Abstract

With existing optical imaging techniques three-dimensional (3-D) mapping of microvascular perfusion within tissue beds is severely limited by the efficient scattering and absorption of light by tissue. To overcome these limitations we have developed a method of optical angiography (OAG) that can generate 3-D angiograms within millimeter tissue depths by analyzing the endogenous optical scattering signal from an illuminated sample. The technique effectively separates the moving and static scattering elements within tissue to achieve high resolution images of blood flow, mapped into the 3-D optically sectioned tissue beds, at speeds that allow for perfusion assessment in vivo. Its development has its origin in Fourier domain optical coherence tomography. We used OAG to visualize the cerebral microcirculation, of adult living mice through the intact cranium, measurements which would be difficult, if not impossible, with other optical imaging techniques.

© 2007 Optical Society of America

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2007

R. K. Wang, "In vivo full range complex Fourier Domain optical coherence tomography," Appl. Phys. Lett. 90, 054103 (2007.
[CrossRef]

2006

A. H. Bachmann, R. A. Leitgeb, and T. Lasser, "Heterodyne Fourier domain optical coherence tomography for full range probing with high axial resolution," Opt. Express 14,1487-1496 (2006).
[CrossRef] [PubMed]

Y. Yasuno, S. Makita, T. Endo, G. Aoki, M. Itoh, and T. Yatagai, "Simultaneous B-M-mode scanning method for real-time full-range Fourier domain optical coherence tomography," Appl. Opt. 45, 1861-1865 (2006)
[CrossRef] [PubMed]

T. Misgeld and M. Kerschensteiner, "In vivo imaging of the diseased nervous system," Nat. Rev. Neurosci. 7, 449-463 (2006).
[CrossRef] [PubMed]

R. K. Wang and Z. H. Ma, "Real-time flow imaging by removing texture pattern artifacts in spectral-domain optical Doppler tomography," Opt. Lett. 31, 3001-3003 (2006).
[CrossRef] [PubMed]

M. Yamanari, S. Makita, V. D. Madjarova, T. Yatagai, and Y. Yasuno, "Fiber-based polarization-sensitive Fourier domain optical coherence tomography using B-scan-oriented polarization modulation method", Opt. Express 14, 6502-6515 (2006).
[CrossRef] [PubMed]

R. K. Wang, Z. Ma, and S. J. Kirkpatrick, "Tissue Doppler optical coherence elastography for real time strain rate and strain mapping of soft tissue," Appl. Phys. Lett.,  89, 144103 (2006)
[CrossRef]

S. J. Kirkpatrick, R. K. Wang, and D. D. Duncan, "OCT-based elastography for large and small deformations," Opt. Express 14, 11585-11597 (2006).
[CrossRef] [PubMed]

S. Makita, Y. Hong, M. Y. T. Yatagai, and Y. Yasuno, "Optical coherence angiography," Opt. Express 14, 7821 (2006).
[CrossRef] [PubMed]

R. K. Wang and Z. H. Ma, "A practical approach to eliminate autocorrelation artefacts for volume-rate spectral domain optical coherence tomography," Phys. Med. Biol. 51, 3231-3239 (2006).
[CrossRef] [PubMed]

2005

2004

2003

2002

S. Jiao, L. H. Wang, "Two-dimensional depth-resolved Mueller matrix of biological tissue measured with double-beam polarization-sensitive optical coherence tomography," Opt Lett. 27, 101-103 (2002).
[CrossRef]

H. W. Ren, Z. H. Ding, Y. H. Zhao,  et al., "Phase-resolved functional optical coherence tomography: simultaneous imaging of in situ tissue structure, blood flow velocity, standard deviation, birefringence, and Stokes vectors in human skin," Opt. Lett. 27, 1702-1704 (2002).
[CrossRef]

2001

W. Drexler,  et al, "Ultrahigh-resolution ophthalmic optical coherence tomography," Nat. Med. 7, 502-507 (2001)
[CrossRef] [PubMed]

