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Journal of Ophthalmology
Volume 2012 (2012), Article ID 406850, 12 pages
http://dx.doi.org/10.1155/2012/406850
Review Article

Collagen Cross-Linking: Current Status and Future Directions

Department of Ophthalmology, University of Rostock, Doberaner Strasse 140, 18057 Rostock, Germany

Received 31 March 2011; Revised 2 November 2011; Accepted 20 November 2011

Academic Editor: Sunil Shah

Copyright © 2012 Marine Hovakimyan et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. Y. S. Rabinowitz, “Keratoconus,” Survey of Ophthalmology, vol. 42, no. 4, pp. 297–319, 1998. View at Publisher · View at Google Scholar · View at Scopus
  2. M. Edwards, C. N. McGhee, and S. Dean, “The genetics of keratoconus,” Clinical and Experimental Ophthalmology, vol. 29, no. 6, pp. 345–351, 2001. View at Publisher · View at Google Scholar · View at Scopus
  3. T. Iwamoto and A. G. DeVoe, “Electron microscopical study of the Fleisher ring,” Archives of Ophthalmology, vol. 94, no. 9, pp. 1579–1584, 1976. View at Scopus
  4. B. F. Fernandes, P. Logan, M. E. Zajdenweber, L. N. Santos, D. P. Cheema, and M. N. Burnier Jr., “Histopathological study of 49 cases of keratoconus,” Pathology, vol. 40, no. 6, pp. 623–626, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  5. T. Iwamoto and A. G. DeVoe, “Particulate structures in keratoconus,” Archives d'Ophtalmologie et Revue Générale d'Ophtalmologie, vol. 35, no. 1, pp. 65–76, 1975. View at Scopus
  6. C. W. Sturbaum and R. L. Peiffer Jr., “Pathology of corneal endothelium in keratoconus,” Ophthalmologica, vol. 206, no. 4, pp. 192–208, 1993. View at Scopus
  7. A. J. Bron, “Keratoconus,” Cornea, vol. 7, no. 3, pp. 163–169, 1988. View at Scopus
  8. A. Ihalainen, T. Salo, H. Forsius, and L. Peltonen, “Increase in type I and type IV collagenolytic activity in primary cultures of keratoconus cornea,” European Journal of Clinical Investigation, vol. 16, no. 1, pp. 78–84, 1986. View at Scopus
  9. M. C. Kenney, M. Chwa, A. I. Opbroek, and D. J. Brown, “Increased gelatinolytic activity in keratoconus keratocyte cultures. A correlation to an altered matrix metalloproteinase-2/tissue inhibitor of metalloproteinase ratio,” Cornea, vol. 13, no. 2, pp. 114–124, 1994. View at Scopus
  10. S. E. Wilson, Y. G. He, J. Weng et al., “Epithelial injury induces keratocyte apoptosis: hypothesized role for the interleukin-1 system in the modulation of corneal tissue organization and wound healing,” Experimental Eye Research, vol. 62, no. 4, pp. 325–327, 1996.
  11. K. M. Meek, S. J. Tuft, Y. Huang et al., “Changes in collagen orientation and distribution in keratoconus corneas,” Investigative Ophthalmology and Visual Science, vol. 46, no. 6, pp. 1948–1956, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  12. J. S. Hwang, J. H. Lee, W. R. Wee, and M. K. Kim, “Effects of multicurve RGP contact lens use on topographic changes in keratoconus,” Korean Journal of Ophthalmology, vol. 24, no. 4, pp. 201–206, 2010.
