Abstract

The purpose of this study was to develop and test a nonlinear optical device to photoactivate riboflavin to produce spatially controlled collagen crosslinking and mechanical stiffening within the cornea. A nonlinear optical device using a variable numerical aperture objective was built and coupled to a Chameleon femtosecond laser. Ex vivo rabbit eyes were then saturated with riboflavin and scanned with various scanning parameters over a 4 mm area in the central cornea. Effectiveness of NLO CXL was assessed by evaluating corneal collagen auto fluorescence (CAF). To determine mechanical stiffening effects, corneas were removed from the eye and subjected to indentation testing using a 1 mm diameter probe and force transducer. NLO CXL was also compared to standard UVA CXL. The NLO CXL delivery device was able to induce a significant increase in corneal stiffness, comparable to the increase produced by standard UVA CXL.

© 2017 Optical Society of America under the terms of the OSA Open Access Publishing Agreement

Full Article  |  PDF Article
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References

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  1. E. Spoerl, M. Huhle, and T. Seiler, “Induction of cross-links in corneal tissue,” Exp. Eye Res. 66(1), 97–103 (1998).
    [PubMed]
  2. G. Wollensak, E. Spoerl, and T. Seiler, “Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus,” Am. J. Ophthalmol. 135(5), 620–627 (2003).
    [PubMed]
  3. F. Raiskup and E. Spoerl, “Corneal crosslinking with riboflavin and ultraviolet A. I. Principles,” Ocul. Surf. 11(2), 65–74 (2013).
    [PubMed]
  4. P. Kamaev, M. D. Friedman, E. Sherr, and D. Muller, “Photochemical kinetics of corneal cross-linking with riboflavin,” Invest. Ophthalmol. Vis. Sci. 53(4), 2360–2367 (2012).
    [PubMed]
  5. D. Chai, R. N. Gaster, R. Roizenblatt, T. Juhasz, D. J. Brown, and J. V. Jester, “Quantitative assessment of UVA-riboflavin corneal cross-linking using nonlinear optical microscopy,” Invest. Ophthalmol. Vis. Sci. 52(7), 4231–4238 (2011).
    [PubMed]
  6. S. Malik, S. Humayun, S. Nayyar, and M. Ishaq, “Determining the efficacy of corneal crosslinking in progressive keratoconus,” Pak. J. Med. Sci. 33(2), 389–392 (2017).
    [PubMed]
  7. P. S. Hersh, R. D. Stulting, D. Muller, D. S. Durrie, and R. K. Rajpal, “United States Multicneter Clinical Trial of Corneal Collagen Crosslinking for Keratoconus Treatment,” Ophthalmology 124, 1259–1270 (2017).
  8. Z. Shalchi, X. Wang, and M. A. Nanavaty, “Safety and efficacy of epithelium removal and transepithelial corneal collagen crosslinking for keratoconus,” Eye (Lond.) 29(1), 15–29 (2015).
    [PubMed]
  9. A. J. Kanellopoulos and G. Asimellis, “Combined laser in situ keratomileusis and prophylactic high-fluence corneal collagen crosslinking for high myopia: two-year safety and efficacy,” J. Cataract Refract. Surg. 41(7), 1426–1433 (2015).
    [PubMed]
  10. M. De Bernardo, L. Capasso, M. Lanza, A. Tortori, S. Iaccarino, M. Cennamo, M. Borrelli, and N. Rosa, “Long-term results of corneal collagen crosslinking for progressive keratoconus,” J. Optom. 8(3), 180–186 (2015).
    [PubMed]
  11. M. Elling, I. Kersten-Gomez, and H. B. Dick, “Photorefractive intrastromal corneal crosslinking for the treatment of myopic refractive errors: Six-month interim findings,” J. Cataract Refract. Surg. 43(6), 789–795 (2017).
    [PubMed]
  12. A. M. Hagem, A. Thorsrud, G. F. Sandvik, M. Råen, and L. Drolsum, “Collagen crosslinking with conventional and accelerated ultraviolet-A irradiation using riboflavin with hydroxypropyl methylcellulose,” J. Cataract Refract. Surg. 43(4), 511–517 (2017).
    [PubMed]
  13. G. Lombardo, N. L. Micali, V. Villari, N. Leone, S. Serrao, D. Rusciano, and M. Lombardo, “Assessment of stromal riboflavin concentration-depth profile in nanotechnology-based transepithelial corneal crosslinking,” J. Cataract Refract. Surg. 43(5), 680–686 (2017).
    [PubMed]
  14. E. Spoerl, M. Mrochen, D. Sliney, S. Trokel, and T. Seiler, “Safety of UVA-riboflavin cross-linking of the cornea,” Cornea 26(4), 385–389 (2007).
    [PubMed]
  15. W. Kaiser and C. G. B. Garrett, “Two-photon excitation in CaF2:Eu2+,” Phys. Rev. Lett. 7(6), 229–231 (1961).
  16. D. Chai, T. Juhasz, D. J. Brown, and J. V. Jester, “Nonlinear optical collagen cross-linking and mechanical stiffening: a possible photodynamic therapeutic approach to treating corneal ectasia,” J. Biomed. Opt. 18(3), 038003 (2013).
    [PubMed]
  17. S. M. Bradford, D. J. Brown, T. Juhasz, E. Mikula, and J. V. Jester, “Nonlinear optical corneal collagen crosslinking of ex vivo rabbit eyes,” J. Cataract Refract. Surg. 42(11), 1660–1665 (2016).
    [PubMed]
  18. W. R. Zipfel, R. M. Williams, and W. W. Webb, “Nonlinear magic: multiphoton microscopy in the biosciences,” Nat. Biotechnol. 21(11), 1369–1377 (2003).
    [PubMed]
  19. I. Levental, K. R. Levental, E. A. Klein, R. Assoian, R. T. Miller, R. G. Wells, and P. A. Janmey, “A simple indentation device for measuring micrometer-scale tissue stiffness,” J. Phys. Condens. Matter 22(19), 194120 (2010).
    [PubMed]
  20. W. C. Hayes, L. M. Keer, G. Herrmann, and L. F. Mockros, “A mathematical analysis for indentation tests of articular cartilage,” J. Biomech. 5(5), 541–551 (1972).
    [PubMed]
  21. E. R. Mikula, S. Bradford, D. J. Brown, T. Juhasz, and J. Jester, “Precise corneal crosslinking (CXL) using a 5 KHz amplified femtosecond laser,” presented at The Association for Research in Vision and Ophthalmology annual meeting, Baltimore, Maryland, 7–11 May 2017.

