Abstract

Many diseases involve either the formation of new blood vessels (e.g., tumor angiogenesis) or the damage of existing ones (e.g., diabetic retinopathy) at the microcirculation level. Optical-resolution photoacoustic microscopy (OR-PAM), capable of imaging microvessels in 3D in vivo down to individual capillaries using endogenous contrast, has the potential to reveal microvascular information critical to the diagnosis and staging of microcirculation-related diseases. In this study, we have developed a dedicated microvascular quantification (MQ) algorithm for OR-PAM to automatically quantify multiple microvascular morphological parameters in parallel, including the vessel diameter distribution, the microvessel density, the vascular tortuosity, and the fractal dimension. The algorithm has been tested on in vivo OR-PAM images of a healthy mouse, demonstrating high accuracy for microvascular segmentation and quantification. The developed MQ algorithm for OR-PAM may greatly facilitate quantitative imaging of tumor angiogenesis and many other microcirculation related diseases in vivo.

© 2014 Optical Society of America

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    [CrossRef] [PubMed]
  2. R. Ma, S. Söntges, S. Shoham, V. Ntziachristos, D. Razansky, “Fast scanning coaxial optoacoustic microscopy,” Biomed. Opt. Express 3(7), 1724–1731 (2012).
    [CrossRef] [PubMed]
  3. K. Maslov, H. F. Zhang, S. Hu, L. V. Wang, “Optical-resolution photoacoustic microscopy for in vivo imaging of single capillaries,” Opt. Lett. 33(9), 929–931 (2008).
    [CrossRef] [PubMed]
  4. L. Song, K. Maslov, L. V. Wang, “Multifocal optical-resolution photoacoustic microscopy in vivo,” Opt. Lett. 36(7), 1236–1238 (2011).
    [CrossRef] [PubMed]
  5. P. Hajireza, W. Shi, R. Zemp, “Label-free in vivo GRIN-lens optical resolution photoacoustic micro-endoscopy,” Laser Phys. Lett. 10(5), 055603 (2013).
    [CrossRef]
  6. S. Hu, L. V. Wang, “Photoacoustic imaging and characterization of the microvasculature,” J. Biomed. Opt. 15(1), 011101 (2010).
    [CrossRef] [PubMed]
  7. S. S. Oladipupo, S. Hu, A. C. Santeford, J. Yao, J. R. Kovalski, R. V. Shohet, K. Maslov, L. V. Wang, J. M. Arbeit, “Conditional HIF-1 induction produces multistage neovascularization with stage-specific sensitivity to VEGFR inhibitors and myeloid cell independence,” Blood 117(15), 4142–4153 (2011).
    [CrossRef] [PubMed]
  8. S. Oladipupo, S. Hu, J. Kovalski, J. J. Yao, A. Santeford, R. E. Sohn, R. Shohet, K. Maslov, L. V. Wang, J. M. Arbeit, “VEGF is essential for hypoxia-inducible factor-mediated neovascularization but dispensable for endothelial sprouting,” Proc. Natl. Acad. Sci. U. S. A. 108(32), 13264–13269 (2011).
    [CrossRef] [PubMed]
  9. J. Folkman, “Angiogenesis in cancer, vascular, rheumatoid and other disease,” Nat. Med. 1(1), 27–30 (1995).
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  10. J. Folkman, M. Bach, J. W. Rowe, F. Davidoff, P. Lambert, C. Hirsch, A. Goldberg, H. H. Hiatt, J. Glass, E. Henshaw, “Tumor angiogenesis: therapeutic implications,” N. Engl. J. Med. 285(21), 1182–1186 (1971).
    [CrossRef] [PubMed]
  11. J. W. Baish, R. K. Jain, “Cancer, angiogenesis and fractals,” Nat. Med. 4(9), 984 (1998).
    [CrossRef] [PubMed]
  12. R. K. Jain, “Normalizing tumor vasculature with anti-angiogenic therapy: A new paradigm for combination therapy,” Nat. Med. 7(9), 987–989 (2001).
    [CrossRef] [PubMed]
  13. B. J. Vakoc, R. M. Lanning, J. A. Tyrrell, T. P. Padera, L. A. Bartlett, T. Stylianopoulos, L. L. Munn, G. J. Tearney, D. Fukumura, R. K. Jain, B. E. Bouma, “Three-dimensional microscopy of the tumor microenvironment in vivo using optical frequency domain imaging,” Nat. Med. 15(10), 1219–1223 (2009).
    [CrossRef] [PubMed]
  14. Y. Gazit, J. W. Baish, N. Safabakhsh, M. Leunig, L. T. Baxter, R. K. Jain, “Fractal characteristics of tumor vascular architecture during tumor growth and regression,” Microcirculation 4(4), 395–402 (1997).
    [CrossRef] [PubMed]
  15. L. Hlatky, P. Hahnfeldt, J. Folkman, “Clinical application of antiangiogenic therapy: Microvessel density, what it does and doesn’t tell us,” J. Natl. Cancer Inst. 94(12), 883–893 (2002).
    [CrossRef] [PubMed]
  16. E. Bullitt, D. L. Zeng, G. Gerig, S. Aylward, S. Joshi, J. K. Smith, W. L. Lin, M. G. Ewend, “Vessel tortuosity and brain tumor malignancy: A blinded study,” Acad. Radiol. 12(10), 1232–1240 (2005).
    [CrossRef] [PubMed]
  17. H. Harada, X. J. Xie, S. Itasaka, L. H. Zeng, Y. X. Zhu, A. Morinibu, K. Shinomiya, M. Hiraoka, “Diameter of tumor blood vessels is a good parameter to estimate HIF-1-active regions in solid tumors,” Biochem. Biophys. Res. Commun. 373(4), 533–538 (2008).
    [CrossRef] [PubMed]
  18. E. Bullitt, G. Gerig, S. M. Pizer, W. L. Lin, S. R. Aylward, “Measuring tortuosity of the intracerebral vasculature from MRA images,” IEEE Trans. Med. Imaging 22(9), 1163–1171 (2003).
    [CrossRef]
  19. A. F. Frangi, W. J. Niessen, K. L. Vincken, M. A. Viergever, “Multiscale vessel enhancement filtering,” Med. Image Comput. Comput. Assisted Intervention 1496, 130–137 (1998).
  20. C. Li, R. Huang, Z. Ding, J. Gatenby, D. N. Metaxas, J. C. Gore, “A level set method for image segmentation in the presence of intensity inhomogeneities with application to MRI,” IEEE Trans. Image Process. 20(7), 2007–2016 (2011).
    [CrossRef]
  21. J. Chen, R. Lin, H. Wang, J. Meng, H. Zheng, L. Song, “Blind-deconvolution optical-resolution photoacoustic microscopy in vivo,” Opt. Express 21(6), 7316–7327 (2013).
    [CrossRef] [PubMed]
  22. R. Fattal, D. Lischinski, M. Werman, “Gradient domain high dynamic range compression,” ACM Trans. Graphics 21, 249–256 (2002).
  23. R. Van Uitert, I. Bitter, “Subvoxel precise skeletons of volumetric data based on fast marching methods,” Med. Phys. 34(2), 627–638 (2007).
    [CrossRef] [PubMed]
  24. R. K. Jain, N. Safabakhsh, A. Sckell, Y. Chen, P. Jiang, L. Benjamin, F. Yuan, E. Keshet, “Endothelial cell death, angiogenesis, and microvascular function after castration in an androgen-dependent tumor: role of vascular endothelial growth factor,” Proc. Natl. Acad. Sci. U. S. A. 95(18), 10820–10825 (1998).
    [CrossRef] [PubMed]
  25. E. Bullitt, D. Zeng, G. Gerig, S. Aylward, S. Joshi, J. K. Smith, W. Lin, M. G. Ewend, “Vessel tortuosity and brain tumor malignancy: a blinded study,” Acad. Radiol. 12(10), 1232–1240 (2005).
    [CrossRef] [PubMed]
  26. A. H. Parikh, J. K. Smith, M. G. Ewend, E. Bullitt, “Correlation of MR perfusion imaging and vessel tortuosity parameters in assessment of intracranial neoplasms,” Technol. Cancer Res. Treat. 3(6), 585–590 (2004).
    [PubMed]
  27. J. W. Baish, R. K. Jain, “Fractals and cancer,” Cancer Res. 60(14), 3683–3688 (2000).
    [PubMed]
  28. S. P. Lalley, D. Gatzouras, “Hausdorff and box dimensions of certain self-affine fractals,” Indiana Univ. Math. J. 41(2), 533–568 (1992).
    [CrossRef]