  13. S. Y. Kang, Y. K. Park, J. S. Song, and H. M. Kim, “Anterior stromal puncture for treatment of contact lens-intolerant keratoconus patients,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 249, no. 1, pp. 89–92, 2011. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  14. C. S. Siganos, G. D. Kymionis, N. Kartakis, M. A. Theodorakis, N. Astyrakakis, and I. G. Pallikaris, “Management of keratoconus with Intacs,” American Journal of Ophthalmology, vol. 135, no. 1, pp. 64–70, 2003. View at Publisher · View at Google Scholar · View at Scopus
  15. J. Colin and F. J. Malet, “Intacs for the correction of keratoconus: two-year follow-up,” Journal of Cataract and Refractive Surgery, vol. 33, no. 1, pp. 69–74, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  16. D. P. Piñero, J. L. Alio, B. El Kady et al., “Refractive and aberrometric outcomes of intracorneal ring segments for keratoconus: mechanical versus femtosecond-assisted procedures,” Ophthalmology, vol. 116, no. 9, pp. 1675–1687, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  17. M. H. Shabayek and J. L. Alió, “Intrastromal corneal ring segment implantation by femtosecond laser for keratoconus correction,” Ophthalmology, vol. 114, no. 9, pp. 1643–1652, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  18. T. Bourcier, V. Borderie, and L. Laroche, “Late bacterial keratitis after implantation of intrastromal corneal ring segments,” Journal of Cataract and Refractive Surgery, vol. 29, no. 2, pp. 407–409, 2003. View at Publisher · View at Google Scholar · View at Scopus
  19. M. Claesson, W. J. Armitage, P. Fagerholm, and U. Stenevi, “Visual outcome in corneal grafts: a preliminary analysis of the Swedish Corneal Transplant Register,” British Journal of Ophthalmology, vol. 86, no. 2, pp. 174–180, 2002. View at Publisher · View at Google Scholar · View at Scopus
  20. J. H. Lass, A. Sugar, B. A. Benetz et al., “Endothelial cell density to predict endothelial graft failure after penetrating keratoplasty,” Archives of Ophthalmology, vol. 128, no. 1, pp. 63–69, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  21. A. J. Epstein, T. N. de Castro, P. R. Laibson, E. J. Cohen, and C. J. Rapuano, “Risk factors for the first episode of corneal graft rejection in keratoconus,” Cornea, vol. 25, no. 9, pp. 1005–1011, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  22. L. Lim, K. Pesudovs, and D. J. Coster, “Penetrating keratoplasty for keratoconus: visual outcome and success,” Ophthalmology, vol. 107, no. 6, pp. 1125–1131, 2000. View at Publisher · View at Google Scholar · View at Scopus
  23. I. Kremer, R. C. Eagle, C. J. Rapuano, and P. R. Laibson, “Histologic evidence of recurrent keratoconus seven years after keratoplasty,” American Journal of Ophthalmology, vol. 119, no. 4, pp. 511–512, 1995. View at Scopus
  24. G. N. Rao, T. John, N. Ishida, and J. V. Aquavella, “Recovery of corneal sensitivity in grafts following penetrating keratoplasty,” Ophthalmology, vol. 92, no. 10, pp. 1408–1411, 1985. View at Scopus
  25. L. Fontana, G. Parente, A. Sincich, and G. Tassinari, “Influence of graft-host interface on the quality of vision after deep anterior lamellar keratoplasty in patients with keratoconus,” Cornea, vol. 30, no. 5, pp. 497–502, 2011. View at Publisher · View at Google Scholar · View at PubMed
  26. E. Spörl, M. Huhle, M. Kasper, and T. Seiler, “Increased rigidity of the cornea caused by intrastromal cross-linking,” Ophthalmologe, vol. 94, no. 12, pp. 902–906, 1997.
  27. Y. Komai and T. Ushiki, “The three-dimensional organization of collagen fibrils in the human cornea and sclera,” Investigative Ophthalmology and Visual Science, vol. 32, no. 8, pp. 2244–2258, 1991. View at Scopus
  28. A. Elsheikh, D. Wang, M. Brown, P. Rama, M. Campanelli, and D. Pye, “Assessment of corneal biomechanical properties and their variation with age,” Current Eye Research, vol. 32, no. 1, pp. 11–19, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  29. T. Seiler, S. Huhle, E. Spoerl, and H. Kunath, “Manifest diabetes and keratoconus: a restrospective case-control study,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 238, no. 10, pp. 822–825, 2000. View at Publisher · View at Google Scholar · View at Scopus
  30. O. Tomkins and H. J. Garzozi, “Collagen cross-linking: strengthening the unstable cornea,” Clinical Ophthalmology, vol. 2, no. 4, pp. 863–867, 2008.
