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Optics Express

Optics Express

  • Editor: C. Martijn de Sterke
  • Vol. 17, Iss. 9 — Apr. 27, 2009
  • pp: 7688–7693
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Noninvasive label-free imaging of microhemodynamics by optical-resolution photoacoustic microscopy

Song Hu, Konstantin Maslov, and Lihong V. Wang  »View Author Affiliations


Optics Express, Vol. 17, Issue 9, pp. 7688-7693 (2009)
http://dx.doi.org/10.1364/OE.17.007688


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Abstract

In vivo microcirculatory imaging facilitates the fundamental understanding of many major diseases. However, existing techniques generally require invasive procedures or exogenous contrast agents, which perturb the intrinsic physiology of the microcirculation. Here, we report on optical-resolution photoacoustic microscopy (OR-PAM) for noninvasive label-free microcirculatory imaging at cellular levels. For the first time, OR-PAM demonstrates quantification of hemoglobin concentration and oxygenation in single microvessels down to capillaries. Using this technique, we imaged several important yet elusive microhemodynamic activities—including vasomotion and vasodilation—in small animals in vivo. OR-PAM enables functional volumetric imaging of the intact microcirculation, thereby providing greatly improved accuracy and versatility for broad biological and clinical applications.

© 2009 Optical Society of America

1. Introduction

The microcirculation plays a central role in the regulation of the metabolic, hemodynamic and thermal state of the individual [1

1. M. D. Stern, “In vivo evaluation of microcirculation by coherent light scattering,” Nature 254, 56–58 (1975). [CrossRef] [PubMed]

]. Many major diseases [2–8

2. J. E. Tooke, “Microvasculature in diabetes,” Cardiovasc. Res. 32, 764–771 (1996). [CrossRef] [PubMed]

] are manifest in the microcirculation before they are clinically evident, which provides a potential early perspective on the origin and progression of such diseases. However, established clinical imaging modalities such as computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and ultrasonography lack the resolution needed for microvascular imaging [9

9. D. M. McDonald and P. L. Choyke, “Imaging of angiogenesis: from microscope to clinic,” Nature Med. 9, 713–725 (2003). [CrossRef] [PubMed]

]. Even with iodine contrast, x-ray imaging cannot image single capillaries. Thus, optical microscopy has been widely used to assess the cellular and molecular features of the microcirculation. Intravital microscopy (IVM), for example, is the gold standard for microcirculation studies. It allows quantification of vessel count, diameter, length, density, permeability, and blood flow velocity. Nevertheless, to observe capillaries in vivo, IVM generally requires trans-illumination and surgical preparation [10

10. A. M. Iga, S. Sarkar, K. M. Sales, M. C. Winslet, and A. M. Seifalian, “Quantitating therapeutic disruption of tumor blood flow with intravital video microscopy,” Cancer Res. 66, 11517–11519 (2006). [CrossRef] [PubMed]

], restricting its application to limited anatomical sites and interfering with the intrinsic microcirculatory function. Additionally, conventional IVM lacks depth resolution that is crucial for extracting the three-dimensional (3D) microvascular morphology. Confocal microscopy [11

11. E. Laemmel, M. Genet, G. Le Goualher, A. Perchant, J. F. Le Gargasson, and E. Vicaut, “Fibered confocal fluorescence microscopy (Cell-viZio) facilitates extended imaging in the field of microcirculation. A comparison with intravital microscopy,” J. Vasc. Res. 41, 400–411 (2004). [CrossRef] [PubMed]

] and two-photon microscopy [12

12. D. Kleinfeld, P. P. Mitra, F. Helmchen, and W. Denk, “Fluctuations and stimulus-induced changes in blood flow observed in individual capillaries in layers 2 through 4 of rat neocortex,” Proc. Natl. Acad. Sci. USA 95, 15741–15746 (1998). [CrossRef] [PubMed]

], noninvasive and possessing excellent depth-sectioning capability, have difficulty in detecting microvessels without exogenous fluorescent agents, which, although having greatly facilitated laboratory research, are still facing challenges in clinical translations [13

13. M. C. Pierce, D. J. Javier, and R. Richards-Kortum, “Optical contrast agents and imaging systems for detection and diagnosis of cancer,” Int. J. Cancer 123, 1979–1990 (2008). [CrossRef] [PubMed]