2013 (2)

P. Hajireza, W. Shi, R. Zemp, “Label-free in vivo GRIN-lens optical resolution photoacoustic micro-endoscopy,” Laser Phys. Lett. 10(5), 055603 (2013).
[CrossRef]

J. Chen, R. Lin, H. Wang, J. Meng, H. Zheng, L. Song, “Blind-deconvolution optical-resolution photoacoustic microscopy in vivo,” Opt. Express 21(6), 7316–7327 (2013).
[CrossRef] [PubMed]

2012 (2)

R. Ma, S. Söntges, S. Shoham, V. Ntziachristos, D. Razansky, “Fast scanning coaxial optoacoustic microscopy,” Biomed. Opt. Express 3(7), 1724–1731 (2012).
[CrossRef] [PubMed]

L. V. Wang, S. Hu, “Photoacoustic tomography: in vivo imaging from organelles to organs,” Science 335(6075), 1458–1462 (2012).
[CrossRef] [PubMed]

2011 (4)

S. S. Oladipupo, S. Hu, A. C. Santeford, J. Yao, J. R. Kovalski, R. V. Shohet, K. Maslov, L. V. Wang, J. M. Arbeit, “Conditional HIF-1 induction produces multistage neovascularization with stage-specific sensitivity to VEGFR inhibitors and myeloid cell independence,” Blood 117(15), 4142–4153 (2011).
[CrossRef] [PubMed]

S. Oladipupo, S. Hu, J. Kovalski, J. J. Yao, A. Santeford, R. E. Sohn, R. Shohet, K. Maslov, L. V. Wang, J. M. Arbeit, “VEGF is essential for hypoxia-inducible factor-mediated neovascularization but dispensable for endothelial sprouting,” Proc. Natl. Acad. Sci. U. S. A. 108(32), 13264–13269 (2011).
[CrossRef] [PubMed]

L. Song, K. Maslov, L. V. Wang, “Multifocal optical-resolution photoacoustic microscopy in vivo,” Opt. Lett. 36(7), 1236–1238 (2011).
[CrossRef] [PubMed]

C. Li, R. Huang, Z. Ding, J. Gatenby, D. N. Metaxas, J. C. Gore, “A level set method for image segmentation in the presence of intensity inhomogeneities with application to MRI,” IEEE Trans. Image Process. 20(7), 2007–2016 (2011).
[CrossRef]

2010 (1)

S. Hu, L. V. Wang, “Photoacoustic imaging and characterization of the microvasculature,” J. Biomed. Opt. 15(1), 011101 (2010).
[CrossRef] [PubMed]

2009 (1)

B. J. Vakoc, R. M. Lanning, J. A. Tyrrell, T. P. Padera, L. A. Bartlett, T. Stylianopoulos, L. L. Munn, G. J. Tearney, D. Fukumura, R. K. Jain, B. E. Bouma, “Three-dimensional microscopy of the tumor microenvironment in vivo using optical frequency domain imaging,” Nat. Med. 15(10), 1219–1223 (2009).
[CrossRef] [PubMed]

2008 (2)

H. Harada, X. J. Xie, S. Itasaka, L. H. Zeng, Y. X. Zhu, A. Morinibu, K. Shinomiya, M. Hiraoka, “Diameter of tumor blood vessels is a good parameter to estimate HIF-1-active regions in solid tumors,” Biochem. Biophys. Res. Commun. 373(4), 533–538 (2008).
[CrossRef] [PubMed]

K. Maslov, H. F. Zhang, S. Hu, L. V. Wang, “Optical-resolution photoacoustic microscopy for in vivo imaging of single capillaries,” Opt. Lett. 33(9), 929–931 (2008).
[CrossRef] [PubMed]

2007 (1)

R. Van Uitert, I. Bitter, “Subvoxel precise skeletons of volumetric data based on fast marching methods,” Med. Phys. 34(2), 627–638 (2007).
[CrossRef] [PubMed]

2005 (2)

E. Bullitt, D. Zeng, G. Gerig, S. Aylward, S. Joshi, J. K. Smith, W. Lin, M. G. Ewend, “Vessel tortuosity and brain tumor malignancy: a blinded study,” Acad. Radiol. 12(10), 1232–1240 (2005).
[CrossRef] [PubMed]

E. Bullitt, D. L. Zeng, G. Gerig, S. Aylward, S. Joshi, J. K. Smith, W. L. Lin, M. G. Ewend, “Vessel tortuosity and brain tumor malignancy: A blinded study,” Acad. Radiol. 12(10), 1232–1240 (2005).
[CrossRef] [PubMed]

2004 (1)

A. H. Parikh, J. K. Smith, M. G. Ewend, E. Bullitt, “Correlation of MR perfusion imaging and vessel tortuosity parameters in assessment of intracranial neoplasms,” Technol. Cancer Res. Treat. 3(6), 585–590 (2004).
[PubMed]

2003 (1)

E. Bullitt, G. Gerig, S. M. Pizer, W. L. Lin, S. R. Aylward, “Measuring tortuosity of the intracerebral vasculature from MRA images,” IEEE Trans. Med. Imaging 22(9), 1163–1171 (2003).
[CrossRef]

2002 (2)

R. Fattal, D. Lischinski, M. Werman, “Gradient domain high dynamic range compression,” ACM Trans. Graphics 21, 249–256 (2002).