  31. E. Spoerl, M. Huhle, and T. Seiler, “Induction of cross-links in corneal tissue,” Experimental Eye Research, vol. 66, no. 1, pp. 97–103, 1998. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  32. E. Spoerl and T. Seiler, “Techniques for stiffening the cornea,” Journal of Refractive Surgery, vol. 15, no. 6, pp. 711–713, 1999. View at Scopus
  33. A. S. McCall, S. Kraft, H. F. Edelhauser et al., “Mechanisms of corneal tissue cross-linking in response to treatment with topical riboflavin and long-wavelength ultraviolet radiation (UVA),” Investigative Ophthalmology and Visual Science, vol. 51, no. 1, pp. 129–138, 2010. View at Scopus
  34. G. Wollensak, E. Spoerl, M. Wilsch, and T. Seiler, “Keratocyte apoptosis after corneal collagen cross-linking using riboflavin/UVA treatment,” Cornea, vol. 23, no. 1, pp. 43–49, 2004. View at Publisher · View at Google Scholar · View at Scopus
  35. G. Wollensak, E. Iomdina, D. D. Dittert, and H. Herbst, “Wound healing in the rabbit cornea after corneal collagen cross-linking with riboflavin and UVA,” Cornea, vol. 26, no. 5, pp. 600–605, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  36. M. Hovakimyan, R. Guthoff, S. Knappe et al., “Short-term corneal response to cross-linking in rabbit eyes assessed by in vivo confocal laser scanning microscopy and histology,” Cornea, vol. 30, no. 2, pp. 196–203, 2011. View at Publisher · View at Google Scholar · View at PubMed
  37. G. Wollensak, “Histological changes in human cornea after cross-linking with riboflavin and ultraviolet A,” Acta Ophthalmologica, vol. 88, no. 2, pp. e17–e18, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  38. M. Q. Salomão, S. S. Chaurasia, A. Sinha-Roy et al., “Corneal wound healing after ultraviolet-A/riboflavin collagen cross-linking: a rabbit study,” Journal of Refractive Surgery, vol. 27, no. 6, pp. 401–407, 2011. View at Publisher · View at Google Scholar · View at PubMed
  39. R. Mencucci, M. Marini, I. Paladini et al., “Effects of riboflavin/UVA corneal cross-linking on keratocytes and collagen fibres in human cornea,” Clinical and Experimental Ophthalmology, vol. 38, no. 1, pp. 49–56, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  40. S. K. Masur, H. S. Dewal, T. T. Dinh, I. Erenburg, and S. Petridou, “Myofibroblasts differentiate from fibroblasts when plated at low density,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 9, pp. 4219–4223, 1996. View at Publisher · View at Google Scholar · View at Scopus
  41. G. Wollensak, E. Spörl, F. Reber, L. Pillunat, and R. Funk, “Corneal endothelial cytotoxicity of riboflavin/UVA treatment in vitro,” Ophthalmic Research, vol. 35, no. 6, pp. 324–328, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  42. G. Wollensak, E. Spoerl, M. Wilsch, and T. Seiler, “Endothelial cell damage after riboflavin-ultraviolet-A treatment in the rabbit,” Journal of Cataract and Refractive Surgery, vol. 29, no. 9, pp. 1786–1790, 2003. View at Publisher · View at Google Scholar · View at Scopus
  43. C. Edmund, “Corneal elasticity and ocular rigidity in normal and keratoconic eyes,” Acta Ophthalmologica, vol. 66, no. 2, pp. 134–140, 1988. View at Scopus
  44. G. Wollensak, E. Spoerl, and T. Seiler, “Stress-strain measurements of human and porcine corneas after riboflavin-ultraviolet-A-induced cross-linking,” Journal of Cataract and Refractive Surgery, vol. 29, no. 9, pp. 1780–1785, 2003. View at Publisher · View at Google Scholar · View at Scopus
  45. M. Kohlhaas, E. Spoerl, T. Schilde, G. Unger, C. Wittig, and L. E. Pillunat, “Biomechanical evidence of the distribution of cross-links in corneastreated with riboflavin and ultraviolet A light,” Journal of Cataract and Refractive Surgery, vol. 32, no. 2, pp. 279–283, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  46. E. Spoerl, G. Wollensak, D. D. Dittert, and T. Seiler, “Thermomechanical behavior of collagen-cross-linked porcine cornea,” Ophthalmologica, vol. 218, no. 2, pp. 136–140, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  47. G. Wollensak and E. Iomdina, “Long-term biomechanical properties of rabbit sclera after collagen crosslinking using riboflavin and ultraviolet A (UVA),” Acta Ophthalmologica, vol. 87, no. 2, pp. 193–198, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  48. G. Wollensak, M. Wilsch, E. Spoerl, and T. Seiler, “Collagen fiber diameter in the rabbit cornea after collagen crosslinking by riboflavin/UVA,” Cornea, vol. 23, no. 5, pp. 503–507, 2004. View at Publisher · View at Google Scholar · View at Scopus
