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Klin Monbl Augenheilkd 2015; 232(12): 1365-1373
DOI: 10.1055/s-0041-109020
Übersicht
Georg Thieme Verlag KG Stuttgart · New York

Nichtlineare Lasermikroskopie in der Ophthalmologie: Physikalische Prinzipien und wegweisende Anwendungen

Nonlinear Microscopy in Ophthalmology: Principles and Pathbreaking Applications
T. Ehmke
1   Biomedizinische Optik, Laser Zentrum Hannover e. V.
,
A. Krüger
1   Biomedizinische Optik, Laser Zentrum Hannover e. V.
,
T. Ripken
1   Biomedizinische Optik, Laser Zentrum Hannover e. V.
,
S. Reiß
2   Institut für Physik, Universität Rostock
3   Augenklinik, Universität Rostock
,
O. Stachs
3   Augenklinik, Universität Rostock
,
A. Heisterkamp
1   Biomedizinische Optik, Laser Zentrum Hannover e. V.
4   Institut für Quantenoptik, Leibniz Universität Hannover
› Author Affiliations
Further Information

Publication History

eingereicht 04 September 2015

akzeptiert 03 November 2015

Publication Date:
17 December 2015 (online)

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Zusammenfassung

Die nichtlineare Lasermikroskopie ist ein nicht invasives bildgebendes Verfahren mit großem technologischen Potenzial und ermöglicht eine hochauflösende und kontrastierte Darstellung von Gewebe als Folge spektraler Signalseparation. Neben der Zweiphotonenfluoreszenz und der 2. Harmonischen können auch Vierwellenmischsignale für eine Bildgebung okularer Strukturen verwendet werden. Dieser Übersichtsartikel stellt die physikalischen Prinzipien der unterschiedlichen Kontrastierungsmöglichkeiten vor. Exemplarisch werden experimentelle Ergebnisse, basierend auf verschiedenen nichtlinearen Signalen gezeigt, potenzielle Möglichkeiten dieser Technologie diskutiert und die Aussicht auf eine Translation dieser Bildgebungstechnik in die klinische Anwendung angesprochen.

Abstract

Nonlinear microscopy is a non-invasive imaging technique which allows a visualization of biological tissue with high signal contrast due to spectral separation combined with high resolution. In addition to two-photon fluorescence and second harmonic signals also four-wave mixing signals can be used for imaging ocular structures. This review article presents the physical principles of different contrast mechanisms. Exemplary experimental results based on various nonlinear signals are shown, opportunities of this technology are discussed and the prospect of translating this imaging technique into a clinical application is addressed.

Schlüsselwörter

nichtlineare Mikroskopie - Zweiphotonenfluoreszenz - Höhere Harmonische - Vierwellenmischung - Kornea - Linse

Key words

nonlinear microscopy - two-photon fluorescence - higher harmonics - four-wave mixing - cornea - lens
 

