Corneal Delivery of Cross-Linking Agents by Iontophoresis for the Treatment of Keratoconus and Related Ophthalmic Compositions (2025)

Evaluating In Vivo Delivery of Riboflavin With Coulomb-Controlled Iontophoresis for Corneal Collagen Cross-Linking: A Pilot Study

Investigative Ophthalmology & Visual Science, 2014

PURPOSE. To evaluate the efficacy of coulomb-controlled iontophoresis (CCI) for delivery of riboflavin prior to corneal collagen cross-linking (CXL). METHODS. The eyes of 20 8-week-old Lewis rats, subject to epithelium-ON (epi-ON, n ¼ 20 eyes) or epithelium-OFF (epi-OFF, n ¼ 20 eyes) conditions, were used to evaluate the in vivo delivery of two riboflavin solutions: 0.1% riboflavin-20% dextran T500 solution (riboflavindextran) and 0.1% riboflavin 5 0-phosphate (riboflavin-phosphate). After systemic intramuscular anesthesia, 0.25 mL of the photosensitizing agent was delivered by either instillation or CCI (2.11 mA/cm 2 for 4 or 10 minutes) into either epithelial condition. The CCI probe on the eye without current served as control. Confocal microscopy of flat-mounted corneas was used to analyze intracorneal penetration and fluorometry was used to quantify riboflavin in the aqueous within 30 minutes of treatment. RESULTS. Instillation and CCI allowed for uniform delivery of riboflavin-dextran throughout the stroma after epithelial debridement. Transepithelial delivery of riboflavin-dextran was not efficacious. Riboflavin-phosphate was successfully delivered in both epithelium conditions. Complete saturation of the cornea was achieved using CCI after removing the epithelium, the epi-ON case allowed for limited diffusion. Increasing the time from 4 to 10 minutes greatly increased the amount of riboflavin detected in the cornea and aqueous humor. CONCLUSIONS. Coulomb-controlled iontophoresis is an effective technique for transepithelial delivery of riboflavin-phosphate into the cornea. This drug delivery method would allow clinicians to significantly shorten the time required for the CXL procedure, with or without epithelial debridement. Whether efficient crosslinking can be achieved through an intact epithelium remains to be demonstrated.

Corneal Cross-linking: Intrastromal Riboflavin Concentration in Iontophoresis-Assisted Imbibition Versus Traditional and Transepithelial Techniques

American Journal of Ophthalmology, 2014

Corneal cross-linking: Intrastromal riboflavin concentration in iontophoresis-assisted imbibition versus traditional and transepithelial techniques Short Title: Corneal cross-linking: Intrastromal riboflavin concentration

Corneal Cross-linking can halt the Progression of Keratoconus, but what is the Best Approach to Treatment?

International Journal of Keratoconus and Ectatic Corneal Diseases, 2015

There are a number of treatment options for keratoconus, but only corneal collagen cross-linking (CXL) appears to halt the progression of the disease. To guarantee effective cross-linking, CXL treatment involves removal of the corneal epithelium prior to riboflavin application and ultraviolet light illumination to ensure that riboflavin reaches the collagen in the stroma—epithelial-on cross-linking (‘Epi-off’ CXL). Several methods of ‘Epi-on’ (transepithelial) CXL have been proposed, as keeping the corneal epithelium intact should be less painful and help avoid other CXL-associated adverse events. The evidence to date is that Epi-off CXL remains the most effective method of strengthening the cornea and slowing keratoconus progression—but transepithelial methods are gaining ground. How to cite this article Raiskup F, Hillen M. Corneal Crosslinking can halt the Progression of Keratoconus, but what is the Best Approach to Treatment? Int J Kerat Ect Cor Dis 2015; 4(2):47-51.