  49. K. M. Bottós, A. L. Hofling-Lima, M. C. Barbosa et al., “Effect of collagen cross-linking in stromal fibril organization in edematous human corneas,” Cornea, vol. 29, no. 7, pp. 789–793, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  50. E. Spoerl, G. Wollensak, and T. Seiler, “Increased resistance of crosslinked cornea against enzymatic digestion,” Current Eye Research, vol. 29, no. 1, pp. 35–40, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  51. R. R. Krueger and J. C. Ramos-Esteban, “How might corneal elasticity help us understand diabetes and intraocular pressure?” Journal of Refractive Surgery, vol. 23, no. 1, pp. 85–88, 2007. View at Scopus
  52. E. Coskunseven, M. R. Jankov II, and F. Hafezi, “Contralateral eye study of corneal collagen cross-Linking with riboflavin and UVA irradiation in patients with keratoconus,” Journal of Refractive Surgery, vol. 25, no. 4, pp. 371–376, 2009. View at Publisher · View at Google Scholar · View at Scopus
  53. G. D. Kymionis, M. A. Grentzelos, G. A. Kounis et al., “Intraocular pressure measurements after corneal collagen crosslinking with riboflavin and ultraviolet A in eyes with keratoconus,” Journal of Cataract and Refractive Surgery, vol. 36, no. 10, pp. 1724–1727, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  54. P. Vinciguerra, E. Albè, A. M. Mahmoud, S. Trazza, F. Hafezi, and C. J. Roberts, “Intra- and postoperative variation in ocular response analyzer parameters in keratoconic eyes after corneal cross-linking,” Journal of Refractive Surgery, vol. 26, no. 9, pp. 669–676, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  55. P. Steven, M. Hovakimyan, R. F. Guthoff, G. Hüttmann, and O. Stachs, “Imaging corneal crosslinking by autofluorescence 2-photon microscopy, second harmonic generation, and fluorescence lifetime measurements,” Journal of Cataract and Refractive Surgery, vol. 36, no. 12, pp. 2150–2159, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  56. I. Jalbert, F. Stapleton, E. Papas, D. F. Sweeney, and M. Coroneo, “In vivo confocal microscopy of the human cornea,” British Journal of Ophthalmology, vol. 87, no. 2, pp. 225–236, 2003. View at Publisher · View at Google Scholar · View at Scopus
  57. C. Mazzotta, C. Traversi, S. Baiocchi, P. Sergio, T. Caporossi, and A. Caporossi, “Conservative treatment of keratoconus by riboflavin-UVA-induced cross-linking of corneal collagen: qualitative investigation,” European Journal of Ophthalmology, vol. 16, no. 4, pp. 530–535, 2006. View at Scopus
  58. C. Mazzotta, A. Balestrazzi, C. Traversi et al., “Treatment of progressive keratoconus by riboflavin-UVA-induced cross-linking of corneal collagen: ultrastructural analysis by Heidelberg retinal tomograph II in vivo confocal microscopy in humans,” Cornea, vol. 26, no. 4, pp. 390–397, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  59. C. Mazzotta, C. Traversi, S. Baiocchi et al., “Corneal healing after riboflavin ultraviolet-a collagen cross-linking determined by confocal laser scanning microscopy in vivo: early and late modifications,” American Journal of Ophthalmology, vol. 146, no. 4, pp. 527–533, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  60. J. O. Croxatto, A. E. Tytiun, and C. J. Argento, “Sequential in vivo confocal microscopy study of corneal wound healing after cross-linking in patients with keratoconus,” Journal of Refractive Surgery, vol. 26, no. 9, pp. 638–645, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  61. S. Esquenazi, J. He, N. Li, and H. E. Bazan, “Immunofluorescence of rabbit corneas after collagen cross-linking treatment with riboflavin and ultraviolet A,” Cornea, vol. 29, no. 4, pp. 412–417, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  62. G. D. Kymionis, V. F. Diakonis, M. Kalyvianaki et al., “One-year follow-up of corneal confocal microscopy after corneal cross-linking