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Optics Express

Optics Express

  • Editor: C. Martijn de Sterke
  • Vol. 18, Iss. 18 — Aug. 30, 2010
  • pp: 18625–18632
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Real-time, contrast enhanced photoacoustic imaging of cancer in a mouse window chamber

Ragnar Olafsson, Daniel R. Bauer, Leonardo G. Montilla, and Russell S. Witte  »View Author Affiliations


Optics Express, Vol. 18, Issue 18, pp. 18625-18632 (2010)
http://dx.doi.org/10.1364/OE.18.018625


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Abstract

A clinical ultrasound scanner and 14 MHz linear array collected real-time photoacoustic images (PAI) during an injection of gold nanorods (GNRs) near the region of a mature PC-3 prostate tumor in mice implanted with a skin flap window chamber. Three dimensional spectroscopic PAI (690-900nm) was also performed to investigate absorption changes near the tumor and enhance specific detection of GNRs. Whereas GNRs improved PAI contrast ( + 18 dB), the photoacoustic spectrum was consistent with the elevated near infrared absorption of GNRs. The versatile imaging platform potentially accelerates development of photoacoustic contrast agents and drug delivery for cancer imaging and therapy.

© 2010 OSA

1. Introduction

According to the American Cancer Society approximately 192,000 U.S. citizens were diagnosed in 2009 with prostate cancer and approximately 27,000 were expected to die from the disease [1

1. A. Jemal, R. Siegel, E. Ward, Y. P. Hao, J. Q. Xu, and M. J. Thun, “Cancer statistics, 2009,” CA Cancer J. Clin. 59(4), 225–249 (2009). [CrossRef] [PubMed]

]. Better diagnosis and treatments are needed to improve this outcome. However therapeutic and imaging agents cost $800 million and $150 million to develop, respectively, making pharmaceutical development a risky business that demands a high rate of return to maintain profitability. A large portion of this development cost lies in the late stages of clinical trials [2

2. E. D. Agdeppa and M. E. Spilker, “A review of imaging agent development,” AAPS J. 11(2), 286–299 (2009). [CrossRef] [PubMed]

]. It is therefore imperative to reject unpromising compounds and agents at an early stage of development. Appropriate in vivo experimental systems can contribute to this process.

One such system is the dorsal skin fold window chamber. It is a well established technique for in vivo optical and fluorescent microscopy of implanted cancers over a period of several weeks [3

3. G. H. Algire and F. Y. Legallais, “Recent developments in the transparent-chamber technique as adapted to the mouse,” J. Natl. Cancer Inst. 10(2), 225–253, 8 (1949). [PubMed]

5

5. Q. Huang, S. Q. Shan, R. D. Braun, J. Lanzen, G. Anyrhambatla, G. H. Kong, M. Borelli, P. Corry, M. W. Dewhirst, and C. Y. Li, “Noninvasive visualization of tumors in rodent dorsal skin window chambers,” Nat. Biotechnol. 17(10), 1033–1035 (1999). [CrossRef] [PubMed]

]. The model has contributed significantly to cancer research and has been extended to imaging modalities other than microscopy [6

6. L. Y. Chen, L. S. Gobar, N. G. Knowles, D. W. Wilson, and H. H. Barrett, “Direct Charged-Particle Imaging System Using an Ultra-Thin Phosphor: Physical Characterization and Dynamic Applications,” IEEE Trans. Nucl. Sci. 56(5), 2628–2635 (2009). [CrossRef]

10

10. A. F. Gmitro, Y. Lin, and M. Farrokh, “A System for Multi-Modality Optical and MR Imaging of Implanted Window Chambers,” Novel Techniques in Microscopy (NTM), NWD4 (2009).

