Retinal Oximetry,” IEEE Trans. Biomed. Eng. 62(9), 2308–2315 (2015).
[Crossref] [PubMed]

J. Yi, S. Chen, X. Shu, A. A. Fawzi, and H. F. Zhang, “Human retinal imaging using visible-light optical coherence tomography guided by scanning laser ophthalmoscopy,” Biomed. Opt. Express 6(10), 3701–3713 (2015).
[Crossref] [PubMed]

Cherkezyan, L.

L. Cherkezyan, H. Subramanian, and V. Backman, “What structural length scales can be detected by the spectral variance of a microscope image?” Opt. Lett. 39(15), 4290–4293 (2014).
[Crossref] [PubMed]

L. Cherkezyan, I. Çapoğlu, H. Subramanian, J. D. Rogers, D. Damania, A. Taflove, and V. Backman, “Interferometric Spectroscopy of Scattered Light Can Quantify the Statistics of Subdiffractional Refractive-Index Fluctuations,” Phys. Rev. Lett. 111(3), 033903 (2013).
[Crossref] [PubMed]

Chiu, S. J.

Choi, M.

J. Kwon, M. Kim, H. Park, B.-M. Kang, Y. Jo, J.-H. Kim, O. James, S.-H. Yun, S.-G. Kim, M. Suh, and M. Choi, “Label-free nanoscale optical metrology on myelinated axons in vivo,” Nat. Commun. 8(1), 1832 (2017).
[Crossref] [PubMed]

Choi, S. S.

Chong, S. P.

Chung, C. K.

Q. V. Hoang, R. A. Linsenmeier, C. K. Chung, and C. A. Curcio, “Photoreceptor inner segments in monkey and human retina: mitochondrial density, optics, and regional variation,” Vis. Neurosci. 19(4), 395–407 (2002).
[Crossref] [PubMed]

Chuttani, R.

L. Qiu, D. K. Pleskow, R. Chuttani, E. Vitkin, J. Leyden, N. Ozden, S. Itani, L. Guo, A. Sacks, J. D. Goldsmith, M. D. Modell, E. B. Hanlon, I. Itzkan, and L. T. Perelman, “Multispectral scanning during endoscopy guides biopsy of dysplasia in Barrett’s esophagus,” Nat. Med. 16(5), 603–606 (2010).
[Crossref] [PubMed]

Cipolloni, P. B.

I. Itzkan, L. Qiu, H. Fang, M. M. Zaman, E. Vitkin, I. C. Ghiran, S. Salahuddin, M. Modell, C. Andersson, L. M. Kimerer, P. B. Cipolloni, K.-H. Lim, S. D. Freedman, I. Bigio, B. P. Sachs, E. B. Hanlon, and L. T. Perelman, “Confocal light absorption and scattering spectroscopic microscopy monitors organelles in live cells with no exogenous labels,” Proc. Natl. Acad. Sci. U.S.A. 104(44), 17255–17260 (2007).
[Crossref] [PubMed]

Clark, B.

Y. Zhu, T. Fearn, G. Mackenzie, I. J. Bigio, S. G. Bown, L. B. Lovat, B. Clark, and J. M. Dunn, “Elastic scattering spectroscopy for detection of cancer risk in Barrett’s esophagus: experimental and clinical validation of error removal by orthogonal subtraction for increasing accuracy,” J. Biomed. Opt. 14, 044022 (2009).

Clausi, D. A.

Cooper, R. F.

Curcio, C. A.

Q. V. Hoang, R. A. Linsenmeier, C. K. Chung, and C. A. Curcio, “Photoreceptor inner segments in monkey and human retina: mitochondrial density, optics, and regional variation,” Vis. Neurosci. 19(4), 395–407 (2002).
[Crossref] [PubMed]

Damania, D.

L. Cherkezyan, I. Çapoğlu, H. Subramanian, J. D. Rogers, D. Damania, A. Taflove, and V. Backman, “Interferometric Spectroscopy of Scattered Light Can Quantify the Statistics of Subdiffractional Refractive-Index Fluctuations,” Phys. Rev. Lett. 111(3), 033903 (2013).
[Crossref] [PubMed]

Davies, H. G.

H. G. Davies, M. H. F. Wilkins, J. Chayen, and L. F. La Cour, “The Use of the Interference Microscope to Determine Dry Mass in Living Cells and as a Quantitative Cytochemical Method,” Quarterly Journal of Microscopical Science s3–95, 271– 304 (1954).