]. Orthogonal polarization spectral (OPS) imaging permits noninvasive microvascular imaging without the use of fluorescent dyes [14

14. W. Groner, J. W. Winkelman, A. G. Harris, C. Ince, G. J. Bouma, K. Messmer, and R. G. Nadeau, “Orthogonal polarization spectral imaging: a new method for study of the microcirculation,” Nature Med. 5, 1209–1212 (1999). [CrossRef] [PubMed]

], paving its way to the bedside. However, OPS provides no depth information and lacks the measurement consistency [15

15. A. Bauer, S. Kofler, M. Thiel, S. Eifert, and F. Christ, “Monitoring of the sublingual microcirculation in cardiac surgery using orthogonal polarization spectral imaging: preliminary results,” Anesthesiology 107, 939–945 (2007). [CrossRef] [PubMed]

] required for longitudinal studies.

To overcome these difficulties, we have developed optical-resolution photoacoustic microscopy (OR-PAM), a noninvasive volumetric microscopy technology capable of detecting the physiologically specific absorption signatures of endogenous chromophores, such as hemoglobin, in vivo. The ability to introduce hemoglobin absorption contrast into the optical-resolution microscopy regime leads to an extremely versatile technique for microcirculation studies, without the limitations of fluorescent labeling and invasiveness. Besides the morphological parameters, such as vessel count, diameter, and length, OR-PAM also validates the quantification of important functional parameters, including total hemoglobin concentration (HbT) and hemoglobin oxygen saturation (sO2) [16

16. H. F. Zhang, K. Maslov, G. Stoica, and L. V. Wang, “Functional photoacoustic microscopy for high-resolution and noninvasive in vivo imaging,” Nature Biotechnol. 24, 848–851 (2006). [CrossRef]

, 17

17. H. F. Zhang, K. Maslov, and L. V. Wang, “In vivo imaging of subcutaneous structures using functional photoacoustic microscopy,” Nature Protoc. 2, 797–804 (2007). [CrossRef]

] down to the capillary level. Multiple attractive features make OR-PAM a valuable tool for microcirculation studies (Table 1), which is demonstrated below by noninvasively monitoring microhemodynamic activities in vivo.

Table 1. Comparison of modern high-resolution microvascular imaging techniques. CM: confocal microscopy; TPM: two-photon microscopy.

table-icon
View This Table

2. Methods

Our OR-PAM system employs nearly diffraction-limited optical focusing with bright field illumination to achieve 5-μm lateral resolution. The axial resolution is calculated to be ~15 μm, based on the transducer bandwidth and the speed of sound in tissue. The cross-sectional scanning (B-scan) rate over a 1-mm distance is ~1 frame per second. The detailed system design is described in [18

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

]. Through time-resolved ultrasonic detection and two-dimensional raster scanning along the transverse plane, the OR-PAM system records the complete 3D microvasculature of the tissue, which can be viewed in direct volumetric rendering (Media 1) or maximum amplitude projection (MAP) image (Fig. 1). All experimental animal procedures were carried out in conformance with the laboratory animal protocol approved by the School of Medicine Animal Studies Committee of Washington University in St. Louis.

Fig. 1. A representative microvascular network in a nude mouse ear imaged in vivo by OR-PAM. (a) MAP image. (b) 3D morphology (Media 1).

3. Results and discussion

Vasodilation, an important vessel activity in regulating tissue oxygen delivery, refers to an increase in vessel diameter. In contrast, vasomotion is a periodic oscillation of the vessel diameter and is not a consequence of the heart beat, respiration, or neuronal input [19

19. C. Aalkaer and H. Nilsson, “Vasomotion: cellular background for the oscillator and for the synchronization of smooth muscle cells,” Br. J. Pharmacol. 144, 605–616 (2005). [CrossRef]

]. Substantive experimental work has suggested that vasomotion might serve as a protective mechanism under conditions of ischemia and be an important indicator of cardiovascular events [20

20. G. O. von Mering, C. B. Arant, T. R. Wessel, S. P. McGorray, C. N. Bairey Merz, B. L. Sharaf, K. M. Smith, M. B. Olson, B. D. Johnson, G. Sopko, E. Handberg, C. J. Pepine, and R. A. Kerensky, “Abnormal coronary vasomotion as a prognostic indicator of cardiovascular events in women: results from the National Heart, Lung, and Blood Institute-Sponsored Women's Ischemia Syndrome Evaluation (WISE),” Circulation 109, 722–725 (2004). [CrossRef] [PubMed]

], but its physiological role and the underlying mechanism remain elusive [21

21. H. Nilsson and C. Aalkjaer, “Vasomotion: mechanisms and physiological importance,” Mol. Interv. 3, 79–89, 51 (2003). [CrossRef]

].

