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Optics Express

Optics Express

  • Editor: C. Martijn de Sterke
  • Vol. 19, Iss. 21 — Oct. 10, 2011
  • pp: 20097–20102
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Real-time handheld optical-resolution photoacoustic microscopy

Parsin Hajireza, Wei Shi, and Roger J. Zemp  »View Author Affiliations


Optics Express, Vol. 19, Issue 21, pp. 20097-20102 (2011)
http://dx.doi.org/10.1364/OE.19.020097


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Abstract

In this paper a new generation of optical-resolution photoacoustic microscopy (OR-PAM) with a wide range of potential clinical applications is demonstrated. Using fast scanning mirrors, an image guide with 30,000 fiber pixels, a refocusing lens and a unique probe we managed to reduce the footprint of an OR-PAM system from a stationary table-top system to a portable, 4cm by 6cm, probe weighing ~500g tethered to a scanning unit. The phantom studies show that the handheld optical-resolution photoacoustic microscope is able to image with ~7μm resolution. For in vivo studies images of the microvasculature in a Swiss Webster mouse ear are shown. The compact, flexible nature of the proposed design and the small footprint of the apparatus increase the usability of OR-PAM for potential clinical applications such as in dermatology.

© 2011 OSA

1. Introduction

Due to limitations of light transport, OR-PAM is used for imaging superficial structures to depths of about 1 mm in tissue [2

2. 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(9), 929–931 (2008). [CrossRef] [PubMed]

,3

3. B. Rao, L. Li, K. Maslov, and L. V. Wang, “Hybrid-scanning optical-resolution photoacoustic microscopy for in vivo vasculature imaging,” Opt. Lett. 35(10), 1521–1523 (2010). [CrossRef] [PubMed]

]. OR-PAM is able to image capillary networks and quantify morphological and functional parameters such as number of vessels, diameter and length of the vessels, total hemoglobin concentration and hemoglobin oxygen saturation [2

2. 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(9), 929–931 (2008). [CrossRef] [PubMed]

,4

4. S. Hu, K. Maslov, and L. V. Wang, “Noninvasive label-free imaging of microhemodynamics by optical-resolution photoacoustic microscopy,” Opt. Express 17(9), 7688–7693 (2009). [CrossRef] [PubMed]

,5

5. H. F. Zhang, K. Maslov, G. Stoica, and L. V. Wang, “Functional photoacoustic microscopy for high-resolution and noninvasive in vivo imaging,” Nat. Biotechnol. 24(7), 848–851 (2006). [CrossRef] [PubMed]

].

Since cancer cells need to consume more oxygen and nutrients to grow compared to other tissues [5

5. H. F. Zhang, K. Maslov, G. Stoica, and L. V. Wang, “Functional photoacoustic microscopy for high-resolution and noninvasive in vivo imaging,” Nat. Biotechnol. 24(7), 848–851 (2006). [CrossRef] [PubMed]

,6

6. H. F. Zhang, K. Maslov, and L. V. Wang, “In vivo imaging of subcutaneous structures using functional photoacoustic microscopy,” Nat. Protoc. 2(4), 797–804 (2007). [CrossRef] [PubMed]

], they signal the onset of angiogenesis and hence have plenty of contrast-providing blood vessels, making OR-PAM a useful tool for tumor imaging. Real-time OR-PAM may have a wide range of potential applications for clinical practice [7

7. W. Shi, S. Kerr, I. Utkin, J. Ranasinghesagara, L. Pan, Y. Godwal, R. J. Zemp, and R. Fedosejevs, “Optical resolution photoacoustic microscopy using novel high-repetition-rate passively Q-switched microchip and fiber lasers,” J. Biomed. Opt. 15(5), 056017 (2010). [CrossRef] [PubMed]

,8

8. W. Shi, P. Hajireza, P. Shao, A. Forbrich, and R. J. Zemp, “In vivo near-realtime volumetric optical-resolution photoacoustic microscopy using a high-repetition-rate nanosecond fiber-laser,” Opt. Express 19(18), 17143–17150 (2011). [CrossRef] [PubMed]

