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Optics Express

Optics Express

  • Editor: C. Martijn de Sterke
  • Vol. 19, Iss. 22 — Oct. 24, 2011
  • pp: 21552–21562
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High-sensitivity in vivo THz transmission imaging of early human breast cancer in a subcutaneous xenograft mouse model

Hua Chen, Te-Hsuen Chen, Tzu-Fang Tseng, Jen-Tang Lu, Chung-Chiu Kuo, Shih-Chen Fu, Wen-Jeng Lee, Yuan-Fu Tsai, Yi-You Huang, Eric Y. Chuang, Yuh-Jing Hwang, and Chi-Kuang Sun  »View Author Affiliations


Optics Express, Vol. 19, Issue 22, pp. 21552-21562 (2011)
http://dx.doi.org/10.1364/OE.19.021552


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Abstract

We performed in vivo THz transmission imaging study on a subcutaneous xenograft mouse model for early human breast cancer detection. With a THz-fiber-scanning transmission imaging system, we continuously monitored the growth of human breast cancer in mice. Our in vivo study not only indicates that THz transmission imaging can distinguish cancer from the surrounding fatty tissue, but also with a high sensitivity. Our in vivo study on the subcutaneous xenograft mouse model will encourage broad and further investigations for future early cancer screening by using THz imaging system.

© 2011 OSA

1. Introduction

The American Cancer Society (ACS) statistics show that breast cancer is one of the most common cancers among women, and the chance of developing invasive breast cancer at some time in a woman's life is about 12% [1

1. A. Jemal, R. Siegel, J. Xu, and E. Ward, “Cancer statistics, 2010,” CA Cancer J. Clin. 60(5), 277–300 (2010). [CrossRef] [PubMed]

]. Moreover, breast cancer is the second leading cause of cancer death in women [1

1. A. Jemal, R. Siegel, J. Xu, and E. Ward, “Cancer statistics, 2010,” CA Cancer J. Clin. 60(5), 277–300 (2010). [CrossRef] [PubMed]

]. The chance that breast cancer will be responsible for a woman's death is about 3% [1

1. A. Jemal, R. Siegel, J. Xu, and E. Ward, “Cancer statistics, 2010,” CA Cancer J. Clin. 60(5), 277–300 (2010). [CrossRef] [PubMed]

]. Accordingly, early high-sensitivity detection of breast cancer allows treatment at an earlier stage and would significantly reduce associated mortality. In clinical practice, the methods to detect breast cancer include physical examination, breast ultrasound, X-ray mammography, and breast MRI. X-ray mammography is the process of using low-dose amplitude X-rays to examine the human breast and is the only proven method for screening breast cancer. X-ray mammography can identify changes in the density of the breast tissue (usually caused by an increase in fibro-glandular tissue or tumors) or calcifications within the tissue that can often indicate the presence of cancer. During the procedure, the breast has to be compressed evenly with a uniform thickness in order to reduce the thickness and thickness fluctuation of tissues for improved image quality. However, there are several problems associated with X-ray mammography. Mammography utilizes ionizing X-ray, which may induce malignancy. Breast lesion may be obscured on X-ray by dense fibro-glandular structure [2

2. S. A. Feig and R. E. Hendrick, “Radiation risk from screening mammography of women aged 40-49 years,” J. Natl. Cancer Inst. Monogr. 22(22), 119–124 (1997). [PubMed]

, 3

3. N. T. Brewer, T. Salz, and S. E. Lillie, “Systematic review: the long-term effects of false-positive mammograms,” Ann. Intern. Med. 146(7), 502–510 (2007). [PubMed]

]. Accordingly, X-ray mammography has a false-negative rate up to 30 percent [3

3. N. T. Brewer, T. Salz, and S. E. Lillie, “Systematic review: the long-term effects of false-positive mammograms,” Ann. Intern. Med. 146(7), 502–510 (2007). [PubMed]

]. In Asian (including Taiwan), the incidence of dense breasts is higher than other Western countries. The cancer detection rate of X-ray mammography is thus even lower [4

4. T. T. Alagaratnam and J. Wong, “Limitations of mammography in Chinese females,” Clin. Radiol. 36(2), 175–177 (1985). [CrossRef] [PubMed]

]. Besides, the average age of breast cancer patients is younger in Asia than other Western countries. Young females (especially of child-bearing age) have more dense breasts and are more susceptible to ionizing radiation. Therefore, a new noninvasive screening examination is needed for better early detection of breast cancer.