2000

1998

S.A. Boppart,  et al, "In vivo cellular optical coherence tomography imaging," Nat. Med. 4, 861-865 (1998)
[CrossRef] [PubMed]

G. Hausler, M. W. Lindner, "Coherence radar and Spectral radar- new tools for dermatological diagnosis," J. Biomed. Opt. 3, 21-31 (1998)
[CrossRef]

1997

1991

D. Huang, E. Swanson, C. Lin, J. Schuman, W. Stinson, W. Chang, M. Hee, T. Flotte, K. Gregory, C. Puliafito, and J. Fujimoto, "Optical coherence tomography,’Science,  254, 1178-1181 (1991)
[CrossRef] [PubMed]

1963

E. A. Bedrosian, "Product theorem for Hilbert transforms," Proc. IEEE,  51, 868-869 (1963).
[CrossRef]

Aoki, G.

Bachmann, A. H.

Bajraszewski, T.

Bedrosian, E. A.

E. A. Bedrosian, "Product theorem for Hilbert transforms," Proc. IEEE,  51, 868-869 (1963).
[CrossRef]

Belabas, N.

Boppart, S. A.

S.A. Boppart,  et al, "In vivo cellular optical coherence tomography imaging," Nat. Med. 4, 861-865 (1998)
[CrossRef] [PubMed]

Bouma, B. E.

Chang, W.

D. Huang, E. Swanson, C. Lin, J. Schuman, W. Stinson, W. Chang, M. Hee, T. Flotte, K. Gregory, C. Puliafito, and J. Fujimoto, "Optical coherence tomography,’Science,  254, 1178-1181 (1991)
[CrossRef] [PubMed]

Chen, Z.

Chen, Z. P.

de Boer, J. F.

Ding, Z. H.

Dorrer, C.

Drexler, W.

Duncan, D. D.

Endo, T.

Fercher, A. F.

Flotte, T.

D. Huang, E. Swanson, C. Lin, J. Schuman, W. Stinson, W. Chang, M. Hee, T. Flotte, K. Gregory, C. Puliafito, and J. Fujimoto, "Optical coherence tomography,’Science,  254, 1178-1181 (1991)
[CrossRef] [PubMed]

Fujimoto, J.

D. Huang, E. Swanson, C. Lin, J. Schuman, W. Stinson, W. Chang, M. Hee, T. Flotte, K. Gregory, C. Puliafito, and J. Fujimoto, "Optical coherence tomography,’Science,  254, 1178-1181 (1991)
[CrossRef] [PubMed]

Fujimoto, J. G.

Gotzinger, E.

E. Gotzinger, M. Pircher, R. A. Leitgeb, and C. K. Hitzenberger, "High speed full range complex spectral domain optical coherence tomography," Opt. Express 13, 583-594 (2005).
[CrossRef] [PubMed]

E. Gotzinger, M. Pircher, and C.K. Hitzenberger, "High speed spectral domain polarization sensitive optical coherence tomography," Opt. Express 13, 217-229 (2005).
[CrossRef]

Gregory, K.

D. Huang, E. Swanson, C. Lin, J. Schuman, W. Stinson, W. Chang, M. Hee, T. Flotte, K. Gregory, C. Puliafito, and J. Fujimoto, "Optical coherence tomography,’Science,  254, 1178-1181 (1991)
[CrossRef] [PubMed]

Hausler, G.

G. Hausler, M. W. Lindner, "Coherence radar and Spectral radar- new tools for dermatological diagnosis," J. Biomed. Opt. 3, 21-31 (1998)
[CrossRef]

Hee, M.

D. Huang, E. Swanson, C. Lin, J. Schuman, W. Stinson, W. Chang, M. Hee, T. Flotte, K. Gregory, C. Puliafito, and J. Fujimoto, "Optical coherence tomography,’Science,  254, 1178-1181 (1991)
[CrossRef] [PubMed]

Hitzenberger, C. K.

Hitzenberger, C.K.