Dellon, E. S.

N. G. Terry, Y. Zhu, M. T. Rinehart, W. J. Brown, S. C. Gebhart, S. Bright, E. Carretta, C. G. Ziefle, M. Panjehpour, J. Galanko, R. D. Madanick, E. S. Dellon, D. Trembath, A. Bennett, J. R. Goldblum, B. F. Overholt, J. T. Woosley, N. J. Shaheen, and A. Wax, “Detection of Dysplasia in Barrett’s Esophagus With In Vivo Depth-Resolved Nuclear Morphology Measurements,” Gastroenterology 140(1), 42–50 (2011).
[Crossref] [PubMed]

Delori, F. C.

F. C. Delori, R. H. Webb, D. H. Sliney, and American National Standards Institute, “Maximum permissible exposures for ocular safety (ANSI 2000), with emphasis on ophthalmic devices,” J. Opt. Soc. Am. A 24(5), 1250–1265 (2007).
[Crossref] [PubMed]

C. N. Keilhauer and F. C. Delori, “Near-Infrared Autofluorescence Imaging of the Fundus: Visualization of Ocular Melanin,” Invest. Ophthalmol. Vis. Sci. 47(8), 3556–3564 (2006).
[Crossref] [PubMed]

Drexler, W.

Duan, L.

J. Yi, Z. Puyang, L. Feng, L. Duan, P. Liang, V. Backman, X. Liu, and H. F. Zhang, “Optical Detection of Early Damage in Retinal Ganglion Cells in a Mouse Model of Partial Optic Nerve Crush Injury,” Invest. Ophthalmol. Vis. Sci. 57(13), 5665–5671 (2016).
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W. Song, L. Zhang, S. Ness, and J. Yi, “Wavelength-dependent optical properties of melanosomes in retinal pigmented epithelium and their changes with melanin bleaching: a numerical study,” Biomed. Opt. Express 8(9), 3966–3980 (2017).
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Biomed. Opt. Express (12)

A. Dubra, Y. Sulai, J. L. Norris, R. F. Cooper, A. M. Dubis, D. R. Williams, and J. Carroll, “Noninvasive imaging of the human rod photoreceptor mosaic using a confocal adaptive optics scanning ophthalmoscope,” Biomed. Opt. Express 2(7), 1864–1876 (2011).
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C. P. Fleming, J. Eckert, E. F. Halpern, J. A. Gardecki, and G. J. Tearney, “Depth resolved detection of lipid using spectroscopic optical coherence tomography,” Biomed. Opt. Express 4(8), 1269–1284 (2013).
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A. Lichtenegger, D. J. Harper, M. Augustin, P. Eugui, M. Muck, J. Gesperger, C. K. Hitzenberger, A. Woehrer, and B. Baumann, “Spectroscopic imaging with spectral domain visible light optical coherence microscopy in Alzheimer’s disease brain samples,” Biomed. Opt. Express 8(9), 4007–4025 (2017).
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B. Vohnsen, “Directional sensitivity of the retina: A layered scattering model of outer-segment photoreceptor pigments,” Biomed. Opt. Express 5(5), 1569–1587 (2014).
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W. Song, L. Zhang, S. Ness, and J. Yi, “Wavelength-dependent optical properties of melanosomes in retinal pigmented epithelium and their changes with melanin bleaching: a numerical study,” Biomed. Opt. Express 8(9), 3966–3980 (2017).
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S. P. Chong, M. Bernucci, H. Radhakrishnan, and V. J. Srinivasan, “Structural and functional human retinal imaging with a fiber-based visible light OCT ophthalmoscope,” Biomed. Opt. Express 8(1), 323–337 (2017).
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A. Dubra and Y. Sulai, “Reflective afocal broadband adaptive optics scanning ophthalmoscope,” Biomed. Opt. Express 2(6), 1757–1768 (2011).
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S. P. Chong, T. Zhang, A. Kho, M. T. Bernucci, A. Dubra, and V. J. Srinivasan, “Ultrahigh resolution retinal imaging by visible light OCT with longitudinal achromatization,” Biomed. Opt. Express 9(4), 1477–1491 (2018).
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L. Scolaro, R. A. McLaughlin, B. R. Klyen, B. A. Wood, P. D. Robbins, C. M. Saunders, S. L. Jacques, and D. D. Sampson, “Parametric imaging of the local attenuation coefficient in human axillary lymph nodes assessed using optical coherence tomography,” Biomed. Opt. Express 3(2), 366–379 (2012).
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J. Yi, Z. Puyang, L. Feng, L. Duan, P. Liang, V. Backman, X. Liu, and H. F. Zhang, “Optical Detection of Early Damage in Retinal Ganglion Cells in a Mouse Model of Partial Optic Nerve Crush Injury,” Invest. Ophthalmol. Vis. Sci. 57(13), 5665–5671 (2016).
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Y. Zhu, T. Fearn, G. Mackenzie, I. J. Bigio, S. G. Bown, L. B. Lovat, B. Clark, and J. M. Dunn, “Elastic scattering spectroscopy for detection of cancer risk in Barrett’s esophagus: experimental and clinical validation of error removal by orthogonal subtraction for increasing accuracy,” J. Biomed. Opt. 14, 044022 (2009).

