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Improved biomechanical stiffening in iontophoresis-assisted transepithelial cross-linking in ex vivo porcine corneas

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Session Details

Session Title: Presented Poster Session: Cornea IV

Venue: Poster Village: Pod 3

First Author: : E.Torres Netto SWITZERLAND

Co Author(s): :    S. Kling   F. Hafezi           

Abstract Details


Transepithelial corneal cross-linking (CXL) has been proposed as a technique to reduce the postoperative time to healing and the risk of corneal infection, but has shown rather disappointing clinical results. This might be due to 1) insufficient riboflavin penetration and 2) insufficient oxygen diffusion. Iontophoresis-assisted transepithelial CXL (I-CXL) may help to improve riboflavin diffusion into the stroma, but does not influence the speed of oxygen diffusion. The latter might be influenced by slowing the CXL irradiation settings, so that sufficient amounts of oxygen can re-diffuse and maintain the cross-linking process. We tested this hypothesis in ex vivo porcine corneas.


Experiments were conducted at the Center for Applied Biotechnology and Molecular Medicine at the University of Zurich, Switzerland.


112 porcine corneas with intact epithelium were obtained from the local slaughterhouse, divided into 7 groups and analyzed. Groups 1, 2 and 3 had epi-off CXL with hypoosmolaric 0.1% riboflavin and 30 minutes at 3 mW/cm2, 10 minutes at 9 mW/cm2, or were not irradiated (control). Groups 4, 5, 6 and 7 had iontophoresis-assisted (Ricrolin®+, Sooft, Italy) transepithelial cross-linking for either 60 minutes at 1.5 mW/cm2, 30 minutes at 3 mW/cm2, 10 minutes at 9 mW/cm2, or were not irradiated (control). Young's modulus and stress after relaxation of 5-mm wide corneal strips were analyzed as an indicator of corneal stiffness.


Among the groups that had I-CXL, stress differences at the end of the relaxation curve were observed between 9mW/cm2 for 10 minutes and 1.5mW/cm2 for 60 minutes (p=0.03), with the latter presenting greater stiffening. Stress was also significantly increased in both conditions submitted to CXL with epithelial removal: 3mW/cm2 for 30 minutes (p<0.001) and 9mW/cm2 for 10 minutes (p=0.03). Young's modulus at 10% strain showed only significant differences between some groups of epithelium-off (CXL): control and both 3mW/cm2 for 30 minutes (p=0.02) and 9mW/cm2 for 10 minutes (p = 0.01).


The biomechanical effect of I-CXL increased significantly when using a low irradiance/long irradiation time setting, doubling the time of the Dresden protocol. Oxygen plays a key role in CXL. In addition to the barrier effect on diffusion, the epithelium has a high rate of oxygen consumption, further restricting stromal oxygen availability in the I-CXL protocols. In conclusion, oxygen diffusion remains a limiting factor even when the issue of riboflavin penetration is addressed in I-CXL. Although clinically rapid protocols are desired, longer irradiation times - even slower than the Dresden protocol – might be needed in order to increase I-CXL efficiency.

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