L. Hlatky, P. Hahnfeldt, J. Folkman, “Clinical application of antiangiogenic therapy: Microvessel density, what it does and doesn’t tell us,” J. Natl. Cancer Inst. 94(12), 883–893 (2002).
[CrossRef] [PubMed]

2001 (1)

R. K. Jain, “Normalizing tumor vasculature with anti-angiogenic therapy: A new paradigm for combination therapy,” Nat. Med. 7(9), 987–989 (2001).
[CrossRef] [PubMed]

2000 (1)

J. W. Baish, R. K. Jain, “Fractals and cancer,” Cancer Res. 60(14), 3683–3688 (2000).
[PubMed]

1998 (3)

R. K. Jain, N. Safabakhsh, A. Sckell, Y. Chen, P. Jiang, L. Benjamin, F. Yuan, E. Keshet, “Endothelial cell death, angiogenesis, and microvascular function after castration in an androgen-dependent tumor: role of vascular endothelial growth factor,” Proc. Natl. Acad. Sci. U. S. A. 95(18), 10820–10825 (1998).
[CrossRef] [PubMed]

J. W. Baish, R. K. Jain, “Cancer, angiogenesis and fractals,” Nat. Med. 4(9), 984 (1998).
[CrossRef] [PubMed]

A. F. Frangi, W. J. Niessen, K. L. Vincken, M. A. Viergever, “Multiscale vessel enhancement filtering,” Med. Image Comput. Comput. Assisted Intervention 1496, 130–137 (1998).

1997 (1)

Y. Gazit, J. W. Baish, N. Safabakhsh, M. Leunig, L. T. Baxter, R. K. Jain, “Fractal characteristics of tumor vascular architecture during tumor growth and regression,” Microcirculation 4(4), 395–402 (1997).
[CrossRef] [PubMed]

1995 (1)

J. Folkman, “Angiogenesis in cancer, vascular, rheumatoid and other disease,” Nat. Med. 1(1), 27–30 (1995).
[CrossRef] [PubMed]

1992 (1)

S. P. Lalley, D. Gatzouras, “Hausdorff and box dimensions of certain self-affine fractals,” Indiana Univ. Math. J. 41(2), 533–568 (1992).
[CrossRef]

1971 (1)

J. Folkman, M. Bach, J. W. Rowe, F. Davidoff, P. Lambert, C. Hirsch, A. Goldberg, H. H. Hiatt, J. Glass, E. Henshaw, “Tumor angiogenesis: therapeutic implications,” N. Engl. J. Med. 285(21), 1182–1186 (1971).
[CrossRef] [PubMed]

Arbeit, J. M.

S. S. Oladipupo, S. Hu, A. C. Santeford, J. Yao, J. R. Kovalski, R. V. Shohet, K. Maslov, L. V. Wang, J. M. Arbeit, “Conditional HIF-1 induction produces multistage neovascularization with stage-specific sensitivity to VEGFR inhibitors and myeloid cell independence,” Blood 117(15), 4142–4153 (2011).
[CrossRef] [PubMed]

S. Oladipupo, S. Hu, J. Kovalski, J. J. Yao, A. Santeford, R. E. Sohn, R. Shohet, K. Maslov, L. V. Wang, J. M. Arbeit, “VEGF is essential for hypoxia-inducible factor-mediated neovascularization but dispensable for endothelial sprouting,” Proc. Natl. Acad. Sci. U. S. A. 108(32), 13264–13269 (2011).
[CrossRef] [PubMed]

Aylward, S.

E. Bullitt, D. L. Zeng, G. Gerig, S. Aylward, S. Joshi, J. K. Smith, W. L. Lin, M. G. Ewend, “Vessel tortuosity and brain tumor malignancy: A blinded study,” Acad. Radiol. 12(10), 1232–1240 (2005).
[CrossRef] [PubMed]

E. Bullitt, D. Zeng, G. Gerig, S. Aylward, S. Joshi, J. K. Smith, W. Lin, M. G. Ewend, “Vessel tortuosity and brain tumor malignancy: a blinded study,” Acad. Radiol. 12(10), 1232–1240 (2005).
[CrossRef] [PubMed]

Aylward, S. R.

E. Bullitt, G. Gerig, S. M. Pizer, W. L. Lin, S. R. Aylward, “Measuring tortuosity of the intracerebral vasculature from MRA images,” IEEE Trans. Med. Imaging 22(9), 1163–1171 (2003).
[CrossRef]

Bach, M.

J. Folkman, M. Bach, J. W. Rowe, F. Davidoff, P. Lambert, C. Hirsch, A. Goldberg, H. H. Hiatt, J. Glass, E. Henshaw, “Tumor angiogenesis: therapeutic implications,” N. Engl. J. Med. 285(21), 1182–1186 (1971).
[CrossRef] [PubMed]

Baish, J. W.

J. W. Baish, R. K. Jain, “Fractals and cancer,” Cancer Res. 60(14), 3683–3688 (2000).
[PubMed]

J. W. Baish, R. K. Jain, “Cancer, angiogenesis and fractals,” Nat. Med. 4(9), 984 (1998).
[CrossRef] [PubMed]

Y. Gazit, J. W. Baish, N. Safabakhsh, M. Leunig, L. T. Baxter, R. K. Jain, “Fractal characteristics of tumor vascular architecture during tumor growth and regression,” Microcirculation 4(4), 395–402 (1997).
[CrossRef] [PubMed]

Bartlett, L. A.

B. J. Vakoc, R. M. Lanning, J. A. Tyrrell, T. P. Padera, L. A. Bartlett, T. Stylianopoulos, L. L. Munn, G. J. Tearney, D. Fukumura, R. K. Jain, B. E. Bouma, “Three-dimensional microscopy of the tumor microenvironment in vivo using optical frequency domain imaging,” Nat. Med. 15(10), 1219–1223 (2009).
[CrossRef] [PubMed]

Baxter, L. T.

Y. Gazit, J. W. Baish, N. Safabakhsh, M. Leunig, L. T. Baxter, R. K. Jain, “Fractal characteristics of tumor vascular architecture during tumor growth and regression,” Microcirculation 4(4), 395–402 (1997).
[CrossRef] [PubMed]

Benjamin, L.

R. K. Jain, N. Safabakhsh, A. Sckell, Y. Chen, P. Jiang, L. Benjamin, F. Yuan, E. Keshet, “Endothelial cell death, angiogenesis, and microvascular function after castration in an androgen-dependent tumor: role of vascular endothelial growth factor,” Proc. Natl. Acad. Sci. U. S. A. 95(18), 10820–10825 (1998).
[CrossRef] [PubMed]

Bitter, I.

R. Van Uitert, I. Bitter, “Subvoxel precise skeletons of volumetric data based on fast marching methods,” Med. Phys. 34(2), 627–638 (2007).
[CrossRef] [PubMed]

Bouma, B. E.

B. J. Vakoc, R. M. Lanning, J. A. Tyrrell, T. P. Padera, L. A. Bartlett, T. Stylianopoulos, L. L. Munn, G. J. Tearney, D. Fukumura, R. K. Jain, B. E. Bouma, “Three-dimensional microscopy of the tumor microenvironment in vivo using optical frequency domain imaging,” Nat. Med. 15(10), 1219–1223 (2009).
[CrossRef] [PubMed]

Bullitt, E.