2017 (5)

S. Malik, S. Humayun, S. Nayyar, and M. Ishaq, “Determining the efficacy of corneal crosslinking in progressive keratoconus,” Pak. J. Med. Sci. 33(2), 389–392 (2017).
[PubMed]

P. S. Hersh, R. D. Stulting, D. Muller, D. S. Durrie, and R. K. Rajpal, “United States Multicneter Clinical Trial of Corneal Collagen Crosslinking for Keratoconus Treatment,” Ophthalmology 124, 1259–1270 (2017).

M. Elling, I. Kersten-Gomez, and H. B. Dick, “Photorefractive intrastromal corneal crosslinking for the treatment of myopic refractive errors: Six-month interim findings,” J. Cataract Refract. Surg. 43(6), 789–795 (2017).
[PubMed]

A. M. Hagem, A. Thorsrud, G. F. Sandvik, M. Råen, and L. Drolsum, “Collagen crosslinking with conventional and accelerated ultraviolet-A irradiation using riboflavin with hydroxypropyl methylcellulose,” J. Cataract Refract. Surg. 43(4), 511–517 (2017).
[PubMed]

G. Lombardo, N. L. Micali, V. Villari, N. Leone, S. Serrao, D. Rusciano, and M. Lombardo, “Assessment of stromal riboflavin concentration-depth profile in nanotechnology-based transepithelial corneal crosslinking,” J. Cataract Refract. Surg. 43(5), 680–686 (2017).
[PubMed]

2016 (1)

S. M. Bradford, D. J. Brown, T. Juhasz, E. Mikula, and J. V. Jester, “Nonlinear optical corneal collagen crosslinking of ex vivo rabbit eyes,” J. Cataract Refract. Surg. 42(11), 1660–1665 (2016).
[PubMed]

2015 (3)

Z. Shalchi, X. Wang, and M. A. Nanavaty, “Safety and efficacy of epithelium removal and transepithelial corneal collagen crosslinking for keratoconus,” Eye (Lond.) 29(1), 15–29 (2015).
[PubMed]

A. J. Kanellopoulos and G. Asimellis, “Combined laser in situ keratomileusis and prophylactic high-fluence corneal collagen crosslinking for high myopia: two-year safety and efficacy,” J. Cataract Refract. Surg. 41(7), 1426–1433 (2015).
[PubMed]

M. De Bernardo, L. Capasso, M. Lanza, A. Tortori, S. Iaccarino, M. Cennamo, M. Borrelli, and N. Rosa, “Long-term results of corneal collagen crosslinking for progressive keratoconus,” J. Optom. 8(3), 180–186 (2015).
[PubMed]

2013 (2)

F. Raiskup and E. Spoerl, “Corneal crosslinking with riboflavin and ultraviolet A. I. Principles,” Ocul. Surf. 11(2), 65–74 (2013).
[PubMed]

D. Chai, T. Juhasz, D. J. Brown, and J. V. Jester, “Nonlinear optical collagen cross-linking and mechanical stiffening: a possible photodynamic therapeutic approach to treating corneal ectasia,” J. Biomed. Opt. 18(3), 038003 (2013).
[PubMed]

2012 (1)

P. Kamaev, M. D. Friedman, E. Sherr, and D. Muller, “Photochemical kinetics of corneal cross-linking with riboflavin,” Invest. Ophthalmol. Vis. Sci. 53(4), 2360–2367 (2012).
[PubMed]

2011 (1)

D. Chai, R. N. Gaster, R. Roizenblatt, T. Juhasz, D. J. Brown, and J. V. Jester, “Quantitative assessment of UVA-riboflavin corneal cross-linking using nonlinear optical microscopy,” Invest. Ophthalmol. Vis. Sci. 52(7), 4231–4238 (2011).
[PubMed]

2010 (1)

I. Levental, K. R. Levental, E. A. Klein, R. Assoian, R. T. Miller, R. G. Wells, and P. A. Janmey, “A simple indentation device for measuring micrometer-scale tissue stiffness,” J. Phys. Condens. Matter 22(19), 194120 (2010).
[PubMed]

2007 (1)

E. Spoerl, M. Mrochen, D. Sliney, S. Trokel, and T. Seiler, “Safety of UVA-riboflavin cross-linking of the cornea,” Cornea 26(4), 385–389 (2007).
[PubMed]

2003 (2)

