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C-EYE PROTOCOLS

Integrated Protocols

C-eye offers a variety of pre-programmed CXL protocols – both epi-on and epi-off – as well as PACK-CXL protocols for your convenience.

Please find below a summary of the recommendations and uses of corneal cross-linking settings displayed in the scientific literature.

Protocols

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Dresden Protocol

  • The so-called “Dresden protocol” is the original epi-off CXL protocol that started corneal cross-linking in 1999.
  • As of 2020, the Dresden protocol remains the benchmark for achieving the highest biomechanical stiffness in CXL.
  • This protocol is primarily used when the strongest biomechanical effect is required, including for the following indications:
    • Aggressive progression of keratoconus
    • Keratoconus in children and adolescents
    • Pellucid marginal degeneration
    • Ectasia after LASIK/PRK/SMILE
    • Bullous keratopathy
    • Sterile corneal melting
How to apply "Ribo-Ker” riboflavin?

How often?

Every 2 minutes, 2-3 drops, over the entire cornea

How long in total?

For 10 minutes

  1. Wollensak G, Spoerl E, and Seiler T, Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol, 2003. 135(5): p. 620-7. Pubmed
  2. Wollensak G, Sporl E, Reber F, Pillunat L, and Funk R, Corneal endothelial cytotoxicity of riboflavin/UVA treatment in vitro. Ophthalmic Res, 2003. 35(6): p. 324-8. Pubmed
  3. Spoerl E, Wollensak G, and Seiler T, Increased resistance of crosslinked cornea against enzymatic digestion. Curr Eye Res, 2004. 29(1): p. 35-40. Pubmed
  4. Spoerl E, Mrochen M, Sliney D, Trokel S, and Seiler T, Safety of UVA-riboflavin cross-linking of the cornea. Cornea, 2007. 26(4): p. 385-9. Pubmed
  5. Mackool RJ, Crosslinking for iatrogenic keratectasia after LASIK and for keratoconus. Journal of cataract and refractive surgery, 2008. 34(6): p. 879; author reply 79. Pubmed
  6. Raiskup-Wolf F, Hoyer A, Spoerl E, and Pillunat LE, Collagen crosslinking with riboflavin and ultraviolet-A light in keratoconus: long-term results. J Cataract Refract Surg, 2008. 34(5): p. 796-801. Pubmed
  7. Koller T, Mrochen M, and Seiler T, Complication and failure rates after corneal crosslinking. J Cataract Refract Surg, 2009. 35(8): p. 1358-62. Pubmed
  8. Caporossi A, Mazzotta C, Baiocchi S, Caporossi T, Denaro R, and Balestrazzi A, Riboflavin-UVA-induced corneal collagen cross-linking in pediatric patients. Cornea, 2012. 31(3): p. 227-31. Pubmed
  9. Chatzis N and Hafezi F, Progression of Keratoconus and Efficacy of Corneal Collagen Cross-linking in Children and Adolescents. J Refract Surg, 2012. 28(11): p. 753-8. PDF
  10. Raiskup F and Spoerl E, Corneal crosslinking with riboflavin and ultraviolet A. I. Principles. Ocul Surf, 2013. 11(2): p. 65-74. Pubmed
  11. Raiskup F, Theuring A, Pillunat LE, and Spoerl E, Corneal collagen crosslinking with riboflavin and ultraviolet-A light in progressive keratoconus: ten-year results. J Cataract Refract Surg, 2015. 41(1): p. 41-6. Pubmed
  12. Khairy HA, Elsawy MF, Said-Ahmed K, Zaki MA, and Mandour SS, Accelerated versus standard corneal cross linking in the treatment of ectasia post refractive surgery and penetrating keratoplasty: a medium term randomized trial. Int J Ophthalmol, 2019. 12(11): p. 1714-1719. Pubmed
  13. Lang PZ, Hafezi NL, Khandelwal SS, Torres-Netto EA, Hafezi F, and Randleman JB, Comparative Functional Outcomes After Corneal Crosslinking Using Standard, Accelerated, and Accelerated With Higher Total Fluence Protocols. Cornea, 2019. 38(4): p. 433-441. Pubmed

A-CXL 10 min

  • Also called “A-CXL”, this accelerated epi-off CXL protocol uses a 10-minute irradiation time at an intensity of 9 mW/cm2, resulting in a standard fluence of 5.4 J/cm².
  • The protocol provides excellent long-term stability in clinical practice, even though it is less biomechanically stable than the Dresden and ELZA High-Fluence protocols in lab tests.
  • It is ideal for cases where maximum biomechanical strength isn’t needed
    • Moderately progressive keratoconus in adults
    • Pellucid marginal degeneration
How to apply "Ribo-Ker” riboflavin?

