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Two-photon retinal theranostics by adaptive compact laser source

Abstract

To avoid a devastating effect of eye vision impairment on the information flow from the eye to our brain, enormous effort is being put during the last decades into the development of more sensitive diagnostics and more efficient therapies of retinal tissue. While morphology can be impressively imaged by optical coherence tomography, molecular-associated pathology information can be provided almost exclusively by auto-fluorescence-based methods. Among the latter, the recently developed fluorescence lifetime imaging ophthalmoscopy (FLIO) has the potential to provide both structural information and interacting pictures at the same time. The requirements for FLIO laser sources are almost orthogonal to the laser sources used in phototherapy that is expected to follow up the FLIO diagnostics. To make theranostics more effective and cheaper, the complete system would need to couple at least the modalities of low-power high-repetition-rate FLIO and precision high-pulse energy-adjustable repetition rate phototherapy. In addition, the intermediate-power high repetition rate for two-photon excitation would also be desired to increase the depth resolution. In our work, compact fiber-laser based on high-speed gain-switched laser diode has been shown to achieve adaptable/independently tunable repetition rate and energy per pulse allowing coupled fluorescence lifetime diagnostics via two-photon excitation and phototherapy via laser-induced photodisruption on a local molecular environment in a complex ex vivo retinal tissue.

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References

  1. 1.

    F.C. Delori, C.K. Dorey, G. Staurenghi, O. Arend, D.G. Goger, J.J. Weiter, In vivo fluorescence of the ocular fundus exhibits retinal pigment epithelium lipofuscin characteristics. Invest. Ophthalmol. Vis. Sci. 36, 718–729 (1995)

    Google Scholar 

  2. 2.

    A. von Rückmann, F.W. Fitzke, A.C. Bird, Distribution of fundus autofluorescence with a scanning laser ophthalmoscope. Br J Ophthalmol. 79, 407–412 (1995). https://doi.org/10.1136/bjo.79.5.407

    Article  Google Scholar 

  3. 3.

    A.F. Fercher, K. Mengedoht, W. Werner, Eye-length measurement by interferometry with partially coherent light. Opt. Lett. 13, 186–188 (1988). https://doi.org/10.1364/OL.13.000186

    ADS  Article  Google Scholar 

  4. 4.

    W. Drexler, U. Morgner, R.K. Ghanta, F.X. Kärtner, J.S. Schuman, J.G. Fujimoto, Ultrahigh-resolution ophthalmic optical coherence tomography. Nat. Med. 7, 502–507 (2001). https://doi.org/10.1038/86589

    Article  Google Scholar 

  5. 5.

    J. Marshall, The ageing retina: physiology or pathology. Eye. 1, 282–295 (1987). https://doi.org/10.1038/eye.1987.47

    Article  Google Scholar 

  6. 6.

    J. Sparrow, T. Duncker, J.R. Sparrow, T. Duncker, Fundus Autofluorescence and RPE Lipofuscin in age-related macular degeneration. Journal of Clinical Medicine. 3, 1302–1321 (2014). https://doi.org/10.3390/jcm3041302

    Article  Google Scholar 

  7. 7.

    J. Teister, A. Liu, D. Wolters, N. Pfeiffer, F.H. Grus, Peripapillary fluorescence lifetime reveals age-dependent changes using fluorescence lifetime imaging ophthalmoscopy in rats. Exp. Eye Res. 176, 110–120 (2018). https://doi.org/10.1016/j.exer.2018.07.008

    Article  Google Scholar 

  8. 8.

    J. Schmidt, S. Peters, L. Sauer, D. Schweitzer, M. Klemm, R. Augsten, N. Müller, M. Hammer, Fundus autofluorescence lifetimes are increased in non-proliferative diabetic retinopathy. Acta Ophthalmol. 95, 33–40 (2017). https://doi.org/10.1111/aos.13174

    Article  Google Scholar 

  9. 9.

    L. Sauer, R.H. Gensure, M. Hammer, P.S. Bernstein, Fluorescence lifetime imaging ophthalmoscopy: A novel way to assess macular telangiectasia type 2. Oph Retina. 2, 587–598 (2018). https://doi.org/10.1016/j.oret.2017.10.008

    Article  Google Scholar 

  10. 10.

    D. Schweitzer, L. Deutsch, M. Klemm, S. Jentsch, M. Hammer, S. Peters, J. Haueisen, U.A. Müller, J. Dawczynski, Fluorescence lifetime imaging ophthalmoscopy in type 2 diabetic patients who have no signs of diabetic retinopathy. JBO, JBOPFO. 20, 061106 (2015). https://doi.org/10.1117/1.JBO.20.6.061106

    Article  Google Scholar 

  11. 11.