Evaluation of Epithelial Integrity with Various Transepithelial Corneal Cross-Linking Protocols for Treatment of Keratoconus

Journal of Ophthalmology, 2014

Purpose. Corneal collagen cross-linking (CXL) has been demonstrated to stiffen cornea and halt progression of ectasia. The original protocol requires debridement of central corneal epithelium to facilitate diffusion of a riboflavin solution to stroma. Recently, transepithelial CXL has been proposed to reduce risk of complications associated with epithelial removal. Aim of the study is to evaluate the impact of various transepithelial riboflavin delivery protocols on corneal epithelium in regard to pain and epithelial integrity in the early postoperative period.Methods. One hundred and sixty six eyes of 104 subjects affected by progressive keratoconus underwent transepithelial CXL using 6 different riboflavin application protocols. Postoperatively, epithelial integrity was evaluated at slit lamp and patients were queried regarding their ocular pain level.Results. One eye had a corneal infection associated with an epithelial defect. No other adverse event including endothelial decompe...

Imaging Mass Spectrometry by Matrix-Assisted Laser Desorption/Ionization and Stress-Strain Measurements in Iontophoresis Transepithelial Corneal Collagen Cross-Linking

BioMed Research International, 2014

Purpose.To compare biomechanical effect, riboflavin penetration and distribution in transepithelial corneal collagen cross-linking with iontophoresis (I-CXL), with standard cross linking (S-CXL) and current transepithelial protocol (TE-CXL).Materials and Methods.The study was divided into two different sections, considering, respectively, rabbit and human cadaver corneas. In both sections corneas were divided according to imbibition protocols and irradiation power. Imaging mass spectrometry by matrix-assisted laser desorption/ionization (MALDI-IMS) and stress-strain measurements were used. Forty-eight rabbit and twelve human cadaver corneas were evaluated.Results.MALDI-IMS showed a deep riboflavin penetration throughout the corneal layers with I-CXL, with a roughly lower concentration in the deepest layers when compared to S-CXL, whereas with TE-CXL penetration was considerably less. In rabbits, there was a significant increase (by 71.9% andP=0.05) in corneal rigidity after I-CXL, w...

Comparison of transepithelial corneal collagen crosslinking with epithelium-off crosslinking in progressive keratoconus

Journal Français d'Ophtalmologie, 2014

To evaluate the safety and efficacy of transepithelial corneal collagen crosslinking (TE-CXL) as compared to epithelium-off crosslinking (epi-off CXL) in progressive keratoconus. Methods. -Records of keratoconus patients treated with TE-CXL or epi-off CXL were reviewed retrospectively. Patients were included if they had at least 12 months follow-up. Pre-and postoperative measurements of visual acuity, refractive errors, keratometry, corneal topography and pachymetry were assessed and compared. Results. -There was no statistically significant difference between two groups at baseline in terms of demographic, refractive and corneal parameters. Mean maximum cone apex curvature (apical K) increased from 51.62 ± 5. Eighty-four diopters (D) to 53.70 ± 5.49 D in the TE-CXL group (n = 17), and decreased from 52.02 ± 4.07 D to 51.22 ± 3.51 in the epi-off CXL group (n = 19) at the end of the follow-up period. The difference between two groups was statistically significant (P = 0.0002). An increase of ≥ 1D in apical K was observed in two of 19 eyes (11%) in the epi-off CXL group, and 11 of 17 eyes (65%) in TE-CXL group at the last follow-up visit, compared to baseline (P < 0.0001). Fourteen patients in the epi-off CXL group exhibited corneal edema

Current review and a simplified "five-point management algorithm" for keratoconus

Indian Journal of Ophthalmology, 2015

Keratoconus is a slowly progressive, noninflammatory ectatic corneal disease characterized by changes in corneal collagen structure and organization. Though the etiology remains unknown, novel techniques are continuously emerging for the diagnosis and management of the disease. Demographical parameters are known to affect the rate of progression of the disease. Common methods of vision correction for keratoconus range from spectacles and rigid gas-permeable contact lenses to other specialized lenses such as piggyback, Rose-K or Boston scleral lenses. Corneal collagen cross-linking is effective in stabilizing the progression of the disease. Intra-corneal ring segments can improve vision by flattening the cornea in patients with mild to moderate keratoconus. Topography-guided custom ablation treatment betters the quality of vision by correcting the refractive error and improving the contact lens fit. In advanced keratoconus with corneal scarring, lamellar or full thickness penetrating keratoplasty will be the treatment of choice. With such a wide spectrum of alternatives available, it is necessary to choose the best possible treatment option for each patient. Based on a brief review of the literature and our own studies we have designed a five-point management algorithm for the treatment of keratoconus.

