Timeline for corneal crosslinking procedures for keratoconus: A review

Abstract

Background: In 1998, corneal crosslinking (CXL) was introduced in animals to halt the progression of keratoconus (KC) and other corneal ectatic disorders by strengthening the cornea.
Aim: The article presents a review of CXL and its evolution over the last 27 years. The article reviews epithelium-on (epi-on) and epithelium-off (epi-off) methods of CXL.
Method: A literature search was conducted in bibliographic databases, including PubMed, ScienceDirect, Scopus, ResearchGate and Google Scholar, to identify peer-reviewed publications relevant to CXL. The search incorporated key terms including ‘keratoconus’, ‘corneal crosslinking’, and ‘cornea’.
Results: A total of 142 records were initially identified across Google Scholar, PubMed, ScienceDirect, Scopus and ResearchGate. After removal of 46 duplicates, 96 titles and abstracts remained for screening. Of these, 37 papers were excluded because they were unrelated to CXL, not available in English or contained incomplete methodological data. Ultimately, 57 publications met the inclusion criteria and were analysed qualitatively in this review.
Conclusion: In the management of KC and corneal ectasia, CXL has emerged as a transformative advancement, shifting care from predominantly rehabilitative strategies to proactive biomechanical stabilisation. Accelerated, transepithelial, thin cornea and combination approaches evolved over time- yet the Dresden protocol remains the benchmark for efficacy and long term stability.
Contribution: This review synthesises published evidence on the development of crosslinking over the past 27 years and describes the evolution of major treatment protocols, including epi-off, epi-on, iontophoresis-assisted, accelerated and thin-cornea techniques. By summarising reported efficacy, safety profiles and clinical considerations, the review provides an overview of how crosslinking approaches have developed and their role in the management of KC and related corneal ectatic disorders.