W. R. Zipfel, R. M. Williams, and W. W. Webb, “Nonlinear magic: multiphoton microscopy in the biosciences,” Nat. Biotechnol. 21(11), 1369–1377 (2003).
[PubMed]

G. Wollensak, E. Spoerl, and T. Seiler, “Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus,” Am. J. Ophthalmol. 135(5), 620–627 (2003).
[PubMed]

1998 (1)

E. Spoerl, M. Huhle, and T. Seiler, “Induction of cross-links in corneal tissue,” Exp. Eye Res. 66(1), 97–103 (1998).
[PubMed]

1972 (1)

W. C. Hayes, L. M. Keer, G. Herrmann, and L. F. Mockros, “A mathematical analysis for indentation tests of articular cartilage,” J. Biomech. 5(5), 541–551 (1972).
[PubMed]

1961 (1)

W. Kaiser and C. G. B. Garrett, “Two-photon excitation in CaF2:Eu2+,” Phys. Rev. Lett. 7(6), 229–231 (1961).

Asimellis, G.

A. J. Kanellopoulos and G. Asimellis, “Combined laser in situ keratomileusis and prophylactic high-fluence corneal collagen crosslinking for high myopia: two-year safety and efficacy,” J. Cataract Refract. Surg. 41(7), 1426–1433 (2015).
[PubMed]

Assoian, R.

I. Levental, K. R. Levental, E. A. Klein, R. Assoian, R. T. Miller, R. G. Wells, and P. A. Janmey, “A simple indentation device for measuring micrometer-scale tissue stiffness,” J. Phys. Condens. Matter 22(19), 194120 (2010).
[PubMed]

Borrelli, M.

M. De Bernardo, L. Capasso, M. Lanza, A. Tortori, S. Iaccarino, M. Cennamo, M. Borrelli, and N. Rosa, “Long-term results of corneal collagen crosslinking for progressive keratoconus,” J. Optom. 8(3), 180–186 (2015).
[PubMed]

Bradford, S. M.

S. M. Bradford, D. J. Brown, T. Juhasz, E. Mikula, and J. V. Jester, “Nonlinear optical corneal collagen crosslinking of ex vivo rabbit eyes,” J. Cataract Refract. Surg. 42(11), 1660–1665 (2016).
[PubMed]

Brown, D. J.

S. M. Bradford, D. J. Brown, T. Juhasz, E. Mikula, and J. V. Jester, “Nonlinear optical corneal collagen crosslinking of ex vivo rabbit eyes,” J. Cataract Refract. Surg. 42(11), 1660–1665 (2016).
[PubMed]

D. Chai, T. Juhasz, D. J. Brown, and J. V. Jester, “Nonlinear optical collagen cross-linking and mechanical stiffening: a possible photodynamic therapeutic approach to treating corneal ectasia,” J. Biomed. Opt. 18(3), 038003 (2013).
[PubMed]

D. Chai, R. N. Gaster, R. Roizenblatt, T. Juhasz, D. J. Brown, and J. V. Jester, “Quantitative assessment of UVA-riboflavin corneal cross-linking using nonlinear optical microscopy,” Invest. Ophthalmol. Vis. Sci. 52(7), 4231–4238 (2011).
[PubMed]

Capasso, L.

M. De Bernardo, L. Capasso, M. Lanza, A. Tortori, S. Iaccarino, M. Cennamo, M. Borrelli, and N. Rosa, “Long-term results of corneal collagen crosslinking for progressive keratoconus,” J. Optom. 8(3), 180–186 (2015).
[PubMed]

Cennamo, M.

M. De Bernardo, L. Capasso, M. Lanza, A. Tortori, S. Iaccarino, M. Cennamo, M. Borrelli, and N. Rosa, “Long-term results of corneal collagen crosslinking for progressive keratoconus,” J. Optom. 8(3), 180–186 (2015).
[PubMed]

Chai, D.

D. Chai, T. Juhasz, D. J. Brown, and J. V. Jester, “Nonlinear optical collagen cross-linking and mechanical stiffening: a possible photodynamic therapeutic approach to treating corneal ectasia,” J. Biomed. Opt. 18(3), 038003 (2013).
[PubMed]

D. Chai, R. N. Gaster, R. Roizenblatt, T. Juhasz, D. J. Brown, and J. V. Jester, “Quantitative assessment of UVA-riboflavin corneal cross-linking using nonlinear optical microscopy,” Invest. Ophthalmol. Vis. Sci. 52(7), 4231–4238 (2011).
[PubMed]

De Bernardo, M.

M. De Bernardo, L. Capasso, M. Lanza, A. Tortori, S. Iaccarino, M. Cennamo, M. Borrelli, and N. Rosa, “Long-term results of corneal collagen crosslinking for progressive keratoconus,” J. Optom. 8(3), 180–186 (2015).
[PubMed]

Dick, H. B.

M. Elling, I. Kersten-Gomez, and H. B. Dick, “Photorefractive intrastromal corneal crosslinking for the treatment of myopic refractive errors: Six-month interim findings,” J. Cataract Refract. Surg. 43(6), 789–795 (2017).
[PubMed]

Drolsum, L.

A. M. Hagem, A. Thorsrud, G. F. Sandvik, M. Råen, and L. Drolsum, “Collagen crosslinking with conventional and accelerated ultraviolet-A irradiation using riboflavin with hydroxypropyl methylcellulose,” J. Cataract Refract. Surg. 43(4), 511–517 (2017).
[PubMed]

Durrie, D. S.