    J.A. Feeks, J.J. Hunter, Adaptive optics two-photon excited fluorescence lifetime imaging ophthalmoscopy of exogenous fluorophores in mice. Biomed. Opt. Express. 8, 2483–2495 (2017). https://doi.org/10.1364/BOE.8.002483

    Article  Google Scholar 

  12. 12.

    C. Dysli, R. Fink, S. Wolf, M.S. Zinkernagel, Fluorescence lifetimes of drusen in age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 58, 4856–4862 (2017). https://doi.org/10.1167/iovs.17-22184

    Article  Google Scholar 

  13. 13.

    L. Sauer, C.B. Komanski, A.S. Vitale, E.D. Hansen, P.S. Bernstein, Fluorescence lifetime imaging ophthalmoscopy (FLIO) in eyes with pigment epithelial detachments due to age-related macular degeneration. Invest Ophthalmol Vis Sci. 60, 3054–3063 (2019). https://doi.org/10.1167/iovs.19-26835

    Article  Google Scholar 

  14. 14.

    D. Schweitzer, S. Schenke, M. Hammer, F. Schweitzer, S. Jentsch, E. Birckner, W. Becker, A. Bergmann, Towards metabolic mapping of the human retina. Microsc. Res. Tech. 70, 410–419 (2007). https://doi.org/10.1002/jemt.20427

    Article  Google Scholar 

  15. 15.

    C. Dysli, S. Wolf, M.Y. Berezin, L. Sauer, M. Hammer, M.S. Zinkernagel, Fluorescence lifetime imaging ophthalmoscopy. Progress in Retinal and Eye Research. 60, 120–143 (2017). https://doi.org/10.1016/j.preteyeres.2017.06.005

    Article  Google Scholar 

  16. 16.

    A. Periasamy, P. Wodnicki, X.F. Wang, S. Kwon, G.W. Gordon, B. Herman, Time-resolved fluorescence lifetime imaging microscopy using a picosecond pulsed tunable dye laser system. Rev. Sci. Instrum. 67, 3722–3731 (1996). https://doi.org/10.1063/1.1147139

    ADS  Article  Google Scholar 

  17. 17.

    A. Ehlers, I. Riemann, M. Stark, K. König, Multiphoton fluorescence lifetime imaging of human hair. Microsc. Res. Tech. 70, 154–161 (2007). https://doi.org/10.1002/jemt.20395

    Article  Google Scholar 

  18. 18.

    B. Leskovar, C.C. Lo, P.R. Hartig, K. Sauer, Photon counting system for subnanosecond fluorescence lifetime measurements. Rev. Sci. Instrum. 47, 1113–1121 (1976). https://doi.org/10.1063/1.1134827

    ADS  Article  Google Scholar 

  19. 19.

    J. Roider, S.H.M. Liew, C. Klatt, H. Elsner, E. Poerksen, J. Hillenkamp, R. Brinkmann, R. Birngruber, Selective retina therapy (SRT) for clinically significant diabetic macular edema. Graefes Arch Clin Exp Ophthalmol. 248, 1263–1272 (2010). https://doi.org/10.1007/s00417-010-1356-3

    Article  Google Scholar 

  20. 20.

    E. Seifert, J. Tode, A. Pielen, D. Theisen-Kunde, C. Framme, J. Roider, Y. Miura, R. Birngruber, R. Brinkmann, Selective retina therapy: toward an optically controlled automatic dosing. J Biomed Opt. 23, 1–12 (2018). https://doi.org/10.1117/1.JBO.23.11.115002

    Article  Google Scholar 

  21. 21.

    S. Al-Hussainy, P.M. Dodson, J.M. Gibson, Pain response and follow-up of patients undergoing panretinal laser photocoagulation with reduced exposure times. Eye 22, 96–99 (2008). https://doi.org/10.1038/sj.eye.6703026

    Article  Google Scholar 

  22. 22.

    S.V. Reddy, D. Husain, Panretinal Photocoagulation: A Review of Complications. Semin Ophthalmol 33, 83–88 (2018). https://doi.org/10.1080/08820538.2017.1353820

    Article  Google Scholar 

  23. 23.