in patients with post laser in situ keratosmileusis ectasia and keratoconus,” American Journal of Ophthalmology, vol. 147, no. 5, pp. 774–778, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  63. T. Seiler and F. Hafezi, “Corneal cross-linking-induced stromal demarcation line,” Cornea, vol. 25, no. 9, pp. 1057–1059, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  64. M. Doors, N. G. Tahzib, F. A. Eggink, T. T. Berendschot, C. A. Webers, and R. M. Nuijts, “Use of anterior segment optical coherence tomography to study corneal changes after collagen cross-linking,” American Journal of Ophthalmology, vol. 148, no. 6, pp. 844–851, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  65. G. Wollensak, E. Spoerl, and T. Seiler, “Riboflavin/ultraviolet-A-induced collagen crosslinking for the treatment of keratoconus,” American Journal of Ophthalmology, vol. 135, no. 5, pp. 620–627, 2003. View at Publisher · View at Google Scholar · View at Scopus
  66. F. Raiskup-Wolf, A. Hoyer, E. Spoerl, and L. E. Pillunat, “Collagen crosslinking with riboflavin and ultraviolet-A light in keratoconus: long-term results,” Journal of Cataract and Refractive Surgery, vol. 34, no. 5, pp. 796–801, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  67. A. Caporossi, C. Mazzotta, S. Baiocchi, and T. Caporossi, “Long-term results of riboflavin ultraviolet a corneal collagen cross-linking for keratoconus in Italy: the siena eye cross study,” American Journal of Ophthalmology, vol. 149, no. 4, pp. 585–593, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  68. P. Vinciguerra, E. Albè, S. Trazza et al., “Refractive, topographic, tomographic, and aberrometric analysis of keratoconic eyes undergoing corneal cross-linking,” Ophthalmology, vol. 116, no. 3, pp. 369–378, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  69. Y. Goldich, Y. Barkana, I. Avni, and D. Zadok, “Goldmann applanation tonometry versus ocular response analyzer for intraocular pressure measurements in keratoconic eyes,” Cornea, vol. 29, no. 9, pp. 1011–1015, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  70. M. Sedaghat, M. Naderi, and M. Zarei-Ghanavati, “Biomechanical parameters of the cornea after collagen crosslinking measured by waveform analysis,” Journal of Cataract and Refractive Surgery, vol. 36, no. 10, pp. 1728–1731, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  71. T. Koller, H. P. Iseli, F. Hafezi, P. Vinciguerra, and T. Seiler, “Scheimpflug imaging of corneas after collagen cross-linking,” Cornea, vol. 28, no. 5, pp. 510–515, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  72. C. Wittig-Silva, M. Whiting, E. Lamoureux, R. G. Lindsay, L. J. Sullivan, and G. R. Snibson, “A randomized controlled trial of corneal collagen cross-linking in progressive keratoconus: preliminary results,” Journal of Refractive Surgery, vol. 24, no. 7, pp. S720–S725, 2008. View at Scopus
  73. P. S. Hersh, S. A. Greenstein, and K. L. Fry, “Corneal collagen crosslinking for keratoconus and corneal ectasia: one-year results,” Journal of Cataract and Refractive Surgery, vol. 37, no. 1, pp. 149–160, 2011. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  74. A. J. Kanellopoulos and P. S. Binder, “Collagen cross-linking (CCL) with sequential topography-guided PRK: a temporizing alternative for keratoconus to penetrating keratoplasty,” Cornea, vol. 26, no. 7, pp. 891–895, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  75. G. D. Kymionis, G. A. Kontadakis, G. A. Kounis et al., “Simultaneous topography-guided PRK followed by corneal collagen cross-linking for keratoconus,” Journal of Refractive Surgery, vol. 25, no. 9, pp. S807–S811, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  76. A. J. Kanellopoulos, “Comparison of sequential vs same-day simultaneous collagen cross-linking and topography-guided PRK for treatment of keratoconus,” Journal of Refractive Surgery, vol. 25, no. 9, pp. S812–S818, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  77. C. C. Chan, M. Sharma, and B. S. Wachler, “Effect of inferior-segment Intacs with and without C3-R on keratoconus,” Journal of Cataract and Refractive Surgery, vol. 33, no. 1, pp. 75–80, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  78. F. Hafezi, M. Mrochen, H. P. Iseli, and T. Seiler, “Collagen crosslinking with ultraviolet-A and hypoosmolar riboflavin solution in thin corneas,” Journal of Cataract and Refractive Surgery, vol. 35, no. 4, pp. 621–624, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  79. F. Hafezi, “Limitation of collagen cross-Linking with hypoosmolar riboflavin solution: failure in an extremely thin cornea,” Cornea, vol. 30, no. 8, pp. 917–919, 2011. View at Publisher · View at Google Scholar · View at PubMed