]. This ability for extensive cross validation with other modalities makes the window chamber ideal for the development of imaging agents. Most techniques available for imaging the window chamber provide high spatial resolution in the lateral dimension, but provide minimal depth information. As the tumor grows to several millimeters within the skin flap, depth imaging becomes especially challenging. Some techniques that can provide depth information such as magnetic resonance imaging (MRI) and optical coherence tomography (OCT) are limited in spatial resolution and penetration depth, respectively [7

7. M. W. Dewhirst, E. T. Ong, R. D. Braun, B. Smith, B. Klitzman, S. M. Evans, and D. Wilson, “Quantification of longitudinal tissue pO2 gradients in window chamber tumours: impact on tumour hypoxia,” Br. J. Cancer 79(11/12), 1717–1722 (1999). [CrossRef] [PubMed]

, 8

8. A. Mariampillai, B. A. Standish, E. H. Moriyama, M. Khurana, N. R. Munce, M. K. K. Leung, J. Jiang, A. Cable, B. C. Wilson, I. A. Vitkin, and V. X. D. Yang, “Speckle variance detection of microvasculature using swept-source optical coherence tomography,” Opt. Lett. 33(13), 1530–1532 (2008). [CrossRef] [PubMed]

].

Photoacoustics (PA) is a promising new imaging technique that uses ultrasonic waves generated when pulsed laser light is absorbed in tissue. PA imaging, like conventional pulse echo (PE) ultrasound is inherently a three dimensional (3D) imaging modality, offering relatively good soft tissue penetration and high axial and lateral resolution [11

11. C. H. Li and L. V. Wang, “Photoacoustic tomography and sensing in biomedicine,” Phys. Med. Biol. 54(19), R59–R97 (2009). [CrossRef] [PubMed]

]. By tuning the wavelength of incident light, spectroscopic images can be acquired for characterizing tissue, tracking contrast agents or mapping blood oxygen saturation [11

11. C. H. Li and L. V. Wang, “Photoacoustic tomography and sensing in biomedicine,” Phys. Med. Biol. 54(19), R59–R97 (2009). [CrossRef] [PubMed]

]. PA contrast agents are optically absorbing dyes and particles. Gold nanorods (GNRs) are particularly promising due to their strong near infrared absorption, which can be tuned by adjusting their aspect ratio [12

12. J. Perez-Juste, I. Pastoriza-Santos, L. M. Liz-Marzan, and P. Mulvaney, “Gold nanorods: Synthesis, characterization and applications,” Coord. Chem. Rev. 249(17-18), 1870–1901 (2005). [CrossRef]

]. They have been investigated for imaging cancer [13

13. A. Agarwal, S. W. Huang, M. O'Donnell, K. C. Day, M. Day, N. Kotov, and S. Ashkenazi, “Targeted gold nanorod contrast agent for prostate cancer detection by photoacoustic imaging,” J. Appl. Phys. 102(6), 064701 (2007). [CrossRef]

, 14

14. S. Mallidi, T. Larson, J. Tam, P. P. Joshi, A. Karpiouk, K. Sokolov, and S. Emelianov, “Multiwavelength photoacoustic imaging and plasmon resonance coupling of gold nanoparticles for selective detection of cancer,” Nano Lett. 9(8), 2825–2831 (2009). [CrossRef] [PubMed]

], inflammation [15

15. K. Kim, A. Agarwal, A. M. McDonald, R. M. Moore, D. D. Myers, R. S. Witte, S. W. Huang, S. Ashkenazi, M. J. Kaplan, T. W. Wakefield, M. O'Donnell, and N. A. Kotov, “In vivo imaging of inflammatory responses by photoacoustics using cell-targeted gold nanorods (GNR) as contrast agent,” Proc. SPIE 2008 6856, 68560H (2008).

], and perfusion [16

16. C. K. Liao, S. W. Huang, C. W. Wei, and P. C. Li, “Nanorod-based flow estimation using a high-frame-rate photoacoustic imaging system,” J. Biomed. Opt. 12(6), 064006 (2007). [CrossRef]

]. When more than one optical wavelength is employed, PA spectroscopy facilitates distinguishing contrast agents from other absorbing structures in the body, such as blood [14

14. S. Mallidi, T. Larson, J. Tam, P. P. Joshi, A. Karpiouk, K. Sokolov, and S. Emelianov, “Multiwavelength photoacoustic imaging and plasmon resonance coupling of gold nanoparticles for selective detection of cancer,” Nano Lett. 9(8), 2825–2831 (2009). [CrossRef] [PubMed]

]. Photoacoustic spectroscopy, therefore, enhances specificity contributing to the photoacoustic image.