The Effect of Sodium Iodide on Stromal Loading, Distribution and Degradation of Riboflavin in a Rabbit Model of Transepithelial Corneal Crosslinking

Clinical Ophthalmology, 2021

Purpose: To evaluate effects of sodium iodide (NaI) on riboflavin concentration in corneal stroma before and during ultraviolet A (UVA) light exposure using a novel transepithelial corneal collagen crosslinking (CXL) procedure (EpiSmart CXL system, CXL Ophthalmics, Encinitas CA). Methods: Riboflavin solutions with NaI (Ribostat, CXL Ophthalmics, Encinitas CA) and without NaI were used for CXL in rabbits using EpiSmart. A pilot study determined sufficient riboflavin loading time. Four rabbits were dosed and monitored. Riboflavin fluorescence intensity was assessed from masked slit-lamp photos. A 12 min loading time was selected. Sixteen additional rabbits received the two formulae in contralateral eyes for CXL. Riboflavin uptake was assessed at 0, 10, 15, 20, 25, and 30 min of UVA exposure using a scale for riboflavin fluorescence previously validated against stromal concentration. Post sacrifice, corneal stromal samples were analyzed for concentrations of riboflavin and riboflavin 5ʹ-phosphate. Results: Eyes dosed with NaI riboflavin had higher riboflavin grades compared to eyes dosed with the NaI-free riboflavin formulation immediately after riboflavin loading and persisting throughout UVA exposure, with significantly higher (P < 0.01 to < 0.05) riboflavin grades from 15 through 25 min of UVA exposure. Riboflavin grades decreased more slowly in eyes dosed with NaI riboflavin through 25 minutes of UVA exposure. Minor conjunctival irritation was noted with or without NaI. Conclusion: The addition of NaI to riboflavin solution is associated with increased riboflavin concentration in corneal stroma throughout a clinically relevant time course of UVA exposure. This effect may be a combination of enhanced epithelial penetration and reduced riboflavin photodegradation and should enhance intrastromal crosslinking.

The Effect of Standard and Transepithelial Ultraviolet Collagen Cross-Linking on Human Corneal Nerves: An Ex Vivo Study

American Journal of Ophthalmology, 2012

Iontophoresis Transcorneal Delivery Technique for Transepithelial Corneal Collagen Crosslinking With Riboflavin in a Rabbit Model

Investigative Opthalmology &amp; Visual Science, 2016

To compare an iontophoresis riboflavin delivery technique for transepithelial corneal collagen crosslinking (I-CXL) with a conventional CXL (C-CXL). Methods We designed 3 experimental sets using 152 New Zealand rabbits to study riboflavin application by iontophoresis using charged riboflavin solution (Ricrolin+ ®) with a 1mA current for 5 min. The first set was to compare riboflavin concentration measured by High-Performance Liquid Chromatography (HPLC) in corneas after iontophoresis or conventional riboflavin application. The second set was to analyze autofluorescence and stromal collagen modification immediately and 14 days after I-CXL or C-CXL, by using nonlinear two-photon Conclusions This experimental study suggests that I-CXL is a promising alternative methodology for riboflavin delivery in crosslinking treatments, preserving the epithelium.

Corneal Absorption of a New Riboflavin-Nanostructured System for Transepithelial Collagen Cross-Linking