2. THz source and detector

3. Mouse treatment and tissue preparation

All animal experiments were approved by the Institutional Animal Care and Use Committee of National Taiwan University, which permitted cancer cell and fatty tissue implantation, mouse anesthetization, and exposition of T-ray on mouse. In our experiment, the animals used were 4-to-6-month-old female BALB/cAnN.Cg-Foxnlnu/CrlNarl mice, selected and purchased from the National Laboratory Animal Center in Taiwan. The BALB/cAnN.Cg-Foxnlnu/CrlNarl mouse is a laboratory mouse from a strain with a genetic mutation that causes a deteriorated or absent thymus, resulting in an inhibited immune system due to a greatly reduced number of T cells. Therefore, they can’t reject cancer cells injection and xenografts of tissues from another species. The breast cancer cells used were MDA MB 231, which were cultivated in L-15 with 10% fetal bovine serum and 1% antibiotics, and the cell concentration was 5×107 with 1 ml of culture media. The injection dosage for each mouse was 0.3ml. The implanted or ex vivo measured fatty tissue was aspirated from 12-week-old female B6.V-Lepob/J mice, and was rinsed three times in the transport medium (NaCl 0.9%(w/v), Glucose 56mM, HEPES 25mM, PSA 10ml, pH 7.4). The cancer cells and fatty tissue implantation as well as in vivo T-ray experiments were all conducted while the mice were anesthetized. We anesthetized the mice by intraperitoneal (IP) injection of ketamine-xylazine (50mg+15mg/kg), and all spectroscopy and imaging experiments were completed in 5 minutes. We then kept the mice warm to help them awake.

For ex vivo measurement of fatty tissue and cancerous tissue, the time from tissue aspiration to measurement was less than 12 hours. The aspirated fatty tissue was minced and filled in a 1mm-thick cell sealed by two 2mm-thick polyethylene (PE) windows, and were measured without other treatment. The grown cancerous tissue was extracted from an implanted mouse. After 2-months cancer growth, we sacrificed the mouse and extracted the cancerous tissue with a visible size of 4mm in diameter. By dissecting the cancerous tissue into a 0.82mm-thick slice, we immediately measured the absorption spectrum. For in vivo measured skin absorption spectrum, without any other treatment to the studied mouse, we stretched the anesthetized mouse dorsal skin, sandwiched it between two 2mm cover glasses, and then positioned the mouse on a platform for THz transmission measurement. The average thickness of the dorsal skin was about 0.6mm according to 10 mice’s measurement and the in vivo absorption coefficients of the dorsal skin was calculated based on the THz attenuation, after calibrating the cover glass reflection and absorption.

4. Ex vivo and in vivo THz absorption spectra

As shown in Fig. 2
Fig. 2 (a) Ex vivo measured absorption spectra of pure water (black solid circles), breast cancerous tissues (red solid circles) and fatty tissues (blue solid circles). (b) In vivo measured absorption spectra of fatty tissues (blue solid circles) and mouse skin (green solid circles). The error bars represent the standard deviation of the mean and the test number is 10.
, we have successfully measured lower THz frequency (from 108 GHz to 143 GHz) absorption spectra of ex vivo fatty tissue and breast cancerous tissue, as well as the first absorption spectra of in vivo mouse skin and fatty tissue. From Fig. 2(a), it is clear that cancerous tissue absorbs much more T-ray than fatty tissue even in the studied low THz regime. The distinguishable contrast between fatty and cancerous tissue under the T-ray illumination is one of the keys to realize T-ray screen imaging in the developed mouse model. The in vivo measured T-ray absorption spectra of mouse skin and fatty tissue is shown in Fig. 2(b), and the absorption coefficients are summarized by 10 mice’s measurement. In Fig. 2, by comparing the results on skin and cancerous tissue, we found that their absorption coefficients in this studied frequency range are very close. However with a relatively uniform skin thickness which does not vary in time significantly, the T-ray attenuation due to skin can be easily calibrated by considering the skin as a uniform and position-independent attenuation background.