P. S. Hersh, R. D. Stulting, D. Muller, D. S. Durrie, and R. K. Rajpal, “United States Multicneter Clinical Trial of Corneal Collagen Crosslinking for Keratoconus Treatment,” Ophthalmology 124, 1259–1270 (2017).

Elling, M.

M. Elling, I. Kersten-Gomez, and H. B. Dick, “Photorefractive intrastromal corneal crosslinking for the treatment of myopic refractive errors: Six-month interim findings,” J. Cataract Refract. Surg. 43(6), 789–795 (2017).
[PubMed]

Friedman, M. D.

P. Kamaev, M. D. Friedman, E. Sherr, and D. Muller, “Photochemical kinetics of corneal cross-linking with riboflavin,” Invest. Ophthalmol. Vis. Sci. 53(4), 2360–2367 (2012).
[PubMed]

Garrett, C. G. B.

W. Kaiser and C. G. B. Garrett, “Two-photon excitation in CaF2:Eu2+,” Phys. Rev. Lett. 7(6), 229–231 (1961).

Gaster, R. N.

D. Chai, R. N. Gaster, R. Roizenblatt, T. Juhasz, D. J. Brown, and J. V. Jester, “Quantitative assessment of UVA-riboflavin corneal cross-linking using nonlinear optical microscopy,” Invest. Ophthalmol. Vis. Sci. 52(7), 4231–4238 (2011).
[PubMed]

Hagem, A. M.

A. M. Hagem, A. Thorsrud, G. F. Sandvik, M. Råen, and L. Drolsum, “Collagen crosslinking with conventional and accelerated ultraviolet-A irradiation using riboflavin with hydroxypropyl methylcellulose,” J. Cataract Refract. Surg. 43(4), 511–517 (2017).
[PubMed]

Hayes, W. C.

W. C. Hayes, L. M. Keer, G. Herrmann, and L. F. Mockros, “A mathematical analysis for indentation tests of articular cartilage,” J. Biomech. 5(5), 541–551 (1972).
[PubMed]

Herrmann, G.

W. C. Hayes, L. M. Keer, G. Herrmann, and L. F. Mockros, “A mathematical analysis for indentation tests of articular cartilage,” J. Biomech. 5(5), 541–551 (1972).
[PubMed]

Hersh, P. S.

P. S. Hersh, R. D. Stulting, D. Muller, D. S. Durrie, and R. K. Rajpal, “United States Multicneter Clinical Trial of Corneal Collagen Crosslinking for Keratoconus Treatment,” Ophthalmology 124, 1259–1270 (2017).

Huhle, M.

E. Spoerl, M. Huhle, and T. Seiler, “Induction of cross-links in corneal tissue,” Exp. Eye Res. 66(1), 97–103 (1998).
[PubMed]

Humayun, S.

S. Malik, S. Humayun, S. Nayyar, and M. Ishaq, “Determining the efficacy of corneal crosslinking in progressive keratoconus,” Pak. J. Med. Sci. 33(2), 389–392 (2017).
[PubMed]

Iaccarino, S.

M. De Bernardo, L. Capasso, M. Lanza, A. Tortori, S. Iaccarino, M. Cennamo, M. Borrelli, and N. Rosa, “Long-term results of corneal collagen crosslinking for progressive keratoconus,” J. Optom. 8(3), 180–186 (2015).
[PubMed]

Ishaq, M.

S. Malik, S. Humayun, S. Nayyar, and M. Ishaq, “Determining the efficacy of corneal crosslinking in progressive keratoconus,” Pak. J. Med. Sci. 33(2), 389–392 (2017).
[PubMed]

Janmey, P. A.

I. Levental, K. R. Levental, E. A. Klein, R. Assoian, R. T. Miller, R. G. Wells, and P. A. Janmey, “A simple indentation device for measuring micrometer-scale tissue stiffness,” J. Phys. Condens. Matter 22(19), 194120 (2010).
[PubMed]

Jester, J. V.

S. M. Bradford, D. J. Brown, T. Juhasz, E. Mikula, and J. V. Jester, “Nonlinear optical corneal collagen crosslinking of ex vivo rabbit eyes,” J. Cataract Refract. Surg. 42(11), 1660–1665 (2016).
[PubMed]

D. Chai, T. Juhasz, D. J. Brown, and J. V. Jester, “Nonlinear optical collagen cross-linking and mechanical stiffening: a possible photodynamic therapeutic approach to treating corneal ectasia,” J. Biomed. Opt. 18(3), 038003 (2013).
[PubMed]

D. Chai, R. N. Gaster, R. Roizenblatt, T. Juhasz, D. J. Brown, and J. V. Jester, “Quantitative assessment of UVA-riboflavin corneal cross-linking using nonlinear optical microscopy,” Invest. Ophthalmol. Vis. Sci. 52(7), 4231–4238 (2011).
[PubMed]

Juhasz, T.

S. M. Bradford, D. J. Brown, T. Juhasz, E. Mikula, and J. V. Jester, “Nonlinear optical corneal collagen crosslinking of ex vivo rabbit eyes,” J. Cataract Refract. Surg. 42(11), 1660–1665 (2016).
[PubMed]

D. Chai, T. Juhasz, D. J. Brown, and J. V. Jester, “Nonlinear optical collagen cross-linking and mechanical stiffening: a possible photodynamic therapeutic approach to treating corneal ectasia,” J. Biomed. Opt. 18(3), 038003 (2013).
[PubMed]

D. Chai, R. N. Gaster, R. Roizenblatt, T. Juhasz, D. J. Brown, and J. V. Jester, “Quantitative assessment of UVA-riboflavin corneal cross-linking using nonlinear optical microscopy,” Invest. Ophthalmol. Vis. Sci. 52(7), 4231–4238 (2011).
[PubMed]

Kaiser, W.