2. Methods

Human prostate cancer cells (PC3N) expressing GFP were implanted in the dorsal skin flap of a severe combined immunodeficient (SCID) mouse. The mouse was cared for in accordance with a protocol approved by the Institutional Animal Care and Use Committee (IACUC) at the University of Arizona. The prostate tumor invasion was monitored during three weeks using a dual modality PE and PA imaging system, in addition to optical and fluorescent microscopy. The experimental setup for collecting ultrasound and photoacoustic images from live mice is depicted in Fig. 1
Fig. 1 Experimental setup for fast, contrast enhanced photoacoustic imaging in the mouse window chamber. a) A side view illustration with the L14-5 linear array (Zonare Medical Systems). The mouse rests on its side with the dorsal skin flap window chamber situated under a custom plastic tank. The window chamber was illuminated from below through the cover slip with near infrared (NIR) light of wavelength λ. Ultrasound and photoacoustic imaging was performed through the skin flap. Gold nanorods were manually injected into the tumor on Day 23. b) Top view of the window chamber. The mouse lies below the tank with only the window chamber skin flap exposed. c) A photograph of the L14-5 linear array positioned in the water tank above the skin flap.
. The dorsal skin flap was stretched and held in place with a titanium window chamber with a glass coverslip on one side [4

4. G. H. Algire and J. U. Schlegel, “Circulatory reactions in photodynamic action,” J. Cell. Comp. Physiol. 35(1), 95–110 (1950). [CrossRef]

]. The skin flap was illuminated from below with a pulsed laser source (optical parametric oscillator, Surelite OPO I-20, Continuum) tunable between 680 and 1000 nm (5 nsec and 20 mJ/pulse at a repetition frequency of 20 Hz). The beam was conditioned with a two lens beam expander and directed upward with a right angle prism. The pulse energy was evenly distributed over the exposed skin within the window chamber such that incident fluence was 16 mJ/cm2, within the ANSI safety guidelines [18

18. Laser Institute of America, “American national standard for safe use of lasers Z136.1” (2000).

].To demonstrate the full capability of the enhanced imaging platform, two different ultrasound transducers were used for imaging. First, a 25 MHz single element ultrasound transducer (Olympus V324; center frequency = 25 MHz, focal length = 12.7 mm, f/# = 1.4) was raster scanned with a 3D motor system (Velmex) in a 6 mm by 14 mm rectangular region of interest along the x- and y-axis respectively with step sizes ∆x = 100 μm and ∆y = 47.6 μm. PA signals, generated with 700 nm illumination, were acquired at the same time as PE signals with a 12 bit, 62.5 MHz acquisition board (PDA12, Signatec). Following a protocol described previously [17

17. D. R. Bauer, R. Olafsson, L. G. Montilla, and R. S. Witte, “In vivo multi-modality photoacoustic and pulse echo tracking of prostate tumor growth using a window chamber,” Proc. SPIE 2010 7564, 75643B (2010).

], the single element transducer and imaging platform was used to track the tumor invasion during 3 + weeks. Three dimensional data sets were acquired on 5 separate days (7, 10, 13, 17, and 23 days after implantation). Long acquisition times (>45 minutes at a single wavelength), however, prevented volumetric and spectroscopic photoacoustic imaging in live mice. Contrast agents could not be monitored in real-time. To overcome these limitations and as a dramatic improvement to the original imaging platform, we implemented a clinical scanner (Zonare Medical Systems) and L14-5 linear array customized for real-time photoacoustic imaging. Three dimensional data were obtained with the 14 MHz transducer by translating it orthogonal to its image plane along the y-axis. Since the 14 MHz probe allowed for simultaneous acquisition of in phase and quadrature (IQ) data on 64 elements (half aperture) with each laser pulse, the acquisition of a 3D PA data (30 mm axial, 12.5 mm lateral, 20 mm elevational) took only 20 seconds for each wavelength. The IQ data was interpolated, upmodulated to 10 MHz, and bandpass filtered in fast time with −6dB cutoff frequencies of 7.5 and 12.5 MHz. A sum delay beamforming algorithm was used to produce volumetric 3D scans, which were further median filtered in the lateral direction with a 5x5 pixel window. The resulting data was logarithmically compressed for display.

