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Corneal cross-linking ready for modified, scientifically based approaches
The concept of corneal collagen cross-linking, or CXL, relies on the potential to induce morphological changes on the fibrils of the anterior stroma by a photochemical process. The interaction between UVA photons and the riboflavin molecules leads to the release of hyperactive free radicals, with the immediate effect of forming fiber-fiber and fiber-matrix bondings. The sustained effect is a substantial cellular remodeling due to the cytotoxicity of these radicals, the intensity of which decreases with depth and time. The effect must be mandatorily confined within the anterior stroma to avoid endothelial damage. A minimum of 400 µm of corneal thickness at the thinnest point is required for safety. This estimation does not consider epithelial hyperplasia, which can be detected only by high-resolution optical coherence tomography.
Experimental evidence has shown the effects of CXL in the corneal stroma. Collagen fibrils appear better organized (entropy gain), more wavy and thicker. Keratocyte density increases after cicatrization between 6 months and 12 months, indicating a certain degree of cell renewal. Finally, the stiffness of the anterior stroma is increased, as well as its resistance to hydration and enzymatic digestion.
The long-term stability of the stromal stiffening effect is poorly documented, due to the inadequate capabilities of the elastography systems currently available for clinical use. Cell renewal of the keratocytes and nerve plexus plays a role that has not been entirely clarified within this domain. Clinical studies have shown real benefits for patients despite the multifactorial interactions that make comparisons between patients and clinical studies very difficult and mainly related to epithelium removal.
The conventional technique of epithelium-off cross-linking (C-CXL), developed with the pioneering work of Spoerl, Wollensak and Seiler, is still the gold standard. However, after 10 years of experience and consistent results from clinical trials, the time has come to investigate possible variations of the parameters used in the initial protocol in order to optimize efficacy, increase safety beyond the 1% complication rate we have at present and, perhaps, broaden indications. We need, however, to be aware that modifications of the initial protocol require a clear understanding of the inner mechanisms of CXL.
For instance, if preserving the epithelium is the added value of transepithelial cross-linking (T-CXL), we must be aware that riboflavin penetration through the epithelium is limited, often unpredictable and inhomogeneous. Consequently, T-CXL inevitably raises the issue of riboflavin bioavailability, which is only partially overcome by the addition of chemical agents facilitating passage of riboflavin into the stroma or by iontophoresis. Another example is the application of the Bunsen-Roscoe law, according to which time and dose rate are reciprocal. This law should theoretically allow us to reduce the time of the procedure, maintaining the kinetics of the chemical reaction, with or without the use of a pulsed mode for the delivery of UVA.
Accelerated CXL (A-CXL) should theoretically achieve at least the same efficacy of C-CXL, with the advantage of making the procedure shorter and cutting down on intraoperative fluctuations of riboflavin bioavailability and corneal hydration. Strategies more specifically sensitive to riboflavin concentration, such as CXL combined with PRK or LASIK or topography-guided CXL, are particularly dependent on a shorter dose distribution.
Prospective, prolonged vigilance and monitoring of results are mandatory with every new technology. The secondary effects of CXL are not yet very well known. In particular, the impact of cross-linking on the penetration of eye drops needs further evaluation. We are also not yet sure about the long-term efficacy of CXL. Finally, refractive changes may occur in connection with the reorganization of collagen fibers, but they have not yet been studied extensively. This could lead us to develop strategies of refractive stromal remodeling by means of a customized CXL technique.
The initial relatively empiric approach is no doubt in the process of changing into a more scientific approach. A clearer understanding of the parameters of riboflavin bioavailability and time-space distribution of UVA doses are contributing in this sense. We are gradually progressing into an era of a more modern CXL, customized case by case, based on measurable results rather than on the individual clinician’s ability or on laborious longitudinal and multiparametric follow-ups.
Technological innovation certainly plays an important role in CXL. It helps us understand the link between clinical efficacy, biomechanical implications and cell renewal, which are the fundamentals of mastering CXL. New technologies for the monitoring of riboflavin bioavailability, fibrils and corneal stiffness will probably be crucial in making the next step forward.
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- David Touboul, MD, is an OSN Europe Edition Board Member and is in charge of the Centre National de Référence du Kératocône (CRNK) at the University of Bordeaux, France. He can be reached at CHU de Bordeaux, site Pellegrin, Centre François Xavier Michelet, place Amélie Raba-Léon Bordeaux, 33000 Bordeaux, France; email: david.touboul@chu-bordeaux.fr.
Disclosure: Touboul has no relevant financial disclosures.