How often?

Every 2 minutes, 2-3 drops, over the entire cornea

How long in total?

For 10 minutes

  1. Richoz O, Hammer A, Tabibian D, Gatzioufas Z, and Hafezi F. The Biomechanical Effect of Corneal Collagen Cross-Linking (CXL) With Riboflavin and UV-A is Oxygen Dependent. Transl Vis Sci Technol. 2013. 2(7): 6 Pubmed
  2. Hammer A, Richoz O, Mosquera S, Tabibian D, Hoogewoud F, and Hafezi F. Corneal biomechanical properties at different corneal collagen cross-linking (CXL) Irradiances. Invest Ophthalmol Vis Sci. 2014. 55(5): 2881-4. Pubmed
  3. Kymionis GD, Tsoulnaras KI, Grentzelos MA, Plaka AD, Mikropoulos DG, Liakopoulos DA, Tsakalis NG, and Pallikaris IG. Corneal stroma demarcation line after standard and high-intensity collagen crosslinking determined with anterior segment optical coherence tomography. J Cataract Refract Surg. 2014. 40(5): 736-40. Pubmed
  4. Shetty R, Nagaraja H, Jayadev C, Pahuja NK, Kurian Kummelil M, and Nuijts RM. Accelerated corneal collagen cross-linking in pediatric patients: two-year follow-up results. Biomed Res Int. 2014. 2014: 894095. Pubmed
  5. Marino GK, Torricelli AA, Giacomin N, Santhiago MR, Espindola R, and Netto MV. Accelerated Corneal Collagen Cross-linking for Postoperative LASIK Ectasia: Two-Year Outcomes. J Refract Surg. 2015. 31(6): 380-4. Pubmed
  6. Pahuja N, Kumar NR, Francis M, Shanbagh S, Shetty R, Ghosh A, and Roy A. Correlation of Clinical and Biomechanical Outcomes of Accelerated Crosslinking (9 mW/cm in 10 minutes) in Keratoconus with Molecular Expression of Ectasia-Related Genes. Curr Eye Res. 2016. 41(11): 1419-23. Pubmed
  7. Hagem AM, Thorsrud A, Sandvik GF, Raen M, and Drolsum L. Collagen crosslinking with conventional and accelerated ultraviolet-A irradiation using riboflavin with hydroxypropyl methylcellulose. J Cataract Refract Surg. 2017. 43(4):  511-517. Pubmed
  8. Hashemi H, Asgari S, Mehravaran S, Miraftab M, Ghaffari R, and Fotouhi A. Corneal Biomechanics After Accelerated Cross-linking: Comparison Between 18 and 9 mW/cm2 Protocols. J Refract Surg. 2017. 33(8): 558-562. Pubmed
  9. Ulusoy DM, Goktas E, Duru N, Ozkose A, Atas M, Yuvaci I, Arifoglu HB, and Zararsiz G. Accelerated corneal crosslinking for treatment of progressive keratoconus in pediatric patients. Eur J Ophthalmol. 2017: 27(3): 319-25. Pubmed
  10. Lang PZ, Hafezi NL, Khandelwal SS, Torres-Netto EA, Hafezi F, Randleman JB. Comparative Functional Outcomes After Corneal Crosslinking Using Standard, Accelerated, and Accelerated With Higher Total Fluence Protocols. Cornea. 2019. 38(4):  433-41. Pubmed
  11. Akkaya S, Ulusoy DM, Duru Z, and Demirtas AA. Long-term Outcomes of Accelerated Corneal Cross-linking in the Treatment of Keratoconus: Comparison of Hypotonic Riboflavin Solution With Standard Riboflavin Solution. J Refract Surg. 2020. 36(2): 110-117. Pubmed
  12. Kobashi H and Tsubota K. Accelerated Versus Standard Corneal Cross-Linking for Progressive Keratoconus: A Meta-Analysis of Randomized Controlled Trials. Cornea. 2019. 39(2): 172-80. Pubmed
  13. Mazzotta C, Raiskup F, Hafezi F, Torres-Netto EA, Armia Balamoun A, Giannaccare G, Bagaglia SA. Long term results of accelerated 9 mW corneal crosslinking for early progressive keratoconus: the Siena Eye-Cross Study 2. Eye Vis (Lond). 2021. 8(1): 16. Pubmed