To demonstrate the full capabilities of the enhanced imaging platform and clinical scanning system, a 10 nM solution of gold nanorods (GNRs, 45 nm x15 nm, peak absorption near 780 nm) was injected into the mature mouse tumor on Day 23. The absorption spectrum of the nanorods was independently measured with a commercial spectrometer (USB4000, Ocean Optics). The injection site was monitored in real-time (at the laser repetition frequency of 20 Hz) for 30 seconds at 700 nm illumination. A 3D PA and PE data set was acquired before and after the injection at 10 different wavelengths (λ = 680-900 nm, Δλ = 25 nm). The vasculature and structure of the skin was captured with an optical transillumination and fluorescent microscope, which also assessed the distribution of tumor cells expressing GFP (Eclipse E600, Nikon). The clinical ultrasound system not only enabled real-time tracking of photoacoustic contrast agents, but it also acquired images fast enough to obtain volumetric, spectroscopic photoacoustic images in living mice with high enhanced detection specificity of GNRs.

3. Results

However, the long acquisition time (40 + minutes) for each wavelength using the single element transducer precluded using it for 3D spectroscopic photoacoustic imaging or real-time dynamic 2D imaging with contrast agents. The clinical ultrasound scanner and 14 MHz array, on the other hand, acquired 2D frames at 20 Hz, limited only by the pulse repetition rate of the laser. This real-time system permitted the acquisition of 3D images of the entire window chamber every 20 seconds per wavelength, or approximately 120 times faster than the single element transducer. To demonstrate enhanced imaging of the mouse window chamber with contrast agents, real time PA imaging was performed before, during and after the injection of GNRs into the tumor as illustrated in Fig. 3
Fig. 3 Photoacoustic data acquired during injection of gold nanorods. a) An image captured 100 msec after the start of the GNR injection. The pink arrow illustrates the shaft of the needle used for the injection. This image corresponds to the red dashed rectangle in the grayscale pulse echo image b) The green arrow (top) points to the TegadermTM acoustic window. The bottom of the skin (bottom) is sagging because the glass coverslip was removed to permit access for the injection needle. The 30 dB dynamic range and the hot colorscale are the same as in Fig. 4. Image c) is a depth vs. time (M-mode) PA image illustrating the evolution of the PA signal at the location of the vertical green dotted line in image a). The plot in d) is the signal intensity as a function of time along the horizontal green line in image c).
. Figure 3b also displays a cross sectional pulse echo image (B-mode) acquired using the same system before the real-time PA imaging. Figure 3c represents the space vs. time PA image (M-Mode) in a plane through the shaft of the injection needle, corresponding to the vertical green dashed line of the initial PA cross sectional image (depicted in Fig. 3a). In this image, a quick bolus can be discerned at the time of injection, followed by a gradual increase in image intensity with time. This increase is illustrated more quantitatively in Fig. 3d, where the image intensity along the green dashed line (in Fig. 3c) increased by 10 dB after 30 seconds. Figure 4
Fig. 4 Example: Orthogonal planes from a three dimensional photoacoustic data set of nanorods injected into a tumor acquired with the real-time clinical scanner and 14 MHz clinical array using 700 nm illumination. The three orthogonal images were selected in the region near the tumor and site of GNR injection.
depicts three orthogonal planes from a volumetric PA image acquired at 700 nm immediately after the injection of GNRs and exhibits the distribution of nanorods near the tumor, as well as endogenous contrast from blood vessels. The XY lateral view clearly depicts the circular outline of the window chamber.

Spectroscopic PA XY images acquired before and after the injection of the GNRs are shown in Fig. 5
Fig. 5 Lateral slices form a multispectral 3D photoacoustic data set acquired with the clinical linear array. Photoacoustic slices were acquired before (top row) and after (bottom row) the injection of GNRs. Each column represents images taken at a particular excitation wavelength (four representative wavelengths displayed). The horizontal green dashed line corresponds to the image cross section shown in Fig. 3.
. In these lateral views from a spectroscopic and volumetric data set, the circular outline of the window chamber can also be discerned. In the central region, there is an increase in image intensity after the injection compared to before the injection. The spectral plot in Fig. 6
Fig. 6 Optical absorption spectrum of GNRs before the injection and changes in the photoacoustic spectrum in the region of interest following the injection of GNRs. The plot with the black squares on the right is the gain in average image intensity within the green rectangle in Fig. 5 primarily due to the nanorods. The green line represents the absorption spectrum of the nanorods measured with a commercial spectrometer.
describes the change in PA signal intensity as a function of laser wavelength. The difference in logarithmic image intensity (i.e., gain) between the “before” and “after” spectroscopic PA images in the region of interest (denoted by a green rectangle) is clearly different than the spectrum measured in a control region located in the upper right corner. The injection of GNRs produced an 18 dB signal increase at the 825-850 nm wavelength (within the region of interest) compared to an average gain of 0.8 dB in the control region far away from the injection. This strongly suggests that the observed increase in image intensity was primarily due to the presence of GNRs in region near the tumor.