To explore vasomotion and vasodilation in response to tissue oxygen variation, first we selected a 1-mm-by-1-mm region in a nude mouse ear. Structural and sO2 images (Fig. 2) were acquired by a dual-wavelength measurement under systemic normoxia. According to the sO2 value, we selected an arteriole-venule pair (A1 and V1 in Fig. 2b), which were almost perpendicular to the B-scan direction (marked by the yellow dashed line in Fig. 2b). In this case, the B-scan image delineates the actual vessel cross section.

Fig. 2. Structural and functional microvascular imaging by OR-PAM in a nude mouse ear in vivo. (a) Structural image acquired at 570 nm. (b) Vessel-by-vessel sO2 mapping based on dual-wavelength (570 nm and 578 nm) measurements. The calculated sO2 values are shown in the color bar. PA: photoacoustic signal amplitude. A1: a representative arteriole; V1: a representative venule. Yellow dashed line: the B-scan position for Fig. 3.

Fig. 3. Vasomotion and vasodilation in response to switching the physiological state between systemic hyperoxia and hypoxia. (a) B-scan monitoring of the changes in the cross section of arteriole A1 (Media 2). (b) B-scan monitoring of the changes in the cross section of venule V1. (c) Changes in arteriolar and venous diameters in response to changes in physiological state (raw data were smoothed via 60-point moving averaging to isolate the effect of vasodilation). (d) Power spectrum of the arteriolar vasomotion tone. (e) Power spectrum of the venous vasomotion tone.

4. Perspectives

In future studies, quantification of the local metabolic rate of oxygen consumption would be an exciting extension [24

24. L. V. Wang, “Prospects of photoacoustic tomography,” Med. Phys. 35, 5758–5767 (2008). [CrossRef]

]. To this end, we need to measure the vessel diameter, blood oxygenation, and blood flow. The first two parameters are currently measurable with OR-PAM, and the photoacoustic Doppler (PAD) technique has been suggested for blood flow measurement in the microcirculation [25

25. H. Fang, K. Maslov, and L. V. Wang, “Photoacoustic Doppler effect from flowing small light-absorbing particles,” Phys. Rev. Lett. 99, 184501 (2007). [CrossRef] [PubMed]

]. One of our future directions is to integrate PAD flow measurement into the OR-PAM system to assess the local metabolic rate at a microscopic level.

Another interesting direction is to combine OR-PAM with other high-resolution imaging tools, such as confocal microscopy and two-photon microscopy, for multi-modality imaging. The fruitful cellular and molecular information provided by them, based on scattering or fluorescence contrast, will be highly complementary.

Acknowledgments

References and links

1.

M. D. Stern, “In vivo evaluation of microcirculation by coherent light scattering,” Nature 254, 56–58 (1975). [CrossRef] [PubMed]

2.

J. E. Tooke, “Microvasculature in diabetes,” Cardiovasc. Res. 32, 764–771 (1996). [CrossRef] [PubMed]

3.

B. I. Levy, G. Ambrosio, A. R. Pries, and H. A. Struijker-Boudier, “Microcirculation in hypertension: a new target for treatment?,” Circulation 104, 735–740 (2001). [CrossRef] [PubMed]

4.

O. Bongard, H. Bounameaux, and B. Fagrell, “Effects of oxygen inhalation on skin microcirculation in patients with peripheral arterial occlusive disease,” Circulation 86, 878–886 (1992). [PubMed]

5.

D. M. McDonald and P. Baluk, “Significance of blood vessel leakiness in cancer,” Cancer Res. 62, 5381–5385 (2002). [PubMed]

6.