W. Kaiser and C. G. B. Garrett, “Two-photon excitation in CaF2:Eu2+,” Phys. Rev. Lett. 7(6), 229–231 (1961).

Kamaev, P.

P. Kamaev, M. D. Friedman, E. Sherr, and D. Muller, “Photochemical kinetics of corneal cross-linking with riboflavin,” Invest. Ophthalmol. Vis. Sci. 53(4), 2360–2367 (2012).
[PubMed]

Kanellopoulos, A. J.

A. J. Kanellopoulos and G. Asimellis, “Combined laser in situ keratomileusis and prophylactic high-fluence corneal collagen crosslinking for high myopia: two-year safety and efficacy,” J. Cataract Refract. Surg. 41(7), 1426–1433 (2015).
[PubMed]

Keer, L. M.

W. C. Hayes, L. M. Keer, G. Herrmann, and L. F. Mockros, “A mathematical analysis for indentation tests of articular cartilage,” J. Biomech. 5(5), 541–551 (1972).
[PubMed]

Kersten-Gomez, I.

M. Elling, I. Kersten-Gomez, and H. B. Dick, “Photorefractive intrastromal corneal crosslinking for the treatment of myopic refractive errors: Six-month interim findings,” J. Cataract Refract. Surg. 43(6), 789–795 (2017).
[PubMed]

Klein, E. A.

I. Levental, K. R. Levental, E. A. Klein, R. Assoian, R. T. Miller, R. G. Wells, and P. A. Janmey, “A simple indentation device for measuring micrometer-scale tissue stiffness,” J. Phys. Condens. Matter 22(19), 194120 (2010).
[PubMed]

Lanza, M.

M. De Bernardo, L. Capasso, M. Lanza, A. Tortori, S. Iaccarino, M. Cennamo, M. Borrelli, and N. Rosa, “Long-term results of corneal collagen crosslinking for progressive keratoconus,” J. Optom. 8(3), 180–186 (2015).
[PubMed]

Leone, N.

G. Lombardo, N. L. Micali, V. Villari, N. Leone, S. Serrao, D. Rusciano, and M. Lombardo, “Assessment of stromal riboflavin concentration-depth profile in nanotechnology-based transepithelial corneal crosslinking,” J. Cataract Refract. Surg. 43(5), 680–686 (2017).
[PubMed]

Levental, I.

I. Levental, K. R. Levental, E. A. Klein, R. Assoian, R. T. Miller, R. G. Wells, and P. A. Janmey, “A simple indentation device for measuring micrometer-scale tissue stiffness,” J. Phys. Condens. Matter 22(19), 194120 (2010).
[PubMed]

Levental, K. R.

I. Levental, K. R. Levental, E. A. Klein, R. Assoian, R. T. Miller, R. G. Wells, and P. A. Janmey, “A simple indentation device for measuring micrometer-scale tissue stiffness,” J. Phys. Condens. Matter 22(19), 194120 (2010).
[PubMed]

Lombardo, G.

G. Lombardo, N. L. Micali, V. Villari, N. Leone, S. Serrao, D. Rusciano, and M. Lombardo, “Assessment of stromal riboflavin concentration-depth profile in nanotechnology-based transepithelial corneal crosslinking,” J. Cataract Refract. Surg. 43(5), 680–686 (2017).
[PubMed]

Lombardo, M.

G. Lombardo, N. L. Micali, V. Villari, N. Leone, S. Serrao, D. Rusciano, and M. Lombardo, “Assessment of stromal riboflavin concentration-depth profile in nanotechnology-based transepithelial corneal crosslinking,” J. Cataract Refract. Surg. 43(5), 680–686 (2017).
[PubMed]

Malik, S.

S. Malik, S. Humayun, S. Nayyar, and M. Ishaq, “Determining the efficacy of corneal crosslinking in progressive keratoconus,” Pak. J. Med. Sci. 33(2), 389–392 (2017).
[PubMed]

Micali, N. L.

G. Lombardo, N. L. Micali, V. Villari, N. Leone, S. Serrao, D. Rusciano, and M. Lombardo, “Assessment of stromal riboflavin concentration-depth profile in nanotechnology-based transepithelial corneal crosslinking,” J. Cataract Refract. Surg. 43(5), 680–686 (2017).
[PubMed]

Mikula, E.

S. M. Bradford, D. J. Brown, T. Juhasz, E. Mikula, and J. V. Jester, “Nonlinear optical corneal collagen crosslinking of ex vivo rabbit eyes,” J. Cataract Refract. Surg. 42(11), 1660–1665 (2016).
[PubMed]

Miller, R. T.

I. Levental, K. R. Levental, E. A. Klein, R. Assoian, R. T. Miller, R. G. Wells, and P. A. Janmey, “A simple indentation device for measuring micrometer-scale tissue stiffness,” J. Phys. Condens. Matter 22(19), 194120 (2010).
[PubMed]

Mockros, L. F.

W. C. Hayes, L. M. Keer, G. Herrmann, and L. F. Mockros, “A mathematical analysis for indentation tests of articular cartilage,” J. Biomech. 5(5), 541–551 (1972).
[PubMed]

Mrochen, M.

E. Spoerl, M. Mrochen, D. Sliney, S. Trokel, and T. Seiler, “Safety of UVA-riboflavin cross-linking of the cornea,” Cornea 26(4), 385–389 (2007).
[PubMed]

Muller, D.