4. Discussion

The window chamber model integrated with a clinical ultrasound scanner is useful for developing photoacoustic imaging technology and screening new cancer drugs or contrast agents. The window chamber permits independent verification of the targeting and binding of agents, as well as detailed characterization of tumor proliferation or regression. In addition to the enhanced acquisition capabilities that a linear array provides, a commercial ultrasound scanner makes it is possible to assess the in vivo sensitivity and spectrum of the contrast agents using a similar system already available for routine ultrasound exams. This can potentially facilitate the translation of imaging technology and drug discovery from benchtop to bedside.

We plan to continue to improve our system in future studies. Rather than injecting directly into the tumor, future studies will involve contrast agent injections directly into the mouse venous system and using GNRs with molecular markers targeted for cancer imaging.

5. Conclusions

Acknowledgements

References and links

1.

A. Jemal, R. Siegel, E. Ward, Y. P. Hao, J. Q. Xu, and M. J. Thun, “Cancer statistics, 2009,” CA Cancer J. Clin. 59(4), 225–249 (2009). [CrossRef] [PubMed]

2.

E. D. Agdeppa and M. E. Spilker, “A review of imaging agent development,” AAPS J. 11(2), 286–299 (2009). [CrossRef] [PubMed]

3.

G. H. Algire and F. Y. Legallais, “Recent developments in the transparent-chamber technique as adapted to the mouse,” J. Natl. Cancer Inst. 10(2), 225–253, 8 (1949). [PubMed]

4.

G. H. Algire and J. U. Schlegel, “Circulatory reactions in photodynamic action,” J. Cell. Comp. Physiol. 35(1), 95–110 (1950). [CrossRef]

5.

Q. Huang, S. Q. Shan, R. D. Braun, J. Lanzen, G. Anyrhambatla, G. H. Kong, M. Borelli, P. Corry, M. W. Dewhirst, and C. Y. Li, “Noninvasive visualization of tumors in rodent dorsal skin window chambers,” Nat. Biotechnol. 17(10), 1033–1035 (1999). [CrossRef] [PubMed]

6.

L. Y. Chen, L. S. Gobar, N. G. Knowles, D. W. Wilson, and H. H. Barrett, “Direct Charged-Particle Imaging System Using an Ultra-Thin Phosphor: Physical Characterization and Dynamic Applications,” IEEE Trans. Nucl. Sci. 56(5), 2628–2635 (2009). [CrossRef]

7.

M. W. Dewhirst, E. T. Ong, R. D. Braun, B. Smith, B. Klitzman, S. M. Evans, and D. Wilson, “Quantification of longitudinal tissue pO2 gradients in window chamber tumours: impact on tumour hypoxia,” Br. J. Cancer 79(11/12), 1717–1722 (1999). [CrossRef] [PubMed]

8.

A. Mariampillai, B. A. Standish, E. H. Moriyama, M. Khurana, N. R. Munce, M. K. K. Leung, J. Jiang, A. Cable, B. C. Wilson, I. A. Vitkin, and V. X. D. Yang, “Speckle variance detection of microvasculature using swept-source optical coherence tomography,” Opt. Lett. 33(13), 1530–1532 (2008). [CrossRef] [PubMed]

9.

R. A. Gatenby, E. T. Gawlinski, A. F. Gmitro, B. Kaylor, and R. J. Gillies, “Acid-mediated tumor invasion: a multidisciplinary study,” Cancer Res. 66(10), 5216–5223 (2006). [CrossRef] [PubMed]

10.

A. F. Gmitro, Y. Lin, and M. Farrokh, “A System for Multi-Modality Optical and MR Imaging of Implanted Window Chambers,” Novel Techniques in Microscopy (NTM), NWD4 (2009).