L. Kuo, M. J. Davis, M. S. Cannon, and W. M. Chilian, “Pathophysiological Consequences of Atherosclerosis Extend into the Coronary Microcirculation - Restoration of Endothelium-Dependent Responses by L-Arginine,” Circ. Res. 70, 465–476 (1992). [PubMed]

7.

D. Hasdai, R. J. Gibbons, D. R. Holmes Jr., S. T Higano, and A. Lerman, “Coronary endothelial dysfunction in humans is associated with myocardial perfusion defects,” Circulation 96, 3390–3395 (1997). [PubMed]

8.

C. Iadecola, “Neurovascular regulation in the normal brain and in Alzheimer's disease,” Nat. Rev. Neurosci. 5, 347–360 (2004). [CrossRef] [PubMed]

9.

D. M. McDonald and P. L. Choyke, “Imaging of angiogenesis: from microscope to clinic,” Nature Med. 9, 713–725 (2003). [CrossRef] [PubMed]

10.

A. M. Iga, S. Sarkar, K. M. Sales, M. C. Winslet, and A. M. Seifalian, “Quantitating therapeutic disruption of tumor blood flow with intravital video microscopy,” Cancer Res. 66, 11517–11519 (2006). [CrossRef] [PubMed]

11.

E. Laemmel, M. Genet, G. Le Goualher, A. Perchant, J. F. Le Gargasson, and E. Vicaut, “Fibered confocal fluorescence microscopy (Cell-viZio) facilitates extended imaging in the field of microcirculation. A comparison with intravital microscopy,” J. Vasc. Res. 41, 400–411 (2004). [CrossRef] [PubMed]

12.

D. Kleinfeld, P. P. Mitra, F. Helmchen, and W. Denk, “Fluctuations and stimulus-induced changes in blood flow observed in individual capillaries in layers 2 through 4 of rat neocortex,” Proc. Natl. Acad. Sci. USA 95, 15741–15746 (1998). [CrossRef] [PubMed]

13.

M. C. Pierce, D. J. Javier, and R. Richards-Kortum, “Optical contrast agents and imaging systems for detection and diagnosis of cancer,” Int. J. Cancer 123, 1979–1990 (2008). [CrossRef] [PubMed]

14.

W. Groner, J. W. Winkelman, A. G. Harris, C. Ince, G. J. Bouma, K. Messmer, and R. G. Nadeau, “Orthogonal polarization spectral imaging: a new method for study of the microcirculation,” Nature Med. 5, 1209–1212 (1999). [CrossRef] [PubMed]

15.

A. Bauer, S. Kofler, M. Thiel, S. Eifert, and F. Christ, “Monitoring of the sublingual microcirculation in cardiac surgery using orthogonal polarization spectral imaging: preliminary results,” Anesthesiology 107, 939–945 (2007). [CrossRef] [PubMed]

16.

H. F. Zhang, K. Maslov, G. Stoica, and L. V. Wang, “Functional photoacoustic microscopy for high-resolution and noninvasive in vivo imaging,” Nature Biotechnol. 24, 848–851 (2006). [CrossRef]

17.

H. F. Zhang, K. Maslov, and L. V. Wang, “In vivo imaging of subcutaneous structures using functional photoacoustic microscopy,” Nature Protoc. 2, 797–804 (2007). [CrossRef]

18.

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

19.

C. Aalkaer and H. Nilsson, “Vasomotion: cellular background for the oscillator and for the synchronization of smooth muscle cells,” Br. J. Pharmacol. 144, 605–616 (2005). [CrossRef]

20.

G. O. von Mering, C. B. Arant, T. R. Wessel, S. P. McGorray, C. N. Bairey Merz, B. L. Sharaf, K. M. Smith, M. B. Olson, B. D. Johnson, G. Sopko, E. Handberg, C. J. Pepine, and R. A. Kerensky, “Abnormal coronary vasomotion as a prognostic indicator of cardiovascular events in women: results from the National Heart, Lung, and Blood Institute-Sponsored Women's Ischemia Syndrome Evaluation (WISE),” Circulation 109, 722–725 (2004). [CrossRef] [PubMed]

21.

