Abstract

A disposable high numerical aperture microendoscope objective has been designed, fabricated, and tested for use with a fiber confocal reflectance microscope. The objective uses high precision LIGA fabricated components to integrate imaging components and hydraulic suction lines into a housing that measures only 3.85 mm in outer diameter and 14.65 mm in length. The hydraulics are used to translate tissue through the focal plane for three dimensional imaging. This device is diffraction limited for λ = 850 nm, has a numerical aperture of 1.0, a field of view of 250 μm, and a working distance of 450 μm. The objective is intended for in vivo imaging of precancerous cells.

© 2007 Optical Society of America

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  1. C. Liang, K. B. Sung, R. Richards-Kortum, and M. R. Descour, "Fiber confocal reflectance microscope (FCRM) for in-vivo imaging," Opt. Express 9, 821-830 (2001).
    [CrossRef] [PubMed]
  2. M. D. Chidley, K. Carlson, M. R. Descour, and R. Richards-Kortum, "Design, assembly, and optical bench testing of a high numerical aperture miniature injection-molded objective for fiber-optic confocal reflectance microscopy," Appl. Opt.  45, 2545-2554 (2006).
    [CrossRef] [PubMed]
  3. M. D. Chidley, C. Liang, M. Descour, K.B. Sung, R. Richards-Kortum, and A. Gillenwater, "Miniature injection-molded optics for fiber optic, in vivo confocal microscopy," in International Optical Design Conference, P. K. Manhart and J. M. Sasian, ed., Proc. SPIE 4832, 126-136 (2002).
    [CrossRef]
  4. K. B. Sung, C. Liang, M. Descour, T. Collier, M. Follen, A. Malpica, R. Richards-KortumNear real time in vivo fibre optic confocal microscopy: sub-cellular structure resolvedJ. of Microsc.,  207, 137-145 (2002).
  5. I. H. El-Sayed, X. Huang, M. A. El-Sayed, " Surface plasmon resonance scattering and absorption of anti-EGFR antibody conjugated gold nanoparticles in cancer diagnostics: applications in oral cancer," Nano Lett.  5, 829-384 (2005).
    [CrossRef] [PubMed]
  6. X. Huang, I. H. El-Sayed, W. Qian, M.A. El-Sayed, "Cancer cell imaging and photothermal therapy in the near-infrared region by using gold nanorods" J Am Chem Soc.  128, 2115-20 (2006).
    [CrossRef] [PubMed]
  7. C. Loo, L. Hirsch, M.H. Lee, E. Chang, J. West, N. Halas, R. Drezek, "Gold nanoshell bioconjugates for molecular imaging in living cells," Opt. Lett.  30, 1012-1014 (2005).
    [CrossRef] [PubMed]
  8. A. W. Lin, N. A. Lewinski, J. L. West, N. J. Halas, R. A. Drezek, "Optically tunable nanoparticle contrast agents for early cancer detection: model-based analysis of gold nanoshells," J Biomed Opt.  10, 064035.
    [PubMed]
  9. K. Sokolov, M. Follen, J. Aaron, I. Pavlova, A. Malpica, R. Lotan, and R. Richards-Kortum, "Real-time vital optical imaging of precancer using anti-epidermal growth factor receptor antibodies conjugated to gold nanopaticles," Cancer Res. 63, 1999-2004 (2003).
    [PubMed]
  10. C. Liang, K.B. Sung, R. Richards-Kortum, and 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]
  11. C. Liang, "Design of miniature microscope objective optics for biomedical imaging," Ph.D. dissertation, The University of Arizona (2002).
  12. .ZEMAX Development Corporation: http://www.zemax.com.
  13. The MEMS Handbook, 2nd Edition, Mohamed Gad-el-Hak, ed., CRC Tayor & Francis, Boca Raton, v.2, MEMS Design and Fabrication, Ch. 5, X-Ray Based Fabrication, 2006.
  14. Olympus Corporation: http://www.olympusconfocal.com/theory/resolutionintro.html
  15. P. D. Burns, "Slanted-Edge MTF for Digital Camera and Scanner Analysis," Proc. IS&T 2000 PICS Conference, 135-138 (2000).

2006 (2)

2005 (2)

C. Loo, L. Hirsch, M.H. Lee, E. Chang, J. West, N. Halas, R. Drezek, "Gold nanoshell bioconjugates for molecular imaging in living cells," Opt. Lett.  30, 1012-1014 (2005).
[CrossRef] [PubMed]

I. H. El-Sayed, X. Huang, M. A. El-Sayed, " Surface plasmon resonance scattering and absorption of anti-EGFR antibody conjugated gold nanoparticles in cancer diagnostics: applications in oral cancer," Nano Lett.  5, 829-384 (2005).
[CrossRef] [PubMed]

2003 (1)

K. Sokolov, M. Follen, J. Aaron, I. Pavlova, A. Malpica, R. Lotan, and R. Richards-Kortum, "Real-time vital optical imaging of precancer using anti-epidermal growth factor receptor antibodies conjugated to gold nanopaticles," Cancer Res. 63, 1999-2004 (2003).
[PubMed]

2002 (2)

K. B. Sung, C. Liang, M. Descour, T. Collier, M. Follen, A. Malpica, R. Richards-KortumNear real time in vivo fibre optic confocal microscopy: sub-cellular structure resolvedJ. of Microsc.,  207, 137-145 (2002).