PLoS ONE, 2013

Corneal collagen cross-linking (CXL) has been described as a promising therapy for keratoconus. According to standard CXL protocol, epithelium should be debrided before treatment to allow penetration of riboflavin into the corneal stroma. However, removal of the epithelium can increase procedure risks. In this study we aim to evaluate stromal penetration of a biocompatible riboflavin-based nanoemulsion system (riboflavin-5-phosphate and riboflavin-base) in rabbit corneas with intact epithelium. Two riboflavin nanoemulsions were developed. Transmittance and absorption coefficient were measured on corneas with intact epithelia after 30, 60, 120, 180, and 240 minutes following exposure to either the nanoemulsions or standard 0.1% or 1% riboflavin-dextran solutions. For the nanoemulsions, the epithelium was removed after measurements to assure that the riboflavin had passed through the hydrophobic epithelium and retained within the stroma. Results were compared to de-epithelialized corneas exposed to 0.1% riboflavin solution and to the same riboflavin nanoemulsions for 30 minutes (standard protocol). Mean transmittance and absorption measured in epithelialized corneas receiving the standard 0.1% riboflavin solution did not reach the levels found on the debrided corneas using the standard technique. Neither increasing the time of exposure nor the concentration of the riboflavin solution from 0.1% to 1% improved riboflavin penetration through the epithelium. When using riboflavin-5-phosphate nanoemulsion for 240 minutes, we found no difference between the mean absorption coefficients to the standard cross-linking protocol (p = 0.54). Riboflavin nanoemulsion was able to penetrate the corneal epithelium, achieving, after 240 minutes, greater stromal concentration when compared to debrided corneas with the standard protocol (p = 0.002). The riboflavin-5-phosphate nanoemulsion diffused better into the stroma than the riboflavin-base nanoemulsion.

Corneal Absorption of a New Riboflavin-Nanostructured

2013

Corneal collagen cross-linking (CXL) has been described as a promising therapy for keratoconus. According to standard CXL protocol, epithelium should be debrided before treatment to allow penetration of riboflavin into the corneal stroma. However, removal of the epithelium can increase procedure risks. In this study we aim to evaluate stromal penetration of a biocompatible riboflavin-based nanoemulsion system (riboflavin-5-phosphate and riboflavin-base) in rabbit corneas with intact epithelium. Two riboflavin nanoemulsions were developed. Transmittance and absorption coefficient were measured on corneas with intact epithelia after 30, 60, 120, 180, and 240 minutes following exposure to either the nanoemulsions or standard 0.1% or 1% riboflavin-dextran solutions. For the nanoemulsions, the epithelium was removed after measurements to assure that the riboflavin had passed through the hydrophobic epithelium and retained within the stroma. Results were compared to de-epithelialized corneas exposed to 0.1% riboflavin solution and to the same riboflavin nanoemulsions for 30 minutes (standard protocol). Mean transmittance and absorption measured in epithelialized corneas receiving the standard 0.1% riboflavin solution did not reach the levels found on the debrided corneas using the standard technique. Neither increasing the time of exposure nor the concentration of the riboflavin solution from 0.1% to 1% improved riboflavin penetration through the epithelium. When using riboflavin-5-phosphate nanoemulsion for 240 minutes, we found no difference between the mean absorption coefficients to the standard cross-linking protocol (p = 0.54). Riboflavin nanoemulsion was able to penetrate the corneal epithelium, achieving, after 240 minutes, greater stromal concentration when compared to debrided corneas with the standard protocol (p = 0.002). The riboflavin-5-phosphate nanoemulsion diffused better into the stroma than the riboflavin-base nanoemulsion.

Ultraviolet A: Visible spectral absorbance of the human cornea after transepithelial soaking with dextran-enriched and dextran-free riboflavin 0.1% ophthalmic solutions

Journal of cataract and refractive surgery, 2015

To evaluate the stromal concentration of 2 commercially available transepithelial riboflavin 0.1% solutions in human donor corneas with the use of spectrophotometry. University of Calabria, Rende, Italy. Experimental study. The absorbance spectra of 12 corneal tissues were measured in the 330 to 700 nm wavelength range using a purpose-designed spectrophotometry setup before and after transepithelial corneal soaking with a 15% dextran-enriched riboflavin 0.1% solution (n = 6) or a hypotonic dextran-free riboflavin 0.1% solution (n = 6). Both ophthalmic solutions contained ethylenediaminetetraacetic acid and trometamol as enhancers. In addition, 4 deepithelialized corneal tissues underwent stromal soaking with a 20% dextran-enriched riboflavin 0.1% solution and were used as controls. All the riboflavin solutions were applied topically for 30 minutes. The stromal concentration of riboflavin was quantified by analysis of absorbance spectra of the cornea collected before and after applic...