A-CXL 5 min

  • This accelerated epi-off CXL protocol uses a 5-minute irradiation time at 18 mW/cm², delivering a standard fluence of 5.4 J/cm². 
  • The protocol is most often used for the following indications:
    • Moderately progressive keratoconus in older adults
    • Slowly progressive early pellucid marginal degeneration
How to apply "Ribo-Ker” riboflavin?

How often?

Every 2 minutes, 2-3 drops, over the entire cornea

How long in total?

For 10 minutes

  1. Gatzioufas Z, Richoz O, Brugnoli E, and Hafezi F. Safety profile of high-fluence corneal collagen cross-linking for progressive keratoconus: preliminary results from a prospective cohort study. J Refract Surg. 2013. 29(12): 846-8. Pubmed
  2. Alnawaiseh M, Rosentreter A, Bohm MR, Eveslage M, Eter N, and Zumhagen L. Accelerated (18 mW/cm2) Corneal Collagen Cross-Linking for Progressive Keratoconus. Cornea, 2015. 34(11): 1427-31. Pubmed
  3. Hashemi H, Miraftab M, Seyedian MA, Hafezi F, Bahrmandy H, Heidarian S, Amanzadeh K, Nikbin H, Fotouhi A, Asgari S. Long-term Results of an Accelerated Corneal Cross-linking Protocol (18 mW/cm2) for the Treatment of Progressive Keratoconus. Am J Ophthalmol, 2015. 160(6): 1164-1170 e1. Pubmed
  4. Kymionis GD, Tsoulnaras KI, Liakopoulos DA, Skatharoudi CA, Grentzelos MA, Tsakalis NG. Corneal Stromal Demarcation Line Depth Following Standard and a Modified High Intensity Corneal Cross-linking Protocol. J Refract Surg, 2016. 32(4): 218-22. Pubmed
  5. Khairy HA, Elsawy MF, Said-Ahmed K, Zaki MA, Mandour SS. Accelerated versus standard corneal cross linking in the treatment of ectasia post refractive surgery and penetrating keratoplasty: a medium term randomized trial. Int J Ophthalmol, 2019. 12(11): 1714-19. Pubmed
  6. Agca A, Tulu B, Yasa D, Kepez Yildiz B, Sucu ME, Genc S, Fazil K, Yildirim Y. Accelerated corneal crosslinking in children with keratoconus: 5-year results and comparison of 2 protocols. J Cataract Refract Surg. 2020. 46(4): 517-23. Pubmed
  7. Kobashi H and Tsubota K. Accelerated Versus Standard Corneal Cross-Linking for Progressive Keratoconus: A Meta-Analysis of Randomized Controlled Trials. Cornea, 2019. 39(2): 172-80. Pubmed
  8. Ozulken K, Aksoy Aydemir G, Aydemir E, Kiziltoprak H, Yuksel E. Comparison of Two Different Accelerated Corneal Cross-linking Procedures Outcomes in Patients with Keratoconus. Balkan Med J, 2020. 37(3): 131-37. Pubmed

ELZA High-Fluence

  • This accelerated high-fluence epi-off CXL protocol was developed at the ELZA Institute in Zurich, Switzerland.
  • It uses a 9 min 15 sec irradiation time at 18 mW/cm², delivering a fluence of 10 J/cm².
  • This protocol is seen as a successor to the “Dresden protocol”, because it provides the same biomechanical stability in a fraction of the time.
  • A clinical study had been performed between 2021 and 2024 at the ELZA Institute, showing success rates similar to the Dresden protocol.

The protocol is most often used for the following indications:

  1. Whenever you would otherwise use the Dresden Protocol
    • Aggressive progression of keratoconus
    • Keratoconus in children and adolescents
    • Pellucid marginal degeneration
    • Ectasia after LASIK/PRK/SMILE
    • Bullous keratopathy
    • Sterile corneal melting
  2. Whenever you do not only want stability, but rather a distinct flattening effect
    • Moderately progressive keratoconus in adults
    • Pellucid marginal degeneration
  3. Sterile corneal melting
    • Provides a strong resistance to enzymatic digestion
How to apply "Ribo-Ker” riboflavin?

