Abstract

For in vivo optical diagnostic technologies to be distributed to the developed and developing worlds, optical imaging systems must be constructed of inexpensive components. We present a fiber-optic confocal reflectance microscope with a cost-effective injection-molded plastic miniature objective lens for in vivo imaging of human tissues in near real time. The measured lateral resolution is less than 2.2 µm, and the measured axial resolution is 10 µm. Confocal images of ex vivo cervical tissue biopsies and in vivo human lip taken at 15 frames/s demonstrate the microscope’s capability of imaging cell morphology and tissue architecture.

© 2005 Optical Society of America

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2004

M. Rajadhyaksha, S. Gonzalez, J. M. Zavislan, “Detectability of contrast agents for confocal reflectance imaging of skin and microcirculation,” J. Biomed. Opt. 9, 323–331 (2004).
[CrossRef] [PubMed]

2003

2002

C. Liang, K. B. Sung, R. R. Richards-Kortum, M. R. Descour, “Design of a high-numerical-aperture miniature microscope objective for an endoscopic fiber confocal reflectance microscope,” Appl. Opt. 41, 4603–4610 (2002).
[CrossRef] [PubMed]

K. B. Sung, C. Liang, M. Descour, T. Collier, M. Follen, A. Malpica, R. Richards-Kortum, “Near real time in vivo fibre optic confocal microscopy: sub-cellular structure resolved,” J. Microsc. 207, 137–145 (2002).
[CrossRef] [PubMed]

K. B. Sung, C. Liang, M. Descour, T. Collier, M. Follen, R. Richards-Kortum, “Fiber-optic confocal reflectance microscope with miniature objective for in vivo imaging of human tissues,” IEEE Trans. Biomed. Eng. 49, 1168–1172 (2002).
[CrossRef] [PubMed]

T. Collier, A. Lacy, R. Richards-Kortum, A. Malpica, M. Follen, “Near real-time confocal microscopy of amelanotic tissue: detection of dysplasia in ex vivo cervical tissue,” Acad. Radiol. 9, 504–512 (2002).
[CrossRef] [PubMed]

2001

J. Knittel, L. Schnieder, G. Buess, B. Messerschmidt, T. Possner, “Endoscope-compatible confocal microscope using a gradient index-lens system,” Opt. Commun. 188, 267–273 (2001).
[CrossRef]

1999

1998

G. J. Tearney, R. H. Webb, B. E. Bouma, “Spectrally encoded confocal microscopy,” Opt. Lett. 23, 1152–1154 (1998).
[CrossRef]

S. B. Cantor, M. F. Mitchell, G. Tortolero-Luna, C. S. Bratka, D. C. Bodurka, R. Richards-Kortum, “Cost-effectiveness analysis of diagnosis and management of cervical squamous intraepithelial lesions,” Obstet. Gynecol. 91, 270–277 (1998).
[CrossRef] [PubMed]

1996

D. L. Dickensheets, G. S. Kino, “Silicon-micromachined scanning confocal optical microscope,” J. Microelectromech. Syst. 7, 38–47 (1996).
[CrossRef]

1995

M. Rajadhyaksha, M. Grossman, D. Esterowitz, R. H. Webb, R. R. Anderson, “In vivo confocal scanning laser microscopy of human skin: melanin provides strong contrast,” J. Invest. Dermatol. 104, 946–952 (1995).
[CrossRef] [PubMed]

1993

1991

1990

H. D. Cavanagh, J. V. Jester, J. Essepian, W. Shields, M. A. Lemp, “Confocal microscopy of the living eye,” CLAO J. 16, 65–73 (1990).
[PubMed]

Anderson, R. R.

M. Rajadhyaksha, R. R. Anderson, R. H. Webb, “Video-rate confocal scanning laser microscope for imaging human tissues in vivo,” Appl. Opt. 38, 2105–2115 (1999).
[CrossRef]

M. Rajadhyaksha, M. Grossman, D. Esterowitz, R. H. Webb, R. R. Anderson, “In vivo confocal scanning laser microscopy of human skin: melanin provides strong contrast,” J. Invest. Dermatol. 104, 946–952 (1995).
[CrossRef] [PubMed]

Aziz, D.

Bodurka, D. C.