E. Bullitt, D. L. Zeng, G. Gerig, S. Aylward, S. Joshi, J. K. Smith, W. L. Lin, M. G. Ewend, “Vessel tortuosity and brain tumor malignancy: A blinded study,” Acad. Radiol. 12(10), 1232–1240 (2005).
[CrossRef] [PubMed]

E. Bullitt, D. Zeng, G. Gerig, S. Aylward, S. Joshi, J. K. Smith, W. Lin, M. G. Ewend, “Vessel tortuosity and brain tumor malignancy: a blinded study,” Acad. Radiol. 12(10), 1232–1240 (2005).
[CrossRef] [PubMed]

A. H. Parikh, J. K. Smith, M. G. Ewend, E. Bullitt, “Correlation of MR perfusion imaging and vessel tortuosity parameters in assessment of intracranial neoplasms,” Technol. Cancer Res. Treat. 3(6), 585–590 (2004).
[PubMed]

E. Bullitt, G. Gerig, S. M. Pizer, W. L. Lin, S. R. Aylward, “Measuring tortuosity of the intracerebral vasculature from MRA images,” IEEE Trans. Med. Imaging 22(9), 1163–1171 (2003).
[CrossRef]

Chen, J.

Chen, Y.

R. K. Jain, N. Safabakhsh, A. Sckell, Y. Chen, P. Jiang, L. Benjamin, F. Yuan, E. Keshet, “Endothelial cell death, angiogenesis, and microvascular function after castration in an androgen-dependent tumor: role of vascular endothelial growth factor,” Proc. Natl. Acad. Sci. U. S. A. 95(18), 10820–10825 (1998).
[CrossRef] [PubMed]

Davidoff, F.

J. Folkman, M. Bach, J. W. Rowe, F. Davidoff, P. Lambert, C. Hirsch, A. Goldberg, H. H. Hiatt, J. Glass, E. Henshaw, “Tumor angiogenesis: therapeutic implications,” N. Engl. J. Med. 285(21), 1182–1186 (1971).
[CrossRef] [PubMed]

Ding, Z.

C. Li, R. Huang, Z. Ding, J. Gatenby, D. N. Metaxas, J. C. Gore, “A level set method for image segmentation in the presence of intensity inhomogeneities with application to MRI,” IEEE Trans. Image Process. 20(7), 2007–2016 (2011).
[CrossRef]

Ewend, M. G.

E. Bullitt, D. Zeng, G. Gerig, S. Aylward, S. Joshi, J. K. Smith, W. Lin, M. G. Ewend, “Vessel tortuosity and brain tumor malignancy: a blinded study,” Acad. Radiol. 12(10), 1232–1240 (2005).
[CrossRef] [PubMed]

E. Bullitt, D. L. Zeng, G. Gerig, S. Aylward, S. Joshi, J. K. Smith, W. L. Lin, M. G. Ewend, “Vessel tortuosity and brain tumor malignancy: A blinded study,” Acad. Radiol. 12(10), 1232–1240 (2005).
[CrossRef] [PubMed]

A. H. Parikh, J. K. Smith, M. G. Ewend, E. Bullitt, “Correlation of MR perfusion imaging and vessel tortuosity parameters in assessment of intracranial neoplasms,” Technol. Cancer Res. Treat. 3(6), 585–590 (2004).
[PubMed]

Fattal, R.

R. Fattal, D. Lischinski, M. Werman, “Gradient domain high dynamic range compression,” ACM Trans. Graphics 21, 249–256 (2002).

Folkman, J.

L. Hlatky, P. Hahnfeldt, J. Folkman, “Clinical application of antiangiogenic therapy: Microvessel density, what it does and doesn’t tell us,” J. Natl. Cancer Inst. 94(12), 883–893 (2002).
[CrossRef] [PubMed]

J. Folkman, “Angiogenesis in cancer, vascular, rheumatoid and other disease,” Nat. Med. 1(1), 27–30 (1995).
[CrossRef] [PubMed]

J. Folkman, M. Bach, J. W. Rowe, F. Davidoff, P. Lambert, C. Hirsch, A. Goldberg, H. H. Hiatt, J. Glass, E. Henshaw, “Tumor angiogenesis: therapeutic implications,” N. Engl. J. Med. 285(21), 1182–1186 (1971).
[CrossRef] [PubMed]

Frangi, A. F.

A. F. Frangi, W. J. Niessen, K. L. Vincken, M. A. Viergever, “Multiscale vessel enhancement filtering,” Med. Image Comput. Comput. Assisted Intervention 1496, 130–137 (1998).

Fukumura, D.

B. J. Vakoc, R. M. Lanning, J. A. Tyrrell, T. P. Padera, L. A. Bartlett, T. Stylianopoulos, L. L. Munn, G. J. Tearney, D. Fukumura, R. K. Jain, B. E. Bouma, “Three-dimensional microscopy of the tumor microenvironment in vivo using optical frequency domain imaging,” Nat. Med. 15(10), 1219–1223 (2009).
[CrossRef] [PubMed]

Gatenby, J.

C. Li, R. Huang, Z. Ding, J. Gatenby, D. N. Metaxas, J. C. Gore, “A level set method for image segmentation in the presence of intensity inhomogeneities with application to MRI,” IEEE Trans. Image Process. 20(7), 2007–2016 (2011).
[CrossRef]

Gatzouras, D.

S. P. Lalley, D. Gatzouras, “Hausdorff and box dimensions of certain self-affine fractals,” Indiana Univ. Math. J. 41(2), 533–568 (1992).
[CrossRef]

Gazit, Y.

Y. Gazit, J. W. Baish, N. Safabakhsh, M. Leunig, L. T. Baxter, R. K. Jain, “Fractal characteristics of tumor vascular architecture during tumor growth and regression,” Microcirculation 4(4), 395–402 (1997).
[CrossRef] [PubMed]

Gerig, G.

E. Bullitt, D. L. Zeng, G. Gerig, S. Aylward, S. Joshi, J. K. Smith, W. L. Lin, M. G. Ewend, “Vessel tortuosity and brain tumor malignancy: A blinded study,” Acad. Radiol. 12(10), 1232–1240 (2005).
[CrossRef] [PubMed]

E. Bullitt, D. Zeng, G. Gerig, S. Aylward, S. Joshi, J. K. Smith, W. Lin, M. G. Ewend, “Vessel tortuosity and brain tumor malignancy: a blinded study,” Acad. Radiol. 12(10), 1232–1240 (2005).
[CrossRef] [PubMed]

E. Bullitt, G. Gerig, S. M. Pizer, W. L. Lin, S. R. Aylward, “Measuring tortuosity of the intracerebral vasculature from MRA images,” IEEE Trans. Med. Imaging 22(9), 1163–1171 (2003).
[CrossRef]

Glass, J.

J. Folkman, M. Bach, J. W. Rowe, F. Davidoff, P. Lambert, C. Hirsch, A. Goldberg, H. H. Hiatt, J. Glass, E. Henshaw, “Tumor angiogenesis: therapeutic implications,” N. Engl. J. Med. 285(21), 1182–1186 (1971).
[CrossRef] [PubMed]

Goldberg, A.

J. Folkman, M. Bach, J. W. Rowe, F. Davidoff, P. Lambert, C. Hirsch, A. Goldberg, H. H. Hiatt, J. Glass, E. Henshaw, “Tumor angiogenesis: therapeutic implications,” N. Engl. J. Med. 285(21), 1182–1186 (1971).
[CrossRef] [PubMed]

Gore, J. C.