E. Gotzinger, M. Pircher, and C.K. Hitzenberger, "High speed spectral domain polarization sensitive optical coherence tomography," Opt. Express 13, 217-229 (2005).
[CrossRef]

Hong, Y.

Huang, D.

D. Huang, E. Swanson, C. Lin, J. Schuman, W. Stinson, W. Chang, M. Hee, T. Flotte, K. Gregory, C. Puliafito, and J. Fujimoto, "Optical coherence tomography,’Science,  254, 1178-1181 (1991)
[CrossRef] [PubMed]

Ippen, E. P.

Itoh, M.

Izatt, J. A.

S. Yazdanfar, A. M. Rollins, and J. A. Izatt, "In vivo imaging of human retinal flow dynamics by color Doppler optical coherence tomography." Arch. Ophthalmol. 121, 235-239 (2003).
[PubMed]

S. Yazdanfar, A. M. Rollins, and J. A. Izatt, "Imaging and velocimetry of the human retinal circulation with color Doppler optical coherence tomography," Opt. Lett. 25, 1448-1450 (2000).
[CrossRef]

Jiao, S.

S. Jiao, L. H. Wang, "Two-dimensional depth-resolved Mueller matrix of biological tissue measured with double-beam polarization-sensitive optical coherence tomography," Opt Lett. 27, 101-103 (2002).
[CrossRef]

Joffre, M.

Kartner, F. X.

Kerschensteiner, M.

T. Misgeld and M. Kerschensteiner, "In vivo imaging of the diseased nervous system," Nat. Rev. Neurosci. 7, 449-463 (2006).
[CrossRef] [PubMed]

Kirkpatrick, S. J.

R. K. Wang, Z. Ma, and S. J. Kirkpatrick, "Tissue Doppler optical coherence elastography for real time strain rate and strain mapping of soft tissue," Appl. Phys. Lett.,  89, 144103 (2006)
[CrossRef]

S. J. Kirkpatrick, R. K. Wang, and D. D. Duncan, "OCT-based elastography for large and small deformations," Opt. Express 14, 11585-11597 (2006).
[CrossRef] [PubMed]

Kowalczyk, A.

Lasser, T.

A. H. Bachmann, R. A. Leitgeb, and T. Lasser, "Heterodyne Fourier domain optical coherence tomography for full range probing with high axial resolution," Opt. Express 14,1487-1496 (2006).
[CrossRef] [PubMed]

A. F. Fercher, W. Drexler, C. K. Hitzenberger, and T. Lasser, "Optical Coherence Tomography - Principles and Applications," Rep. Prog. Phys.  66, 239-303 (2003).
[CrossRef]

Leitgeb, R.

Leitgeb, R. A.

Li, X. D.

Likforman, J. P.

Lin, C.

D. Huang, E. Swanson, C. Lin, J. Schuman, W. Stinson, W. Chang, M. Hee, T. Flotte, K. Gregory, C. Puliafito, and J. Fujimoto, "Optical coherence tomography,’Science,  254, 1178-1181 (1991)
[CrossRef] [PubMed]

Lindner, J. R.

J. R. Lindner, "Microbubbles in medical imaging: current applications and future directions," Nat. Rev. Drug Discovery 3, 527-532 (2004).
[CrossRef]

Lindner, M. W.

G. Hausler, M. W. Lindner, "Coherence radar and Spectral radar- new tools for dermatological diagnosis," J. Biomed. Opt. 3, 21-31 (1998)
[CrossRef]

Ma, Z.

R. K. Wang, Z. Ma, and S. J. Kirkpatrick, "Tissue Doppler optical coherence elastography for real time strain rate and strain mapping of soft tissue," Appl. Phys. Lett.,  89, 144103 (2006)
[CrossRef]

Ma, Z. H.