5. Experimental setup of the THz transmission imaging system

The significant contrast between fatty tissue and cancerous tissue under the T-ray illumination makes the application of T-ray imaging to identify breast cancer in the developed animal model possible, which is an important first step even though we have neglected the fibrous tissues in our animal model. Accordingly, we developed a fiber-scanning transmission T-ray imaging system based on the same YIG oscillator module and the Schottky diode detector. It was performed at 108GHz. Figure 3(a)
Fig. 3 (a) Schematic diagram of the THz fiber-scanning transmission imaging system. (b) Photograph of the T-ray imaging system. (c) A direct 2D (x-y) 10mm × 10mm scanning image of air. Power transmission was measured at different fiber bending angles, and the maximum angle-induced 1D fiber bending loss is about 10%. The S/N ratio of the imaging system is 105:1.
shows the schematic diagram of fiber-scanning [16

16. C.-M. Chiu, H.-W. Chen, Y.-R. Huang, Y.-J. Hwang, W.-J. Lee, H. Y. Huang, and C. K. Sun, “All-terahertz fiber-scanning near-field microscopy,” Opt. Lett. 34(7), 1084–1086 (2009), http://www.opticsinfobase.org/ol/abstract.cfm?URI=ol-34-7-1084. [CrossRef] [PubMed]

, 17

17. J.-Y. Lu, C.-M. Chiu, C.-C. Kuo, C.-H. Lai, H.-C. Chang, Y.-J. Hwang, C.-L. Pan, and C.-K. Sun, “Terahertz scanning imaging with a subwavelength plastic fiber,” Appl. Phys. Lett. 92(8), 084102 (2008). [CrossRef]

, 27

27. J.-Y. Lu, C.-C. Kuo, C.-M. Chiu, H.-W. Chen, Y.-J. Hwang, C.-L. Pan, and C.-K. Sun, “THz interferometric imaging using subwavelength plastic fiber based THz endoscopes,” Opt. Express 16(4), 2494–2501 (2008), http://www.opticsinfobase.org/abstract.cfm?URI=oe-16-4-2494. [CrossRef] [PubMed]

] THz imaging system. The highly flexible THz sub-wavelength PE fiber adopted was with a diameter of 600μm and a length of 40cm [27

27. J.-Y. Lu, C.-C. Kuo, C.-M. Chiu, H.-W. Chen, Y.-J. Hwang, C.-L. Pan, and C.-K. Sun, “THz interferometric imaging using subwavelength plastic fiber based THz endoscopes,” Opt. Express 16(4), 2494–2501 (2008), http://www.opticsinfobase.org/abstract.cfm?URI=oe-16-4-2494. [CrossRef] [PubMed]

29

29. H.-W. Chen, Y.-T. Li, C. L. Pan, J. L. Kuo, J. Y. Lu, L. J. Chen, and C.-K. Sun, “Investigation on spectral loss characteristics of subwavelength terahertz fibers,” Opt. Lett. 32(9), 1017–1019 (2007), http://www.opticsinfobase.org/ol/abstract.cfm?URI=ol-32-9-1017. [CrossRef] [PubMed]

]. The T-ray, emitted from YIG oscillator module, was first modulated by a chopper, and then collimated by a pair of off-axis parabolic mirrors and focused into the fiber with a substantially low attenuation constant ~10−3cm−1 [28

28. L.-J. Chen, H.-W. Chen, T.-F. Kao, J.-Y. Lu, and C.-K. Sun, “Low-loss subwavelength plastic fiber for terahertz waveguiding,” Opt. Lett. 31(3), 308–310 (2006), http://www.opticsinfobase.org/ol/abstract.cfm?URI=ol-31-3-308. [CrossRef] [PubMed]

30

30. Y.-W. Huang, T.-F. Tseng, C.-C. Kuo, Y. J. Hwang, and C.-K. Sun, “Fiber-based swept-source terahertz radar,” Opt. Lett. 35(9), 1344–1346 (2010), http://www.opticsinfobase.org/abstract.cfm?URI=ol-35-9-1344. [CrossRef] [PubMed]

]. Behind the fiber output end, a PE lens was used to focus T-ray onto the anesthetized mouse and then the transmitted power was detected by the Schottky diode detector. The power on the surface of the mouse skin is about 1mW [31

31. E. Berry, G. C. Walker, A. J. Fitzgerald, N. N. Zinov'ev, M. Chamberlain, S. W. Smye, R. E. Miles, and M. A. Smith, “Do in vivo terahertz imaging systems comply with safety guidelines?” J. Laser Appl. 15(3), 192–198 (2003). [CrossRef]

] and it is safe according to the current guidelines [12

12. K.-H. Ng, “Non-ionizing radiations: sources, biological effects, emissions and exposures,” in Proceedings of the International Conference on Non-Ionizing Radiation at UNITEN (ICNIR2003) Electromagnetic Fields and Our Health (Selangor, Malaysia, 2003), pp. 1–16.