Y. N. Mirabal, S. K. Chang, E. N. Atkinson, A. Malpica, M. Follen, and R. Richards-Kortum, “Reflectance spectroscopy for in vivo detection of cervical precancer,” J. Biomed. Opt. 7(4), 587–594 (2002).
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F. E. Robles, C. Wilson, G. Grant, and A. Wax, “Molecular imaging true-colour spectroscopic optical coherence tomography,” Nat. Photonics 5(12), 744–747 (2011).
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M. Hunter, V. Backman, G. Popescu, M. Kalashnikov, C. W. Boone, A. Wax, V. Gopal, K. Badizadegan, G. D. Stoner, and M. S. Feld, “Tissue Self-Affinity and Polarized Light Scattering in the Born Approximation: A New Model for Precancer Detection,” Phys. Rev. Lett. 97(13), 138102 (2006).
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L. Cherkezyan, I. Çapoğlu, H. Subramanian, J. D. Rogers, D. Damania, A. Taflove, and V. Backman, “Interferometric Spectroscopy of Scattered Light Can Quantify the Statistics of Subdiffractional Refractive-Index Fluctuations,” Phys. Rev. Lett. 111(3), 033903 (2013).
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D. J. Faber, M. C. G. Aalders, E. G. Mik, B. A. Hooper, M. J. C. van Gemert, and T. G. van Leeuwen, “Oxygen Saturation-Dependent Absorption and Scattering of Blood,” Phys. Rev. Lett. 93(2), 028102 (2004).
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Proc. Natl. Acad. Sci. U.S.A. (2)

Z. Liu, K. Kurokawa, F. Zhang, J. J. Lee, and D. T. Miller, “Imaging and quantifying ganglion cells and other transparent neurons in the living human retina,” Proc. Natl. Acad. Sci. U.S.A. 114(48), 12803–12808 (2017).
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Supplementary Material (2)

NameDescription
» Visualization 1       This video demonstrates the operation of visible and near infrared optical coherence tomography for human retinal imaging
» Visualization 2       This video shows the efficacy of using achromatizing lens in vnOCT to correct longitudinal chromatic aberration by human eyes.

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Figures (10)

