Transepithelial Iontophoresis Corneal Collagen Cross-linking for Progressive Keratoconus: Initial Clinical Outcomes

Vinciguerra, Paolo; Randleman, J. Bradley; Romano, Vito; Legrottaglie, Emanuela Filomena; Rosetta, Pietro; Camesasca, Fabrizio I.; Piscopo, Raffaele; Azzolini, Claudio; Vinciguerra, Riccardo

doi:10.3928/1081597x-20141021-06

Cited by 104 publications

(80 citation statements)

References 23 publications

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“…For iontophoresis, up to 15-month followup data have been published, with reported cessation of disease progression and improvements in keratometric and visual parameters. [7][8][9] The longer-term relative efficacy of all these transepithelial techniques compared to epithelium-off CXL remains unknown.…”

Section: Discussionmentioning

confidence: 99%

“…Another method involves iontophoresis, in which negatively charged riboflavin is driven through the epithelium down an electrical gradient. [7][8][9] Previous studies to quantify riboflavin penetration through an intact epithelium have used high-performance liquid chromatography (HPLC) [10][11][12] and fluorescence microscopy. [13][14][15][16][17] High-performance liquid chromatography, in which the sample is dissolved in a solvent for analysis, can accurately quantify the concentration of riboflavin in a whole block of tissue, but is unable to provide information about the concentration at different depths within the corneal stroma (unless lamella sections are prepared and separately dissolved).…”

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confidence: 99%

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Transepithelial Riboflavin Absorption in an Ex Vivo Rabbit Corneal Model

Gore

O’Brart

French

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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Citation: Gore DM, O'Brart D, French P, Dunsby C, Allan BD. Transepithelial riboflavin absorption in an ex vivo rabbit corneal model. Invest Ophthalmol Vis Sci. 2015;56:5006-5011. DOI:10.1167/iovs.15-16903 PURPOSE. To measure depth-specific riboflavin concentrations in corneal stroma using twophoton fluorescence microscopy and compare commercially available transepithelial corneal collagen cross-linking (CXL) protocols. METHODS.Transepithelial CXL riboflavin preparations-MedioCross TE, Ribocross TE, Paracel plus VibeX Xtra, and iontophoresis with Ricrolinþ-were applied to the corneal surface of fresh postmortem rabbit eyes in accordance with manufacturers' recommendations for clinical use. Riboflavin 0.1% (VibeX Rapid) was applied after corneal epithelial debridement as a positive control. After riboflavin application, eyes were snap frozen in liquid nitrogen. Corneal cross sections 35-lm thick were cut on a cryostat, mounted on a slide, and imaged by two-photon fluorescence microscopy. Mean (SD) concentrations were calculated from five globes tested for each protocol.RESULTS. Peak riboflavin concentration of 0.09% (60.01) was observed within the most superficial stroma (stromal depth 0-10 lm) in positive controls (epithelium-off). At the same depth, peak stromal riboflavin concentrations for MedioCross TE, Ricrolinþ, Paracel/Xtra, and Ribocross TE were 0.054% (60.01), 0.031% (0.003), 0.021% (60.001), and 0.015% (60.004), respectively. At a depth of 300 lm (within the demarcation zone commonly seen after corneal cross-linking), the stromal concentration in epithelium-off positive controls was 0.075% (60.006), while at the same depth MedioCross TE and Ricrolinþ achieved 0.018% (60.006) and 0.016% (0.002), respectively. None of the remaining transepithelial protocols achieved concentrations above 0.005% at this same 300-lm depth. Overall, MedioCross TE was the best-performing transepithelial formulation.CONCLUSIONS. Corneal epithelium is a significant barrier to riboflavin absorption into the stroma. Existing commercial transepithelial CXL protocols achieve relatively low riboflavin concentrations in the anterior corneal stroma when compared to gold standard epithelium-off absorption. Reduced stromal riboflavin concentration may compromise the efficacy of riboflavin/ultraviolet corneal CXL.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Transepithelial Riboflavin Absorption in an Ex Vivo Rabbit Corneal Model

Gore

O’Brart

French

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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“…Preliminary clinical studies have also been encouraging, with reported cessation of disease progression with up to 15 months follow-up and improvements in keratometric and visual parameters. [24][25][26] However, the relative efficacy of this technique compared to epithelium-off CXL remains to be determined especially over longer-term follow-up, and current randomized prospective studies comparing the two techniques (clinicaltrials.gov.uk NCT02117999, NCT01868620, ISRCT 04451470) have yet to be reported. * Unpaired Student's t-test comparing riboflavin concentration versus control at a depth of 300 lm (depth chosen to correlate with demarcation zone commonly seen after corneal cross-linking).…”