  80. K. M. Bottós, J. L. Dreyfuss, C. V. Regatieri et al., “Immunofluorescence confocal microscopy of porcine corneas following collagen cross-linking treatment with riboflavin and ultraviolet A,” Journal of Refractive Surgery, vol. 24, no. 7, pp. S715–S719, 2008. View at Scopus
  81. S. Hayes, D. P. O'Brart, L. S. Lamdin et al., “Effect of complete epithelial debridement before riboflavin-ultraviolet-A corneal collagen crosslinking therapy,” Journal of Cataract and Refractive Surgery, vol. 34, no. 4, pp. 657–661, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  82. K. Samaras, D. P. O'Brart, J. Doutch, S. Hayes, J. Marshall, and K. M. Meek, “Effect of epithelial retention and removal on ribofl avin absorption in porcine corneas,” Journal of Refractive Surgery, vol. 25, no. 9, pp. S771–S775, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  83. G. D. Kymionis, V. F. Diakonis, E. Coskunseven, M. Jankov, S. H. Yoo, and I. G. Pallikaris, “Customized pachymetric guided epithelial debridement for corneal collagen cross linking,” BMC Ophthalmology, vol. 9, no. 1, article 10, 2009. View at Publisher · View at Google Scholar · View at PubMed
  84. S. Baiocchi, C. Mazzotta, D. Cerretani, T. Caporossi, and A. Caporossi, “Corneal crosslinking: riboflavin concentration in corneal stroma exposed with and without epithelium,” Journal of Cataract and Refractive Surgery, vol. 35, no. 5, pp. 893–899, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  85. V. Kaya, C. A. Utine, and O. F. Yilmaz, “Efficacy of corneal collagen cross-linking using a custom epithelial debridement technique in thin corneas: a confocal microscopy study,” Journal of Refractive Surgery, vol. 27, no. 6, pp. 444–450, 2011. View at Publisher · View at Google Scholar · View at PubMed
  86. R. Pinelli, “BAK: a better alternative to epithelium removal in cross linking,” Ophthalmology Times Europe, vol. 2, pp. 36–38, 2006.
  87. B. McCarey and H. Edelhauser, “In vivo corneal epithelial permeability following treatment with prostaglandin analogs (correction of analoges) with or without benzalkonium chloride,” Journal of Ocular Pharmacology and Therapeutics, vol. 23, no. 5, pp. 445–451, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  88. G. Wollensak and E. Iomdina, “Biomechanical and histological changes after corneal crosslinking with and without epithelial debridement,” Journal of Cataract and Refractive Surgery, vol. 35, no. 3, pp. 540–546, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  89. A. Kissner, E. Spoerl, R. Jung, K. Spekl, L. E. Pillunat, and F. Raiskup, “Pharmacological modification of the epithelial permeability by benzalkonium chloride in UVA/Riboflavin corneal collagen cross-linking,” Current Eye Research, vol. 35, no. 8, pp. 715–721, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  90. A. Leccisotti and T. Islam, “Transepithelial corneal collagen cross-linking in keratoconus,” Journal of Refractive Surgery, vol. 26, no. 12, pp. 942–948, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  91. M. Kohlhaas, E. Spoerl, A. Speck, T. Schilde, D. Sandner, and L. E. Pillunat, “A new treatment of keratectasia after LASIK with riboflavin/UVA light cross-linking,” Klinische Monatsblätter für Augenheilkunde, vol. 222, no. 5, pp. 430–436, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  92. F. Hafezi, J. Kanellopoulos, R. Wiltfang, and T. Seiler, “Corneal collagen crosslinking with riboflavin and ultraviolet A to treat induced keratectasia after laser in situ keratomileusis,” Journal of Cataract and Refractive Surgery, vol. 33, no. 12, pp. 2035–2040, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  93. P. Vinciguerra, F. I. Camesasca, E. Albè, and S. Trazza, “Corneal collagen cross-linking for ectasia after excimer laser refractive surgery: 1-year results,” Journal of Refractive Surgery, vol. 26, no. 7, pp. 486–497, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  94. G. D. Kymionis, D. M. Portaliou, V. F. Diakonis et al., “Management of post laser in situ Keratomileusis ectasia with simultaneous Topography Guided Photorefractive Keratectomy and Collagen Cross-Linking,” Open Ophthalmology Journal, vol. 5, pp. 11–13, 2011. View at Publisher · View at Google Scholar · View at PubMed