]. Recently a real-time B-scan OR-PAM system was demonstrated [9

9. L. Wang, K. Maslov, J. Yao, B. Rao, and L. V. Wang, “Fast voice-coil scanning optical-resolution photoacoustic microscopy,” Opt. Lett. 36(2), 139–141 (2011). [CrossRef] [PubMed]

] with scanning speed up to 40 Hz over 1-mm range or 20 Hz over 9-mm range. In order to develop a real-time OR-PAM system a high laser pulse repetition rate (PRR) and fast data acquisition and display system are required. Laser systems such as flash lamp-pumped laser systems (PRR ~up to100 Hz) and diode- pumped solid-state Q-switched lasers (PRR ~up to few kHz) typically do not have high enough repetition rates for real-time C-scan imaging [7

7. W. Shi, S. Kerr, I. Utkin, J. Ranasinghesagara, L. Pan, Y. Godwal, R. J. Zemp, and R. Fedosejevs, “Optical resolution photoacoustic microscopy using novel high-repetition-rate passively Q-switched microchip and fiber lasers,” J. Biomed. Opt. 15(5), 056017 (2010). [CrossRef] [PubMed]

].

Currently laser systems with repetition rates greater than 100 kHz, adequate pulse durations, and energies for real-time OR-PAM have not yet been widely explored for photoacoustic imaging [7

7. W. Shi, S. Kerr, I. Utkin, J. Ranasinghesagara, L. Pan, Y. Godwal, R. J. Zemp, and R. Fedosejevs, “Optical resolution photoacoustic microscopy using novel high-repetition-rate passively Q-switched microchip and fiber lasers,” J. Biomed. Opt. 15(5), 056017 (2010). [CrossRef] [PubMed]

]. We introduce a high repetition rate, inexpensive, compact laser source for realizing high frame rate photoacoustic imaging [7

7. W. Shi, S. Kerr, I. Utkin, J. Ranasinghesagara, L. Pan, Y. Godwal, R. J. Zemp, and R. Fedosejevs, “Optical resolution photoacoustic microscopy using novel high-repetition-rate passively Q-switched microchip and fiber lasers,” J. Biomed. Opt. 15(5), 056017 (2010). [CrossRef] [PubMed]

,8

8. W. Shi, P. Hajireza, P. Shao, A. Forbrich, and R. J. Zemp, “In vivo near-realtime volumetric optical-resolution photoacoustic microscopy using a high-repetition-rate nanosecond fiber-laser,” Opt. Express 19(18), 17143–17150 (2011). [CrossRef] [PubMed]

].

Another limitation of current OR-PAM systems is their lack of flexibility. The present OR-PAM systems are mostly mounted as a table-top device with a large footprint. However, recently we introduced label free optical-resolution photoacoustic micro-endoscopy to enable access to internal body cavities [10

10. P. Hajireza, W. Shi, P. Shao, S. Kerr, and R. J. Zemp, “Optical-resolution photoacoustic micro-endoscopy using image-guide fibers and fiber laser technology,” Proc. SPIE 7899, 78990P, 78990P-6 (2011). [CrossRef]

]. Thus far, however, an external ultrasound transducer is required. To extend the potential range of applications, for the first time, we demonstrate a handheld real-time optical-resolution photoacoustic microscope (HH-OR-PAM) with a 4 cm by 6 cm footprint and weight of less than 500 g using image guide fibers and a unique fiber laser system. Additionally, the capability of HH-OR-PAM is demonstrated by phantom and in vivo (microvasculature in a Swiss Webster mouse ear) studies based on a customized nanosecond-pulsed tunable fiber laser with repetition rates of up to 600 kHz, enabling near real-time C-scan and volumetric imaging.

