Abstract
PurposeTo determine the effect of Ultraviolet-A collagen cross-linking with hypo-osmolar and iso-osmolar riboflavin solutions on stromal collagen ultrastructure in normal and keratoconus ex vivo human corneas.MethodsUsing small-angle X-ray scattering, measurements of collagen D-periodicity, fibril diameter and interfibrillar spacing were made at 1 mm intervals across six normal post-mortem corneas (two above physiological hydration (swollen) and four below (unswollen)) and two post-transplant keratoconus corneal buttons (one swollen; one unswollen), before and after hypo-osmolar cross-linking. The same parameters were measured in three other unswollen normal corneas before and after iso-osmolar cross-linking and in three pairs of swollen normal corneas, in which only the left was cross-linked (with iso-osmolar riboflavin).ResultsHypo-osmolar cross-linking resulted in an increase in corneal hydration in all corneas. In the keratoconus corneas and unswollen normal corneas, this was accompanied by an increase in collagen interfibrillar spacing (p<0.001); an increase in fibril diameter was also seen in two out of four unswollen normal corneas and one unswollen keratoconus cornea (p<0.001). Iso-osmolar cross-linking resulted in a decrease in tissue hydration in the swollen normal corneas only. Although there was no consistent treatment-induced change in hydration in the unswollen normal samples, iso-osmolar cross-linking of these corneas did result in a compaction of collagen fibrils and a reduced fibril diameter (p<0.001); these changes were not seen in the swollen normal corneas. Collagen D-periodicity was not affected by either treatment.ConclusionThe observed structural changes following Ultraviolet-A cross-linking with hypo-osmolar or iso-osmolar riboflavin solutions are more likely a consequence of treatment-induced changes in tissue hydration rather than cross-linking.
Highlights
Corneal collagen cross-linking therapy is a technique that uses a combination of riboflavin and ultraviolet-A light (UVA) to induce cross-linking in stromal collagen and thereby treat corneal ectasia occurring in keratoconus [1,2,3] or following laser refractive surgery [4,5,6]
A recent modification to the technique in which the standard isoosmolar riboflavin solution is substituted with a hypo-osmolar riboflavin solution to induce stromal swelling and increase stromal thickness prior to crosslinking, has enabled the treatment to be performed on very thin keratoconus corneas (,400 mm) that would not have previously been eligible for riboflavin/UVA treatment [12]
Tissue hydration increased in both keratoconus corneas following hypo-osmolar riboflavin/UVA cross-linking. This was accompanied by an increase in collagen interfibrillar spacing (p,0.001) (Figure 1)
Summary
Corneal collagen cross-linking therapy is a technique that uses a combination of riboflavin (vitamin B2) and ultraviolet-A light (UVA) to induce cross-linking in stromal collagen and thereby treat corneal ectasia occurring in keratoconus [1,2,3] or following laser refractive surgery [4,5,6]. The subsequent exposure of the cornea to UVA light is thought to result in photodynamic cross-linking when the riboflavin, excited by UVA, creates free radicals leading to cross-linking of collagen [11]. Until recently, this treatment was deemed unsuitable for corneas with a stromal thickness of less than 400 mm due to the potential for damage to the endothelium and deeper ocular structures [11]. A recent modification to the technique in which the standard isoosmolar riboflavin solution (containing dextran) is substituted with a hypo-osmolar riboflavin solution (without dextran) to induce stromal swelling and increase stromal thickness prior to crosslinking, has enabled the treatment to be performed on very thin keratoconus corneas (,400 mm) that would not have previously been eligible for riboflavin/UVA treatment [12]
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