S. B. Cantor, M. F. Mitchell, G. Tortolero-Luna, C. S. Bratka, D. C. Bodurka, R. Richards-Kortum, “Cost-effectiveness analysis of diagnosis and management of cervical squamous intraepithelial lesions,” Obstet. Gynecol. 91, 270–277 (1998).
[CrossRef] [PubMed]

Bouma, B. E.

Bratka, C. S.

S. B. Cantor, M. F. Mitchell, G. Tortolero-Luna, C. S. Bratka, D. C. Bodurka, R. Richards-Kortum, “Cost-effectiveness analysis of diagnosis and management of cervical squamous intraepithelial lesions,” Obstet. Gynecol. 91, 270–277 (1998).
[CrossRef] [PubMed]

Bray, F.

J. Ferlay, F. Bray, P. Pisani, D. M. Parkin, Globocan 2000: Cancer Incidence, Mortality and Prevalence Worldwide (World Health Organization International Agency for Research on Cancer, Lyon, 2001).

Buess, G.

J. Knittel, L. Schnieder, G. Buess, B. Messerschmidt, T. Possner, “Endoscope-compatible confocal microscope using a gradient index-lens system,” Opt. Commun. 188, 267–273 (2001).
[CrossRef]

Cantor, S. B.

S. B. Cantor, M. F. Mitchell, G. Tortolero-Luna, C. S. Bratka, D. C. Bodurka, R. Richards-Kortum, “Cost-effectiveness analysis of diagnosis and management of cervical squamous intraepithelial lesions,” Obstet. Gynecol. 91, 270–277 (1998).
[CrossRef] [PubMed]

Cavanagh, H. D.

H. D. Cavanagh, J. V. Jester, J. Essepian, W. Shields, M. A. Lemp, “Confocal microscopy of the living eye,” CLAO J. 16, 65–73 (1990).
[PubMed]

Chan, N. Y.

Chidley, M. D.

M. D. Chidley, C. Liang, M. Descour, K. B. Sung, R. Richards-Kortum, A. Gillenwater, “Miniature injection-molded optics for fiber-optic, in vivo confocal microscopy,” in International Optical Design Conference,P. K. Manhart, J. M. Sasian, eds., Proc. SPIE4832, 126–136 (2002).

M. D. Chidley, M. Descour, Optical Sciences Center, University of Arizona, 1630 E. University Boulevard, Tucson, Arizona 85721, are preparing a manuscript to be called “Design, assembly, and testing of high NA miniature injection-molded objective for laser confocal reflectance microscopy.”

Collier, T.

K. B. Sung, C. Liang, M. Descour, T. Collier, M. Follen, R. Richards-Kortum, “Fiber-optic confocal reflectance microscope with miniature objective for in vivo imaging of human tissues,” IEEE Trans. Biomed. Eng. 49, 1168–1172 (2002).
[CrossRef] [PubMed]

T. Collier, A. Lacy, R. Richards-Kortum, A. Malpica, M. Follen, “Near real-time confocal microscopy of amelanotic tissue: detection of dysplasia in ex vivo cervical tissue,” Acad. Radiol. 9, 504–512 (2002).
[CrossRef] [PubMed]

K. B. Sung, C. Liang, M. Descour, T. Collier, M. Follen, A. Malpica, R. Richards-Kortum, “Near real time in vivo fibre optic confocal microscopy: sub-cellular structure resolved,” J. Microsc. 207, 137–145 (2002).
[CrossRef] [PubMed]

Contag, C. H.

Descour, M.

K. B. Sung, C. Liang, M. Descour, T. Collier, M. Follen, R. Richards-Kortum, “Fiber-optic confocal reflectance microscope with miniature objective for in vivo imaging of human tissues,” IEEE Trans. Biomed. Eng. 49, 1168–1172 (2002).
[CrossRef] [PubMed]

K. B. Sung, C. Liang, M. Descour, T. Collier, M. Follen, A. Malpica, R. Richards-Kortum, “Near real time in vivo fibre optic confocal microscopy: sub-cellular structure resolved,” J. Microsc. 207, 137–145 (2002).
[CrossRef] [PubMed]

M. D. Chidley, C. Liang, M. Descour, K. B. Sung, R. Richards-Kortum, A. Gillenwater, “Miniature injection-molded optics for fiber-optic, in vivo confocal microscopy,” in International Optical Design Conference,P. K. Manhart, J. M. Sasian, eds., Proc. SPIE4832, 126–136 (2002).