2. System description

Figure 1a
Fig. 1 (a) Experimental setup of our HH-OR-PAM imaging system employing a high repetition rate diode- pumped pulsed Ytterbium fiber laser with up to 600 kHz pulse repetition rate and pulse widths of 1ns. FLD: fiber laser driver, Yb: Ytterbium, M: mirror, Gs: glass, PD: Photodiode, FG1: function generator channel 1, FG2: function generator channel 2, DX: X axis mirror driver, DY: Y axis mirror driver, OL: objective lens, A: amplifier (Olympus 5900PR). (b) The structure of the handheld probe. The light at the end of the fiber is refocused using a pair of glass aspheric lenses with 350 to 700nm AR Coating. Then the light passes through an oblique 10-mm fused silica prism. The photoacoustic signals directed upward to the prism’s diagonal will be deflected to a focused transducer (f = 19mm). AL: glass aspheric lenses, UST: ultrasound transducer, P: prism, IMF: index-matching fluid. (c) The prototype of the handheld probe. AL: glass aspheric lenses, UST: ultrasound transducer, P: prism, IMF: index-matching fluid.
shows the experimental setup of the laser scanning HH-OR-PAM. A pulsed fiber laser (YLP-G, IPG Photonics Corporation.) with second-harmonic wavelength of 532nm is able to provide tunable average output power up to 13W and pulse energy up to 20µJ. A glass slide is used to deflect a small amount of light into a photodiode. The photodiode is used to trigger the high speed data acquisition card (Gage card CS8289). The laser beam passes through a 2D galvanometer scanning mirror system (6230H, Cambridge Technology Inc.). The mirrors are controlled by separate drivers. These drivers can run with an analog control signal or a digital waveform depending on the study requirement.

In this experiment the mirrors were driven with sine waves generated by a two channel function generator (Tektronix AFG3022B). The frequency of the control signal determines the speed of scanning, while the peak-to-peak amplitude determines the angle of the scanning mirrors and eventually the field of view. In this experiment, the fast and slow scanning rates are fixed at 400 Hz and 1 Hz respectively, providing 2 C-scan frames per second. Using an objective lens (f = 18 mm), the scanning light via mirrors was coupled to the 1m-long image guide fiber with 30,000 individual single mode fiber elements (Sumitomo IGN-08/30). The field of view is limited by the diameter of the image guide (800µm). The end of the fiber is connected to the handheld probe.

Figure 1b shows the structure of the handheld probe. The light at the end of the fiber is refocused using a pair of aspheric glass lenses with 350 to 700nm AR Coating (Thorlabs 350260 and 352220). Then the light passes through an oblique 10-mm fused silica prism. The photoacoustic signals directed upward to the prism’s diagonal will be deflected to a 10-MHz focused ultrasound transducer (19-mm focus, 6-mm active element, f# = 3.17, CD International Inc). Calculations show that most of the acoustic energy is preserved at the prism interface within 45 ± 13.4 degrees within the angular acceptance of the transducer [7

7. W. Shi, S. Kerr, I. Utkin, J. Ranasinghesagara, L. Pan, Y. Godwal, R. J. Zemp, and R. Fedosejevs, “Optical resolution photoacoustic microscopy using novel high-repetition-rate passively Q-switched microchip and fiber lasers,” J. Biomed. Opt. 15(5), 056017 (2010). [CrossRef] [PubMed]

]. Optical index-matching fluid is used in order to allow the top-down laser illumination to be guided to the imaging target without optical refractive path variation. Acoustic attenuation loss in index-matching fluid is only slightly greater than water [11

11. J. C. Ranasinghesagara, Y. Jian, X. Chen, K. Mathewson, and R. J. Zemp, “Photoacoustic technique for assessing optical scattering properties of turbid media,” J. Biomed. Opt. 14(4), 040504 (2009). [CrossRef] [PubMed]

]; therefore, it is also used for ultrasonic coupling.

3. Result and discussion

In our experiments the fiber laser is utilized to produce 100mW; however, considering coupling efficiency of the image guide and other optical losses, at the end of the handheld probe the power is reduced to 45mW. The PRR is set to 160 kHz, therefore the pulse energy on the sample is calculated as ~0.3 µJ. This power is fixed for the entire experiment. The high speed and slow speed scanning mirror are driven by 400Hz and 1Hz analog sine wave respectively with 400mV peak-to-peak voltage.