Fig. 1
Fig. 1 System setup and characterization of vnOCT for human retinal imaging. (a) The schematic of the vnOCT system. BD: beam dump; PC: polarization controller. EFs: two edge filters. (b) Photograph of the fiber components of wavelength division multiplexers (WDM) and fiber coupler (FC). The light paths from the visible and NIR light source, to the reference arm and eye, and back to two spectrometers are labeled. The splicing sites are pointed by yellow arrows. (c-d) The spectral split of the 90/10 fiber coupler and the WDM. The shape of the spectrum is slightly changed in panel (c) and (d) due to the different spectral characteristics of the fiber coupler and the WDM. (e) Examples of the interferogram by the fiber cascade of WDM and FC in the vnOCT system. The spectra were direct output from two spectrometers.
Fig. 2
Fig. 2 Characterization of the roll-off curves for visible channel in (a) and NIR channel in (b). The 2nd order polynomial fitting was provided to quantify the system roll-off.
Fig. 3
Fig. 3 The design of the achromatizing lens (AL) for vnOCT system. (a) Photograph and schematic design of the lens (dimension in millimeters). The glass materials are H-ZF88 for the center piece, and S-FPL53 for the two end pieces. (b) The chromatic focal shift in the sample arm with and without the achromatizing lens. (c-d) The spot diagrams at different viewing angles for 550nm and 900nm, without and with the achromatizing lens. The principle ray is 900nm. Bar is 75 μm in (c) and 37.5 μm in (d).
Fig. 4
Fig. 4 Human retinal imaging over a 30°x30° viewing angle by vnOCT from a healthy male subject aged 31. (a-h) The representative OCT images, without using the achromatizing lens (AL). Either NIR channel or visible channel can be in focus at each acquisition but not together. (i-l) The representative OCT images with the achromatizing lens. Both channels can be in focus simultaneously. All images are displayed in logarithmic scale. The en face projections are composed on 512x512 pixels. B-scan images are composed of 4096 A-lines.
Fig. 5
Fig. 5 Flow chart of the data processing method for the ELSS analysis by vnOCT.
Fig. 6
Fig. 6 Demonstration of the data processing method for ELSS analysis by vnOCT. (a) The theoretical prediction of the backscattering spectra from a 50µm thickness of whole blood. Two gray bands show the bandwidth coverage of our vnOCT system. (b) An example of the cross-sectional B-scan images from visible and NIR channels with a major blood vessel labeled. (c) The averaged A-line signal over the major blood vessel in panel (b). The depth starts from the retinal surface. The gray area labels the top 50μm depth range used for integration. (d) An example of a B-scan image color-encoded by VN ratio after intensity scaling. Anatomical layers were labeled. IPL: inner plexiform layer; INL: inner nuclear layer; OPL: outer plexiform layer; ONL: outer nuclear layer; IS/OS: inner and outer segment junction of photoreceptors; OS: outer segment; C: choroid.
Fig. 7
Fig. 7 Elastic light scattering spectroscopic analysis at the peripapillary region from a healthy male subject aged 31. (a-b) The representative 20°x20° en face projection of the peripapillary region. Signal form the labeled vessels (white arrows) were averaged to serve as the in vivo spectral reference. After scaling the NIR channel, the VN ratio from the labeled vessels are 0.60 ± 0.04 (mean ± sem). (c-d) The cross-sectional B-scan images from visible and NIR channels at the dashed lines in panel (a) and (b), with the boundary of neural fiber layer (NFL) demarcated. (e-f) The en face maps for the NFL thickness, and VN ratio averaged from the superficial 50μm of tissue. (g-h) The NFL thickness and VN ratio with respect to the radial angle within the shaded circular region. A 7x7 moving average was performed on the VN ratio map. The high VN ratio around the rim of optic nerve head (indicated by the white arrow) is an artefact due to the failure of the segmentation. T, S, N, I stands for temporal, superior, nasal, and inferior. The blue dots are individual data points, and the red curves are the average value over 15 degrees.
Fig. 8
Fig. 8 Elastic light scattering spectroscopic analysis at the macular region. (a-b) The representative 30°x30° en face projection of the macular region from visible and NIR channel. Signal form the labeled vessels (white arrows) were averaged to serve as the in vivo spectral reference. After scaling the NIR channel, the VN ratio from the labeled vessels are 0.60 ± 0.06 (mean ± sem). (c-d) The corresponding maps for NFL thickness, and the averaged VN ratio from the top 50μm layers. A 7x7 moving average was performed on the VN ratio map. (e) VN ratio within the shaded area in (d), with respect to the radial angle.
Fig. 9
Fig. 9 Elastic light scattering spectroscopic analysis at the macular region on the outer retina. (a) The zoomed-in B-scan images at the outer retina from two channels. The depth range of outer segment (OS) of photoreceptors, and RPE were labeled. (b-c) The en face maps of VN ratio from OS and RPE. A 7x7 moving average was performed on the VN ratio maps. (d-e) The angular dependence of VN ratio from OS and RPE within the shaded area in (b). (f-g) The dependence of VN ratio on the radial distance from the foveal center, r, within the shaded area in (b).
Fig. 10
Fig. 10 (a) Step-wise processing method for image segmentation for the edges for nerve fiber layer, IS/OS, and Bruch’s membrane. (b) Example of the image segmentation on a representative B-scan image.

Tables (1)

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Table 1 Part list for optics in the sample arm

Equations (5)

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Φ vis MP E vis + Φ NIR MP E NIR <1,
I(λ,z)= I 0 (λ)R(λ)exp[2 μ t (λ)z],
μ t = μ s a(g)+ μ a ,
a(g)=1exp[ (1g) 0.6651 0.1555 ],
Σ z l (λ)= 0 z l I I 0 dz= R(λ) 2 μ t (λ) [1exp(2 μ t (λ) z l )] .

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