  95. L. Spadea, “Corneal collagen cross-linking with riboflavin and UVA irradiation in pellucid marginal degeneration,” Journal of Refractive Surgery, vol. 26, no. 5, pp. 375–377, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  96. G. D. Kymionis, A. E. Karavitaki, G. A. Kounis, D. M. Portaliou, S. H. Yoo, and I. G. Pallikaris, “Management of pellucid marginal corneal degeneration with simultaneous customized photorefractive keratectomy and collagen crosslinking,” Journal of Cataract and Refractive Surgery, vol. 35, no. 7, pp. 1298–1301, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  97. A. Stojanovic, J. Zhang, X. Chen, T. A. Nitter, S. Chen, and Q. Wang, “Topography-guided transepithelial surface ablation followed by corneal collagen cross-linking performed in a single combined procedure for the treatment of keratoconus and pellucid marginal degeneration,” Journal of Refractive Surgery, vol. 26, no. 2, pp. 145–152, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  98. S. A. Martins, J. C. Combs, G. Noguera et al., “Antimicrobial efficacy of riboflavin/UVA combination (365 nm) in vitro for bacterial and fungal isolates: a potential new treatment for infectious keratitis,” Investigative Ophthalmology and Visual Science, vol. 49, no. 8, pp. 3402–3408, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  99. A. Sauer, V. Letscher-Bru, C. Speeg-Schatz et al., “In vitro efficacy of antifungal treatment using riboflavin/UV-A (365 nm) combination and amphotericin B,” Investigative Ophthalmology and Visual Science, vol. 51, no. 8, pp. 3950–3953, 2010. View at Scopus
  100. H. P. Iseli, M. A. Thiel, F. Hafezi, J. Kampmeier, and T. Seiler, “Ultraviolet a/riboflavin corneal cross-linking for infectious keratitis associated with corneal melts,” Cornea, vol. 27, no. 5, pp. 590–594, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  101. K. Makdoumi, J. Mortensen, and S. Crafoord, “Infectious keratitis treated with corneal crosslinking,” Cornea, vol. 29, no. 12, pp. 1353–1358, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  102. T. M. Ferrari, M. Leozappa, M. Lorusso, E. Epifani, and L. M. Ferrari, “Escherichia coli keratitis treated with ultraviolet A/riboflavin corneal cross-linking: a case report,” European Journal of Ophthalmology, vol. 19, no. 2, pp. 295–297, 2009. View at Scopus
  103. G. Wollensak, H. Aurich, D. T. Pham, and C. Wirbelauer, “Hydration behavior of porcine cornea crosslinked with riboflavin and ultraviolet A,” Journal of Cataract and Refractive Surgery, vol. 33, no. 3, pp. 516–521, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  104. V. Kozobolis, G. Labiris, M. Gkika et al., “UV-A collagen cross-linking treatment of bullous keratopathy combined with corneal ulcer,” Cornea, vol. 29, no. 2, pp. 235–238, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  105. N. Ehlers, J. Hjortdal, K. Nielsen, and A. Søndergaard, “Riboflavin-UVA treatment in the management of edema and nonhealing ulcers of the cornea,” Journal of Refractive Surgery, vol. 25, no. 9, pp. S803–S806, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  106. M. M. V. Cordeiro Barbosa, J. B. Barbosa Jr., F. E. Hirai, and A. L. Hofling-Lima, “Effect of cross-linking on corneal thickness in patients with corneal edema,” Cornea, vol. 29, no. 6, pp. 613–617, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  107. G. Wollensak, H. Aurich, C. Wirbelauer, and D. T. Pham, “Potential use of riboflavin/UVA cross-linking in bullous keratopathy,” Ophthalmic Research, vol. 41, no. 2, pp. 114–117, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  