Reevaluating the Effectiveness of Corneal Collagen Cross-linking and Its True Biomechanical Effect in Human Eyes

Abstract

The induction of cross-links in corneal tissue appears to be a promising technique to increase its stiffness and this has been the basis of treatment of keratoconus (KC) and corneal ectatic disease. However, there exists a striking discrepancy between the reported biomechanical effects of corneal collagen cross-linking (CXL) in vitro compared to in vivo, and this has not received much attention in the literature. Despite the documentation of an increase in corneal stiffness in vitro by many investigators, reports that provide evidence of measurable and consistent biomechanical changes in corneal rigidity in vivo after CXL are lacking. Indeed, the absence of documented in vivo biomechanical improvement in CXL-treated corneas is a conundrum, which needs to be further explored. To explain this discrepancy, it has been postulated that biomechanical changes induced by CXL are too subtle to be measured by currently available diagnostic tools or have characteristics not discernible by these technologies. However, the dynamic bidirectional applanation device (Ocular Response Analyzer) and dynamic Scheimpflug analyzer instruments (Corvis ST) have demonstrated the ability to quantify even subtle biomechanical differences in untreated KC corneas of different ectatic degree, and document the reduction in corneal hysteresis (CH) and corneal resistance factor (CRF) in situations where the corneal stiffness is reduced, such as after laser in situ keratomileusis and surface ablation procedures. It has also been possible to demonstrate an altered CH and CRF in patients with diabetes, smoking habit, glaucoma, Fuchs’ dystrophy, and corneal edema. It is puzzling that these diagnostic tools could document subtle biomechanical changes in these situations, yet fail to measure the purported changes induced by CXL on corneas with progressive KC. This failure to document significant and consistent biomechanical changes in corneal rigidity could suggest that CXL does not induce a simple reversal of the particular biomechanical deficits that characterize KC, or make the cornea significantly more resistant to bending forces as has been widely postulated. The absence of measurable biomechanical change in living KC corneas after CXL could be a consequence of biomechanical strengthening which is insignificant compared to the marked weakening caused by preexisting alteration of the collagen structure, disorganization of collagen fiber intertwining, and compromised structural–mechanical homogeneity that are hallmarks of keratoconic disease, especially in corneas with progressive KC. The changes in the cornea induced by CXL that have been described in vivo may instead be driven by a wound healing process in response to the removal of the corneal epithelial layer and subsequent exposure to riboflavin and ultraviolet-A (UVA). This paper will present evidence that sustains this hypothesis. How to cite this article Gatinel D. Reevaluating the Effect­iveness of Corneal Collagen Cross-linking and Its True Biomechanical Effect in Human Eyes. Int J Kerat Ect Cor Dis 2017;6(1):34-41.

Mechanical behaviour of healthy versus alkali-lesioned corneas by a porcine organ culture model

“…Despite evidences suggesting the beneficial effect of riboflavin/UV-A corneal phototherapy, different studies report contrasting outcomes [8,10,[20][21][22][23]. Due to this disagreement in the literature, further experimental data are necessary to understand the mechanical behaviour of corneal tissues and represent a prerequisite for the formulation and validation of constitutive models.…”

Effect of accelerated corneal crosslinking on ocular response analyzer waveform-derived parameters in progressive keratoconus

“…Thus, after corneal CXL, new covalent bonds form between collagen fibers (25) . In a review, Gatinel suggested that differences between these mechanisms may explain why the CRF and the CH are insufficient to detect biomechanical changes (26) . Accordingly, CXL treatment does not affect corneal biomechanics.…”