M. D. Chidley, M. Descour, Optical Sciences Center, University of Arizona, 1630 E. University Boulevard, Tucson, Arizona 85721, are preparing a manuscript to be called “Design, assembly, and testing of high NA miniature injection-molded objective for laser confocal reflectance microscopy.”

Descour, M. R.

Dickensheets, D. L.

D. L. Dickensheets, G. S. Kino, “Silicon-micromachined scanning confocal optical microscope,” J. Microelectromech. Syst. 7, 38–47 (1996).
[CrossRef]

Donaldson, L.

Essepian, J.

H. D. Cavanagh, J. V. Jester, J. Essepian, W. Shields, M. A. Lemp, “Confocal microscopy of the living eye,” CLAO J. 16, 65–73 (1990).
[PubMed]

Esterowitz, D.

M. Rajadhyaksha, M. Grossman, D. Esterowitz, R. H. Webb, R. R. Anderson, “In vivo confocal scanning laser microscopy of human skin: melanin provides strong contrast,” J. Invest. Dermatol. 104, 946–952 (1995).
[CrossRef] [PubMed]

Ferlay, J.

J. Ferlay, F. Bray, P. Pisani, D. M. Parkin, Globocan 2000: Cancer Incidence, Mortality and Prevalence Worldwide (World Health Organization International Agency for Research on Cancer, Lyon, 2001).

Follen, M.

K. B. Sung, C. Liang, M. Descour, T. Collier, M. Follen, R. Richards-Kortum, “Fiber-optic confocal reflectance microscope with miniature objective for in vivo imaging of human tissues,” IEEE Trans. Biomed. Eng. 49, 1168–1172 (2002).
[CrossRef] [PubMed]

K. B. Sung, C. Liang, M. Descour, T. Collier, M. Follen, A. Malpica, R. Richards-Kortum, “Near real time in vivo fibre optic confocal microscopy: sub-cellular structure resolved,” J. Microsc. 207, 137–145 (2002).
[CrossRef] [PubMed]

T. Collier, A. Lacy, R. Richards-Kortum, A. Malpica, M. Follen, “Near real-time confocal microscopy of amelanotic tissue: detection of dysplasia in ex vivo cervical tissue,” Acad. Radiol. 9, 504–512 (2002).
[CrossRef] [PubMed]

Gan, X.

Gillenwater, A.

M. D. Chidley, C. Liang, M. Descour, K. B. Sung, R. Richards-Kortum, A. Gillenwater, “Miniature injection-molded optics for fiber-optic, in vivo confocal microscopy,” in International Optical Design Conference,P. K. Manhart, J. M. Sasian, eds., Proc. SPIE4832, 126–136 (2002).

Gmitro, A. F.

Gonzalez, S.

M. Rajadhyaksha, S. Gonzalez, J. M. Zavislan, “Detectability of contrast agents for confocal reflectance imaging of skin and microcirculation,” J. Biomed. Opt. 9, 323–331 (2004).
[CrossRef] [PubMed]

Grossman, M.

M. Rajadhyaksha, M. Grossman, D. Esterowitz, R. H. Webb, R. R. Anderson, “In vivo confocal scanning laser microscopy of human skin: melanin provides strong contrast,” J. Invest. Dermatol. 104, 946–952 (1995).
[CrossRef] [PubMed]

Gu, M.

Hopkins, M. F.

Jester, J. V.

H. D. Cavanagh, J. V. Jester, J. Essepian, W. Shields, M. A. Lemp, “Confocal microscopy of the living eye,” CLAO J. 16, 65–73 (1990).
[PubMed]

Kino, G. S.

T. D. Wang, C. H. Contag, M. J. Mandella, N. Y. Chan, G. S. Kino, “Dual-axes confocal microscopy with post-objective scanning and low-coherence heterodyne detection,” Opt. Lett. 28, 1915–1917 (2003).

D. L. Dickensheets, G. S. Kino, “Silicon-micromachined scanning confocal optical microscope,” J. Microelectromech. Syst. 7, 38–47 (1996).
[CrossRef]

Knittel, J.

