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Handheld subcellular-resolution single-fiber confocal microscope using high-reflectivity two-axis vertical combdrive silicon microscanner

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Abstract

We introduce a handheld single-fiber laser-scanning confocal microscope, incorporating a high-reflectivity two-axis silicon vertical combdrive microscanner, aimed at in vivo early detection of epithelial precancers. The approach adopted is motivated by need for a portable, economical, biopsy-free, early precancer screening technology in low-infrastructure environments. Our microelectromechanical system (MEMS) based handheld probe integrates the microscanners with miniature objective lens system and flexible electrical routing in a forward-imaging configuration, with 4.8 mm distal probe tip outer diameter for unrestricted imaging access in biological sites such as the oral cavity and cervix. Reflectance confocal videos of a USAF 1951 resolution target and biological samples were obtained over 200 μm × 110 μm field of view, with 0.80 and 9.55 μm lateral and axial resolution, at 3.5–5.0 frames per second. With improvements to objective numerical aperture, our probe can enable precise evaluation of nuclear size, density, nucleus-to-cytoplasm ratio and cell density, which are important visual identifiers of epithelial precancers.

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References

  • American Cancer Society, Cancer Facts and Figures (2007)

  • Cancer Research UK, CancerStats Reports: Worldwide Cancer (2005)

  • J.E. Bugaj, S. Achilefu, R.B. Dorshow, R. Rajagopalan, Novel fluorescent contrast agents for optical imaging of in vivo tumors based on a receptor-targeted dye-peptide conjugate platform. J. Biomed. Opt. 6, 122 (2001)

    Article  Google Scholar 

  • K.D. Carlson, Fiber Optic Confocal Microscope: In Vivo Precancer Detection, Ph.D. Dissertation, University of Texas at Austin (2006)

  • K.D. Carlson, M. Chidley, K.-B. Sung, M. Descour, A. Gillenwater, M. Follen, R. Richards-Kortum, In vivo fiber-optic confocal reflectance microscope with an injection-molded plastic miniature objective lens. Appl. Opt. 44, 1792 (2005)

    Article  Google Scholar 

  • T. Collier, P. Shen, B.d. Pradier, K. Sung, R. Richards-Kortum, Near Real Time Confocal Microscopy of Amelanotic Tissue: Dynamics of Aceto-Whitening Enable Nuclear Segmentation. Opt. Express 6, 40 (2000)

    Google Scholar 

  • M.N. Cooke, J.P. Fisher, D. Dean, C. Rimnac, A.G. Mikos, Use of stereolithography to manufacture critical-sized 3D biodegradable scaffolds for bone ingrowth. J. Biomed. Materi. Res. 64B, 65 (2002)

    Article  Google Scholar 

  • T. Dabbs, M. Glass, Fiber-optic confocal microscope: FOCON. Appl. Opt. 31, 3030 (1992)

    Article  Google Scholar 

  • D.L. Dickensheets, G.S. Kino, Micromachined scanning confocal optical microscope. Opt. Lett. 21, 764 (1996)

    Google Scholar 

  • D.L. Dickensheets, G.S. Kino, Silicon-micromachined scanning confocal optical microscope. Journal of Microelectromechanical Systems 7, 38 (1998)

    Article  Google Scholar 

  • R.A. Drezek, T. Collier, C.K. Brookner, A. Malpica, R. Lotan, R. Richards-Kortum, M. Follen, Laser scanning confocal microscopy of cervical tissue before and after application of acetic acid. Am. J. Obstet. Gynecol. 182, 1135 (2000)

    Article  Google Scholar 

  • B.A. Flusberg, J.C. Jung, E.D. Cocker, E.P. Anderson, M.J. Schnitzer, In vivo brain imaging using a portable 3.9 gram twophoton fluorescence microendoscope. Opt. Lett. 30, 2272 (2005)

    Article  Google Scholar 

  • L. Giniunas, R. Juskaitis, S.V. Shatalin, Scanning fiber-optic microscope. Electron. Lett. 27, 724 (1991)

    Article  Google Scholar 

  • A.F. Gmitro, D. Aziz, Confocal microscopy through a fiber-optic imaging bundle. Opt. Lett. 18, 565 (1993)

    Google Scholar 

  • D. Hah, P.R. Patterson, H.D. Nguyen, H. Toshiyoshi, M.C. Wu, Theory and Experiments of Angular Vertical Comb-Drive Actuators for Scanning Micromirrors. IEEE J. Sel. Top. Quantum Electron. 10, 505 (2004)

    Article  Google Scholar 

  • E.R. Hsu, E.V. Anslyn, S. Dharmawardhane, R. Alizadeh-Naderi, J.S. Aaron, K.V. Sokolov, A.K. El-naggar, A.M. Gillenwater, R. Richards-Kortum, A Far-red Fluorescent Contrast Agent to Image Epidermal Growth Factor Receptor Expression. Photochem. Photobiol. 79, 272 (2004)

    Article  Google Scholar 

  • U. Krishnamoorthy, D. Lee, O. Solgaard, Self-aligned vertical electrostatic combdrives for micromirror actuation. Journal of Microelectromechanical Systems 12, 458 (2003)

    Article  Google Scholar 

  • K. Kumar, K. Hoshino, H.-J. Shin, R. Richards-Kortum, X.J. Zhang, High-reflectivity two-axis vertical combdrive microscanners for sub-cellular scale confocal imaging applications. Proc. IEEE/LEOS International Conference on Optical MEMS and Their Applications 120 (2006)

  • S. Kwon, V. Milanovic, L.P. Lee, Vertical combdrive based 2-D gimbaled micromirrors with large static rotation by backside island isolation. IEEE J. Sel. Top. Quantum Electron. 10, 498 (2004)