, 31

31. E. Berry, G. C. Walker, A. J. Fitzgerald, N. N. Zinov'ev, M. Chamberlain, S. W. Smye, R. E. Miles, and M. A. Smith, “Do in vivo terahertz imaging systems comply with safety guidelines?” J. Laser Appl. 15(3), 192–198 (2003). [CrossRef]

]. Finally, the collected signals were analyzed by a lock-in amplifier. The picture was obtained by a direct 2D (x-y) scanning of the fiber output end and detector. From Fig. 3(c), a 10mm×10mm scanning image in air, which took less than 5 minutes to acquire, we calculated that the maximum angle-induced 1D fiber bending loss in 10mm was about 10% and the S/N ratio of room-temperature imaging system was higher than 105:1.

6. THz transmission imaging of a visible cancer: a proof-of-principle study

The imaging specificity and resolution were demonstrated by imaging a visible breast cancer developed in the subcutaneous xenograft mouse model and the test number was 5. Here we show one mouse’s experimental image. After the cancer cells subcutaneously implanted into a mouse’s dorsal area [32

32. M. S. Gee, R. Upadhyay, H. Bergquist, H. Alencar, F. Reynolds, M. Maricevich, R. Weissleder, L. Josephson, and U. Mahmood, “Human breast cancer tumor models: molecular imaging of drug susceptibility and dosing during HER2/neu-targeted therapy,” Radiology 248(3), 925–935 (2008). [CrossRef] [PubMed]

], a visible breast tumor with a size about 2.1mm×3.2mm×1.3mm was developed on the 46th day, as photographed in Fig. 4(a)
Fig. 4 (a)-(e) Photos of a mouse taken during preparation: (a) A visible breast tumor with a size about 2.1mm×3.2mm×1.3mm developed on the 46th day after the cancer cell implantation; (b)-(c) Fat implantation; (d)-(e) Stretched mouse dorsal skin with area 15mm×10mm and sandwiched by two 2mm cover glasses. (f) In vivo THz imaging of a visible cancer in mouse dorsal skin. The color bar is defined as α from 1.4mm−1 to 2.1mm−1.
. We then injected fatty tissue to embed the tumor (Fig. 4(b)) and sandwiched the embedded dorsal area by two cover glasses (Fig. 4(e)). The thickness of the specific sandwiched tissue, including skin, fatty tissue and the hidden tumor, was 3.8mm. A 5mm×5mm transmitted THz fiber-scanning absorption image of the tumor area is shown in Fig. 4(f). The color bar is defined as absorption constant α from 1.40mm−1 to 2.10mm−1, while 2.10mm−1 is the maximum absorption coefficient measured in the sandwiched tissue including fatty tissue and tumor, while the background of the image was defined as 1.40 mm−1<α<1.45 mm−1, corresponding to in vivo spectral measurement on fatty tissue. From the scanning image, it is clear that the high T-ray absorption of breast tumor is to provide endogenous contrast under T-ray imaging so that it would easily reveal itself from the background absorption. The observed high T-ray absorption area agrees well with the tumor, both in size and shape. From the scanning image, it is also clear that the image resolution is much better than λ (2.8mm), which was achieved not just by the small detection area of the Schottky detector, but also due to the nonlinear relationship between α and transmitted power. By analyzing image, the 2D resolution of our imaging system is 1.1mm × 2.4mm. Meanwhile, this test image also indicates that our THz imaging was able to measure the absorptive change ∆α as low as 0.01 mm−1.

