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Corneal Cross-Linking

The Science Beyond the Myths and Misconceptions

Rubinfeld, Roy S., MD, MA*,†; Caruso, Ciro, MD; Ostacolo, Carmine, PharmD§

doi: 10.1097/ICO.0000000000001912

Purpose: There has been a recent explosion in the variety of techniques used to accomplish corneal cross-linking (CXL) for the treatment of ectatic corneal diseases. To understand the success or failure of various techniques, we review the physicochemical basis of corneal CXL and re-evaluate the current principles and long-standing conventional wisdom in the light of recent, compelling, and sometimes contradictory research.

Methods: Two clinicians and a medicinal chemist developed a list of current key topics, controversies, and questions in the field of corneal CXL based on information from current literature, medical conferences, and discussions with international practitioners of CXL.

Results: Standard corneal CXL with removal of the corneal epithelium is a safe and efficacious procedure for the treatment of corneal ectasias. However, the necessity of epithelium removal is painful for patients, involves risk and requires significant recovery time. Attempts to move to transepithelial corneal CXL have been hindered by the lack of a coherent understanding of the physicochemistry of corneal CXL. Misconceptions about the applicability of the Bunsen–Roscoe law of reciprocity and the Lambert–Beer law in CXL hamper the ability to predict the effect of ultraviolet A energy during CXL. Improved understanding of CXL may also expand the treatment group for corneal ectasia to those with thinner corneas. Finally, it is essential to understand the role of oxygen in successful CXL.

Conclusions: Improved understanding of the complex interactions of riboflavin, ultraviolet A energy and oxygen in corneal CXL may provide a successful route to transepithelial corneal CXL.

*Department of Ophthalmology, Georgetown University Medical Center/Washington Hospital Center, Washington, DC;

Re:Vision Private Practice, Rockville, MD;

Corneal Transplant Centre, Pellegrini Hospital, Naples, Italy; and

§Department of Pharmacy, University Federico II of Naples, Naples, Italy.

Correspondence: Roy S. Rubinfeld, MD, MA, Re:Vision, 11200 Rockville Pike, Suite 150, Rockville, MD 20852 (e-mail:

R.S. Rubinfeld has a financial interest with CXL Ophthalmics (Encinitas, CA). Drs. Rubinfeld and Caruso have separate and competing patents related to transepithelial crosslinking. The remaining author has no funding or conflicts of interest to disclose

Received July 27, 2018

Received in revised form January 11, 2019

Accepted January 12, 2019

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