In order to show the ability of the proposed design, different phantom targets have been imaged as shown in Fig. 2
Fig. 2 (a) and (b) network of carbon fibers with ~7.5µm diameter which are as small as capillary sized blood vessels. (c) Human hair with a diameter of ~100µm.
. Figure 2a and 2b shows a network of carbon fibers with ~7.5µm diameter which are as small as capillary sized blood vessels. Figure 2c shows an image of a human hair with a diameter of ~100µm. For the in vivo studies, we employed the HH-OR-PAM to image the microvasculature in the ear of a Swiss Webster mouse. All the experimental procedures were carried out in conformity with the laboratory animal protocol approved by the University of Alberta Animal Use and Care Committee. Authors are also trained and certified in order to use mice in the research work. During the imaging session the animal was anaesthetized using a breathing anesthesia system (E-Z Anesthesia, Euthanex Corp.). Figure 3
Fig. 3 Microvasculature in the ear of a Swiss Webster mouse.
shows images of the microvasculature in the ear of a Swiss Webster mouse. A 2D Hessian-based Frangi Vesselness filter [12

12. R. Manniesing and W. Niessen, “Multiscale vessel enhancing diffusion in CT angiography noise filtering,” Inf. Process. Med. Imaging 19, 138–149 (2005). [CrossRef] [PubMed]

] was used to filter C-scan maximum amplitude projection (MAP) images to preferentially select tubular structures while rejecting noise.

Measuring the average signal amplitude and the standard deviation of the noise, the signal-to-noise ratio for the carbon fiber is calculated as ~22dB. Fitting individual carbon fiber signal amplitude to a Gaussian function, the full-width-half-maximum (FWHM) is calculated approximately 8.7µm (Fig. 4
Fig. 4 FWHM due to fitting individual carbon fiber signal amplitude to a Gaussian function.
). The measured FWHM shown in Fig. 4 is partly due to the 7.5-μm width of the carbon fiber itself [7

7. W. Shi, S. Kerr, I. Utkin, J. Ranasinghesagara, L. Pan, Y. Godwal, R. J. Zemp, and R. Fedosejevs, “Optical resolution photoacoustic microscopy using novel high-repetition-rate passively Q-switched microchip and fiber lasers,” J. Biomed. Opt. 15(5), 056017 (2010). [CrossRef] [PubMed]

]. In order to measure the true optical lateral resolution, the convolution of a 2-D Gaussian beam with a carbon fiber is simulated for a range of spot-sizes, and compared with measurements [7

7. W. Shi, S. Kerr, I. Utkin, J. Ranasinghesagara, L. Pan, Y. Godwal, R. J. Zemp, and R. Fedosejevs, “Optical resolution photoacoustic microscopy using novel high-repetition-rate passively Q-switched microchip and fiber lasers,” J. Biomed. Opt. 15(5), 056017 (2010). [CrossRef] [PubMed]

]. Using this technique, the optical lateral resolution is estimated as 7µm. As mentioned the fast and slow speed mirror scanning rates are set at 400 Hz and 1 Hz respectively, with the laser repetition-rate set at 160 kHz. This corresponds to 2 volumetric-scans (composed of 400 B-scans per volume) per second. C-scans are formed from maximum-intensity projections of A-scan lines and contain 200 non-uniformly-spaced pixels in the X-direction and and 400 in the Y-direction, respectively. Higher C-scan frame rates are easily attainable; however, the field-of-view must be sacrificed if the resolution is to be maintained.