Can the Effect of Transepithelial Corneal Collagen Cross-linking Be Improved by Increasing the Duration of Topical Riboflavin Application? An In Vivo Confocal Microscopy Study

Eye & Contact Lens: Science & Clinical Practice, 2014

To evaluate the effect of transepithelial corneal collagen crosslinking (CXL) with prolonged riboflavin application by in vivo confocal microscopy and to compare this effect with that of standard CXL with complete epithelial debridement. Methods: In eyes with progressive keratoconus, CXL procedure was performed with standard technique and transepithelial technique after prolonged riboflavin drop application for 2 hr. Patients were evaluated with in vivo confocal microscopic examination preoperatively and at postoperative months 1 and 6. Results: The depth of CXL effect was similar in both groups (i.e., 380.866103.23 mm in standard CXL group and 342.2668.6 mm in transepithelial CXL group) (P=0.4). The endothelial cell counts and morphological parameters (i.e., pleomorphism and polymegathism) were not significantly affected in both groups (P.0.05 for all). In the standard CXL group, in vivo confocal microscopy revealed anterior stromal acellular hyperreflective honeycomb edema with posteriorly gradually decreasing reflectivity and increasing number of keratocytes and some sheets of longitudinally aligned filamentary deposits. The keratocytes were seen to repopulate in the posterior-to-anterior direction. In transepithelial CXL group, although the depth of CXL effect was similar, less pronounced keratocyte damage, extracellular matrix hyperreflectivity, and sheets of filamentary deposits at the posterior stroma was observed. Conclusions: Transepithelial CXL with prolonged peroperative riboflavin application can achieve similar depth of effect in the stroma with less pronounced confocal microscopic changes as compared with the standard CXL with complete epithelial debridement.

A study of stromal riboflavin absorption in exvivo porcine corneas using new and existing delivery protocols for corneal cross‐linking

Acta Ophthalmologica, 2015

PurposeTo indirectly measure stromal riboflavin penetration using commercially available riboflavin solutions and new and existing epithelium‐off, trans‐epithelial and iontophoresis‐assisted delivery protocols.MethodsForty porcine eyes were divided into eight groups. Group 1: Ricrolin applied to the de‐epithelialised cornea for 30 min; Group 2: epithelium‐intact, no treatment; Groups 3–5: epithelium‐intact, 30‐min application of Ricrolin TE, Mediocross TE or ParaCel/Vibex, respectively. Group 6: epithelium‐intact, Ricrolin+ iontophoresis‐assisted delivery for 5 min; Group 7: epithelium‐intact, Ricrolin+ iontophoresis‐assisted delivery for 5 min with a 20‐min riboflavin soak; and Group 8: epithelium‐intact, Ricrolin+ iontophoresis‐assisted delivery for 5 min, 15‐min soak and another 5 min of iontophoresis. After a saline wash, light transmission spectra were obtained from each cornea, before and after epithelial removal.ResultsCorneas in groups 1 and 8 showed a distinct riboflavin ab...

Corneal light backscattering after transepithelial corneal crosslinking using iontophoresis in donor human corneal tissue

Journal of cataract and refractive surgery, 2015

To analyze the spatial distribution and time course of corneal light backscattering before and after transepithelial corneal crosslinking using iontophoresis. Fondazione G.B. Bietti-IRCCS, Rome, Italy. Experimental study. Three donor human eyes with an intact corneal epithelium had transepithelial iontophoresis corneal crosslinking (using rapid ultraviolet-A [UVA] irradiation), and 3 donor eyes without corneal epithelium had standard corneal crosslinking (using standard UVA irradiation). In addition, 3 donor eyes had iontophoresis and rapid corneal crosslinking after corneal deepithelialization (epi-off iontophoresis corneal crosslinking). Scheimpflug images (Pentacam HR) of each eye globe were acquired before and immediately after administration of riboflavin 0.1% solutions and 5, 10, 30, and 120 minutes after the corneal crosslinking procedures. Corneal light backscattering was quantified across the anterior 280 μm thickness at several points from the optical center to 3.0 mm from...

Quantitative analysis of corneal stromal riboflavin concentration without epithelial removal

Journal of Cataract and Refractive Surgery, 2018

To compare the corneal stromal riboflavin concentration and distribution using 2 transepithelial corneal crosslinking (CXL) systems.