7. THz imaging of early breast cancer

With a high THz absorption contrast between fatty tissue and cancer, the THz transmission imaging system should then be able to in vivo detect the early cancer before it is visible or sensitive to any other means. To this aim, we developed a different subcutaneous xenograft mouse model to test the sensitivity, and the test number was 16. After the cancer cells injection, on the 6th day, we anesthetized the mouse and implanted mouse fatty tissue to embed the cancer cells (the place was marked after cancer cells implantation). Starting from the 13th day, we imaged the cancer implanted area every 3~4 days until the cancer was visible. During T-ray imaging, we anesthetized the mouse and sandwiched the dorsal cancer area by two cover glasses. After finishing the imaging acquisition, we kept the mice warm to help it awake. In the following Fig. 5
Fig. 5 A series of THz images according to the screening time from the 13th day to the 33th day after the cancer cell implantation. Early cancer development was detected on the 23th day, and the induced absorption coefficient change was 0.25mm−1, corresponding to a cancer volume of 1.3mm3. For the images from the 23th day to the 33th day, the color bar was defined according to the maximum measured absorption coefficient, while from the 13th day to the 17th day, the image color bar was defined according to the 23th day.
and Fig. 6
Fig. 6 Another series of THz images according to the screening time from the 18th day to the 30th day after the cancer cell implantation in the specific mouse.
, we show 2 series of experimental images to demonstrate the possibility and sensitivity of our THz imaging system to early detect breast cancer. Figure 5 shows thus acquired 10mm×10mm THz screening images on the mouse according to the imaging time from the 13th day to the 33th day after cancer cell implantation. For the images acquired on the 23th day to the 33th day, the color bar is defined according to the maximum measured T-ray absorption coefficient of the sandwiched tissues, while from the 13th to the 17th day, the color bar is defined as high as 1.7mm−1 according to the 23th day for comparison. It is clear that the detected absorption change in early cancer development starts on the 23th day and the absorption change ∆α is 0.25 mm−1. The early cancer development induced absorption change starts to be detected on the 18th day in another mouse, and the corresponding 10mm×10mm THz screening images from the 18th day to the 30th day after cancer cell implantation are shown in Fig. 6. The color bar is defined according to the maximum measured T-ray absorption coefficient of the sandwiched tissues, and the cancer cells embedded in fat induces absorption change ∆α as small as 0.15 mm−1.

In order to estimate the tumor volume, we introduce the concept of cell absorption cross section (σ). The cancer cell absorption cross section σ is defined as: σ=α/N=α×Vcell, where N is the number of absorbing cell per unit volume and Vcell is the volume of a single cancer cell. If the cancer cells embedded in fat induces absorption change ∆α, the cancer cell density N can be describe as: N = ∆α/σ=∆α/(α ×Vcell). The 3D volume of the total cancerous tissue V can then be evaluated. Through the THz absorption spectrum shown in Fig. 2, we calibrated the value of the absorption cross section. As shown in Fig. 5, the detected absorption change in early cancer development on the 23th day corresponds to a total cancerous tissue volume V of 1.3mm3, while the early cancer development in another mouse shown in Fig. 6 is with 0.8mm3 in volume on the 18th day. According to the S/N ratio of our imaging system (∆α = 0.01 mm−1), the minimum detectable volume on breast cancer can thus be estimated to be 0.05mm3. By improving the system noise level (through cryogenic temperature systems) and by lengthening the data acquisition time, the minimum detectable volume could be highly improved. This high sensitivity performance of T-ray imaging on cancer cells is primarily contributed from the high absorption constant on the adopted wavelength range, which sacrifices the penetration capability. Compared with X-ray mammography, the sensitivity of X-ray mammography depends on the density of the breast [33

33. S. J. Nass, I. C. Henderson, and J. C. Lashof, “Mammography and beyond: developing techniques for the early detection of breast cancer,” in Institute of Medicine (National Academy Press, 2001).

] and current X-ray mammography can detect breast cancers as small as 2mm in diameter [34

34. A. C. M. Onuigbo, M. E. Cuffy-Hallam, N. A. Dunsmore, and E. S. Zinreich, “Mammography reveals a 2-mm intraductal breast carcinoma,” Hosp. Physician 37, 61–64 (2001).

]. Compared with the state of the art clinical X-ray mammography, THz imaging is thus with a potential to serve as an alternative method to early detect breast cancer with a much smaller size.

8. Discussion

9. Conclusions

In conclusion, in vivo T-ray breast cancer imaging is demonstrated in a subcutaneous xenograft mouse study by using a transmission-based room-temperature-operating system. Owing to the high THz absorption contrast between breast cancer cells and fatty tissues, we successfully achieved in vivo early detection of breast cancer in the developed mouse model. The detection limit of the cancerous tissue volume in our THz room-temperature-operating imaging system was 0.05mm3. Moreover, our demonstrated THz transmission imaging system is compact, noninvasive, and non-ionizing, and could provide a unique and sensitive means to image early breast cancer development in the subcutaneous xenograft mouse model without the need of exogenous contrast.