J. Knittel, L. Schnieder, G. Buess, B. Messerschmidt, T. Possner, “Endoscope-compatible confocal microscope using a gradient index-lens system,” Opt. Commun. 188, 267–273 (2001).
[CrossRef]

Lacy, A.

T. Collier, A. Lacy, R. Richards-Kortum, A. Malpica, M. Follen, “Near real-time confocal microscopy of amelanotic tissue: detection of dysplasia in ex vivo cervical tissue,” Acad. Radiol. 9, 504–512 (2002).
[CrossRef] [PubMed]

Lemp, M. A.

H. D. Cavanagh, J. V. Jester, J. Essepian, W. Shields, M. A. Lemp, “Confocal microscopy of the living eye,” CLAO J. 16, 65–73 (1990).
[PubMed]

Liang, C.

K. B. Sung, C. Liang, M. Descour, T. Collier, M. Follen, A. Malpica, R. Richards-Kortum, “Near real time in vivo fibre optic confocal microscopy: sub-cellular structure resolved,” J. Microsc. 207, 137–145 (2002).
[CrossRef] [PubMed]

C. Liang, K. B. Sung, R. R. Richards-Kortum, M. R. Descour, “Design of a high-numerical-aperture miniature microscope objective for an endoscopic fiber confocal reflectance microscope,” Appl. Opt. 41, 4603–4610 (2002).
[CrossRef] [PubMed]

K. B. Sung, C. Liang, M. Descour, T. Collier, M. Follen, R. Richards-Kortum, “Fiber-optic confocal reflectance microscope with miniature objective for in vivo imaging of human tissues,” IEEE Trans. Biomed. Eng. 49, 1168–1172 (2002).
[CrossRef] [PubMed]

M. D. Chidley, C. Liang, M. Descour, K. B. Sung, R. Richards-Kortum, A. Gillenwater, “Miniature injection-molded optics for fiber-optic, in vivo confocal microscopy,” in International Optical Design Conference,P. K. Manhart, J. M. Sasian, eds., Proc. SPIE4832, 126–136 (2002).

Malpica, A.

T. Collier, A. Lacy, R. Richards-Kortum, A. Malpica, M. Follen, “Near real-time confocal microscopy of amelanotic tissue: detection of dysplasia in ex vivo cervical tissue,” Acad. Radiol. 9, 504–512 (2002).
[CrossRef] [PubMed]

K. B. Sung, C. Liang, M. Descour, T. Collier, M. Follen, A. Malpica, R. Richards-Kortum, “Near real time in vivo fibre optic confocal microscopy: sub-cellular structure resolved,” J. Microsc. 207, 137–145 (2002).
[CrossRef] [PubMed]

Mandella, M. J.

McLaren, W.

W. McLaren, J. Tan, M. Quinn, “Detection of cervical neoplasia using non-invasive fibre-optic confocal microscopy,” in Proceedings of 5th International Multidisciplinary Congress EUROGIN 2003, J. Monsonego, ed. (Monduzzi Editore, Paris, 2003), pp. 213–217.

Messerschmidt, B.

J. Knittel, L. Schnieder, G. Buess, B. Messerschmidt, T. Possner, “Endoscope-compatible confocal microscope using a gradient index-lens system,” Opt. Commun. 188, 267–273 (2001).
[CrossRef]

Mitchell, M. F.

S. B. Cantor, M. F. Mitchell, G. Tortolero-Luna, C. S. Bratka, D. C. Bodurka, R. Richards-Kortum, “Cost-effectiveness analysis of diagnosis and management of cervical squamous intraepithelial lesions,” Obstet. Gynecol. 91, 270–277 (1998).
[CrossRef] [PubMed]

Parkin, D. M.

J. Ferlay, F. Bray, P. Pisani, D. M. Parkin, Globocan 2000: Cancer Incidence, Mortality and Prevalence Worldwide (World Health Organization International Agency for Research on Cancer, Lyon, 2001).

Pisani, P.

J. Ferlay, F. Bray, P. Pisani, D. M. Parkin, Globocan 2000: Cancer Incidence, Mortality and Prevalence Worldwide (World Health Organization International Agency for Research on Cancer, Lyon, 2001).