  • Literatur

  • 1 Hoerauf H, Wirbelauer C, Scholz C et al. Slit-lamp-adapted optical coherence tomography of the anterior segment. Graefes Arch Clin Exp Ophthalmol 2000; 238: 8-18
    CrossrefPubMedGoogle Scholar
  • 2 Steinert RF, Huang D eds. Anterior Segment Optical Coherence Tomography. Thorofare: SLACK Incorporated; 2008
    Google Scholar
  • 3 Garcia jr. JP, Rosen RB. Anterior segment imaging: optical coherence tomography versus ultrasound biomicroscopy. Ophthalmic Surg Lasers Imaging 2008; 39: 476-484
    CrossrefPubMedGoogle Scholar
  • 4 Salim S. The role of anterior segment optical coherence tomography in glaucoma. J Ophthalmol 2012; 2012: 476801
    PubMedGoogle Scholar
  • 5 Sharma R, Sharma A, Arora T et al. Application of anterior segment optical coherence tomography in glaucoma. Surv Ophthalmol 2014; 59: 311-327
    CrossrefPubMedGoogle Scholar
  • 6 Huang D, Swanson EA, Lin CP et al. Optical coherence tomography. Science 1991; 254: 1178-1181
    CrossrefPubMedGoogle Scholar
  • 7 Fercher AF. Optical coherence tomography. J Biomed Opt 1996; 1: 157-173
    CrossrefPubMedGoogle Scholar
  • 8 Wojtkowski M, Srinivasan V, Fujimoto JG et al. Three-dimensional retinal imaging with high-speed ultrahigh-resolution optical coherence tomography. Ophthalmology 2005; 112: 1734-1746
    CrossrefPubMedGoogle Scholar
  • 9 Hee MR, Izatt JA, Swanson EA et al. Optical coherence tomography of the human retina. Arch Ophthalmol 1995; 113: 325-332
    CrossrefPubMedGoogle Scholar
  • 10 Huang D, Li Y, Tang M. Anterior Eye Imaging with Optical Coherence Tomography. In: Drexler W, Fujimoto JG, eds. Optical Coherence Tomography – Technology and Applications. Berlin, Heidelberg: Springer; 2008: 961-982
    CrossrefGoogle Scholar
  • 11 Drexler W, Fujimoto JG. Retinal Optical Coherence Tomography. In: Drexler W, Fujimoto JG, eds. Optical Coherence Tomography – Technology and Applications. Berlin, Heidelberg: Springer; 2008: 983-1046
    CrossrefGoogle Scholar
  • 12 Ventura BV, Moraes jr. HV, Kara-Junior N et al. Role of optical coherence tomography on corneal surface laser ablation. J Ophthalmol 2012; 2012: 676740
    PubMedGoogle Scholar
  • 13 Guthoff RF, Zhivov A, Stachs O. In vivo confocal microscopy, an inner vision of the cornea – a major review. Clin Experiment Ophthalmol 2009; 37: 100-117
    CrossrefPubMedGoogle Scholar
  • 14 Krüger A, Hovakimyan M, Ramirez DF et al. Combined nonlinear and femtosecond confocal laser-scanning microscopy of rabbit corneas after photochemical cross-linking. Invest Ophthalmol Vis Sci 2011; 52: 4247-4255
    CrossrefPubMedGoogle Scholar
  • 15 Allgeier S, Zhivov A, Eberle F et al. Image reconstruction of the subbasal nerve plexus with in vivo confocal microscopy. Invest Ophthalmol Vis Sci 2011; 52: 5022-5028
    CrossrefPubMedGoogle Scholar
  • 16 Knappe S, Stachs O, Zhivov A et al. Results of confocal microscopy examinations after collagen cross-linking with riboflavin and UVA light in patients with progressive keratoconus. Ophthalmologica 2011; 225: 95-104
    CrossrefPubMedGoogle Scholar
  • 17 Petroll WM, Weaver M, Vaidya S et al. Quantitative 3-dimensional corneal imaging in vivo using a modified HRT-RCM confocal microscope. Cornea 2013; 32: e36-43
    CrossrefPubMedGoogle Scholar
  • 18 Masters BR, So PTC. The Genesis of Nonlinear Microscopies and Their Impact on Modern Developments. In: Masters BR, So PTC, eds. Handbook of Biomedical Nonlinear Optical Microscopy. Oxford: Oxford University Press; 2008: 5-29
    Google Scholar
  • 19 Xu C, Wise FW. Recent Advances in Fiber Lasers for Nonlinear Microscopy. Nat Photonics 2013; 7: 875-882
    CrossrefPubMedGoogle Scholar
  • 20 Balu M, Baldacchini T, Carter J et al. Effect of excitation wavelength on penetration depth in nonlinear optical microscopy of turbid media. J Biomed Opt 2009; 14 : 010508
    PubMedGoogle Scholar
  • 21 Jacques SL. Optical properties of biological tissues: a review. Phys Med Biol 2013; 58: R37-R61
    CrossrefPubMedGoogle Scholar
  • 22 Arrigoni M, Ziegs W. Neue Ultrakurzpuls OPOs. Laser + Photonik 2011; 4: 58-60
    PubMedGoogle Scholar
  • 23 Göppert-Mayer M. Über Elementarakte mit zwei Quantensprüngen. Annalen der Physik 1931; 401: 273-294