    R.H. Guymer, Z. Wu, L.A.B. Hodgson, E. Caruso, K.H. Brassington, N. Tindill, K.Z. Aung, M.B. McGuinness, E.L. Fletcher, F.K. Chen, U. Chakravarthy, J.J. Arnold, W.J. Heriot, S.R. Durkin, J.J. Lek, C.A. Harper, S.S. Wickremasinghe, S.S. Sandhu, E.K. Baglin, P. Sharangan, S. Braat, C.D. Luu, Laser Intervention In Early Stages Of Age-Related Macular Degeneration Study Group, Subthreshold Nanosecond Laser Intervention In Age-Related Macular Degeneration: The LEAD randomized controlled clinical trial. Ophthalmology 126, 829–838 (2019). https://doi.org/10.1016/j.ophtha.2018.09.015

    Article  Google Scholar 

  24. 24.

    W.R. Calhoun, I.K. Ilev, Effect of therapeutic femtosecond laser pulse energy, repetition rate, and numerical aperture on laser-induced second and third harmonic generation in corneal tissue. Lasers Med. Sci. 30, 1341–1346 (2015). https://doi.org/10.1007/s10103-015-1726-5

    Article  Google Scholar 

  25. 25.

    Z. Hu, H. Zhang, A. Mordovanakis, Y.M. Paulus, Q. Liu, X. Wang, X. Yang, High-precision, non-invasive anti-microvascular approach via concurrent ultrasound and laser irradiation. Sci. Rep. 7, 40243 (2017). https://doi.org/10.1038/srep40243

    ADS  Article  Google Scholar 

  26. 26.

    J.P.M. Wood, O. Shibeeb, M. Plunkett, R.J. Casson, G. Chidlow, Retinal damage profiles and neuronal effects of laser treatment: comparison of a conventional photocoagulator and a novel 3-nanosecond pulse laser. Invest. Ophthalmol. Vis. Sci. 54, 2305–2318 (2013). https://doi.org/10.1167/iovs.12-11203

    Article  Google Scholar 

  27. 27.

    Y. Takatsuna, S. Yamamoto, Y. Nakamura, T. Tatsumi, M. Arai, Y. Mitamura, Long-term therapeutic efficacy of the subthreshold micropulse diode laser photocoagulation for diabetic macular edema. Jpn. J. Ophthalmol. 55, 365–369 (2011). https://doi.org/10.1007/s10384-011-0033-3

    Article  Google Scholar 

  28. 28.

    G. Schuele, H. Elsner, C. Framme, J. Roider, R. Birngruber, R. Brinkmann, Optoacoustic real-time dosimetry for selective retina treatment. JBO, JBOPFO. 10, 064022 (2005). https://doi.org/10.1117/1.2136327

    Article  Google Scholar 

  29. 29.

    Y.M. Paulus, A. Jain, H. Nomoto, C. Sramek, R.F. Gariano, D. Andersen, G. Schuele, L.-S. Leung, T. Leng, D. Palanker, Selective retinal therapy with microsecond exposures using a continuous line scanning laser. Retina 31, 380 (2011). https://doi.org/10.1097/IAE.0b013e3181e76da6

    Article  Google Scholar 

  30. 30.

    R.R. Anderson, J.A. Parrish, Selective photothermolysis: precise microsurgery by selective absorption of pulsed radiation. Science 220, 524–527 (1983). https://doi.org/10.1126/science.6836297

    ADS  Article  Google Scholar 

  31. 31.

    W.T. Ham, R.C. Williams, H.A. Mueller, D. Guerry, A.M. Clarke, W.J. Geeraets, Effects of laser radiation on the mammalian eye*†. Trans. N. Y. Acad. Sci. 28, 517–526 (1966). https://doi.org/10.1111/j.2164-0947.1966.tb02368.x

    Article  Google Scholar 

  32. 32.

    J. Petelin, B. Podobnik, R. Petkovšek, Burst shaping in a fiber-amplifier chain seeded by a gain-switched laser diode. Appl. Opt. 54, 4629–4634 (2015). https://doi.org/10.1364/AO.54.004629

    ADS  Article  Google Scholar 

  33. 33.

    M. Šajn, J. Petelin, V. Agrež, M. Vidmar, R. Petkovšek, DFB diode seeded low repetition rate fiber laser system operating in burst mode. Opt. Laser Technol. 88, 99–103 (2017). https://doi.org/10.1016/j.optlastec.2016.09.006

    ADS  Article  Google Scholar 

  34. 34.

    W. Becker, Advanced Time-Correlated Single Photon Counting Techniques, Springer-Verlag, Berlin Heidelberg, 2005. //www.springer.com/la/book/9783540260479. Accessed September 6, 2018.