P. S. Hersh, R. D. Stulting, D. Muller, D. S. Durrie, and R. K. Rajpal, “United States Multicneter Clinical Trial of Corneal Collagen Crosslinking for Keratoconus Treatment,” Ophthalmology 124, 1259–1270 (2017).

P. Kamaev, M. D. Friedman, E. Sherr, and D. Muller, “Photochemical kinetics of corneal cross-linking with riboflavin,” Invest. Ophthalmol. Vis. Sci. 53(4), 2360–2367 (2012).
[PubMed]

Nanavaty, M. A.

Z. Shalchi, X. Wang, and M. A. Nanavaty, “Safety and efficacy of epithelium removal and transepithelial corneal collagen crosslinking for keratoconus,” Eye (Lond.) 29(1), 15–29 (2015).
[PubMed]

Nayyar, S.

S. Malik, S. Humayun, S. Nayyar, and M. Ishaq, “Determining the efficacy of corneal crosslinking in progressive keratoconus,” Pak. J. Med. Sci. 33(2), 389–392 (2017).
[PubMed]

Råen, M.

A. M. Hagem, A. Thorsrud, G. F. Sandvik, M. Råen, and L. Drolsum, “Collagen crosslinking with conventional and accelerated ultraviolet-A irradiation using riboflavin with hydroxypropyl methylcellulose,” J. Cataract Refract. Surg. 43(4), 511–517 (2017).
[PubMed]

Raiskup, F.

F. Raiskup and E. Spoerl, “Corneal crosslinking with riboflavin and ultraviolet A. I. Principles,” Ocul. Surf. 11(2), 65–74 (2013).
[PubMed]

Rajpal, R. K.

P. S. Hersh, R. D. Stulting, D. Muller, D. S. Durrie, and R. K. Rajpal, “United States Multicneter Clinical Trial of Corneal Collagen Crosslinking for Keratoconus Treatment,” Ophthalmology 124, 1259–1270 (2017).

Roizenblatt, R.

D. Chai, R. N. Gaster, R. Roizenblatt, T. Juhasz, D. J. Brown, and J. V. Jester, “Quantitative assessment of UVA-riboflavin corneal cross-linking using nonlinear optical microscopy,” Invest. Ophthalmol. Vis. Sci. 52(7), 4231–4238 (2011).
[PubMed]

Rosa, N.

M. De Bernardo, L. Capasso, M. Lanza, A. Tortori, S. Iaccarino, M. Cennamo, M. Borrelli, and N. Rosa, “Long-term results of corneal collagen crosslinking for progressive keratoconus,” J. Optom. 8(3), 180–186 (2015).
[PubMed]

Rusciano, D.

G. Lombardo, N. L. Micali, V. Villari, N. Leone, S. Serrao, D. Rusciano, and M. Lombardo, “Assessment of stromal riboflavin concentration-depth profile in nanotechnology-based transepithelial corneal crosslinking,” J. Cataract Refract. Surg. 43(5), 680–686 (2017).
[PubMed]

Sandvik, G. F.

A. M. Hagem, A. Thorsrud, G. F. Sandvik, M. Råen, and L. Drolsum, “Collagen crosslinking with conventional and accelerated ultraviolet-A irradiation using riboflavin with hydroxypropyl methylcellulose,” J. Cataract Refract. Surg. 43(4), 511–517 (2017).
[PubMed]

Seiler, T.

E. Spoerl, M. Mrochen, D. Sliney, S. Trokel, and T. Seiler, “Safety of UVA-riboflavin cross-linking of the cornea,” Cornea 26(4), 385–389 (2007).
[PubMed]

G. Wollensak, E. Spoerl, and T. Seiler, “Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus,” Am. J. Ophthalmol. 135(5), 620–627 (2003).
[PubMed]

E. Spoerl, M. Huhle, and T. Seiler, “Induction of cross-links in corneal tissue,” Exp. Eye Res. 66(1), 97–103 (1998).
[PubMed]

Serrao, S.

G. Lombardo, N. L. Micali, V. Villari, N. Leone, S. Serrao, D. Rusciano, and M. Lombardo, “Assessment of stromal riboflavin concentration-depth profile in nanotechnology-based transepithelial corneal crosslinking,” J. Cataract Refract. Surg. 43(5), 680–686 (2017).
[PubMed]

Shalchi, Z.

Z. Shalchi, X. Wang, and M. A. Nanavaty, “Safety and efficacy of epithelium removal and transepithelial corneal collagen crosslinking for keratoconus,” Eye (Lond.) 29(1), 15–29 (2015).
[PubMed]

Sherr, E.

P. Kamaev, M. D. Friedman, E. Sherr, and D. Muller, “Photochemical kinetics of corneal cross-linking with riboflavin,” Invest. Ophthalmol. Vis. Sci. 53(4), 2360–2367 (2012).
[PubMed]

Sliney, D.

E. Spoerl, M. Mrochen, D. Sliney, S. Trokel, and T. Seiler, “Safety of UVA-riboflavin cross-linking of the cornea,” Cornea 26(4), 385–389 (2007).
[PubMed]

Spoerl, E.