C. Li, R. Huang, Z. Ding, J. Gatenby, D. N. Metaxas, J. C. Gore, “A level set method for image segmentation in the presence of intensity inhomogeneities with application to MRI,” IEEE Trans. Image Process. 20(7), 2007–2016 (2011).
[CrossRef]

Hahnfeldt, P.

L. Hlatky, P. Hahnfeldt, J. Folkman, “Clinical application of antiangiogenic therapy: Microvessel density, what it does and doesn’t tell us,” J. Natl. Cancer Inst. 94(12), 883–893 (2002).
[CrossRef] [PubMed]

Hajireza, P.

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J. Folkman, M. Bach, J. W. Rowe, F. Davidoff, P. Lambert, C. Hirsch, A. Goldberg, H. H. Hiatt, J. Glass, E. Henshaw, “Tumor angiogenesis: therapeutic implications,” N. Engl. J. Med. 285(21), 1182–1186 (1971).
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J. Folkman, M. Bach, J. W. Rowe, F. Davidoff, P. Lambert, C. Hirsch, A. Goldberg, H. H. Hiatt, J. Glass, E. Henshaw, “Tumor angiogenesis: therapeutic implications,” N. Engl. J. Med. 285(21), 1182–1186 (1971).
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H. Harada, X. J. Xie, S. Itasaka, L. H. Zeng, Y. X. Zhu, A. Morinibu, K. Shinomiya, M. Hiraoka, “Diameter of tumor blood vessels is a good parameter to estimate HIF-1-active regions in solid tumors,” Biochem. Biophys. Res. Commun. 373(4), 533–538 (2008).
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S. Oladipupo, S. Hu, J. Kovalski, J. J. Yao, A. Santeford, R. E. Sohn, R. Shohet, K. Maslov, L. V. Wang, J. M. Arbeit, “VEGF is essential for hypoxia-inducible factor-mediated neovascularization but dispensable for endothelial sprouting,” Proc. Natl. Acad. Sci. U. S. A. 108(32), 13264–13269 (2011).
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S. Hu, L. V. Wang, “Photoacoustic imaging and characterization of the microvasculature,” J. Biomed. Opt. 15(1), 011101 (2010).
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K. Maslov, H. F. Zhang, S. Hu, L. V. Wang, “Optical-resolution photoacoustic microscopy for in vivo imaging of single capillaries,” Opt. Lett. 33(9), 929–931 (2008).
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C. Li, R. Huang, Z. Ding, J. Gatenby, D. N. Metaxas, J. C. Gore, “A level set method for image segmentation in the presence of intensity inhomogeneities with application to MRI,” IEEE Trans. Image Process. 20(7), 2007–2016 (2011).
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B. J. Vakoc, R. M. Lanning, J. A. Tyrrell, T. P. Padera, L. A. Bartlett, T. Stylianopoulos, L. L. Munn, G. J. Tearney, D. Fukumura, R. K. Jain, B. E. Bouma, “Three-dimensional microscopy of the tumor microenvironment in vivo using optical frequency domain imaging,” Nat. Med. 15(10), 1219–1223 (2009).
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J. W. Baish, R. K. Jain, “Cancer, angiogenesis and fractals,” Nat. Med. 4(9), 984 (1998).
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Y. Gazit, J. W. Baish, N. Safabakhsh, M. Leunig, L. T. Baxter, R. K. Jain, “Fractal characteristics of tumor vascular architecture during tumor growth and regression,” Microcirculation 4(4), 395–402 (1997).
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Jiang, P.

R. K. Jain, N. Safabakhsh, A. Sckell, Y. Chen, P. Jiang, L. Benjamin, F. Yuan, E. Keshet, “Endothelial cell death, angiogenesis, and microvascular function after castration in an androgen-dependent tumor: role of vascular endothelial growth factor,” Proc. Natl. Acad. Sci. U. S. A. 95(18), 10820–10825 (1998).
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Joshi, S.

E. Bullitt, D. Zeng, G. Gerig, S. Aylward, S. Joshi, J. K. Smith, W. Lin, M. G. Ewend, “Vessel tortuosity and brain tumor malignancy: a blinded study,” Acad. Radiol. 12(10), 1232–1240 (2005).
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E. Bullitt, D. L. Zeng, G. Gerig, S. Aylward, S. Joshi, J. K. Smith, W. L. Lin, M. G. Ewend, “Vessel tortuosity and brain tumor malignancy: A blinded study,” Acad. Radiol. 12(10), 1232–1240 (2005).
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R. K. Jain, N. Safabakhsh, A. Sckell, Y. Chen, P. Jiang, L. Benjamin, F. Yuan, E. Keshet, “Endothelial cell death, angiogenesis, and microvascular function after castration in an androgen-dependent tumor: role of vascular endothelial growth factor,” Proc. Natl. Acad. Sci. U. S. A. 95(18), 10820–10825 (1998).
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S. Oladipupo, S. Hu, J. Kovalski, J. J. Yao, A. Santeford, R. E. Sohn, R. Shohet, K. Maslov, L. V. Wang, J. M. Arbeit, “VEGF is essential for hypoxia-inducible factor-mediated neovascularization but dispensable for endothelial sprouting,” Proc. Natl. Acad. Sci. U. S. A. 108(32), 13264–13269 (2011).
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S. S. Oladipupo, S. Hu, A. C. Santeford, J. Yao, J. R. Kovalski, R. V. Shohet, K. Maslov, L. V. Wang, J. M. Arbeit, “Conditional HIF-1 induction produces multistage neovascularization with stage-specific sensitivity to VEGFR inhibitors and myeloid cell independence,” Blood 117(15), 4142–4153 (2011).
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[CrossRef] [PubMed]

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B. J. Vakoc, R. M. Lanning, J. A. Tyrrell, T. P. Padera, L. A. Bartlett, T. Stylianopoulos, L. L. Munn, G. J. Tearney, D. Fukumura, R. K. Jain, B. E. Bouma, “Three-dimensional microscopy of the tumor microenvironment in vivo using optical frequency domain imaging,” Nat. Med. 15(10), 1219–1223 (2009).
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Y. Gazit, J. W. Baish, N. Safabakhsh, M. Leunig, L. T. Baxter, R. K. Jain, “Fractal characteristics of tumor vascular architecture during tumor growth and regression,” Microcirculation 4(4), 395–402 (1997).
[CrossRef] [PubMed]

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C. Li, R. Huang, Z. Ding, J. Gatenby, D. N. Metaxas, J. C. Gore, “A level set method for image segmentation in the presence of intensity inhomogeneities with application to MRI,” IEEE Trans. Image Process. 20(7), 2007–2016 (2011).
[CrossRef]

Lin, R.

Lin, W.

E. Bullitt, D. Zeng, G. Gerig, S. Aylward, S. Joshi, J. K. Smith, W. Lin, M. G. Ewend, “Vessel tortuosity and brain tumor malignancy: a blinded study,” Acad. Radiol. 12(10), 1232–1240 (2005).
[CrossRef] [PubMed]

Lin, W. L.