11.

C. H. Li and L. V. Wang, “Photoacoustic tomography and sensing in biomedicine,” Phys. Med. Biol. 54(19), R59–R97 (2009). [CrossRef] [PubMed]

12.

J. Perez-Juste, I. Pastoriza-Santos, L. M. Liz-Marzan, and P. Mulvaney, “Gold nanorods: Synthesis, characterization and applications,” Coord. Chem. Rev. 249(17-18), 1870–1901 (2005). [CrossRef]

13.

A. Agarwal, S. W. Huang, M. O'Donnell, K. C. Day, M. Day, N. Kotov, and S. Ashkenazi, “Targeted gold nanorod contrast agent for prostate cancer detection by photoacoustic imaging,” J. Appl. Phys. 102(6), 064701 (2007). [CrossRef]

14.

S. Mallidi, T. Larson, J. Tam, P. P. Joshi, A. Karpiouk, K. Sokolov, and S. Emelianov, “Multiwavelength photoacoustic imaging and plasmon resonance coupling of gold nanoparticles for selective detection of cancer,” Nano Lett. 9(8), 2825–2831 (2009). [CrossRef] [PubMed]

15.

K. Kim, A. Agarwal, A. M. McDonald, R. M. Moore, D. D. Myers, R. S. Witte, S. W. Huang, S. Ashkenazi, M. J. Kaplan, T. W. Wakefield, M. O'Donnell, and N. A. Kotov, “In vivo imaging of inflammatory responses by photoacoustics using cell-targeted gold nanorods (GNR) as contrast agent,” Proc. SPIE 2008 6856, 68560H (2008).

16.

C. K. Liao, S. W. Huang, C. W. Wei, and P. C. Li, “Nanorod-based flow estimation using a high-frame-rate photoacoustic imaging system,” J. Biomed. Opt. 12(6), 064006 (2007). [CrossRef]

17.

D. R. Bauer, R. Olafsson, L. G. Montilla, and R. S. Witte, “In vivo multi-modality photoacoustic and pulse echo tracking of prostate tumor growth using a window chamber,” Proc. SPIE 2010 7564, 75643B (2010).

18.

Laser Institute of America, “American national standard for safe use of lasers Z136.1” (2000).

OCIS Codes
(110.7170) Imaging systems : Ultrasound
(170.1870) Medical optics and biotechnology : Dermatology
(170.3880) Medical optics and biotechnology : Medical and biological imaging
(170.5120) Medical optics and biotechnology : Photoacoustic imaging
(170.6510) Medical optics and biotechnology : Spectroscopy, tissue diagnostics

ToC Category:
Medical Optics and Biotechnology

History
Original Manuscript: June 9, 2010
Revised Manuscript: July 23, 2010
Manuscript Accepted: July 28, 2010
Published: August 16, 2010

Virtual Issues
Vol. 5, Iss. 13 Virtual Journal for Biomedical Optics

Citation
Ragnar Olafsson, Daniel R. Bauer, Leonardo G. Montilla, and Russell S. Witte, "Real-time, contrast enhanced photoacoustic imaging of cancer in a mouse window chamber," Opt. Express 18, 18625-18632 (2010)
http://www.opticsinfobase.org/oe/abstract.cfm?URI=oe-18-18-18625