Possner, T.

J. Knittel, L. Schnieder, G. Buess, B. Messerschmidt, T. Possner, “Endoscope-compatible confocal microscope using a gradient index-lens system,” Opt. Commun. 188, 267–273 (2001).
[CrossRef]

Quinn, M.

W. McLaren, J. Tan, M. Quinn, “Detection of cervical neoplasia using non-invasive fibre-optic confocal microscopy,” in Proceedings of 5th International Multidisciplinary Congress EUROGIN 2003, J. Monsonego, ed. (Monduzzi Editore, Paris, 2003), pp. 213–217.

Rajadhyaksha, M.

M. Rajadhyaksha, S. Gonzalez, J. M. Zavislan, “Detectability of contrast agents for confocal reflectance imaging of skin and microcirculation,” J. Biomed. Opt. 9, 323–331 (2004).
[CrossRef] [PubMed]

M. Rajadhyaksha, R. R. Anderson, R. H. Webb, “Video-rate confocal scanning laser microscope for imaging human tissues in vivo,” Appl. Opt. 38, 2105–2115 (1999).
[CrossRef]

M. Rajadhyaksha, M. Grossman, D. Esterowitz, R. H. Webb, R. R. Anderson, “In vivo confocal scanning laser microscopy of human skin: melanin provides strong contrast,” J. Invest. Dermatol. 104, 946–952 (1995).
[CrossRef] [PubMed]

Richards-Kortum, R.

K. B. Sung, C. Liang, M. Descour, T. Collier, M. Follen, R. Richards-Kortum, “Fiber-optic confocal reflectance microscope with miniature objective for in vivo imaging of human tissues,” IEEE Trans. Biomed. Eng. 49, 1168–1172 (2002).
[CrossRef] [PubMed]

K. B. Sung, C. Liang, M. Descour, T. Collier, M. Follen, A. Malpica, R. Richards-Kortum, “Near real time in vivo fibre optic confocal microscopy: sub-cellular structure resolved,” J. Microsc. 207, 137–145 (2002).
[CrossRef] [PubMed]

T. Collier, A. Lacy, R. Richards-Kortum, A. Malpica, M. Follen, “Near real-time confocal microscopy of amelanotic tissue: detection of dysplasia in ex vivo cervical tissue,” Acad. Radiol. 9, 504–512 (2002).
[CrossRef] [PubMed]

S. B. Cantor, M. F. Mitchell, G. Tortolero-Luna, C. S. Bratka, D. C. Bodurka, R. Richards-Kortum, “Cost-effectiveness analysis of diagnosis and management of cervical squamous intraepithelial lesions,” Obstet. Gynecol. 91, 270–277 (1998).
[CrossRef] [PubMed]

M. D. Chidley, C. Liang, M. Descour, K. B. Sung, R. Richards-Kortum, A. Gillenwater, “Miniature injection-molded optics for fiber-optic, in vivo confocal microscopy,” in International Optical Design Conference,P. K. Manhart, J. M. Sasian, eds., Proc. SPIE4832, 126–136 (2002).

Richards-Kortum, R. R.

Rouse, A. R.

Sabharwal, Y. S.

Schnieder, L.

J. Knittel, L. Schnieder, G. Buess, B. Messerschmidt, T. Possner, “Endoscope-compatible confocal microscope using a gradient index-lens system,” Opt. Commun. 188, 267–273 (2001).
[CrossRef]

Sheppard, C. J. R.

Shields, W.

H. D. Cavanagh, J. V. Jester, J. Essepian, W. Shields, M. A. Lemp, “Confocal microscopy of the living eye,” CLAO J. 16, 65–73 (1990).
[PubMed]

Sung, K. B.