Section: Discussionmentioning

confidence: 99%

“…[19][20][21][22][23] Initial clinical studies report improvements in keratometric and visual parameters. [24][25][26] Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc. iovs.arvojournals.org j ISSN: 1552-5783…”

Section: Methodsmentioning

confidence: 99%

A Comparison of Different Corneal Iontophoresis Protocols for Promoting Transepithelial Riboflavin Penetration

Gore

O’Brart

French

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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Citation: Gore DM, O'Brart DP, French P, Dunsby C, Allan BD. A comparison of different corneal iontophoresis protocols for promoting transepithelial riboflavin penetration. Invest Ophthalmol Vis Sci. 2015;56:7908-7914. DOI:10.1167/iovs.15-17569 PURPOSE. To measure corneal riboflavin penetration using different transepithelial iontophoresis protocols. METHODS.Freshly enucleated rabbit eyes were divided into nine treatment groups of 4 eyes. One group, in which 0.1% wt/vol riboflavin was applied for 30 minutes without iontophoresis after corneal epithelial debridement, acted as a control. The remaining groups were treated with an intact epithelium using different riboflavin formulations and varying iontophoresis current, soak, and rinse times. After riboflavin application, eyes were snap frozen in liquid nitrogen. Corneal cross sections 35 lm thick were then imaged immediately by two-photon fluorescence microscopy, using image processing software to quantify stromal riboflavin concentration at different corneal depths.RESULTS. In the epithelium-on iontophoresis treatment groups, greater stromal riboflavin penetration was achieved with higher-concentration riboflavin solutions, greater iontophoresis dosage, and longer solution contact times. A protocol utilizing 0.25% wt/vol riboflavin with benzalkonium chloride (BAC) 0.01% and two cycles of applied current and subsequent soaking (1 mA 5 minutes, soak 5 minutes; 0.5 mA 5 minutes, soak 5 minutes) achieved similar stromal riboflavin penetration to epithelium-off controls. The best-performing non-BACcontaining protocol produced stromal riboflavin penetration approximately 60% that of epithelium-off controls. Riboflavin solutions containing saline resulted in minimal stromal penetration. Riboflavin loading within the epithelium was equivalent to or higher than that in the subjacent stroma, despite rinsing the ocular surface with balanced salt solution.CONCLUSIONS. Modified iontophoresis protocols can significantly improve transepithelial riboflavin penetration in experimental corneal collagen cross-linking.

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“…However, corneas without the epithelium seem to benefit more compared to corneas with it [22][23][24]. Noticeably better results were obtained with epi-on CXL using iontophoresis, but the relative efficacy of that technique compared to standard epithelium-off CXL still remains to be determined [25].…”

Section: Keratoconus -Disease and Therapymentioning

confidence: 99%

Corneal Cross-Linking: An Example of Photoinduced Polymerization as a Treatment Modality in Keratoconus

Kubrak-Kisza¹,

Kisza²,

Misiuk-Hojło³

2016

Polim. Med.

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The cornea is one of the principal refractive elements in the human eye and plays a crucial role in the process of vision. Keratoconus is the most common corneal dystrophy, found mostly among young adults. It is characterized by a reduced number of collagen cross-links in the corneal stroma, resulting in reduced biomechanical stability and an abnormal shape of the cornea. These changes lead to progressive myopia, corneal thinning, central scarring and irregular astigmatism, causing severely impaired vision. Hard contact lenses, photorefractive keratectomy or intracorneal rings are the most common treatment options for refractive error caused by keratoconus. However, these techniques do not treat the underlying cause of the corneal ectasia and therefore are not able to stop the progression of the disease. Riboflavin photoinduced polymerization of corneal collagen, also known as corneal cross-linking (CXL), has been introduced as the first therapy which, by stabilizing the structure of the cornea, prevents the progression of keratoconus. It stiffens the cornea using the photo-sensitizer riboflavin in combination with ultraviolet irradiation. This is a current review of the CXL procedure as a therapy for keratoconus, which relies on photoinduced polymerization of human tissue. We have focused on its biomechanical and physiological influences on the human cornea and have reviewed the previous and current biochemical theories behind cross-linking reactions in the cornea (Polim. Med. 2016, 46, 1, 89-94).

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Transepithelial Iontophoresis Corneal Collagen Cross-linking for Progressive Keratoconus: Initial Clinical Outcomes

Cited by 104 publications

References 23 publications

Transepithelial Riboflavin Absorption in an Ex Vivo Rabbit Corneal Model

Transepithelial Riboflavin Absorption in an Ex Vivo Rabbit Corneal Model

A Comparison of Different Corneal Iontophoresis Protocols for Promoting Transepithelial Riboflavin Penetration

Corneal Cross-Linking: An Example of Photoinduced Polymerization as a Treatment Modality in Keratoconus

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