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References

  1. A. Jemal, R. Siegel, E. Ward, Y. P. Hao, J. Q. Xu, and M. J. Thun, “Cancer statistics, 2009,” CA Cancer J. Clin. 59(4), 225–249 (2009). [CrossRef] [PubMed]
  2. E. D. Agdeppa and M. E. Spilker, “A review of imaging agent development,” AAPS J. 11(2), 286–299 (2009). [CrossRef] [PubMed]
  3. G. H. Algire and F. Y. Legallais, “Recent developments in the transparent-chamber technique as adapted to the mouse,” J. Natl. Cancer Inst. 10(2), 225–253, 8 (1949). [PubMed]
  4. G. H. Algire and J. U. Schlegel, “Circulatory reactions in photodynamic action,” J. Cell. Comp. Physiol. 35(1), 95–110 (1950). [CrossRef]
  5. Q. Huang, S. Q. Shan, R. D. Braun, J. Lanzen, G. Anyrhambatla, G. H. Kong, M. Borelli, P. Corry, M. W. Dewhirst, and C. Y. Li, “Noninvasive visualization of tumors in rodent dorsal skin window chambers,” Nat. Biotechnol. 17(10), 1033–1035 (1999). [CrossRef] [PubMed]
  6. L. Y. Chen, L. S. Gobar, N. G. Knowles, D. W. Wilson, and H. H. Barrett, “Direct Charged-Particle Imaging System Using an Ultra-Thin Phosphor: Physical Characterization and Dynamic Applications,” IEEE Trans. Nucl. Sci. 56(5), 2628–2635 (2009). [CrossRef]
  7. M. W. Dewhirst, E. T. Ong, R. D. Braun, B. Smith, B. Klitzman, S. M. Evans, and D. Wilson, “Quantification of longitudinal tissue pO2 gradients in window chamber tumours: impact on tumour hypoxia,” Br. J. Cancer 79(11/12), 1717–1722 (1999). [CrossRef] [PubMed]
  8. A. Mariampillai, B. A. Standish, E. H. Moriyama, M. Khurana, N. R. Munce, M. K. K. Leung, J. Jiang, A. Cable, B. C. Wilson, I. A. Vitkin, and V. X. D. Yang, “Speckle variance detection of microvasculature using swept-source optical coherence tomography,” Opt. Lett. 33(13), 1530–1532 (2008). [CrossRef] [PubMed]
  9. R. A. Gatenby, E. T. Gawlinski, A. F. Gmitro, B. Kaylor, and R. J. Gillies, “Acid-mediated tumor invasion: a multidisciplinary study,” Cancer Res. 66(10), 5216–5223 (2006). [CrossRef] [PubMed]
  10. A. F. Gmitro, Y. Lin, and M. Farrokh, “A System for Multi-Modality Optical and MR Imaging of Implanted Window Chambers,” Novel Techniques in Microscopy (NTM), NWD4 (2009).
  11. C. H. Li and L. V. Wang, “Photoacoustic tomography and sensing in biomedicine,” Phys. Med. Biol. 54(19), R59–R97 (2009). [CrossRef] [PubMed]
  12. J. Perez-Juste, I. Pastoriza-Santos, L. M. Liz-Marzan, and P. Mulvaney, “Gold nanorods: Synthesis, characterization and applications,” Coord. Chem. Rev. 249(17-18), 1870–1901 (2005). [CrossRef]
  13. A. Agarwal, S. W. Huang, M. O'Donnell, K. C. Day, M. Day, N. Kotov, and S. Ashkenazi, “Targeted gold nanorod contrast agent for prostate cancer detection by photoacoustic imaging,” J. Appl. Phys. 102(6), 064701 (2007). [CrossRef]
  14. S. Mallidi, T. Larson, J. Tam, P. P. Joshi, A. Karpiouk, K. Sokolov, and S. Emelianov, “Multiwavelength photoacoustic imaging and plasmon resonance coupling of gold nanoparticles for selective detection of cancer,” Nano Lett. 9(8), 2825–2831 (2009). [CrossRef] [PubMed]
  15. K. Kim, A. Agarwal, A. M. McDonald, R. M. Moore, D. D. Myers, R. S. Witte, S. W. Huang, S. Ashkenazi, M. J. Kaplan, T. W. Wakefield, M. O'Donnell, and N. A. Kotov, “In vivo imaging of inflammatory responses by photoacoustics using cell-targeted gold nanorods (GNR) as contrast agent,” Proc. SPIE 2008 6856, 68560H (2008).
  16. C. K. Liao, S. W. Huang, C. W. Wei, and P. C. Li, “Nanorod-based flow estimation using a high-frame-rate photoacoustic imaging system,” J. Biomed. Opt. 12(6), 064006 (2007). [CrossRef]
  17. D. R. Bauer, R. Olafsson, L. G. Montilla, and R. S. Witte, “In vivo multi-modality photoacoustic and pulse echo tracking of prostate tumor growth using a window chamber,” Proc. SPIE 2010 7564, 75643B (2010).
  18. Laser Institute of America, “American national standard for safe use of lasers Z136.1” (2000).

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