C. Liang, K.B. Sung, R. Richards-Kortum, and 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]

2001 (1)

Aaron, J.

K. Sokolov, M. Follen, J. Aaron, I. Pavlova, A. Malpica, R. Lotan, and R. Richards-Kortum, "Real-time vital optical imaging of precancer using anti-epidermal growth factor receptor antibodies conjugated to gold nanopaticles," Cancer Res. 63, 1999-2004 (2003).
[PubMed]

Carlson, K.

Chang, E.

Chidley, M. D.

Collier, T.

K. B. Sung, C. Liang, M. Descour, T. Collier, M. Follen, A. Malpica, R. Richards-KortumNear real time in vivo fibre optic confocal microscopy: sub-cellular structure resolvedJ. of Microsc.,  207, 137-145 (2002).

Descour, M.

K. B. Sung, C. Liang, M. Descour, T. Collier, M. Follen, A. Malpica, R. Richards-KortumNear real time in vivo fibre optic confocal microscopy: sub-cellular structure resolvedJ. of Microsc.,  207, 137-145 (2002).

Descour, M. R.

Descour, M.R.

Drezek, R.

Drezek, R. A.

A. W. Lin, N. A. Lewinski, J. L. West, N. J. Halas, R. A. Drezek, "Optically tunable nanoparticle contrast agents for early cancer detection: model-based analysis of gold nanoshells," J Biomed Opt.  10, 064035.
[PubMed]

El-Sayed,

I. H. El-Sayed, X. Huang, M. A. El-Sayed, " Surface plasmon resonance scattering and absorption of anti-EGFR antibody conjugated gold nanoparticles in cancer diagnostics: applications in oral cancer," Nano Lett.  5, 829-384 (2005).
[CrossRef] [PubMed]

El-Sayed, I. H.

X. Huang, I. H. El-Sayed, W. Qian, M.A. El-Sayed, "Cancer cell imaging and photothermal therapy in the near-infrared region by using gold nanorods" J Am Chem Soc.  128, 2115-20 (2006).
[CrossRef] [PubMed]

El-Sayed, M.A.

X. Huang, I. H. El-Sayed, W. Qian, M.A. El-Sayed, "Cancer cell imaging and photothermal therapy in the near-infrared region by using gold nanorods" J Am Chem Soc.  128, 2115-20 (2006).
[CrossRef] [PubMed]

El-Sayed, X.

I. H. El-Sayed, X. Huang, M. A. El-Sayed, " Surface plasmon resonance scattering and absorption of anti-EGFR antibody conjugated gold nanoparticles in cancer diagnostics: applications in oral cancer," Nano Lett.  5, 829-384 (2005).
[CrossRef] [PubMed]

Follen, M.

K. Sokolov, M. Follen, J. Aaron, I. Pavlova, A. Malpica, R. Lotan, and R. Richards-Kortum, "Real-time vital optical imaging of precancer using anti-epidermal growth factor receptor antibodies conjugated to gold nanopaticles," Cancer Res. 63, 1999-2004 (2003).
[PubMed]

K. B. Sung, C. Liang, M. Descour, T. Collier, M. Follen, A. Malpica, R. Richards-KortumNear real time in vivo fibre optic confocal microscopy: sub-cellular structure resolvedJ. of Microsc.,  207, 137-145 (2002).

Halas, N.

Halas, N. J.

A. W. Lin, N. A. Lewinski, J. L. West, N. J. Halas, R. A. Drezek, "Optically tunable nanoparticle contrast agents for early cancer detection: model-based analysis of gold nanoshells," J Biomed Opt.  10, 064035.
[PubMed]

Hirsch, L.

Huang, I. H.

I. H. El-Sayed, X. Huang, M. A. El-Sayed, " Surface plasmon resonance scattering and absorption of anti-EGFR antibody conjugated gold nanoparticles in cancer diagnostics: applications in oral cancer," Nano Lett.  5, 829-384 (2005).
[CrossRef] [PubMed]

Huang, X.

X. Huang, I. H. El-Sayed, W. Qian, M.A. El-Sayed, "Cancer cell imaging and photothermal therapy in the near-infrared region by using gold nanorods" J Am Chem Soc.  128, 2115-20 (2006).
[CrossRef] [PubMed]

Lee, M.H.