    Article  Google Scholar 

  • D. Lee, Design and fabrication of SOI-based micromirrors for optical applications, Ph. D. Dissertation, Stanford University (2007)

  • J.T.C. Liu, M.J. Mandella, H. Ra, L.K. Wong, O. Solgaard, G.S. Kino, W. Piyawattanametha, C.H. Contag, T.D. Wang, Miniature near-infrared dual-axes confocal microscope utilizing a two-dimensional microelectromechanical systems scanner. Opt. Lett. 32, 256 (2007)

    Article  Google Scholar 

  • K.C. Maitland, H.-J. Shin, H. Ra, D. Lee, O. Solgaard, R. Richards-Kortum, Single fiber confocal microscope with a two-axis gimbaled MEMS scanner for cellular imaging. Opt. Express 14, 8604 (2006)

    Article  Google Scholar 

  • R.G. McKinnell, R.E. Parchment, A.O. Perantoni, G.B. Pierce, The Biological Basis of Cancer, 2nd editionnd edn. (Cambridge University Press, New York, 2006), p. 14

    Google Scholar 

  • D.L. Nida, M.S. Rahman, K.D. Carlson, R. Richards-Kortum, M. Follen, Fluorescent nanocrystals for use in early cervical cancer detection. Gynecol. Oncol. 99, S89 (2005)

    Article  Google Scholar 

  • Y. Pan, H. Xie, G.K. Fedder, Endoscopic optical coherence tomography based on a microelectromechanical mirror. Opt. Lett. 26, 1966 (2001)

    Article  Google Scholar 

  • W. Piyawattanametha, R.P.J. Barretto, T.H. Ko, B.A. Flusberg, E.D. Cocker, H. Ra, D. Lee, O. Solgaard, M.J. Schnitzer, Fast-scanning two-photon fluorescence imaging based on a microelectromechanical systems two-dimensional scanning mirror. Opt. Lett. 31, 2018 (2006)

    Article  Google Scholar 

  • A.L. Polglase, W.J. McLaren, S.A. Skinner, R. Kiesslich, M.F. Neurath, P.M. Delaney, A fluorescence confocal endomicroscope for in vivo microscopy of the upper- and the lower-GI tract. Gastrointest. Endosc. 62, 686 (2005)

    Article  Google Scholar 

  • H. Ra, W. Piyawattanametha, Y. Taguchi, D. Lee, M.J. Mandella, O. Solgaard, Two-Dimensional MEMS Scanner for Dual-Axes Confocal Microscopy. Journal of Microelectromechanical Systems 16, 969 (2007)

    Article  Google Scholar 

  • M. Rajadhyaksha, R.R. Anderson, R.H. Webb, Video-rate confocal scanning laser microscope for imaging human tissues in vivo. Appl. Opt. 38, 2105 (1999)

    Article  Google Scholar 

  • A.R. Rouse, A. Kano, J.A. Udovich, S.M. Kroto, A.F. Gmitro, Design and demonstration of a miniature catheter for a confocal microendoscope. Appl. Opt. 43, 5763 (2004)

    Article  Google Scholar 

  • M.A.F. Scarparo, Q.J. Chen, A.S. Miller, J.H. Zhang, S.D. Allen, Mechanisms of carbon dioxide laser stereolithography in epoxy-based materials. J. Appl. Polym. Sci. 62, 491 (1996)

    Article  Google Scholar 

  • H.-J. Shin, M.C. Pierce, D. Lee, H. Ra, O. Solgaard, R. Richards-Kortum, Fiber-optic confocal microscope using a MEMS scanner and miniature objective lens. Opt. Express 15, 9113 (2007)

    Article  Google Scholar 

  • P.R. Srinivas, B.S. Kramer, S. Srivastava, Trends in biomarker research for cancer detection. The Lancet Oncol. 2, 698 (2001)

    Article  Google Scholar 

  • R.H. Webb, Optics for laser rasters. Appl. Opt. 23, 3680 (1984)

    Google Scholar 

  • H. Xie, Y. Pan, G.K. Fedder, Endoscopic optical coherence tomographic imaging with a CMOS-MEMS micromirror. Sens. Actuators A Phys. 103, 237 (2003)

    Article  Google Scholar 

  • L. Zhou, J.M. Kahn, K.S.J. Pister, Scanning micromirrors fabricated by an SOI/SOI waferbonding process. Journal of Microelectromechanical Systems 15, 24 (2006)

    Article  Google Scholar 

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Acknowledgments

Financial support for this research from the Wallace H. Coulter Foundation Early Career Award 2006–08 is gratefully acknowledged. The silicon microscanners were fabricated at Stanford Nanofabrication Facility (supported by National Science Foundation grant ECS 9731293) and Microelectronics Research Center at University of Texas at Austin (supported by National Science Foundation grant ECS 0335765), under the National Nanofabrication Infrastructure Network. The authors wish to thank Dr. H. J. Shin, Dr. M. C. Pierce, and Prof. R. Richards-Kortum with Department of Bioengineering, Rice University, for providing the miniature objective system and access to their confocal imaging setup.

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Authors and Affiliations

  1. Department of Electrical and Computer Engineering, University of Texas at Austin, Austin, TX, 78712, USA

    Karthik Kumar

  2. Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, 78712, USA

    Kazunori Hoshino & Xiaojing Zhang

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  1. Karthik Kumar
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  2. Kazunori Hoshino
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  3. Xiaojing Zhang
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Correspondence to Karthik Kumar.

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Kumar, K., Hoshino, K. & Zhang, X. Handheld subcellular-resolution single-fiber confocal microscope using high-reflectivity two-axis vertical combdrive silicon microscanner. Biomed Microdevices 10, 653–660 (2008). https://doi.org/10.1007/s10544-008-9176-5

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