E. Bullitt, D. L. Zeng, G. Gerig, S. Aylward, S. Joshi, J. K. Smith, W. L. Lin, M. G. Ewend, “Vessel tortuosity and brain tumor malignancy: A blinded study,” Acad. Radiol. 12(10), 1232–1240 (2005).
[CrossRef] [PubMed]

E. Bullitt, G. Gerig, S. M. Pizer, W. L. Lin, S. R. Aylward, “Measuring tortuosity of the intracerebral vasculature from MRA images,” IEEE Trans. Med. Imaging 22(9), 1163–1171 (2003).
[CrossRef]

Lischinski, D.

R. Fattal, D. Lischinski, M. Werman, “Gradient domain high dynamic range compression,” ACM Trans. Graphics 21, 249–256 (2002).

Ma, R.

Maslov, K.

L. Song, K. Maslov, L. V. Wang, “Multifocal optical-resolution photoacoustic microscopy in vivo,” Opt. Lett. 36(7), 1236–1238 (2011).
[CrossRef] [PubMed]

S. Oladipupo, S. Hu, J. Kovalski, J. J. Yao, A. Santeford, R. E. Sohn, R. Shohet, K. Maslov, L. V. Wang, J. M. Arbeit, “VEGF is essential for hypoxia-inducible factor-mediated neovascularization but dispensable for endothelial sprouting,” Proc. Natl. Acad. Sci. U. S. A. 108(32), 13264–13269 (2011).
[CrossRef] [PubMed]

S. S. Oladipupo, S. Hu, A. C. Santeford, J. Yao, J. R. Kovalski, R. V. Shohet, K. Maslov, L. V. Wang, J. M. Arbeit, “Conditional HIF-1 induction produces multistage neovascularization with stage-specific sensitivity to VEGFR inhibitors and myeloid cell independence,” Blood 117(15), 4142–4153 (2011).
[CrossRef] [PubMed]

K. Maslov, H. F. Zhang, S. Hu, L. V. Wang, “Optical-resolution photoacoustic microscopy for in vivo imaging of single capillaries,” Opt. Lett. 33(9), 929–931 (2008).
[CrossRef] [PubMed]

Meng, J.

Metaxas, D. N.

C. Li, R. Huang, Z. Ding, J. Gatenby, D. N. Metaxas, J. C. Gore, “A level set method for image segmentation in the presence of intensity inhomogeneities with application to MRI,” IEEE Trans. Image Process. 20(7), 2007–2016 (2011).
[CrossRef]

Morinibu, A.

H. Harada, X. J. Xie, S. Itasaka, L. H. Zeng, Y. X. Zhu, A. Morinibu, K. Shinomiya, M. Hiraoka, “Diameter of tumor blood vessels is a good parameter to estimate HIF-1-active regions in solid tumors,” Biochem. Biophys. Res. Commun. 373(4), 533–538 (2008).
[CrossRef] [PubMed]

Munn, L. L.

B. J. Vakoc, R. M. Lanning, J. A. Tyrrell, T. P. Padera, L. A. Bartlett, T. Stylianopoulos, L. L. Munn, G. J. Tearney, D. Fukumura, R. K. Jain, B. E. Bouma, “Three-dimensional microscopy of the tumor microenvironment in vivo using optical frequency domain imaging,” Nat. Med. 15(10), 1219–1223 (2009).
[CrossRef] [PubMed]

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A. F. Frangi, W. J. Niessen, K. L. Vincken, M. A. Viergever, “Multiscale vessel enhancement filtering,” Med. Image Comput. Comput. Assisted Intervention 1496, 130–137 (1998).

Ntziachristos, V.

Oladipupo, S.

S. Oladipupo, S. Hu, J. Kovalski, J. J. Yao, A. Santeford, R. E. Sohn, R. Shohet, K. Maslov, L. V. Wang, J. M. Arbeit, “VEGF is essential for hypoxia-inducible factor-mediated neovascularization but dispensable for endothelial sprouting,” Proc. Natl. Acad. Sci. U. S. A. 108(32), 13264–13269 (2011).
[CrossRef] [PubMed]

Oladipupo, S. S.

S. S. Oladipupo, S. Hu, A. C. Santeford, J. Yao, J. R. Kovalski, R. V. Shohet, K. Maslov, L. V. Wang, J. M. Arbeit, “Conditional HIF-1 induction produces multistage neovascularization with stage-specific sensitivity to VEGFR inhibitors and myeloid cell independence,” Blood 117(15), 4142–4153 (2011).
[CrossRef] [PubMed]

Padera, T. P.

B. J. Vakoc, R. M. Lanning, J. A. Tyrrell, T. P. Padera, L. A. Bartlett, T. Stylianopoulos, L. L. Munn, G. J. Tearney, D. Fukumura, R. K. Jain, B. E. Bouma, “Three-dimensional microscopy of the tumor microenvironment in vivo using optical frequency domain imaging,” Nat. Med. 15(10), 1219–1223 (2009).
[CrossRef] [PubMed]

Parikh, A. H.

A. H. Parikh, J. K. Smith, M. G. Ewend, E. Bullitt, “Correlation of MR perfusion imaging and vessel tortuosity parameters in assessment of intracranial neoplasms,” Technol. Cancer Res. Treat. 3(6), 585–590 (2004).
[PubMed]

Pizer, S. M.

E. Bullitt, G. Gerig, S. M. Pizer, W. L. Lin, S. R. Aylward, “Measuring tortuosity of the intracerebral vasculature from MRA images,” IEEE Trans. Med. Imaging 22(9), 1163–1171 (2003).
[CrossRef]

Razansky, D.

Rowe, J. W.

J. Folkman, M. Bach, J. W. Rowe, F. Davidoff, P. Lambert, C. Hirsch, A. Goldberg, H. H. Hiatt, J. Glass, E. Henshaw, “Tumor angiogenesis: therapeutic implications,” N. Engl. J. Med. 285(21), 1182–1186 (1971).
[CrossRef] [PubMed]

Safabakhsh, N.

R. K. Jain, N. Safabakhsh, A. Sckell, Y. Chen, P. Jiang, L. Benjamin, F. Yuan, E. Keshet, “Endothelial cell death, angiogenesis, and microvascular function after castration in an androgen-dependent tumor: role of vascular endothelial growth factor,” Proc. Natl. Acad. Sci. U. S. A. 95(18), 10820–10825 (1998).
[CrossRef] [PubMed]

Y. Gazit, J. W. Baish, N. Safabakhsh, M. Leunig, L. T. Baxter, R. K. Jain, “Fractal characteristics of tumor vascular architecture during tumor growth and regression,” Microcirculation 4(4), 395–402 (1997).
[CrossRef] [PubMed]

Santeford, A.

S. Oladipupo, S. Hu, J. Kovalski, J. J. Yao, A. Santeford, R. E. Sohn, R. Shohet, K. Maslov, L. V. Wang, J. M. Arbeit, “VEGF is essential for hypoxia-inducible factor-mediated neovascularization but dispensable for endothelial sprouting,” Proc. Natl. Acad. Sci. U. S. A. 108(32), 13264–13269 (2011).
[CrossRef] [PubMed]

Santeford, A. C.