For a 400 by 400µm field of view (FOV) the average step size for the X and Y directions are calculated as 2 and 1µm, respectively. Since the scanning trajectory of the laser scanning system employs sine wave driving waveforms, the step size at the middle of scanning trajectory can be larger compare to its edge. Using Eq. (1) and Eq. (2) the worst case step sizes for the X and Y directions are calculated as ~3µm and 2µm respectively.
ΔX= FOVx× π× FR× PRR1,
(1)
ΔY= FOVy× 2 × FR 1× SR,
(2)
where FR is Fast scanning rate, SR is slow scanning rate, FOVx is field of view in X direction, FOVy is field of view in Y direction and PPR is pulse repetition rate. The lateral spatial resolution (FWHM) is calculated as ~7μm, or Gaussian sigma parameter, σ = FWHM / (2√2ln2) ~3μm. Considering the total area of the fiber bundle with 30,000 individual single mode fibers, we obtained the diameter of each strand to be about 4μm which is close to the measured lateral resolution. This shows that the system is almost at optimal resolution. For the in vivo study, assuming that the depth of the laser focus is ~200μm below the tissue surface and that the numerical aperture of the lens is about 0.16, the calculated laser surface fluence is ~8mJ/cm2 which is lower than the American National Standard Institute (ANSI) safety limit (20 mJ/cm2) [13

13. Laser Institute of America, American National Standard for Safe Use of Lasers ANSI Z136.1–2007 (American National Standards Institute, Inc., 2007).

].

Fiber-based imaging systems have been demonstrated before [14

14. G. O. Fruhwirth, S. Ameer-Beg, R. Cook, T. Watson, T. Ng, and F. Festy, “Fluorescence lifetime endoscopy using TCSPC for the measurement of FRET in live cells,” Opt. Express 18(11), 11148–11158 (2010). [CrossRef] [PubMed]

16

16. K. Sokolov, K. B. Sung, T. Collier, A. Clark, D. Arifler, A. Lacy, M. Descour, and R. Richards-Kortum, “Endoscopic microscopy,” Dis. Markers 18(5-6), 269–291 (2002). [PubMed]

]. Such systems also rely on image-guide fibers, miniature fiber bundles capable of transmitting images. Many such systems require the use of an exogenous fluorescent dye or contrast agent. HH-OR-PAM would provide the ability to image microvessels, and with improved resolution, potentially cells and subcellular structures similar to fluorescence (confocal) micro-endoscopes, but without necessarily requiring an exogenous contrast agent.

We anticipate that the HH-OR-PAM system will open up new possibilities for clinical and pre-clinical uses, such as functional brain mapping, cancer imaging and detection, assessing completeness of melanoma resection, imaging of angiogenesis to assess therapeutic efficacy, etc. The proposed label-free system will have potential for translational research because it will be compact and potentially portable, real-time, cost-effective. It will permit clinical imaging of different parts of body that were previously inaccessible.

4. Conclusion

Acknowledgment

We gratefully acknowledge funding from NSERC (355544-2008, 375340-2009, STPGP 396444), Terry- Fox Foundation and the Canadian Cancer Society (TFF 019237, TFF 019240, CCS 2011-700718), the Alberta Cancer Research Institute (ACB 23728), the Canada Foundation for Innovation, Leaders Opportunity Fund (18472), Alberta Advanced Education & Technology, Small Equipment Grants Program (URSI09007SEG), Microsystems Technology Research Initiative (MSTRI RES0003166), University of Alberta Startup Funds, and Alberta Ingenuity/Alberta Innovates scholarships for graduate and undergraduate students.

References and links

1.

W. Shi, P. Hajireza, P. Shao, S. Kerr, and R. J. Zemp, “Real-time optical-resolution photoacoustic microscopy using fiber-laser technology,” Proc. SPIE 7899, 789939, 789939-6 (2011). [CrossRef]

2.

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(9), 929–931 (2008). [CrossRef] [PubMed]

3.

B. Rao, L. Li, K. Maslov, and L. V. Wang, “Hybrid-scanning optical-resolution photoacoustic microscopy for in vivo vasculature imaging,” Opt. Lett. 35(10), 1521–1523 (2010). [CrossRef] [PubMed]

4.

S. Hu, K. Maslov, and L. V. Wang, “Noninvasive label-free imaging of microhemodynamics by optical-resolution photoacoustic microscopy,” Opt. Express 17(9), 7688–7693 (2009). [CrossRef] [PubMed]

5.