Acknowledgment

The authors would like to acknowledge stimulating discussions with Ping-Chin Cheng. This work was supported by the Institutional Animal Care and Use Committee of National Taiwan University, the Molecular Imaging Center of National Taiwan University, and the National Science Council of Taiwan under grants NSC-97-2221-E-002-047-MY3 and NSC-99-2120-M-002-013.

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L.-J. Chen, H.-W. Chen, T.-F. Kao, J.-Y. Lu, and C.-K. Sun, “Low-loss subwavelength plastic fiber for terahertz waveguiding,” Opt. Lett. 31(3), 308–310 (2006), http://www.opticsinfobase.org/ol/abstract.cfm?URI=ol-31-3-308. [CrossRef] [PubMed]

29.

H.-W. Chen, Y.-T. Li, C. L. Pan, J. L. Kuo, J. Y. Lu, L. J. Chen, and C.-K. Sun, “Investigation on spectral loss characteristics of subwavelength terahertz fibers,” Opt. Lett. 32(9), 1017–1019 (2007), http://www.opticsinfobase.org/ol/abstract.cfm?URI=ol-32-9-1017. [CrossRef] [PubMed]

30.

Y.-W. Huang, T.-F. Tseng, C.-C. Kuo, Y. J. Hwang, and C.-K. Sun, “Fiber-based swept-source terahertz radar,” Opt. Lett. 35(9), 1344–1346 (2010), http://www.opticsinfobase.org/abstract.cfm?URI=ol-35-9-1344. [CrossRef] [PubMed]

31.

E. Berry, G. C. Walker, A. J. Fitzgerald, N. N. Zinov'ev, M. Chamberlain, S. W. Smye, R. E. Miles, and M. A. Smith, “Do in vivo terahertz imaging systems comply with safety guidelines?” J. Laser Appl. 15(3), 192–198 (2003). [CrossRef]

32.

M. S. Gee, R. Upadhyay, H. Bergquist, H. Alencar, F. Reynolds, M. Maricevich, R. Weissleder, L. Josephson, and U. Mahmood, “Human breast cancer tumor models: molecular imaging of drug susceptibility and dosing during HER2/neu-targeted therapy,” Radiology 248(3), 925–935 (2008). [CrossRef] [PubMed]

33.

S. J. Nass, I. C. Henderson, and J. C. Lashof, “Mammography and beyond: developing techniques for the early detection of breast cancer,” in Institute of Medicine (National Academy Press, 2001).

34.

A. C. M. Onuigbo, M. E. Cuffy-Hallam, N. A. Dunsmore, and E. S. Zinreich, “Mammography reveals a 2-mm intraductal breast carcinoma,” Hosp. Physician 37, 61–64 (2001).

35.

H. Chen, W.-J. Lee, H.-Y. Huang, C.-M. Chiu, Y.-F. Tsai, T.-F. Tseng, J.-T. Lu, W.-L. Lai, and C.-K. Sun, “Performance of THz fiber-scanning near-field microscopy to diagnose breast tumors,” Opt. Express 19(20), 19523–19531 (2011), http://www.opticsinfobase.org/oe/abstract.cfm?URI=oe-19-20-19523. [CrossRef]

OCIS Codes
(170.3880) Medical optics and biotechnology : Medical and biological imaging
(110.6795) Imaging systems : Terahertz imaging

ToC Category:
Medical Optics and Biotechnology

History
Original Manuscript: July 18, 2011
Revised Manuscript: August 19, 2011
Manuscript Accepted: September 9, 2011
Published: October 18, 2011

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

Citation
Hua Chen, Te-Hsuen Chen, Tzu-Fang Tseng, Jen-Tang Lu, Chung-Chiu Kuo, Shih-Chen Fu, Wen-Jeng Lee, Yuan-Fu Tsai, Yi-You Huang, Eric Y. Chuang, Yuh-Jing Hwang, and Chi-Kuang Sun, "High-sensitivity in vivo THz transmission imaging of early human breast cancer in a subcutaneous xenograft mouse model," Opt. Express 19, 21552-21562 (2011)
http://www.opticsinfobase.org/oe/abstract.cfm?URI=oe-19-22-21552


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