S. S. Oladipupo, S. Hu, A. C. Santeford, J. Yao, J. R. Kovalski, R. V. Shohet, K. Maslov, L. V. Wang, J. M. Arbeit, “Conditional HIF-1 induction produces multistage neovascularization with stage-specific sensitivity to VEGFR inhibitors and myeloid cell independence,” Blood 117(15), 4142–4153 (2011).
[CrossRef] [PubMed]

Sckell, A.

R. K. Jain, N. Safabakhsh, A. Sckell, Y. Chen, P. Jiang, L. Benjamin, F. Yuan, E. Keshet, “Endothelial cell death, angiogenesis, and microvascular function after castration in an androgen-dependent tumor: role of vascular endothelial growth factor,” Proc. Natl. Acad. Sci. U. S. A. 95(18), 10820–10825 (1998).
[CrossRef] [PubMed]

Shi, W.

P. Hajireza, W. Shi, R. Zemp, “Label-free in vivo GRIN-lens optical resolution photoacoustic micro-endoscopy,” Laser Phys. Lett. 10(5), 055603 (2013).
[CrossRef]

Shinomiya, K.

H. Harada, X. J. Xie, S. Itasaka, L. H. Zeng, Y. X. Zhu, A. Morinibu, K. Shinomiya, M. Hiraoka, “Diameter of tumor blood vessels is a good parameter to estimate HIF-1-active regions in solid tumors,” Biochem. Biophys. Res. Commun. 373(4), 533–538 (2008).
[CrossRef] [PubMed]

Shoham, S.

Shohet, R.

S. Oladipupo, S. Hu, J. Kovalski, J. J. Yao, A. Santeford, R. E. Sohn, R. Shohet, K. Maslov, L. V. Wang, J. M. Arbeit, “VEGF is essential for hypoxia-inducible factor-mediated neovascularization but dispensable for endothelial sprouting,” Proc. Natl. Acad. Sci. U. S. A. 108(32), 13264–13269 (2011).
[CrossRef] [PubMed]

Shohet, R. V.

S. S. Oladipupo, S. Hu, A. C. Santeford, J. Yao, J. R. Kovalski, R. V. Shohet, K. Maslov, L. V. Wang, J. M. Arbeit, “Conditional HIF-1 induction produces multistage neovascularization with stage-specific sensitivity to VEGFR inhibitors and myeloid cell independence,” Blood 117(15), 4142–4153 (2011).
[CrossRef] [PubMed]

Smith, J. K.

E. Bullitt, D. L. Zeng, G. Gerig, S. Aylward, S. Joshi, J. K. Smith, W. L. Lin, M. G. Ewend, “Vessel tortuosity and brain tumor malignancy: A blinded study,” Acad. Radiol. 12(10), 1232–1240 (2005).
[CrossRef] [PubMed]

E. Bullitt, D. Zeng, G. Gerig, S. Aylward, S. Joshi, J. K. Smith, W. Lin, M. G. Ewend, “Vessel tortuosity and brain tumor malignancy: a blinded study,” Acad. Radiol. 12(10), 1232–1240 (2005).
[CrossRef] [PubMed]

A. H. Parikh, J. K. Smith, M. G. Ewend, E. Bullitt, “Correlation of MR perfusion imaging and vessel tortuosity parameters in assessment of intracranial neoplasms,” Technol. Cancer Res. Treat. 3(6), 585–590 (2004).
[PubMed]

Sohn, R. E.

S. Oladipupo, S. Hu, J. Kovalski, J. J. Yao, A. Santeford, R. E. Sohn, R. Shohet, K. Maslov, L. V. Wang, J. M. Arbeit, “VEGF is essential for hypoxia-inducible factor-mediated neovascularization but dispensable for endothelial sprouting,” Proc. Natl. Acad. Sci. U. S. A. 108(32), 13264–13269 (2011).
[CrossRef] [PubMed]

Song, L.

Söntges, S.

Stylianopoulos, T.

B. J. Vakoc, R. M. Lanning, J. A. Tyrrell, T. P. Padera, L. A. Bartlett, T. Stylianopoulos, L. L. Munn, G. J. Tearney, D. Fukumura, R. K. Jain, B. E. Bouma, “Three-dimensional microscopy of the tumor microenvironment in vivo using optical frequency domain imaging,” Nat. Med. 15(10), 1219–1223 (2009).
[CrossRef] [PubMed]

Tearney, G. J.

B. J. Vakoc, R. M. Lanning, J. A. Tyrrell, T. P. Padera, L. A. Bartlett, T. Stylianopoulos, L. L. Munn, G. J. Tearney, D. Fukumura, R. K. Jain, B. E. Bouma, “Three-dimensional microscopy of the tumor microenvironment in vivo using optical frequency domain imaging,” Nat. Med. 15(10), 1219–1223 (2009).
[CrossRef] [PubMed]

Tyrrell, J. A.

B. J. Vakoc, R. M. Lanning, J. A. Tyrrell, T. P. Padera, L. A. Bartlett, T. Stylianopoulos, L. L. Munn, G. J. Tearney, D. Fukumura, R. K. Jain, B. E. Bouma, “Three-dimensional microscopy of the tumor microenvironment in vivo using optical frequency domain imaging,” Nat. Med. 15(10), 1219–1223 (2009).
[CrossRef] [PubMed]

Vakoc, B. J.

B. J. Vakoc, R. M. Lanning, J. A. Tyrrell, T. P. Padera, L. A. Bartlett, T. Stylianopoulos, L. L. Munn, G. J. Tearney, D. Fukumura, R. K. Jain, B. E. Bouma, “Three-dimensional microscopy of the tumor microenvironment in vivo using optical frequency domain imaging,” Nat. Med. 15(10), 1219–1223 (2009).
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A. F. Frangi, W. J. Niessen, K. L. Vincken, M. A. Viergever, “Multiscale vessel enhancement filtering,” Med. Image Comput. Comput. Assisted Intervention 1496, 130–137 (1998).

Vincken, K. L.

A. F. Frangi, W. J. Niessen, K. L. Vincken, M. A. Viergever, “Multiscale vessel enhancement filtering,” Med. Image Comput. Comput. Assisted Intervention 1496, 130–137 (1998).

Wang, H.

Wang, L. V.