F. Raiskup and E. Spoerl, “Corneal crosslinking with riboflavin and ultraviolet A. I. Principles,” Ocul. Surf. 11(2), 65–74 (2013).
[PubMed]

E. Spoerl, M. Mrochen, D. Sliney, S. Trokel, and T. Seiler, “Safety of UVA-riboflavin cross-linking of the cornea,” Cornea 26(4), 385–389 (2007).
[PubMed]

G. Wollensak, E. Spoerl, and T. Seiler, “Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus,” Am. J. Ophthalmol. 135(5), 620–627 (2003).
[PubMed]

E. Spoerl, M. Huhle, and T. Seiler, “Induction of cross-links in corneal tissue,” Exp. Eye Res. 66(1), 97–103 (1998).
[PubMed]

Stulting, R. D.

P. S. Hersh, R. D. Stulting, D. Muller, D. S. Durrie, and R. K. Rajpal, “United States Multicneter Clinical Trial of Corneal Collagen Crosslinking for Keratoconus Treatment,” Ophthalmology 124, 1259–1270 (2017).

Thorsrud, A.

A. M. Hagem, A. Thorsrud, G. F. Sandvik, M. Råen, and L. Drolsum, “Collagen crosslinking with conventional and accelerated ultraviolet-A irradiation using riboflavin with hydroxypropyl methylcellulose,” J. Cataract Refract. Surg. 43(4), 511–517 (2017).
[PubMed]

Tortori, A.

M. De Bernardo, L. Capasso, M. Lanza, A. Tortori, S. Iaccarino, M. Cennamo, M. Borrelli, and N. Rosa, “Long-term results of corneal collagen crosslinking for progressive keratoconus,” J. Optom. 8(3), 180–186 (2015).
[PubMed]

Trokel, S.

E. Spoerl, M. Mrochen, D. Sliney, S. Trokel, and T. Seiler, “Safety of UVA-riboflavin cross-linking of the cornea,” Cornea 26(4), 385–389 (2007).
[PubMed]

Villari, V.

G. Lombardo, N. L. Micali, V. Villari, N. Leone, S. Serrao, D. Rusciano, and M. Lombardo, “Assessment of stromal riboflavin concentration-depth profile in nanotechnology-based transepithelial corneal crosslinking,” J. Cataract Refract. Surg. 43(5), 680–686 (2017).
[PubMed]

Wang, X.

Z. Shalchi, X. Wang, and M. A. Nanavaty, “Safety and efficacy of epithelium removal and transepithelial corneal collagen crosslinking for keratoconus,” Eye (Lond.) 29(1), 15–29 (2015).
[PubMed]

Webb, W. W.

W. R. Zipfel, R. M. Williams, and W. W. Webb, “Nonlinear magic: multiphoton microscopy in the biosciences,” Nat. Biotechnol. 21(11), 1369–1377 (2003).
[PubMed]

Wells, R. G.

I. Levental, K. R. Levental, E. A. Klein, R. Assoian, R. T. Miller, R. G. Wells, and P. A. Janmey, “A simple indentation device for measuring micrometer-scale tissue stiffness,” J. Phys. Condens. Matter 22(19), 194120 (2010).
[PubMed]

Williams, R. M.

W. R. Zipfel, R. M. Williams, and W. W. Webb, “Nonlinear magic: multiphoton microscopy in the biosciences,” Nat. Biotechnol. 21(11), 1369–1377 (2003).
[PubMed]

Wollensak, G.

G. Wollensak, E. Spoerl, and T. Seiler, “Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus,” Am. J. Ophthalmol. 135(5), 620–627 (2003).
[PubMed]

Zipfel, W. R.

W. R. Zipfel, R. M. Williams, and W. W. Webb, “Nonlinear magic: multiphoton microscopy in the biosciences,” Nat. Biotechnol. 21(11), 1369–1377 (2003).
[PubMed]

Am. J. Ophthalmol. (1)

G. Wollensak, E. Spoerl, and T. Seiler, “Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus,” Am. J. Ophthalmol. 135(5), 620–627 (2003).
[PubMed]

Cornea (1)

E. Spoerl, M. Mrochen, D. Sliney, S. Trokel, and T. Seiler, “Safety of UVA-riboflavin cross-linking of the cornea,” Cornea 26(4), 385–389 (2007).
[PubMed]

Exp. Eye Res. (1)

E. Spoerl, M. Huhle, and T. Seiler, “Induction of cross-links in corneal tissue,” Exp. Eye Res. 66(1), 97–103 (1998).
[PubMed]

Eye (Lond.) (1)

Z. Shalchi, X. Wang, and M. A. Nanavaty, “Safety and efficacy of epithelium removal and transepithelial corneal collagen crosslinking for keratoconus,” Eye (Lond.) 29(1), 15–29 (2015).
[PubMed]

Invest. Ophthalmol. Vis. Sci. (2)

P. Kamaev, M. D. Friedman, E. Sherr, and D. Muller, “Photochemical kinetics of corneal cross-linking with riboflavin,” Invest. Ophthalmol. Vis. Sci. 53(4), 2360–2367 (2012).
[PubMed]

D. Chai, R. N. Gaster, R. Roizenblatt, T. Juhasz, D. J. Brown, and J. V. Jester, “Quantitative assessment of UVA-riboflavin corneal cross-linking using nonlinear optical microscopy,” Invest. Ophthalmol. Vis. Sci. 52(7), 4231–4238 (2011).
[PubMed]

J. Biomech. (1)

W. C. Hayes, L. M. Keer, G. Herrmann, and L. F. Mockros, “A mathematical analysis for indentation tests of articular cartilage,” J. Biomech. 5(5), 541–551 (1972).
[PubMed]