R. K. Wang and Z. H. Ma, "A practical approach to eliminate autocorrelation artefacts for volume-rate spectral domain optical coherence tomography," Phys. Med. Biol. 51, 3231-3239 (2006).
[CrossRef] [PubMed]

R. K. Wang and Z. H. Ma, "Real-time flow imaging by removing texture pattern artifacts in spectral-domain optical Doppler tomography," Opt. Lett. 31, 3001-3003 (2006).
[CrossRef] [PubMed]

Madjarova, V. D.

Makita, S.

Milner, T. E.

Misgeld, T.

T. Misgeld and M. Kerschensteiner, "In vivo imaging of the diseased nervous system," Nat. Rev. Neurosci. 7, 449-463 (2006).
[CrossRef] [PubMed]

Morgner, U.

Nassif, N.

Nelson, J. S.

Pierce, M. C.

Pircher, M.

E. Gotzinger, M. Pircher, R. A. Leitgeb, and C. K. Hitzenberger, "High speed full range complex spectral domain optical coherence tomography," Opt. Express 13, 583-594 (2005).
[CrossRef] [PubMed]

E. Gotzinger, M. Pircher, and C.K. Hitzenberger, "High speed spectral domain polarization sensitive optical coherence tomography," Opt. Express 13, 217-229 (2005).
[CrossRef]

Pitris, C.

Puliafito, C.

D. Huang, E. Swanson, C. Lin, J. Schuman, W. Stinson, W. Chang, M. Hee, T. Flotte, K. Gregory, C. Puliafito, and J. Fujimoto, "Optical coherence tomography,’Science,  254, 1178-1181 (1991)
[CrossRef] [PubMed]

Ren, H. W.

Rollins, A. M.

S. Yazdanfar, A. M. Rollins, and J. A. Izatt, "In vivo imaging of human retinal flow dynamics by color Doppler optical coherence tomography." Arch. Ophthalmol. 121, 235-239 (2003).
[PubMed]

S. Yazdanfar, A. M. Rollins, and J. A. Izatt, "Imaging and velocimetry of the human retinal circulation with color Doppler optical coherence tomography," Opt. Lett. 25, 1448-1450 (2000).
[CrossRef]

Schmetterer, L.

Schuman, J.

D. Huang, E. Swanson, C. Lin, J. Schuman, W. Stinson, W. Chang, M. Hee, T. Flotte, K. Gregory, C. Puliafito, and J. Fujimoto, "Optical coherence tomography,’Science,  254, 1178-1181 (1991)
[CrossRef] [PubMed]

Srinivas, S.

Sticker, M.

Stinson, W.

D. Huang, E. Swanson, C. Lin, J. Schuman, W. Stinson, W. Chang, M. Hee, T. Flotte, K. Gregory, C. Puliafito, and J. Fujimoto, "Optical coherence tomography,’Science,  254, 1178-1181 (1991)
[CrossRef] [PubMed]

Swanson, E.

D. Huang, E. Swanson, C. Lin, J. Schuman, W. Stinson, W. Chang, M. Hee, T. Flotte, K. Gregory, C. Puliafito, and J. Fujimoto, "Optical coherence tomography,’Science,  254, 1178-1181 (1991)
[CrossRef] [PubMed]

Tearney, G. J.

Tearney, G.J.

Tomlins, P. H.

P.H. Tomlins and R.K. Wang, "Theory, development and applications of optical coherence tomography," J Phys. D: Appl. Phys. 38, 2519-2535 (2005)
[CrossRef]

Vakoc, B. J.

Wang, L. H.

S. Jiao, L. H. Wang, "Two-dimensional depth-resolved Mueller matrix of biological tissue measured with double-beam polarization-sensitive optical coherence tomography," Opt Lett. 27, 101-103 (2002).
[CrossRef]

Wang, R. K.