H. Nilsson and C. Aalkjaer, “Vasomotion: mechanisms and physiological importance,” Mol. Interv. 3, 79–89, 51 (2003). [CrossRef]

22.

S. Bertuglia, A. Colantuoni, G. Coppini, and M. Intaglietta, “Hypoxia- or hyperoxia-induced changes in arteriolar vasomotion in skeletal muscle microcirculation,” Am. J. Physiol. 260, H362–372 (1991). [PubMed]

23.

K. Lorentz, A. Zayas-Santiago, S. Tummala, and J. J. Derwent, “Scanning laser ophthalmoscope-particle tracking method to assess blood velocity during hypoxia and hyperoxia,” Adv. Exp. Med. Biol. 614, 253–261 (2008). [CrossRef] [PubMed]

24.

L. V. Wang, “Prospects of photoacoustic tomography,” Med. Phys. 35, 5758–5767 (2008). [CrossRef]

25.

H. Fang, K. Maslov, and L. V. Wang, “Photoacoustic Doppler effect from flowing small light-absorbing particles,” Phys. Rev. Lett. 99, 184501 (2007). [CrossRef] [PubMed]

OCIS Codes
(110.5120) Imaging systems : Photoacoustic imaging
(170.3880) Medical optics and biotechnology : Medical and biological imaging
(180.5810) Microscopy : Scanning microscopy
(170.2655) Medical optics and biotechnology : Functional monitoring and imaging

ToC Category:
Medical Optics and Biotechnology

History
Original Manuscript: February 26, 2009
Revised Manuscript: March 26, 2009
Manuscript Accepted: March 30, 2009
Published: April 24, 2009

Virtual Issues
Vol. 4, Iss. 6 Virtual Journal for Biomedical Optics

Citation
Song Hu, Konstantin Maslov, and Lihong V. Wang, "Noninvasive label-free imaging of microhemodynamics by optical-resolution photoacoustic microscopy," Opt. Express 17, 7688-7693 (2009)
http://www.opticsinfobase.org/oe/abstract.cfm?URI=oe-17-9-7688