How often?

Every 2 minutes, 2-3 drops, over the entire cornea

How long in total?

For 10 minutes

  1. Hafezi NL, Aydemir ME, Lu NJ, Torres-Netto EA, Hillen M, Koppen C. Effect of accelerated high-fluence riboflavin and rose bengal-mediated corneal cross-linking on resistance to enzymatic digestion. BMC Ophthalmol. 2024. 24(1): 37. Pubmed, PDF.
  2. Hafezi NL, Aydemir ME, Lu NJ, Torres-Netto EA, Hillen M, Koppen C. The Resistance of Riboflavin/UV-A Corneal Cross-Linking to Enzymatic Digestion Is Oxygen-Independent. Cornea. 2024. 43(7): 895-98. Pubmed, Article.
  3. Aydemir ME, Hafezi NL, Lu NJ, Torres-Netto EA, Hillen M, Koppen C, Hafezi F. Combining Riboflavin/UV-A Light and Rose Bengal/Green Light Corneal Cross-Linking Increases the Resistance of Corneal Enzymatic Digestion. Transl Vis Sci Technol. 2024. 13(1): 30. Pubmed, PDF.
  4. Abrishamchi R, Abdshahzadeh H, Hillen M, Hafezi N, Torres-Netto EA, Aslanides IM, Chen S, Randleman JB, Hafezi F. High-Fluence Accelerated Epithelium-Off Corneal Cross-Linking Protocol Provides Dresden Protocol-Like Corneal Strengthening. Transl Vis Sci Technol. 2021. 10(5): 10. Pubmed, PDF.

ELZA sub400 2nd Gen

  • The «sub400» protocol has been developed to treat thin and ultrathin corneas between 200 µm and 400 µm of stromal thickness.
  • The first generation of the sub400 protocol has been published in the American Journal of Ophthalmology in 2021 and uses a starting fluence of 5.4 J/cm2 at 400 µm of thickness.
  • The 2nd generation sub400 protocol starts with a high fluence of 10 J/cm2 at 400 µm.
  • This protocol can be used for the following indications:
    • Keratoconus
    • Postoperative ectasia
    • PMD
    • Keratoglobus
    • Terrien Marginal Degeneration (TMD)
How to apply "Ribo-Ker” riboflavin?

How often?

Every 2 minutes, 2-3 drops, over the entire cornea

How long in total?

For 10 minutes

  1. Hafezi F, Gatzioufas Z, Seiler TG, Seiler T. Corneal collagen cross-linking for Terrien marginal degeneration. J Refract Surg. 2014. 30(7): 498-500. Pubmed.
  2. Richoz O, Tabibian D, Hammer A, Majo F, Nicolas M, Hafezi F. The effect of standard and high-fluence corneal cross-linking (CXL) on cornea and limbus. Invest Ophthalmol Vis Sci. 2014. 55(9): 5783-7. Pubmed.
  3. Kling S, Hafezi F. An Algorithm to Predict the Biomechanical Stiffening Effect in Corneal Cross-linking. J Refract Surg. 2017. 33(2): 128-36. Pubmed.
  4. Hafezi F, Kling S, Gilardoni F, Hafezi N, Hillen M, Abrishamchi R, Gomes JAP, Mazzotta C, Randleman JB, Torres-Netto EA. Individualized Corneal Cross-linking With Riboflavin and UV-A in Ultrathin Corneas: The Sub400 Protocol. Am J Ophthalmol. 2021. 224: 133-42. Pubmed.
  5. Alvarado-Villacorta R, Davila-Avila N, Hernandez-Quintela E. Comment on: Individualized Corneal Cross-linking With Riboflavin and UV-A in Ultrathin Corneas: The Sub400 Protocol. Am J Ophthalmol. 2022. 233: 243-45. Pubmed.
  6. Hafezi F, Kling S, Gilardoni F, Hafezi N, Hillen M, Abrishamchi R, Gomes JAP, Mazzotta C, Randleman JB, Torres-Netto EA. Reply to Comment on: Individualized Corneal Cross-Linking With Riboflavin and UV-A in Ultrathin Corneas: The Sub400 Protocol. Am J Ophthalmol. 2022. 233: 243-45. Pubmed.
  7. Polido J, Dos Xavier Santos Araujo ME, Alexander JG, Cabral T, Ambrosio R, Jr., Freitas D. Pediatric Crosslinking: Current Protocols and Approach. Ophthalmol Ther. 2022. 11(3): 983-99. Pubmed.
  8. Karaca EE, Asfuroglu Y, Ulusoy DM, Evren Kemer O. Evaluating the safety and effectiveness of the sub-400 corneal cross-linking protocol: initial clinical and morphological findings. Int Ophthalmol. 2024. 45(1): 16. Pubmed.