    CrossrefPubMedGoogle Scholar
  • 24 Denk W, Strickler JH, Webb WW. Two-photon laser scanning fluorescence microscopy. Science 1990; 248: 73-76
    CrossrefPubMedGoogle Scholar
  • 25 So PT, Dong Cy. Masters BR et al. Two-Photon excitation fluorescence microscopy. Ann Rev Biomed Eng 2000; 2: 399-429
    CrossrefPubMedGoogle Scholar
  • 26 Helmchen F, Denk W. Deep tissue two-photon microscopy. Nat Methods 2005; 2: 932-940
    CrossrefPubMedGoogle Scholar
  • 27 Campagnola PJ, Loew LM. Second-harmonic imaging microscopy for visualizing biomolecular arrays in cells, tissues and organisms. Nat Biotechnol 2003; 21: 1356-1360
    CrossrefPubMedGoogle Scholar
  • 28 Olivier N, Luengo-Oroz MA, Duloquin L et al. Cell lineage reconstruction of early zebrafish embryos using label-free nonlinear microscopy. Science 2010; 329: 967-971
    CrossrefPubMedGoogle Scholar
  • 29 Williams RM, Zipfel WR, Webb WW. Interpreting second-harmonic generation images of collagen I fibrils. Biophys J 2005; 88: 1377-1386
    CrossrefPubMedGoogle Scholar
  • 30 Campagnola P. Second harmonic generation imaging microscopy: applications to diseases diagnostics. Anal Chem 2011; 83: 3224-3231
    CrossrefPubMedGoogle Scholar
  • 31 Plotnikov SV, Millard AC, Campagnola PJ et al. Characterization of the myosin-based source for second-harmonic generation from muscle sarcomeres. Biophys J 2006; 90: 693-703
    CrossrefPubMedGoogle Scholar
  • 32 Aptel F, Olivier N, Deniset-Besseau A et al. Multimodal nonlinear imaging of the human cornea. Invest Ophthalmol Vis Sci 2010; 51: 2459-2465
    CrossrefPubMedGoogle Scholar
  • 33 Ehmke T, Nitzsche TH, Knebl A et al. Molecular orientation sensitive second harmonic microscopy by radially and azimuthally polarized light. Biomed Opt Express 2014; 5: 2231-2246
    CrossrefPubMedGoogle Scholar
  • 34 Ehmke T, Knebl A, Reiss S et al. Spectral behavior of second harmonic signals from organic and non-organic materials in multiphoton microscopy. AIP Adv 2015; 5: 084903
    CrossrefPubMedGoogle Scholar
  • 35 Mahou P, Olivier N, Labroille G et al. Combined third-harmonic generation and four-wave mixing microscopy of tissues and embryos. Biomed Opt Express 2011; 2: 2837-2849
    CrossrefPubMedGoogle Scholar
  • 36 Munhoz F, Rigneault H, Brasselet S. Polarization-resolved four-wave mixing microscopy for structural imaging in thick tissues. J Opt Soc Am B 2012; 29: 1541-1550
    CrossrefPubMedGoogle Scholar
  • 37 Ehmke T, Knebl A, Heisterkamp A. Four-wave mixing microscopy: a high potential nonlinear imaging method. Proceedings of SPIE 2015; 9329: 932912
    PubMedGoogle Scholar
  • 38 Dunn KW, Young PA. Principles of multiphoton microscopy. Nephron Exp Nephrol 2006; 103: e33-e40
    CrossrefPubMedGoogle Scholar
  • 39 Zipfel WR, Williams RM, Webb WW. Nonlinear magic: multiphoton microscopy in the biosciences. Nat Biotechnol 2003; 21: 1369-1377
    CrossrefPubMedGoogle Scholar
  • 40 Boyd RW ed. Nonlinear Optics. 3rd. edn. San Diego: Academic Press; 2008
    Google Scholar
  • 41 Latour G, Gusachenko I, Kowalczuk L et al. In vivo structural imaging of the cornea by polarization-resolved second harmonic microscopy. Biomed Opt Express 2012; 3: 1-15
    CrossrefPubMedGoogle Scholar
  • 42 Zumbusch A, Holtom GR, Xie XS. Three-dimensional vibrational imaging by coherent anti-stokes raman scattering. Phys Rev Lett 1999; 82: 4142-4145
    CrossrefPubMedGoogle Scholar
  • 43 Evans CL, Xie XS. Coherent anti-stokes Raman scattering microscopy: chemical imaging for biology and medicine. Annu Rev Anal Chem (Palo Alto Calif) 2008; 1: 883-909
    CrossrefPubMedGoogle Scholar
  • 44 Min W, Lu S, Rueckel M et al. Near-degenerate four-wave-mixing microscopy. Nano Lett 2009; 9: 2423-2426
    CrossrefPubMedGoogle Scholar
  • 45 Koehler MJ, König K, Elsner P et al. In vivo assessment of human skin aging by multiphoton laser scanning tomography. Opt Lett 2006; 31: 2879-2881
    CrossrefPubMedGoogle Scholar
  • 46 Steven P, Müller M, Koop N et al. Comparison of Cornea Module and DermaInspect for noninvasive imaging of ocular surface pathologies. J Biomed Opt 2009; 14: 064040
    CrossrefPubMedGoogle Scholar