Lewinski, N. A.

A. W. Lin, N. A. Lewinski, J. L. West, N. J. Halas, R. A. Drezek, "Optically tunable nanoparticle contrast agents for early cancer detection: model-based analysis of gold nanoshells," J Biomed Opt.  10, 064035.
[PubMed]

Liang, C.

Lin, A. W.

A. W. Lin, N. A. Lewinski, J. L. West, N. J. Halas, R. A. Drezek, "Optically tunable nanoparticle contrast agents for early cancer detection: model-based analysis of gold nanoshells," J Biomed Opt.  10, 064035.
[PubMed]

Loo, C.

Lotan, R.

K. Sokolov, M. Follen, J. Aaron, I. Pavlova, A. Malpica, R. Lotan, and R. Richards-Kortum, "Real-time vital optical imaging of precancer using anti-epidermal growth factor receptor antibodies conjugated to gold nanopaticles," Cancer Res. 63, 1999-2004 (2003).
[PubMed]

Malpica, A.

K. Sokolov, M. Follen, J. Aaron, I. Pavlova, A. Malpica, R. Lotan, and R. Richards-Kortum, "Real-time vital optical imaging of precancer using anti-epidermal growth factor receptor antibodies conjugated to gold nanopaticles," Cancer Res. 63, 1999-2004 (2003).
[PubMed]

K. B. Sung, C. Liang, M. Descour, T. Collier, M. Follen, A. Malpica, R. Richards-KortumNear real time in vivo fibre optic confocal microscopy: sub-cellular structure resolvedJ. of Microsc.,  207, 137-145 (2002).

Pavlova, I.

K. Sokolov, M. Follen, J. Aaron, I. Pavlova, A. Malpica, R. Lotan, and R. Richards-Kortum, "Real-time vital optical imaging of precancer using anti-epidermal growth factor receptor antibodies conjugated to gold nanopaticles," Cancer Res. 63, 1999-2004 (2003).
[PubMed]

Qian, W.

X. Huang, I. H. El-Sayed, W. Qian, M.A. El-Sayed, "Cancer cell imaging and photothermal therapy in the near-infrared region by using gold nanorods" J Am Chem Soc.  128, 2115-20 (2006).
[CrossRef] [PubMed]

Richards-Kortum, R.

M. D. Chidley, K. Carlson, M. R. Descour, and R. Richards-Kortum, "Design, assembly, and optical bench testing of a high numerical aperture miniature injection-molded objective for fiber-optic confocal reflectance microscopy," Appl. Opt.  45, 2545-2554 (2006).
[CrossRef] [PubMed]

K. Sokolov, M. Follen, J. Aaron, I. Pavlova, A. Malpica, R. Lotan, and R. Richards-Kortum, "Real-time vital optical imaging of precancer using anti-epidermal growth factor receptor antibodies conjugated to gold nanopaticles," Cancer Res. 63, 1999-2004 (2003).
[PubMed]

K. B. Sung, C. Liang, M. Descour, T. Collier, M. Follen, A. Malpica, R. Richards-KortumNear real time in vivo fibre optic confocal microscopy: sub-cellular structure resolvedJ. of Microsc.,  207, 137-145 (2002).

C. Liang, K.B. Sung, R. Richards-Kortum, and 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]

C. Liang, K. B. Sung, R. Richards-Kortum, and M. R. Descour, "Fiber confocal reflectance microscope (FCRM) for in-vivo imaging," Opt. Express 9, 821-830 (2001).
[CrossRef] [PubMed]

Sokolov, K.

K. Sokolov, M. Follen, J. Aaron, I. Pavlova, A. Malpica, R. Lotan, and R. Richards-Kortum, "Real-time vital optical imaging of precancer using anti-epidermal growth factor receptor antibodies conjugated to gold nanopaticles," Cancer Res. 63, 1999-2004 (2003).
[PubMed]

Sung, K. B.

K. B. Sung, C. Liang, M. Descour, T. Collier, M. Follen, A. Malpica, R. Richards-KortumNear real time in vivo fibre optic confocal microscopy: sub-cellular structure resolvedJ. of Microsc.,  207, 137-145 (2002).

C. Liang, K. B. Sung, R. Richards-Kortum, and M. R. Descour, "Fiber confocal reflectance microscope (FCRM) for in-vivo imaging," Opt. Express 9, 821-830 (2001).
[CrossRef] [PubMed]

Sung, K.B.

West, J.

West, J. L.