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References

  1. M. D. Stern, "In vivo evaluation of microcirculation by coherent light scattering," Nature 254, 56-58 (1975). [CrossRef] [PubMed]
  2. J. E. Tooke, "Microvasculature in diabetes," Cardiovasc. Res. 32, 764-771 (1996). [CrossRef] [PubMed]
  3. B. I. Levy, G. Ambrosio, A. R. Pries, and H. A. Struijker-Boudier, "Microcirculation in hypertension: a new target for treatment?," Circulation 104, 735-740 (2001). [CrossRef] [PubMed]
  4. O. Bongard, H. Bounameaux, and B. Fagrell, "Effects of oxygen inhalation on skin microcirculation in patients with peripheral arterial occlusive disease," Circulation 86, 878-886 (1992). [PubMed]
  5. D. M. McDonald and P. Baluk, "Significance of blood vessel leakiness in cancer," Cancer Res. 62, 5381-5385 (2002). [PubMed]
  6. L. Kuo, M. J. Davis, M. S. Cannon, and W. M. Chilian, "Pathophysiological Consequences of Atherosclerosis Extend into the Coronary Microcirculation - Restoration of Endothelium-Dependent Responses by L-Arginine," Circ. Res. 70, 465-476 (1992). [PubMed]
  7. D. Hasdai, R. J. Gibbons, D. R. Holmes, Jr., S. T. Higano, and A. Lerman, "Coronary endothelial dysfunction in humans is associated with myocardial perfusion defects," Circulation 96, 3390-3395 (1997). [PubMed]
  8. C. Iadecola, "Neurovascular regulation in the normal brain and in Alzheimer's disease," Nat. Rev. Neurosci. 5, 347-360 (2004). [CrossRef] [PubMed]
  9. D. M. McDonald, and P. L. Choyke, "Imaging of angiogenesis: from microscope to clinic," Nature Med. 9, 713-725 (2003). [CrossRef] [PubMed]
  10. A. M. Iga, S. Sarkar, K. M. Sales, M. C. Winslet, and A. M. Seifalian, "Quantitating therapeutic disruption of tumor blood flow with intravital video microscopy," Cancer Res. 66, 11517-11519 (2006). [CrossRef] [PubMed]
  11. E. Laemmel, M. Genet, G. Le Goualher, A. Perchant, J. F. Le Gargasson, and E. Vicaut, "Fibered confocal fluorescence microscopy (Cell-viZio) facilitates extended imaging in the field of microcirculation. A comparison with intravital microscopy," J. Vasc. Res. 41, 400-411 (2004). [CrossRef] [PubMed]
  12. D. Kleinfeld, P. P. Mitra, F. Helmchen, and W. Denk, "Fluctuations and stimulus-induced changes in blood flow observed in individual capillaries in layers 2 through 4 of rat neocortex," Proc. Natl. Acad. Sci. USA 95, 15741-15746 (1998). [CrossRef] [PubMed]
  13. M. C. Pierce, D. J. Javier, and R. Richards-Kortum, "Optical contrast agents and imaging systems for detection and diagnosis of cancer," Int. J. Cancer 123, 1979-1990 (2008). [CrossRef] [PubMed]
  14. W. Groner, J. W. Winkelman, A. G. Harris, C. Ince, G. J. Bouma, K. Messmer, and R. G. Nadeau, "Orthogonal polarization spectral imaging: a new method for study of the microcirculation," Nature Med. 5, 1209-1212 (1999). [CrossRef] [PubMed]
  15. A. Bauer, S. Kofler, M. Thiel, S. Eifert, and F. Christ, "Monitoring of the sublingual microcirculation in cardiac surgery using orthogonal polarization spectral imaging: preliminary results," Anesthesiology 107, 939-945 (2007). [CrossRef] [PubMed]
  16. H. F. Zhang, K. Maslov, G. Stoica, and L. V. Wang, "Functional photoacoustic microscopy for high-resolution and noninvasive in vivo imaging," Nature Biotechnol. 24, 848-851 (2006). [CrossRef]
  17. H. F. Zhang, K. Maslov, and L. V. Wang, "In vivo imaging of subcutaneous structures using functional photoacoustic microscopy," Nature Protoc. 2, 797-804 (2007). [CrossRef]
  18. K. Maslov, H. F. Zhang, S. Hu, and L. V. Wang, "Optical-resolution photoacoustic microscopy for in vivo imaging of single capillaries," Opt. Lett. 33, 929-931 (2008). [CrossRef] [PubMed]
  19. C. Aalkaer, and H. Nilsson, "Vasomotion: cellular background for the oscillator and for the synchronization of smooth muscle cells," Br. J. Pharmacol. 144, 605-616 (2005). [CrossRef]
  20. G. O. von Mering, C. B. Arant, T. R. Wessel, S. P. McGorray, C. N. Bairey Merz, B. L. Sharaf, K. M. Smith, M. B. Olson, B. D. Johnson, G. Sopko, E. Handberg, C. J. Pepine, and R. A. Kerensky, "Abnormal coronary vasomotion as a prognostic indicator of cardiovascular events in women: results from the National Heart, Lung, and Blood Institute-Sponsored Women's Ischemia Syndrome Evaluation (WISE)," Circulation 109, 722-725 (2004). [CrossRef] [PubMed]
  21. H. Nilsson, and C. Aalkjaer, "Vasomotion: mechanisms and physiological importance," Mol. Interv. 3, 79-89, 51 (2003). [CrossRef]
  22. S. Bertuglia, A. Colantuoni, G. Coppini, and M. Intaglietta, "Hypoxia- or hyperoxia-induced changes in arteriolar vasomotion in skeletal muscle microcirculation," Am. J. Physiol. 260, H362-372 (1991). [PubMed]
  23. K. Lorentz, A. Zayas-Santiago, S. Tummala, and J. J. Derwent, "Scanning laser ophthalmoscope-particle tracking method to assess blood velocity during hypoxia and hyperoxia," Adv. Exp. Med. Biol. 614, 253-261 (2008). [CrossRef] [PubMed]
  24. L. V. Wang, "Prospects of photoacoustic tomography," Med. Phys. 35, 5758-5767 (2008). [CrossRef]
  25. H. Fang, K. Maslov, and L. V. Wang, "Photoacoustic Doppler effect from flowing small light-absorbing particles," Phys. Rev. Lett. 99, 184501 (2007). [CrossRef] [PubMed]

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