R. K. Wang, "In vivo full range complex Fourier Domain optical coherence tomography," Appl. Phys. Lett. 90, 054103 (2007.
[CrossRef]

R. K. Wang and Z. H. Ma, "A practical approach to eliminate autocorrelation artefacts for volume-rate spectral domain optical coherence tomography," Phys. Med. Biol. 51, 3231-3239 (2006).
[CrossRef] [PubMed]

R. K. Wang and Z. H. Ma, "Real-time flow imaging by removing texture pattern artifacts in spectral-domain optical Doppler tomography," Opt. Lett. 31, 3001-3003 (2006).
[CrossRef] [PubMed]

S. J. Kirkpatrick, R. K. Wang, and D. D. Duncan, "OCT-based elastography for large and small deformations," Opt. Express 14, 11585-11597 (2006).
[CrossRef] [PubMed]

R. K. Wang, Z. Ma, and S. J. Kirkpatrick, "Tissue Doppler optical coherence elastography for real time strain rate and strain mapping of soft tissue," Appl. Phys. Lett.,  89, 144103 (2006)
[CrossRef]

P.H. Tomlins and R.K. Wang, "Theory, development and applications of optical coherence tomography," J Phys. D: Appl. Phys. 38, 2519-2535 (2005)
[CrossRef]

R. K. Wang, "Modelling Optical Properties of Soft Tissue by Fractal Distribution of Scatters," J. Mod. Opt.,  47, 103-120 (2000).

White, B. R.

Wojtkowski, M.

Yamanari, M.

Yasuno, Y.

Yatagai, M. Y. T.

Yatagai, T.

Yazdanfar, S.

S. Yazdanfar, A. M. Rollins, and J. A. Izatt, "In vivo imaging of human retinal flow dynamics by color Doppler optical coherence tomography." Arch. Ophthalmol. 121, 235-239 (2003).
[PubMed]

S. Yazdanfar, A. M. Rollins, and J. A. Izatt, "Imaging and velocimetry of the human retinal circulation with color Doppler optical coherence tomography," Opt. Lett. 25, 1448-1450 (2000).
[CrossRef]

Yun, S. H.

Zawadzki, R. J.

Zhang, J.

Zhao, Y. H.

Appl. Opt.

Appl. Phys. Lett.

R. K. Wang, Z. Ma, and S. J. Kirkpatrick, "Tissue Doppler optical coherence elastography for real time strain rate and strain mapping of soft tissue," Appl. Phys. Lett.,  89, 144103 (2006)
[CrossRef]

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Supplementary Material (3)

» Media 1: AVI (2541 KB)     
» Media 2: AVI (3617 KB)     
» Media 3: AVI (3119 KB)     

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Figures (6)

Fig. 1.
Fig. 1.

Schematic of the OAG system used to collect the 3-D spectral interferogram data cube to perform the 3-D angiogram of thick tissue in vivo. CCD represents the charge coupled device, PC the polarization controller. Note that the mirror is mounted on the piezo-stage that moves at a constant speed, otherwise it is stationary. The sample was sliced with priority in the lateral direction, x, by raster-scanning the focused beam spot using a pair of X-Y galvanometer scanners to built a 3-D volume data set. During the imaging, the sample surface was adjusted just below the zero delay line to avoid the static image crossing the negative space.

Fig. 2.
Fig. 2.

A cross-section (slice) of an adult mouse brain with the skull intact was imaged with OAG in vivo. (A) The data set representing the slice contains 2-D real-valued spectral interferogram in x-λ (2.2 mm by 112 nm centered at 842nm). (B) The imaging result obtained from (A) by OAG. It is separated by the zero delay line into two equal spaces. The normal OCT image is located in the bottom region (2.2 by 1.7 mm) showing microstructures. The signals from the moving blood cells are located in the upper region (also 2.2 by 1.7 mm). (C) Folded and fused final OAG image (2.2 by 1.7 mm) of the slice showing the location of moving blood (red color) within the cortex and mininges where there are more blood vessels than in the skull bone. A threshold above the noise floor of 15 decibels (dB) was used in the flow image before the image fusion took place to avoid the background noise. Both (B) and (C) images are displayed after log-compression of the OAG data to enhance the imaging contrast into the depth due to the fact that the light attenuation into the scattering tissue roughly follows the Beer-Lambert law. The scale bar in (B) and (C) represents 500 μm.