108. F. Hafezi, P. Dejica, and F. Majo, “Modified corneal collagen crosslinking reduces corneal oedema and diurnal visual fluctuations in Fuchs dystrophy,” British Journal of Ophthalmology, vol. 94, no. 5, pp. 660–661, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  109. C. I. Herrmann, T. Hammer, and G. I. Duncker, “Hazeformation (corneal scarring) after cross-linking therapy in keratoconus,” Ophthalmologe, vol. 105, no. 5, pp. 485–487, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  110. C. Mazzotta, A. Balestrazzi, S. Baiocchi, C. Traversi, and A. Caporossi, “Stromal haze after combined riboflavin-UVA corneal collagen cross-linking in keratoconus: in vivo confocal microscopic evaluation,” Clinical and Experimental Ophthalmology, vol. 35, no. 6, pp. 580–582, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  111. F. Raiskup, A. Hoyer, and E. Spoerl, “Permanent corneal haze after riboflavin-UVA-induced cross-linking in keratoconus,” Journal of Refractive Surgery, vol. 25, no. 9, pp. S824–S828, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  112. S. A. Greenstein, K. L. Fry, J. Bhatt, and P. S. Hersh, “Natural history of corneal haze after collagen crosslinking for keratoconus and corneal ectasia: scheimpflug and biomicroscopic analysis,” Journal of Cataract and Refractive Surgery, vol. 36, no. 12, pp. 2105–2114, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  113. L. S. Lim, R. Beuerman, L. Lim, and D. T. Tan, “Late-onset deep stromal scarring after riboflavin-UV-A corneal collagen cross-linking for mild keratoconus,” Archives of Ophthalmology, vol. 129, no. 3, pp. 360–362, 2011. View at Publisher · View at Google Scholar · View at PubMed
  114. G. D. Kymionis, D. M. Portaliou, V. F. Diakonis et al., “Posterior linear stromal haze formation after simultaneous photorefractive keratectomy followed by corneal collagen cross-linking,” Investigative Ophthalmology and Visual Science, vol. 51, no. 10, pp. 5030–5033, 2010. View at Scopus
  115. K. V. Zamora and J. J. Males, “Polymicrobial keratitis after a collagen cross-linking procedure with postoperative use of a contact lens: a case report,” Cornea, vol. 28, no. 4, pp. 474–476, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  116. M. Pollhammer and C. Cursiefen, “Bacterial keratitis early after corneal crosslinking with riboflavin and ultraviolet-A,” Journal of Cataract and Refractive Surgery, vol. 35, no. 3, pp. 588–589, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  117. S. Garcia-Delpech, M. Díaz-Llopis, P. Udaondo, and D. Salom, “Fusarium keratitis 3 weeks after healed corneal cross-linking,” Journal of Refractive Surgery, vol. 26, no. 12, pp. 994–995, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  118. C. Koppen, J. C. Vryghem, L. Gobin, and M. J. Tassignon, “Keratitis and corneal scarring after UVA/riboflavin cross-linking for keratoconus,” Journal of Refractive Surgery, vol. 25, no. 9, pp. S819–S823, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  119. P. Rama, F. di Matteo, S. Matuska, G. Paganoni, and A. Spinelli, “Acanthamoeba keratitis with perforation after corneal crosslinking and bandage contact lens use,” Journal of Cataract and Refractive Surgery, vol. 35, no. 4, pp. 788–791, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  120. G. D. Kymionis, D. M. Portaliou, D. I. Bouzoukis et al., “Herpetic keratitis with iritis after corneal crosslinking with riboflavin and ultraviolet A for keratoconus,” Journal of Cataract and Refractive Surgery, vol. 33, no. 11, pp. 1982–1984, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  121. G. D. Kymionis, D. I. Bouzoukis, V. F. Diakonis, D. M. Portaliou, A. I. Pallikaris, and S. H. Yoo, “Diffuse lamellar keratitis after corneal crosslinking in a patient with post-laser in situ keratomileusis corneal ectasia,” Journal of Cataract and Refractive Surgery, vol. 33, no. 12, pp. 2135–2137, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  122. P. Rodríguez-Ausín, R. Gutiérrez-Ortega, A. Arance-Gil, M. Romero-Jimenez, and G. Fuentes-Páez, “Keratopathy after cross-linking for keratoconus,” Cornea, vol. 30, no. 9, pp. 1051–1053, 2011. View at Publisher · View at Google Scholar · View at PubMed