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The Science and Clinical Evolution of Corneal Cross-Linking: Mechanism of Action, Ultra-Structural Changes, Clinical Indications, and Emerging Treatment Strategies.

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Related Experiment Video

Updated: May 12, 2026

Three Different Protocols of Corneal Collagen Crosslinking in Keratoconus: Conventional, Accelerated and Iontophoresis
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Corneal cross-linking.

Farhad Hafezi1, Sabine Kling2, Nikki L Hafezi3

  • 1ELZA Institute, Webereistrasse 2, CH-8953, Dietikon, Switzerland; Laboratory for Ocular Cell Biology, University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland; Faculty of Medicine, University of Geneva, Rue Michel-Servet 1, CH-1206, Geneva, Switzerland; Department of Ophthalmology, University of Wenzhou, Ouhai District, Wenzhou, 325015, China; Department of Ophthalmology, NYU Grossman School of Medicine, 550 1st Avenue, New York, NY, 10016, United States; National Eye Institute of Uzbekistan, Tashkent, Uzbekistan.

Progress in Retinal and Eye Research
|December 16, 2024
PubMed
Summary
This summary is machine-generated.

Corneal cross-linking (CXL) has evolved from the original Dresden protocol to accelerated methods, improving efficiency and expanding applications beyond keratoconus to include infectious keratitis and vision enhancement. These advancements offer safer, faster treatments for various eye conditions.

Keywords:
CXLCorneal biomechanicsCorneal cross-linkingCorneal ectasiaEpithelium-off CXLEpithelium-on CXLGreen lightInfectious keratitisKeratoconusPACK-CXLRiboflavinRose bengalUltraviolet-A

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Area of Science:

  • Ophthalmology
  • Biomedical Engineering
  • Photochemistry

Background:

  • The original Dresden protocol for corneal cross-linking (CXL) stiffens the cornea to treat progressive keratoconus but requires epithelial debridement and a minimum corneal thickness.
  • Limitations of the Dresden protocol include procedure duration, need for epithelial removal, and thickness restrictions, driving the development of improved CXL techniques.
  • Corneal cross-linking generates reactive oxygen species (ROS) to strengthen stromal molecules, counteracting ectasia-induced weakening.

Purpose of the Study:

  • To review advancements in corneal cross-linking (CXL) that have led to shorter, safer, and more versatile procedures.
  • To explore the expanded applications of CXL beyond corneal ectasia, including infectious keratitis and vision correction.
  • To discuss the scientific discoveries enabling improved CXL protocols and their clinical impact.

Main Methods:

  • Review of scientific literature on corneal cross-linking (CXL) advancements.
  • Analysis of photochemical reactions and the role of oxygen in CXL efficacy.
  • Comparison of different CXL protocols, including accelerated methods and PACK-CXL (photoactivated chromophore for keratitis-CXL).

Main Results:

  • Accelerated CXL protocols significantly shorten procedure time, enhance clinical workflow, and improve patient compliance while maintaining efficacy and safety.
  • CXL applications have expanded to treat corneal neovascularization, sterile melting, dry eye, and infectious keratitis (PACK-CXL).
  • PACK-CXL utilizes ROS for pathogen killing and cross-linking for protease resistance, with variations using different chromophores and light sources.
  • Combining CXL with excimer ablation improves visual acuity and may reduce the need for corneal transplantation.

Conclusions:

  • Modern CXL techniques offer significant improvements over the original Dresden protocol, providing faster, less invasive, and broader therapeutic options.
  • Corneal cross-linking is a versatile treatment that modulates corneal physiology and biochemistry, addressing a range of ocular conditions.
  • Future directions include combining CXL with refractive surgery for enhanced visual outcomes and potentially eliminating the need for corneal transplants.