J. Biomed. Opt. (1)

D. Chai, T. Juhasz, D. J. Brown, and J. V. Jester, “Nonlinear optical collagen cross-linking and mechanical stiffening: a possible photodynamic therapeutic approach to treating corneal ectasia,” J. Biomed. Opt. 18(3), 038003 (2013).
[PubMed]

J. Cataract Refract. Surg. (5)

S. M. Bradford, D. J. Brown, T. Juhasz, E. Mikula, and J. V. Jester, “Nonlinear optical corneal collagen crosslinking of ex vivo rabbit eyes,” J. Cataract Refract. Surg. 42(11), 1660–1665 (2016).
[PubMed]

M. Elling, I. Kersten-Gomez, and H. B. Dick, “Photorefractive intrastromal corneal crosslinking for the treatment of myopic refractive errors: Six-month interim findings,” J. Cataract Refract. Surg. 43(6), 789–795 (2017).
[PubMed]

A. M. Hagem, A. Thorsrud, G. F. Sandvik, M. Råen, and L. Drolsum, “Collagen crosslinking with conventional and accelerated ultraviolet-A irradiation using riboflavin with hydroxypropyl methylcellulose,” J. Cataract Refract. Surg. 43(4), 511–517 (2017).
[PubMed]

G. Lombardo, N. L. Micali, V. Villari, N. Leone, S. Serrao, D. Rusciano, and M. Lombardo, “Assessment of stromal riboflavin concentration-depth profile in nanotechnology-based transepithelial corneal crosslinking,” J. Cataract Refract. Surg. 43(5), 680–686 (2017).
[PubMed]

A. J. Kanellopoulos and G. Asimellis, “Combined laser in situ keratomileusis and prophylactic high-fluence corneal collagen crosslinking for high myopia: two-year safety and efficacy,” J. Cataract Refract. Surg. 41(7), 1426–1433 (2015).
[PubMed]

J. Optom. (1)

M. De Bernardo, L. Capasso, M. Lanza, A. Tortori, S. Iaccarino, M. Cennamo, M. Borrelli, and N. Rosa, “Long-term results of corneal collagen crosslinking for progressive keratoconus,” J. Optom. 8(3), 180–186 (2015).
[PubMed]

J. Phys. Condens. Matter (1)

I. Levental, K. R. Levental, E. A. Klein, R. Assoian, R. T. Miller, R. G. Wells, and P. A. Janmey, “A simple indentation device for measuring micrometer-scale tissue stiffness,” J. Phys. Condens. Matter 22(19), 194120 (2010).
[PubMed]

Nat. Biotechnol. (1)

W. R. Zipfel, R. M. Williams, and W. W. Webb, “Nonlinear magic: multiphoton microscopy in the biosciences,” Nat. Biotechnol. 21(11), 1369–1377 (2003).
[PubMed]

Ocul. Surf. (1)

F. Raiskup and E. Spoerl, “Corneal crosslinking with riboflavin and ultraviolet A. I. Principles,” Ocul. Surf. 11(2), 65–74 (2013).
[PubMed]

Ophthalmology (1)

P. S. Hersh, R. D. Stulting, D. Muller, D. S. Durrie, and R. K. Rajpal, “United States Multicneter Clinical Trial of Corneal Collagen Crosslinking for Keratoconus Treatment,” Ophthalmology 124, 1259–1270 (2017).

Pak. J. Med. Sci. (1)

S. Malik, S. Humayun, S. Nayyar, and M. Ishaq, “Determining the efficacy of corneal crosslinking in progressive keratoconus,” Pak. J. Med. Sci. 33(2), 389–392 (2017).
[PubMed]

Phys. Rev. Lett. (1)

W. Kaiser and C. G. B. Garrett, “Two-photon excitation in CaF2:Eu2+,” Phys. Rev. Lett. 7(6), 229–231 (1961).

Other (1)

E. R. Mikula, S. Bradford, D. J. Brown, T. Juhasz, and J. Jester, “Precise corneal crosslinking (CXL) using a 5 KHz amplified femtosecond laser,” presented at The Association for Research in Vision and Ophthalmology annual meeting, Baltimore, Maryland, 7–11 May 2017.

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Figures (8)

Fig. 1
Fig. 1 Schematic of designed delivery device with software controlled x, y scanners, variable beam expander, and objective with attached cone and contact glass.
Fig. 2
Fig. 2 Schematic of indentation device used to measure the mechanical stiffness of the crosslinked region of the corneal stroma.
Fig. 3
Fig. 3 Images taken of the two photon focal volume in a tank of riboflavin solution as the beam expander setting (A) and depth (B) were increased in steps, used to measure the size of the focal volume and depth below the contact glass.
Fig. 4
Fig. 4 As the beam expander setting increased from 0 to 5 the volume of the focal spot decreased more than 18 fold in both water (blue circles) and corneal tissue (orange triangles).
Fig. 5
Fig. 5 Plotted force required to indent the corneal stroma to 10% thickness. The orange, taller, graph shows the data for a single indentation cycle of a sample crosslinked with 900 mW, and the blue, shorter, graph shows the same data for a control cornea.
Fig. 6
Fig. 6 Both UVA (green) and NLO (blue) treated eyes were significantly stiffer than controls (black) with P values less than 0.001.
Fig. 7
Fig. 7 Examples of CAF images for UVA CXL, NLO CXL, and control samples.
Fig. 8
Fig. 8 CAF intensity was not significantly different between UVA (green) or NLO (blue) treatment groups.

Tables (1)

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Table 1 Calculated axial and lateral length, focal volume, and NA

Equations (1)

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ω= o.532λ 2 [ 1 n n 2 N A 2 ].

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