H. F. Zhang, K. Maslov, G. Stoica, and L. V. Wang, “Functional photoacoustic microscopy for high-resolution and noninvasive in vivo imaging,” Nat. Biotechnol. 24(7), 848–851 (2006). [CrossRef] [PubMed]

6.

H. F. Zhang, K. Maslov, and L. V. Wang, “In vivo imaging of subcutaneous structures using functional photoacoustic microscopy,” Nat. Protoc. 2(4), 797–804 (2007). [CrossRef] [PubMed]

7.

W. Shi, S. Kerr, I. Utkin, J. Ranasinghesagara, L. Pan, Y. Godwal, R. J. Zemp, and R. Fedosejevs, “Optical resolution photoacoustic microscopy using novel high-repetition-rate passively Q-switched microchip and fiber lasers,” J. Biomed. Opt. 15(5), 056017 (2010). [CrossRef] [PubMed]

8.

W. Shi, P. Hajireza, P. Shao, A. Forbrich, and R. J. Zemp, “In vivo near-realtime volumetric optical-resolution photoacoustic microscopy using a high-repetition-rate nanosecond fiber-laser,” Opt. Express 19(18), 17143–17150 (2011). [CrossRef] [PubMed]

9.

L. Wang, K. Maslov, J. Yao, B. Rao, and L. V. Wang, “Fast voice-coil scanning optical-resolution photoacoustic microscopy,” Opt. Lett. 36(2), 139–141 (2011). [CrossRef] [PubMed]

10.

P. Hajireza, W. Shi, P. Shao, S. Kerr, and R. J. Zemp, “Optical-resolution photoacoustic micro-endoscopy using image-guide fibers and fiber laser technology,” Proc. SPIE 7899, 78990P, 78990P-6 (2011). [CrossRef]

11.

J. C. Ranasinghesagara, Y. Jian, X. Chen, K. Mathewson, and R. J. Zemp, “Photoacoustic technique for assessing optical scattering properties of turbid media,” J. Biomed. Opt. 14(4), 040504 (2009). [CrossRef] [PubMed]

12.

R. Manniesing and W. Niessen, “Multiscale vessel enhancing diffusion in CT angiography noise filtering,” Inf. Process. Med. Imaging 19, 138–149 (2005). [CrossRef] [PubMed]

13.

Laser Institute of America, American National Standard for Safe Use of Lasers ANSI Z136.1–2007 (American National Standards Institute, Inc., 2007).

14.

G. O. Fruhwirth, S. Ameer-Beg, R. Cook, T. Watson, T. Ng, and F. Festy, “Fluorescence lifetime endoscopy using TCSPC for the measurement of FRET in live cells,” Opt. Express 18(11), 11148–11158 (2010). [CrossRef] [PubMed]

15.

S. Tang, W. Jung, D. McCormick, T. Xie, J. Su, Y. C. Ahn, B. J. Tromberg, and Z. Chen, “Design and implementation of fiber-based multiphoton endoscopy with microelectromechanical systems scanning,” J. Biomed. Opt. 14(3), 034005 (2009). [CrossRef] [PubMed]

16.

K. Sokolov, K. B. Sung, T. Collier, A. Clark, D. Arifler, A. Lacy, M. Descour, and R. Richards-Kortum, “Endoscopic microscopy,” Dis. Markers 18(5-6), 269–291 (2002). [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: July 25, 2011
Revised Manuscript: September 9, 2011
Manuscript Accepted: September 9, 2011
Published: September 29, 2011

Virtual Issues
Vol. 6, Iss. 11 Virtual Journal for Biomedical Optics

Citation
Parsin Hajireza, Wei Shi, and Roger J. Zemp, "Real-time handheld optical-resolution photoacoustic microscopy," Opt. Express 19, 20097-20102 (2011)
http://www.opticsinfobase.org/oe/abstract.cfm?URI=oe-19-21-20097