Corneal collagen cross-linking (CXL) in thin corneas

Eye and Vision, 2015

Corneal collagen cross-linking (CXL) is a therapeutic procedure aiming at increasing the corneal stiffness in the keratoconus eyes by induction of cross-links within the extracellular matrix. It is achieved by ultraviolet-A (370 nm) irradiation of the cornea after saturation with the photosensitizer riboflavin. In the conventional CXL protocol, a minimum de-epithelialized corneal thickness of 400 μm is recommended to avoid potential irradiation damage to the corneal endothelium. In advanced keratoconus, however, stromal thickness is often lower than 400 μm, which limits the application of CXL in that category. Efforts have been undertaken to modify the conventional CXL procedure to be applicable in thin corneas. The current review discusses different techniques employed to achieve this end and their results. The overall safety and efficacy of the modified CXL protocols are good, as most of them managed to halt the progression of keratectasia without postoperative complications. However, the evidence of safety and efficacy in the use of modified CXL protocols is still limited to few studies with few patients involved. Controlled studies with long-term follow-up are required to confirm the safety and efficacy of the modified protocols.

Transepithelial Iontophoresis Versus Standard Corneal Collagen Cross-linking: 1-Year Results of a Prospective Clinical Study

Journal of Refractive Surgery, 2016

orneal collagen cross-linking (CXL) is currently the only treatment able to slow or halt the progression of ectatic disease. Long-term follow-up studies on CXL refer to the standard technique (S-CXL), which entails epithelial debridement to allow riboflavin (hydrophilic) penetration in the corneal stroma; otherwise the corneal epithelium (lipophilic) reduces its permeability. 5 Nevertheless, epithelial removal causes postoperative pain, 6 delayed visual recovery, and increased risks of infection. Transepithelial cross-linking (TE-CXL) was introduced to avoid these threats. The original dextran-containing solutions have been reported to be ineffective for TE-CXL, 9-11 but other formulations of riboflavin (with chemical enhancers) showed equivocal results in clinical studies. Conversely, preliminary results have shown that transepithelial cross-linking with iontophoresis (I-CXL) is able to increase the riboflavin concentration inside the stroma compared to other TE-CXL techniques together with histological changes. Pilot clinical findings using I-CXL with 19 and without 20 epithelial removal have also reported encouraging results. In this study, we compared 1-year results of two groups of patients with keratoconus who C

Pediatric keratoconus and iontophoretic corneal crosslinking: refractive and topographic evidence in patients underwent general and topical anesthesia, 18months of follow-up

International Ophthalmology, 2015

To evaluate the efficiency and safety of iontophoretic transepithelial corneal crosslinking in pediatric patients with progressive keratoconus underwent general or topical anesthesia in 18 months follow-up. 13 patients (13 eyes) diagnosed with progressive keratoconus underwent corneal CXL with iontophoresis (I-CXL). Riboflavin solution was administered by iontophoresis for 5 min, and then UV-A irradiation (10 mW/cm) was performed for 9 min. Preoperative and post-operative visits at 1, 6, 12, and 18 months assessed the following parameters: uncorrected visual acuity (UCVA), best-corrected visual acuity (BCVA), slit-lamp biomicroscopy, corneal topography, optical tomography, and pachymetry with Pentacam (Oculus Optikgeräte GmbH, Wetzlar, Germany), endothelial biomicroscopy (Konan Specular Microscope; Konan Medical, Inc., Hyogo, Japan). The paired Student t test was used to compare data during the follow-up. 10 males and 3 females with a mean age of 15.4 ± 1.7 years (range 11-18 years) were included. The results showed a stabilization of the refractive UCVA and BCVA as early as the first post-operative month, with a slight improvement over time. The Kmax remained stable throughout follow-up (p = 0.04). Transepithelial collagen crosslinking by iontophoresis, unlike other transepithelial techniques seems to halt pediatric keratoconus progression over 18 months. This is the second study evaluating CXL with iontophoresis in pediatric patients with progressive keratoconus with 18 months of follow-up using two different ways of anesthesia.