Open Mode

  • The open mode allows for any customized combination of intensity and irradiation time as long as the total fluence is not exceeding 10 J/cm2.
  • Background: besides the most established CXL protocols, there are other, less widespread protocols that require a different combination of intensity and irradiation time.
  • The surgeon will proceed at their own risk.
  • The mode of UV-A irradiation is continuous light.
How to apply "Ribo-Ker” riboflavin?

Depends on the protocol chosen

ELZA PACK-CXL 01 and 02

  • Accelerated high-fluence PACK-CXL protocol using 10 and 15 J/cm2
  • Recent evidence shows that
    • The corneal endothelium, even when perfectly transparent, can tolerate high fluences up to 15 J/cm² without damage (Seiler et al., 2019)
    • The opaque infected cornea transmits much less UV light than a transparent cornea, so the fluence arriving at the level of the endothelium is even further attenuated (Lu et al, 2024)
    • Higher fluences do not only kill more micro-organisms, they also increase the tissue’s resistance to digestion.
  • This protocol is currently most often used in:
    • Infectious keratitis of bacterial and fungal origin
    • Sterile corneal melting
How to apply "Ribo-Ker” riboflavin?

Perform gentle debridement of dead epithelium over the ulcer

How often?

Every 2 minutes, 2-3 drops, over the entire cornea

How long in total?