K. B. Sung, C. Liang, M. Descour, T. Collier, M. Follen, A. Malpica, R. Richards-Kortum, “Near real time in vivo fibre optic confocal microscopy: sub-cellular structure resolved,” J. Microsc. 207, 137–145 (2002).
[CrossRef] [PubMed]

C. Liang, K. B. Sung, R. R. Richards-Kortum, M. R. Descour, “Design of a high-numerical-aperture miniature microscope objective for an endoscopic fiber confocal reflectance microscope,” Appl. Opt. 41, 4603–4610 (2002).
[CrossRef] [PubMed]

K. B. Sung, C. Liang, M. Descour, T. Collier, M. Follen, R. Richards-Kortum, “Fiber-optic confocal reflectance microscope with miniature objective for in vivo imaging of human tissues,” IEEE Trans. Biomed. Eng. 49, 1168–1172 (2002).
[CrossRef] [PubMed]

M. D. Chidley, C. Liang, M. Descour, K. B. Sung, R. Richards-Kortum, A. Gillenwater, “Miniature injection-molded optics for fiber-optic, in vivo confocal microscopy,” in International Optical Design Conference,P. K. Manhart, J. M. Sasian, eds., Proc. SPIE4832, 126–136 (2002).

Tan, J.

W. McLaren, J. Tan, M. Quinn, “Detection of cervical neoplasia using non-invasive fibre-optic confocal microscopy,” in Proceedings of 5th International Multidisciplinary Congress EUROGIN 2003, J. Monsonego, ed. (Monduzzi Editore, Paris, 2003), pp. 213–217.

Tearney, G. J.

Tortolero-Luna, G.

S. B. Cantor, M. F. Mitchell, G. Tortolero-Luna, C. S. Bratka, D. C. Bodurka, R. Richards-Kortum, “Cost-effectiveness analysis of diagnosis and management of cervical squamous intraepithelial lesions,” Obstet. Gynecol. 91, 270–277 (1998).
[CrossRef] [PubMed]

Wang, T. D.

Webb, R. H.

Zavislan, J. M.

M. Rajadhyaksha, S. Gonzalez, J. M. Zavislan, “Detectability of contrast agents for confocal reflectance imaging of skin and microcirculation,” J. Biomed. Opt. 9, 323–331 (2004).
[CrossRef] [PubMed]

Acad. Radiol.

T. Collier, A. Lacy, R. Richards-Kortum, A. Malpica, M. Follen, “Near real-time confocal microscopy of amelanotic tissue: detection of dysplasia in ex vivo cervical tissue,” Acad. Radiol. 9, 504–512 (2002).
[CrossRef] [PubMed]

Appl. Opt.

CLAO J.

H. D. Cavanagh, J. V. Jester, J. Essepian, W. Shields, M. A. Lemp, “Confocal microscopy of the living eye,” CLAO J. 16, 65–73 (1990).
[PubMed]

IEEE Trans. Biomed. Eng.

K. B. Sung, C. Liang, M. Descour, T. Collier, M. Follen, R. Richards-Kortum, “Fiber-optic confocal reflectance microscope with miniature objective for in vivo imaging of human tissues,” IEEE Trans. Biomed. Eng. 49, 1168–1172 (2002).
[CrossRef] [PubMed]

J. Biomed. Opt.

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Figures (8)

Fig. 1
Fig. 1

Schematic of fiber-optic confocal reflectance microscope (FOCM).

Fig. 2
Fig. 2

Optical design of miniature objective lenses used in FOCM. Here the fiber bundle is located to the left of the lenses, with oil immersion. The sample is placed to the right, with water immersion. (a) Previous glass lens design with eight lens elements. (b) New plastic lens design with five lens elements utilizing aspheric surfaces.

Fig. 3
Fig. 3

Injection-molded plastic objective lens assembled and disassembled with U.S. coins.

Fig. 4
Fig. 4

Image of U.S. Air Force resolution test target demonstrating the lateral resolution of the plastic objective lens with the FOCM. The linewidths of the smallest element are 2.19 µm. The scale bar is 20 µm.

Fig. 5
Fig. 5

Axial response of the FOCM with the plastic objective was measured by translation of a reflective grating through the focal plane of the objective in 1-µm steps and acquisition of an image at each axial position. The bright region of the image was averaged for each image and plotted versus the axial position. The FWHM is approximately 10 µm.

Fig. 6
Fig. 6

Image of 4.3-µm polystyrene microspheres imbedded in gelatin. The scale bar is 20 µm.

Fig. 7
Fig. 7

Image of the epithelium of a normal cervical biopsy. The image plane is approximately 200 µm below the surface. The scale bar is 20 µm.

Fig. 8
Fig. 8

Image of epithelium of the lower lip of a normal volunteer. The scale bar is 20 µm.

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