A. W. Lin, N. A. Lewinski, J. L. West, N. J. Halas, R. A. Drezek, "Optically tunable nanoparticle contrast agents for early cancer detection: model-based analysis of gold nanoshells," J Biomed Opt.  10, 064035.
[PubMed]

Appl. Opt. (2)

Cancer Res. (1)

K. Sokolov, M. Follen, J. Aaron, I. Pavlova, A. Malpica, R. Lotan, and R. Richards-Kortum, "Real-time vital optical imaging of precancer using anti-epidermal growth factor receptor antibodies conjugated to gold nanopaticles," Cancer Res. 63, 1999-2004 (2003).
[PubMed]

J Am Chem Soc (1)

X. Huang, I. H. El-Sayed, W. Qian, M.A. El-Sayed, "Cancer cell imaging and photothermal therapy in the near-infrared region by using gold nanorods" J Am Chem Soc.  128, 2115-20 (2006).
[CrossRef] [PubMed]

J Biomed Opt (1)

A. W. Lin, N. A. Lewinski, J. L. West, N. J. Halas, R. A. Drezek, "Optically tunable nanoparticle contrast agents for early cancer detection: model-based analysis of gold nanoshells," J Biomed Opt.  10, 064035.
[PubMed]

J. of Microsc. (1)

K. B. Sung, C. Liang, M. Descour, T. Collier, M. Follen, A. Malpica, R. Richards-KortumNear real time in vivo fibre optic confocal microscopy: sub-cellular structure resolvedJ. of Microsc.,  207, 137-145 (2002).

Nano Lett. (1)

I. H. El-Sayed, X. Huang, M. A. El-Sayed, " Surface plasmon resonance scattering and absorption of anti-EGFR antibody conjugated gold nanoparticles in cancer diagnostics: applications in oral cancer," Nano Lett.  5, 829-384 (2005).
[CrossRef] [PubMed]

Opt. Express (1)

Opt. Lett. (1)

Other (6)

M. D. Chidley, C. Liang, M. Descour, K.B. Sung, R. Richards-Kortum, and A. Gillenwater, "Miniature injection-molded optics for fiber optic, in vivo confocal microscopy," in International Optical Design Conference, P. K. Manhart and J. M. Sasian, ed., Proc. SPIE 4832, 126-136 (2002).
[CrossRef]

C. Liang, "Design of miniature microscope objective optics for biomedical imaging," Ph.D. dissertation, The University of Arizona (2002).

.ZEMAX Development Corporation: http://www.zemax.com.

The MEMS Handbook, 2nd Edition, Mohamed Gad-el-Hak, ed., CRC Tayor & Francis, Boca Raton, v.2, MEMS Design and Fabrication, Ch. 5, X-Ray Based Fabrication, 2006.

Olympus Corporation: http://www.olympusconfocal.com/theory/resolutionintro.html

P. D. Burns, "Slanted-Edge MTF for Digital Camera and Scanner Analysis," Proc. IS&T 2000 PICS Conference, 135-138 (2000).

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Figures (9)

Fig. 1.
Fig. 1.

Miniature Microscope Objective Layout

Fig. 2.
Fig. 2.

Theoretical performance of the microendoscope objective. (a) Geometric spot diagrams for three radial image positions: on-axis, 0.707 field, and full field. (b) Distortion plot in percentage of deviation from chief ray location. (c) Modulation transfer function plot for the same image field positions in (a).

Fig. 3.
Fig. 3.

Schematic of back reflections from some of the surfaces in objective. (a) surface 3, (b) surface 2, (c) surface 1, (d) tissue.

Fig. 4.
Fig. 4.

Opto-mechanical assembly schematic of microendoscope objective.

Fig. 5.
Fig. 5.

LIGA manufactured self-centering ring for glass element in objective. (a) Front view of self-centering ring. (b) Side view of self-centering ring showing the flexing direction of ring.

Fig. 6.
Fig. 6.

Pictures of actual microendoscope objective and components. (a) Some components used in the objective (lenses, objective layers, and ferrule). (b) Assembled microendoscoe objective.

Fig. 7.
Fig. 7.

Sequence of pictures showing the integration of the fiber bundle with objective.

Fig. 8.
Fig. 8.

Optical performance results for microendoscope objective. (a) USAF resolution target imaged by objective. (b) Slanted-edge data acquisition locations for upper right corner.

Fig. 9.
Fig. 9.

MTF and SR performance for microendoscope object at four edges of a square.

Tables (5)

Tables Icon

Table 1. Design Specifications for Third Generation Objective.

Tables Icon

Table 2. Miniature Microscope Objective Lens Prescription

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Table 3. Tolerances for miniature optics in microendoscope objective.

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Table 4. Monte Carlo tolerance results for objective.

Tables Icon

Table 5. Back reflection irradiance comparison to signal irradiance.

Equations (2)

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Minimum _ Diameter object = fullFOV + 2 tan [ sin 1 ( NA obj n obj ) ] WD
Minimum _ Diameter image = fullFOV m + 2 tan [ sin 1 ( NA img n img ) ] z '

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