Swelling studies have shed light on the location of cross-links. In an\u00a0in vitro<\/i>\u00a0study, Wollensak et al<\/em>.\u00a0[2]<\/strong>\u00a0<\/strong>demonstrated that cross-linked pig corneas placed in a humidity chamber swell less than untreated corneas. However, the deturgescent agent dextran is normally included to limit swelling caused by the riboflavin, and it was not clear whether the altered swelling properties were caused by the presence of dextran within the cross-linked tissue or whether it was due to the cross-links themselves. In a more recent study in which corneal buttons were allowed to swell freely in saline solution (and consequently leach proteoglycans and riboflavin solution from the tissue), no difference was found in the swelling rate of riboflavin\/UVA treated, riboflavin-only treated, or untreated corneas [3]<\/strong>\u00a0suggesting the absence of significant collagen-proteoglycan cross-linking.<\/p>\n Hayes et al<\/em>.\u00a0[3]<\/strong> also showed that cross-linking does not increase the bulk separation between adjacent collagen molecules within fibrils. This, together with their swelling results, led the authors to conclude that cross-linking predominates within and between molecules on the fibril surfaces, and within proteoglycan core proteins in the interfibrillar space\u00a0[3]<\/strong>. If the latter is the case, it may be that the term \u201ccollagen cross-linking\u201d, so often used to describe cross-linking, is in fact an incomplete description of the mechanism.<\/p>\n
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