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References

  1. W. Shi, P. Hajireza, P. Shao, S. Kerr, and R. J. Zemp, “Real-time optical-resolution photoacoustic microscopy using fiber-laser technology,” Proc. SPIE7899, 789939, 789939-6 (2011). [CrossRef]
  2. 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(9), 929–931 (2008). [CrossRef] [PubMed]
  3. B. Rao, L. Li, K. Maslov, and L. V. Wang, “Hybrid-scanning optical-resolution photoacoustic microscopy for in vivo vasculature imaging,” Opt. Lett.35(10), 1521–1523 (2010). [CrossRef] [PubMed]
  4. S. Hu, K. Maslov, and L. V. Wang, “Noninvasive label-free imaging of microhemodynamics by optical-resolution photoacoustic microscopy,” Opt. Express17(9), 7688–7693 (2009). [CrossRef] [PubMed]
  5. H. F. Zhang, K. Maslov, G. Stoica, and L. V. Wang, “Functional photoacoustic microscopy for high-resolution and noninvasive in vivo imaging,” Nat. Biotechnol.24(7), 848–851 (2006). [CrossRef] [PubMed]
  6. H. F. Zhang, K. Maslov, and L. V. Wang, “In vivo imaging of subcutaneous structures using functional photoacoustic microscopy,” Nat. Protoc.2(4), 797–804 (2007). [CrossRef] [PubMed]
  7. W. Shi, S. Kerr, I. Utkin, J. Ranasinghesagara, L. Pan, Y. Godwal, R. J. Zemp, and R. Fedosejevs, “Optical resolution photoacoustic microscopy using novel high-repetition-rate passively Q-switched microchip and fiber lasers,” J. Biomed. Opt.15(5), 056017 (2010). [CrossRef] [PubMed]
  8. W. Shi, P. Hajireza, P. Shao, A. Forbrich, and R. J. Zemp, “In vivo near-realtime volumetric optical-resolution photoacoustic microscopy using a high-repetition-rate nanosecond fiber-laser,” Opt. Express19(18), 17143–17150 (2011). [CrossRef] [PubMed]
  9. L. Wang, K. Maslov, J. Yao, B. Rao, and L. V. Wang, “Fast voice-coil scanning optical-resolution photoacoustic microscopy,” Opt. Lett.36(2), 139–141 (2011). [CrossRef] [PubMed]
  10. P. Hajireza, W. Shi, P. Shao, S. Kerr, and R. J. Zemp, “Optical-resolution photoacoustic micro-endoscopy using image-guide fibers and fiber laser technology,” Proc. SPIE7899, 78990P, 78990P-6 (2011). [CrossRef]
  11. J. C. Ranasinghesagara, Y. Jian, X. Chen, K. Mathewson, and R. J. Zemp, “Photoacoustic technique for assessing optical scattering properties of turbid media,” J. Biomed. Opt.14(4), 040504 (2009). [CrossRef] [PubMed]
  12. R. Manniesing and W. Niessen, “Multiscale vessel enhancing diffusion in CT angiography noise filtering,” Inf. Process. Med. Imaging19, 138–149 (2005). [CrossRef] [PubMed]
  13. Laser Institute of America, American National Standard for Safe Use of Lasers ANSI Z136.1–2007 (American National Standards Institute, Inc., 2007).
  14. G. O. Fruhwirth, S. Ameer-Beg, R. Cook, T. Watson, T. Ng, and F. Festy, “Fluorescence lifetime endoscopy using TCSPC for the measurement of FRET in live cells,” Opt. Express18(11), 11148–11158 (2010). [CrossRef] [PubMed]
  15. S. Tang, W. Jung, D. McCormick, T. Xie, J. Su, Y. C. Ahn, B. J. Tromberg, and Z. Chen, “Design and implementation of fiber-based multiphoton endoscopy with microelectromechanical systems scanning,” J. Biomed. Opt.14(3), 034005 (2009). [CrossRef] [PubMed]
  16. K. Sokolov, K. B. Sung, T. Collier, A. Clark, D. Arifler, A. Lacy, M. Descour, and R. Richards-Kortum, “Endoscopic microscopy,” Dis. Markers18(5-6), 269–291 (2002). [PubMed]

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