Fig. 3.
Fig. 3.

A volume of 2.2x2.2x1.7 mm3 of an adult mouse brain with the skull intact was imaged with OAG in vivo. The imaging time to obtain this 3-D OAG image took about 50s using current system setup (Fig. 1). (A), The 2-D x-y projection view of cerebro-vascular flow within the scanned volume that maps the detailed blood vessel network, including the capillaries. (B), Complete 3-D view of the blood flow map merged into the 3-D microstructures available in the positive space of the OAG output. The 3-D volume rendering of the blood vessel network skeleton is shown to illustrate how the blood vessels are orientated and localized in the 3-D microstructure of tissue. Using suitable software, this 3-D view could be rotated, cut and examined from any angle to illustrate the spatial relationship between the blood flow and tissue microstructures. See also movie1.avi (2.5MB) and movie2.avi (3.5MB).

Fig. 4.
Fig. 4.

The entire cerebro-vascular flow over the cortex of an adult mouse with the skull intact was imaged with OAG in vivo. (A) and (B) are the projection views of blood perfusion before and after the right carotid artery was blocked. Over the entire cortex, the majority of capillaries showing in (A) underwent undetected in (B), and furthermore, the diameters of the blood-flow-reconstructed vessels apparently became smaller in (B). Both are the indications of the blood flow slowing down in the entire cortex, rather than in the right hemisphere, after blocking the right carotid artery. It took ∼13 minutes to acquire the 3-D data to obtain (A) or (B) using the current system setup (Fig. 1). The projection image was obtained from OAG scans of 16 different regions one by one, which were then mosaiced to form (A)/(B). The area marked with dashed green box represents 8 by 10 mm^2. (C) Photograph of the skull with the skin folded aside, taken right after the experiments where viewing the vasculatures through the skull is impossible. (D) Photograph showing blood vessels over the cortex after the skull and the meninges of the same mouse were carefully removed. The superficial major blood vessels show excellent correspondence with those in (A) and (B). The contrast of this photograph as a whole was digitally enhanced to better illustrate the blood vessels.

Fig. 5.
Fig. 5.

Comparison of blood perfusion projection images obtained from an adult mouse brain with the skull intact in vivo by use of (A) OAG and (B) phase resolved DOCT, respectively. The projection images were obtained from the physical dimension of a volume 2.2x2.2x1.7 mm3. In obtaining (A) and (B), the pixel values were normalized by the maximum pixel value in each image, and then log compressed to give the images that were displayed using the colorbar shown in the bottom that has a scale of [-30dB 0].

Fig. 6.
Fig. 6.

[Movie3.avi (3.0MB)] 3-D rendered video showing that the OAG and Doppler OCT can be combined to quantify the blood flow within individual blood vessels shown in Fig. 5. In this particular movie, the projection of OAG flow image is given at the bottom of the frames, and the result from DOCT is updated frame by frame. The color bar represents -2.1mm/s (blue) to 2.1mm/s (red). The velocities calculated are the projections of true velocity vectors onto the incident beam direction (which was shone from the top into sample).

Equations (5)

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

B t 1 t 2 = cos ( 2 π f 0 t 1 + 2 π ( f M f D ) t 2 + ϕ )
H ˜ t 1 t 2 = cos ( 2 π ( f M f D ) t 2 + 2 π f 0 t 1 + ϕ ) + j sin ( 2 π ( f M f D ) t 2 + 2 π f 0 t 1 + ϕ )
H ˜ t 1 t 2 = cos ( 2 π ( f M f D ) t 2 + 2 π f 0 t 1 + ϕ ) j sin ( 2 π ( f M f D ) t 2 + 2 π f 0 t 1 + ϕ )
B 1 λ x = cos ( 4 π ( z s + ( v ref + v s ) x v x ) λ + φ x z λ )
f 0 = z s , t 1 = 2 λ , f M = 2 v ref λ , f D = 2 v s λ , t 2 = t x

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