For 20 minutes

  1. Lu NJ, Meier P, Reina G, Aydemir ME, Eitner S, Koliwer-Brandl H, Egli A, Kissling V, Wick P, Hafezi F. Transmission Rates of UV-A and Green Light in an ex vivo Corneal Cross-linking Model for Infectious Keratitis. J Cataract Refract Surg. 2024
  2. Olshaker H, Achiron A, Chorny A, Hafezi F, Yahalomi T, Kratz A, Tsumi E, Lu NJ, Knyazer B. Accelerated high fluence photoactivated chromophore for infectious keratitis-corneal cross-linking (PACK-CXL) at the slit lamp: a pilot study. Front Pharmacol. 2023. 14: 1229095. Pubmed.
  3. Lu NJ, Koliwer-Brandl H, Hillen M, Egli A, Hafezi F. High-Fluence Accelerated PACK-CXL for Bacterial Keratitis Using Riboflavin/UV-A or Rose Bengal/Green in the Ex Vivo Porcine Cornea. Transl Vis Sci Technol. 2023. 12(9): 14. Pubmed.
  4. Lu NJ, Koliwer-Brandl H, Gilardoni F, Hafezi N, Knyazer B, Achiron A, Zbinden R, Egli A, Hafezi F. The Antibacterial Efficacy of High-Fluence PACK Cross-Linking Can Be Accelerated. Transl Vis Sci Technol. 2023. 12(2): 12. Pubmed.
  5. Hafezi F, Hosny M, Shetty R, Knyazer B, Chen S, Wang Q, Hashemi H, Torres-Netto EA, Group P-CW. PACK-CXL vs. antimicrobial therapy for bacterial, fungal, and mixed infectious keratitis: a prospective randomized phase 3 trial. Eye Vis (Lond). 2022. 9(1): 2. Pubmed.
  6. Achiron A, Elhaddad O, Regev T, Krakauer Y, Tsumi E, Hafezi F, Knyazer B. PACK Cross-Linking as Adjuvant Therapy Improves Clinical Outcomes in Culture-Confirmed Bacterial Keratitis. Cornea. 2022. 41(9): 1069-73. Pubmed.
  7. Li M, Yu T, Gao X, Wu XY. Accelerated corneal collagen cross-linking in clinical management of infectious keratitis. J Int Med Res. 2020. 48(6): 300060520926411. Pubmed.
  8. Knyazer B, Krakauer Y, Tailakh MA, Achiron A, Hecht I, Lifshitz T, Torres-Netto EA, Hafezi NL, Hafezi F. Accelerated Corneal Cross-linking as an Adjunct Therapy in the Management of Presumed Bacterial Keratitis: A Cohort Study. J Refract Surg. 2020. 36(4): 258-64. Pubmed.
  9. Kling S, Hufschmid FS, Torres-Netto EA, Randleman JB, Willcox M, Zbinden R, Hafezi F. High Fluence Increases the Antibacterial Efficacy of PACK Cross-Linking. Cornea. 2020. 39(8): 1020-26
  10. Seiler TG, Batista A, Frueh BE, Koenig K. Riboflavin Concentrations at the Endothelium During Corneal Cross-Linking in Humans. Invest Ophthalmol Vis Sci. 2019. 60(6): 2140-45. Pubmed.
  11. Knyazer B, Krakauer Y, Baumfeld Y, Lifshitz T, Kling S, Hafezi F. Accelerated Corneal Cross-Linking With Photoactivated Chromophore for Moderate Therapy-Resistant Infectious Keratitis. Cornea. 2018. 37(4): 528-31. Pubmed.
  12. Hafezi F. PACK-Cross-Linking bei infektiöser Keratitis. Der Augenspiegel. 2017. März: 50-52
  13. Tabibian D, Mazzotta C, Hafezi F. PACK-CXL: Corneal cross-linking in infectious keratitis. Eye Vis (Lond). 2016. 3: 11. Pubmed.
  14. Hafezi F, Kling S. Photoactivated Chromophore for Moderate to Severe Infectious Keratitis as an Adjunct Therapy: A Randomized Controlled Trial. Am J Ophthalmol. 2016. 168: 293-94. Pubmed.
  15. Gallhoefer NS, Spiess BM, Guscetti F, Hilbe M, Hartnack S, Hafezi F, Pot SA. Penetration depth of corneal cross-linking with riboflavin and UV-A (CXL) in horses and rabbits. Vet Ophthalmol. 2016. 19(4): 275-84. Pubmed.
  16. Tabibian D, Richoz O, Hafezi F. PACK-CXL: Corneal Cross-linking for Treatment of Infectious Keratitis. J Ophthalmic Vis Res. 2015. 10(1): 77-80. Pubmed.
  17. Tabibian D, Richoz O, Riat A, Schrenzel J, Hafezi F. Accelerated photoactivated chromophore for keratitis-corneal collagen cross-linking as a first-line and sole treatment in early fungal keratitis. J Refract Surg. 2014. 30(12): 855-7. Pubmed.
  18. Spiess BM, Pot SA, Florin M, Hafezi F. Corneal collagen cross-linking (CXL) for the treatment of melting keratitis in cats and dogs: a pilot study. Vet Ophthalmol. 2014. 17(1): 1-11. Pubmed.
  19. Said DG, Gatzioufas Z, Hafezi F. Author reply: To PMID 24576886. Ophthalmology. 2014. 121(12): e68. Pubmed.
  20. Said DG, Elalfy MS, Gatzioufas Z, El-Zakzouk ES, Hassan MA, Saif MY, Zaki AA, Dua HS, Hafezi F. Collagen cross-linking with photoactivated riboflavin (PACK-CXL) for the treatment of advanced infectious keratitis with corneal melting. Ophthalmology. 2014. 121(7): 1377-82. Pubmed.
  21. Richoz O, Kling S, Hoogewoud F, Hammer A, Tabibian D, Francois P, Schrenzel J, Hafezi F. Antibacterial efficacy of accelerated photoactivated chromophore for keratitis-corneal collagen cross-linking (PACK-CXL). J Refract Surg. 2014. 30(12): 850-4. Pubmed.
  22. Pot SA, Gallhofer NS, Matheis FL, Voelter-Ratson K, Hafezi F, Spiess BM. Corneal collagen cross-linking as treatment for infectious and noninfectious corneal melting in cats and dogs: results of a prospective, nonrandomized, controlled trial. Vet Ophthalmol. 2014. 17(4): 250-60. Pubmed.
  23. Hafezi F, Randleman JB. PACK-CXL: defining CXL for infectious keratitis. J Refract Surg. 2014. 30(7): 438-9. Pubmed.
  24. Richoz O, Gatzioufas Z, Hafezi F. Corneal Collagen Cross-Linking for the Treatment of Acanthamoeba Keratitis. Cornea. 2013. 32(10): e189. Pubmed.
  25. Iseli HP, Thiel MA, Hafezi F, Kampmeier J, Seiler T. Ultraviolet A/riboflavin corneal cross-linking for infectious keratitis associated with corneal melts. Cornea. 2008. 27(5): 590-4. Pubmed.