  35. 35.

    J.P.M. Wood, M. Plunkett, V. Previn, G. Chidlow, R.J. Casson, Nanosecond pulse lasers for retinal applications. Lasers Surg. Med. 43, 499–510 (2011). https://doi.org/10.1002/lsm.21087

    Article  Google Scholar 

  36. 36.

    B. Považay, R. Brinkmann, M. Stoller, R. Kessler, Selective Retina Therapy, in High resolution imaging in microscopy and ophthalmology: New frontiers in biomedical optics, ed. by J.F. Bille (Springer, Cham, 2019), pp. 237–259. https://doi.org/10.1007/978-3-030-16638-0_11

    Chapter  Google Scholar 

  37. 37.

    W. Denk, J.H. Strickler, W.W. Webb, Two-photon laser scanning fluorescence microscopy. Science 248, 73–76 (1990). https://doi.org/10.1126/science.2321027

    ADS  Article  Google Scholar 

  38. 38.

    I. Saytashev, R. Glenn, G.A. Murashova, S. Osseiran, D. Spence, C.L. Evans, M. Dantus, Multiphoton excited hemoglobin fluorescence and third harmonic generation for non-invasive microscopy of stored blood. Biomed Opt Express. 7, 3449–3460 (2016). https://doi.org/10.1364/BOE.7.003449

    Article  Google Scholar 

  39. 39.

    NAD(P)H fluorescence lifetime measurements in fixed biological tissues. - PubMed - NCBI, (n.d.). https://www.ncbi.nlm.nih.gov/pubmed/31553966. Accessed March 17, 2020.

  40. 40.

    D. Schweitzer, E.R. Gaillard, J. Dillon, R.F. Mullins, S. Russell, B. Hoffmann, S. Peters, M. Hammer, C. Biskup, Time-resolved autofluorescence imaging of human donor retina tissue from donors with significant extramacular drusen. Invest. Ophthalmol. Vis. Sci. 53, 3376–3386 (2012). https://doi.org/10.1167/iovs.11-8970

    Article  Google Scholar 

  41. 41.

    G. Keiser, Light-tissue interactions, in Biophotonics: Concepts to applications, ed. by G. Keiser (Springer, Singapore, 2016), pp. 147–196. https://doi.org/10.1007/978-981-10-0945-7_6

    Chapter  Google Scholar 

  42. 42.

    E. Dimitrow, I. Riemann, A. Ehlers, M.J. Koehler, J. Norgauer, P. Elsner, K. König, M. Kaatz, Spectral fluorescence lifetime detection and selective melanin imaging by multiphoton laser tomography for melanoma diagnosis. Exp. Dermatol. 18, 509–515 (2009). https://doi.org/10.1111/j.1600-0625.2008.00815.x

    Article  Google Scholar 

  43. 43.

    M.F.G. Wood, N. Vurgun, M.A. Wallenburg, I.A. Vitkin, Effects of formalin fixation on tissue optical polarization properties. Phys. Med. Biol. 56, N115–N122 (2011). https://doi.org/10.1088/0031-9155/56/8/N01

    Article  Google Scholar 

  44. 44.

    M.A. Mainster, G.T. Timberlake, R.H. Webb, G.W. Hughes, Scanning laser ophthalmoscopy. Clin. Appl. Ophthalmol. 89, 852–857 (1982). https://doi.org/10.1016/s0161-6420(82)34714-4

    Article  Google Scholar 

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Acknowledgements

The work was primarily carried out in the framework of the GOSTOP program, which is partially financed by the Republic of Slovenia – Ministry of Education, Science and Sport, and the European Union – European Regional Development Fund, as well as in the framework of L7-7561 Project, which is financed by the Slovenian Research Agency ARRS. In addition, this work was also partially supported by other projects of the Slovenian Research Agency ARRS (L2-9240, L2-9254, P2-0270, P1-0060). We would like to acknowledge also the group of prof. B. Drnovšek Olup on the Department of Ophthalmology of the University Medical Clinical Centre Ljubljana to provide us the access to the ex vivo samples of the retinal tissue.

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Correspondence to Rok Petkovšek.

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Podlipec, R., Mur, J., Petelin, J. et al. Two-photon retinal theranostics by adaptive compact laser source. Appl. Phys. A 126, 405 (2020). https://doi.org/10.1007/s00339-020-03587-2

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Keywords

  • Adaptable fiber laser
  • Retinal tissue
  • Theranostics
  • Multimodal imaging
  • Fluorescence lifetime imaging