L. V. Wang, S. Hu, “Photoacoustic tomography: in vivo imaging from organelles to organs,” Science 335(6075), 1458–1462 (2012).
[CrossRef] [PubMed]

L. Song, K. Maslov, L. V. Wang, “Multifocal optical-resolution photoacoustic microscopy in vivo,” Opt. Lett. 36(7), 1236–1238 (2011).
[CrossRef] [PubMed]

S. S. Oladipupo, S. Hu, A. C. Santeford, J. Yao, J. R. Kovalski, R. V. Shohet, K. Maslov, L. V. Wang, J. M. Arbeit, “Conditional HIF-1 induction produces multistage neovascularization with stage-specific sensitivity to VEGFR inhibitors and myeloid cell independence,” Blood 117(15), 4142–4153 (2011).
[CrossRef] [PubMed]

S. Oladipupo, S. Hu, J. Kovalski, J. J. Yao, A. Santeford, R. E. Sohn, R. Shohet, K. Maslov, L. V. Wang, J. M. Arbeit, “VEGF is essential for hypoxia-inducible factor-mediated neovascularization but dispensable for endothelial sprouting,” Proc. Natl. Acad. Sci. U. S. A. 108(32), 13264–13269 (2011).
[CrossRef] [PubMed]

S. Hu, L. V. Wang, “Photoacoustic imaging and characterization of the microvasculature,” J. Biomed. Opt. 15(1), 011101 (2010).
[CrossRef] [PubMed]

K. Maslov, H. F. Zhang, S. Hu, L. V. Wang, “Optical-resolution photoacoustic microscopy for in vivo imaging of single capillaries,” Opt. Lett. 33(9), 929–931 (2008).
[CrossRef] [PubMed]

Werman, M.

R. Fattal, D. Lischinski, M. Werman, “Gradient domain high dynamic range compression,” ACM Trans. Graphics 21, 249–256 (2002).

Xie, X. J.

H. Harada, X. J. Xie, S. Itasaka, L. H. Zeng, Y. X. Zhu, A. Morinibu, K. Shinomiya, M. Hiraoka, “Diameter of tumor blood vessels is a good parameter to estimate HIF-1-active regions in solid tumors,” Biochem. Biophys. Res. Commun. 373(4), 533–538 (2008).
[CrossRef] [PubMed]

Yao, J.

S. S. Oladipupo, S. Hu, A. C. Santeford, J. Yao, J. R. Kovalski, R. V. Shohet, K. Maslov, L. V. Wang, J. M. Arbeit, “Conditional HIF-1 induction produces multistage neovascularization with stage-specific sensitivity to VEGFR inhibitors and myeloid cell independence,” Blood 117(15), 4142–4153 (2011).
[CrossRef] [PubMed]

Yao, J. J.

S. Oladipupo, S. Hu, J. Kovalski, J. J. Yao, A. Santeford, R. E. Sohn, R. Shohet, K. Maslov, L. V. Wang, J. M. Arbeit, “VEGF is essential for hypoxia-inducible factor-mediated neovascularization but dispensable for endothelial sprouting,” Proc. Natl. Acad. Sci. U. S. A. 108(32), 13264–13269 (2011).
[CrossRef] [PubMed]

Yuan, F.

R. K. Jain, N. Safabakhsh, A. Sckell, Y. Chen, P. Jiang, L. Benjamin, F. Yuan, E. Keshet, “Endothelial cell death, angiogenesis, and microvascular function after castration in an androgen-dependent tumor: role of vascular endothelial growth factor,” Proc. Natl. Acad. Sci. U. S. A. 95(18), 10820–10825 (1998).
[CrossRef] [PubMed]

Zemp, R.

P. Hajireza, W. Shi, R. Zemp, “Label-free in vivo GRIN-lens optical resolution photoacoustic micro-endoscopy,” Laser Phys. Lett. 10(5), 055603 (2013).
[CrossRef]

Zeng, D.

E. Bullitt, D. Zeng, G. Gerig, S. Aylward, S. Joshi, J. K. Smith, W. Lin, M. G. Ewend, “Vessel tortuosity and brain tumor malignancy: a blinded study,” Acad. Radiol. 12(10), 1232–1240 (2005).
[CrossRef] [PubMed]

Zeng, D. L.

E. Bullitt, D. L. Zeng, G. Gerig, S. Aylward, S. Joshi, J. K. Smith, W. L. Lin, M. G. Ewend, “Vessel tortuosity and brain tumor malignancy: A blinded study,” Acad. Radiol. 12(10), 1232–1240 (2005).
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Figures (9)

Fig. 1
Fig. 1

Schematic of the OR-PAM system. AP, aperture; CL, convex lens; FC, fiber coupler; SMF, single-mode optical fiber; Obj, objective; UST, ultrasonic transducer; AL, acoustic lens; SO, silicone oil; EA, electrical amplifier; DAQ, data acquisition; PC, personal computer.

Fig. 2
Fig. 2

Overall flow chart of the microvascular quantification algorithm.

Fig. 3
Fig. 3

Image illustration of the major steps for vessel extraction. (A) and (B), The original 2D OR-PAM image slices; (a) and (d) The Hessian matrix feature maps; (b) and (e) The fractional-differential enhanced feature maps; (c) and (f) The final images with extracted blood vessels.

Fig. 4
Fig. 4

Flow chart of the two-step augmented fast marching method (AFMM) for centerline extraction.

Fig. 5
Fig. 5

Computed vascular centerlines overlaid with a segmented volumetric OR-PAM image.

Fig. 6
Fig. 6

Comparison of the vessel extraction results using different algorithms. (a) The original 2D OR-PAM image slice; (b) Image with vessels extracted using a level set based algorithm [20]; (c) Image with vessels extracted using a traditional Hessian matrix algorithm developed for DSA and MRA [19]; (d) Image with vessels extracted using our modified Hessian matrix algorithm dedicated to OR-PAM.

Fig. 7
Fig. 7

Comparison of representative cross-section intensity profiles between the original and segmented images. (a) and (h), The original 2D OR-PAM sub-images (corresponding to the dash boxes 1 and 2 in Fig. 6); (b) and (i), The segmented images of (a) and (h) using the level set method; (c) and (j), The segmented images of (a) and (h) using the traditional Hessian matrix method developed for DSA and MRA; (d) and (k), The segmented images of (a) and (h) using our method dedicated to OR-PAM; (e) – (g) and (l) – (n), Blue lines: normalized intensity profiles corresponding to the yellow dash lines in the original images, red lines: extracted vessels corresponding to the yellow dash lines in the segmented images.

Fig. 8
Fig. 8

Vessel extraction in a volumetric OR-PAM image of a mouse ear in vivo. (a) The original volumetric OR-PAM image with depth encoded in color; (b) OR-PAM image with vessels extracted using the algorithm in [8]; (c) OR-PAM image with vessels extracted using our MQ algorithm. The color scale represents depth along z axis below the skin surface of the mouse.

Fig. 9
Fig. 9

Quantification of microvascular parameters with OR-PAM. (a) and (b) In vivo OR-PAM images of two different regions of a mouse ear; (c) In vivo OR-PAM image of the dorsal region of the same mouse; (d) The vessel diameter distribution; (E) Computed microvessel density (MVD), fractal dimension (FD), and vascular tortuosity—in three different metrics including the distance metric (DM), the inflection count metric (ICM), and the sum of angles metric (SOAM). The color scale represents depth along z axis below the skin surface of the mouse.

Equations (7)

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H hfe =a+b H hp (u,v),
H=[ 2 I(x,y,s) x 2 2 I(x,y,s) xy 2 I(x,y,s) yx 2 I(x,y,s) y 2 ],
f(s)= λ 2 ={ 0,if λ 2 >0 0,if| λ 1 |>ε=0.2 λ 2 ,else .
f= max s min s s max | f(s) |,
g= 1 1+ ( m f ' ) γ ,
MVD= Total Vessel Length Observed Volume .
D= lim r0 logN(r) log( r 1 )

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