Xtra, Refractive 1 & 2

  • High-intensity low-fluence accelerated CXL protocols used in refractive surgery
  • A number of different irradiation protocols have been published. They all share a fluence that is distinctly lower than the 5.4 J/cm² standard fluence.
  • Indications include:
    • LASIK Xtra
    • SMILE Xtra
    • PRK Xtra
How to apply "Ribo-Ker” riboflavin?

How often?

Every 1 minute, 2-3 drops, over the entire cornea

How long in total?

For 5 minutes

  1. Kaiser KP, Biller ML, Jandewerth T, Davidova P, Hemkeppler E, Lwowski C, Bohm M, Kohnen T. Biomechanical corneal effects of LASIK Xtra compared with conventional FS-LASIK in high myopic eyes. J Cataract Refract Surg. 2025. 51(2): 106-12. Pubmed.
  2. Lu NJ, Hafezi F, Torres-Netto EA, Assaf JF, Aslanides IM, Awwad ST, Chen S, Cui LL, Koppen C. Effect of fluence levels on prophylactic corneal cross-linking for laser in situ keratomileusis and transepithelial photorefractive keratectomy. Acta Ophthalmol. 2023. 101(2): e185-e96. Pubmed.
  3. Dong R, Zhang Y, Yuan Y, Liu Y, Wang Y, Chen Y. A prospective randomized self-controlled study of LASIK combined with accelerated cross-linking for high myopia in Chinese: 24-month follow-up. BMC Ophthalmol. 2022. 22(1): 280. Pubmed.
  4. Kohnen T, Lwowski C, Hemkeppler E, de’Lorenzo N, Petermann K, Forster R, Herzog M, Bohm M. Comparison of Femto-LASIK With Combined Accelerated Cross-linking to Femto-LASIK in High Myopic Eyes: A Prospective Randomized Trial. Am J Ophthalmol. 2020. 211: 42-55. Pubmed.
  5. Osman IM, Helaly HA, Abou Shousha M, AbouSamra A, Ahmed I. Corneal Safety and Stability in Cases of Small Incision Lenticule Extraction with Collagen Cross-Linking (SMILE Xtra). J Ophthalmol. 2019. 2019: 6808062. Pubmed.
  6. Lim EWL, Lim L. Review of Laser Vision Correction (LASIK, PRK and SMILE) with Simultaneous Accelerated Corneal Crosslinking – Long-term Results. Curr Eye Res. 2019. 44(11): 1171-80. Pubmed.
  7. Randleman JB, Su JP, Scarcelli G. Biomechanical Changes After LASIK Flap Creation Combined With Rapid Cross-Linking Measured With Brillouin Microscopy. J Refract Surg. 2017. 33(6): 408-14. Pubmed.
  8. Ng AL, Kwok PS, Wu RT, Jhanji V, Woo VC, Chan TC. Comparison of the Demarcation Line on ASOCT After Simultaneous LASIK and Different Protocols of Accelerated Collagen Crosslinking: A Bilateral Eye Randomized Study. Cornea. 2017. 36(1): 74-77. Pubmed.
  9. Kanellopoulos AJ, Asimellis G, Salvador-Culla B, Chodosh J, Ciolino JB. High-irradiance CXL combined with myopic LASIK: flap and residual stroma biomechanical properties studied ex-vivo. Br J Ophthalmol. 2015. 99(6): 870-4. Pubmed.
  10. Ganesh S, Brar S. Clinical Outcomes of Small Incision Lenticule Extraction with Accelerated Cross-Linking (ReLEx SMILE Xtra) in Patients with Thin Corneas and Borderline Topography. J Ophthalmol. 2015. 2015: 263412. Pubmed.

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