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The aim of this study is to present mathematical formulas describing all forces involved in Goldmann applanation tonometry to calculate the measurement error of the true intraocular pressure as a function of the surface tension of the tear film, the corneal modulus of elasticity, the corneal thickness and the average apical corneal radius of curvature.The portion of the indented cornea has been modeled as a shell having a uniform thickness. To assess corneal behavior during applanation tonometry, the physical equations of the deformation of a symmetrical shell due to an applanating force as well as the surface tension of the tear film and intraocular pressure have been used.Formulas to calculate the true intraocular pressure, the pulling force of the tear film on the tonometer cone and the measurement error with the Goldmann applanation tonometer are provided. These mathematical models can be used to estimate the true intraocular pressure of each single patient by correcting the pressure measured with Goldmann applanation tonometry with enhanced accuracy.

In the present study (clinical trial registration number: NCT05019768), we compared the clinical outcome of corneal cross-linking with either the standard Dresden (sCXL) or the accelerated custom-fast (aCFXL) ultraviolet A irradiation protocol using riboflavin–D-α-tocopheryl poly(ethylene glycol)-1000 succinate for progressive keratoconus. Fifty-four eyes of forty-one patients were randomized to either of the two CXL protocols and checked before treatment and at the 2-year follow-up. The sCXL group was subjected to CXL with 30 min of pre-soaking and 3 mW/cm2 UVA irradiation for 30 min. The aCFXL group was subjected to CXL with 10 min of pre-soaking and UVA irradiation of 1.8 ± 0.9 mW/cm2 for 10 min ± 1.5 min. In both groups, a solution of riboflavin–vitamin E TPGS was used. Uncorrected distance visual acuity, corrected distance visual acuity, pachymetry, Scheimpflug tomography, and corneal hysteresis were performed at baseline and after 24 months. Both groups showed a statistically significant improvement in corrected distance visual acuity, and keratometric and corneal hysteresis compared to baseline conditions, no statistically significant differences in outcomes between the two groups were observed. Improvement in refractive, topographic, and biomechanical parameters were observed after sCXL and aCFXL, making the riboflavin–VE-TPGS solution an effective option as a permeation enhancer in CXL procedures. Deeper stromal penetration of riboflavin could be complemented by photo-protection against UVA and free radicals formed during photoinduced processes.

Background: Corneal collagen cross-linking (CXL) has become the gold standard for mild and moderate stages to stop the progression of keratoconus. We analyzed some corneal topography indices to compare iontophoresis epi-on and iontophoresis epi-off techniques throughout a two-year follow-up. Methods: A total of 64 eyes of 49 patients who underwent CXL were recruited. In 30 eyes the epi-off technique was performed, whereas the remaining 34 eyes were treated with the epi-on technique. All patients underwent a complete ophthalmologic examination that included CDVA, central and thinnest corneal thickness, Schirmer test I, TBUT test, and the Ocular Surface Disease Index. Results: In both groups, a significant improvement in visual function was recorded. No statistically significant differences between Kmax, Mean K, Flat K, Steep K values were found. Statistically significant differences (p < 0.05) between the epi-on and epi-off groups’ pachymetry before and after 24 months follow-up as well as between the epi-on and epi-off groups’ topographically thinnest point in the immediate post-surgery and 24 months after surgery were recorded. Conclusion: Our study highlighted that both techniques are valid in mid-term corneal stabilization. The advantage of the new iontophoresis epi-off cross-linking technique could be found in a faster imbibing time of the cornea, therefore reducing surgical times, with a lower risk of complications.

The purpose of the study was to determine the decrease in pachymetry of very thin corneas with advanced keratoconus due to corneal compaction from the ultraviolet-A (UV-A) irradiation phase of transepithelial (epi-on) cross-linking. Twenty removed corneal buttons were obtained from patients who underwent penetrating keratoplasty for advanced keratoconus. Removed corneal buttons selected from among the post-surgical specimens for this study had intact epithelium, no scarring or surgical cautery, endothelial cell density >2500 cells/mm2, and average pachymetry over the measured points of below 400 μm. Corneas were mounted in a Franz chamber. Each epithelial surface was soaked in isotonic riboflavin and D-alpha-tocopheryl polyethylene glycol 1000 succinate (Ribocross® IROMED Group, Italy) for 15 min. Pachymetry was measured at three points over both the shielded and unshielded corneal halves for each corneal button. Surfaces were then washed in saline to remove the Ribocross®. Shields from UV-A irradiation over half of each cornea were then fixed to stand 5 mm above the test corneas. UV-A irradiation using the custom fast cross-linking (CF-CXL) protocol was then performed for the typical 10 ± 1.5 min, for a total energy of 1.08 ± 0.6 J/cm2 after which pachymetry was re-measured. The average percent change in pachymetry was −0.43% ± 0.38% (maximum −1.06%) in the shielded half. Pachymetry change was −6.2% ± 2.2% (maximum 12%) in the cross-linked halves. In conclusion, we estimate that the change in corneal thickness from corneal compaction due to the cross-linking reaction itself was −5.8% ± 2.2%. Scanning electron microscopy of cross-linked corneal segments showed stromal fiber contraction.

This study aimed to test the effectiveness of a solution of chlorhexidine (CHX) and D-α-tocopheryl polyethylene glycol succinate (Vitamin E TPGS or TPGS) in the treatment of Acanthamoeba keratitis (AK) via a prospective, interventional case series study. Twenty-nine consecutive patients with AK were enrolled. At baseline, best-corrected visual acuity (BCVA), slit lamp examination, confocal microscopy, and polymerase chain reaction (PCR) were performed. Topical therapy with CHX 0.02% and VE-TPGS 0.2% was administered hourly/24 h for the first day, hourly in the daytime for the next three days, and finally, every two hours in the daytime up to one month. BCVA and ocular inflammation were recorded after two weeks, four weeks, and three months from baseline. Mean logMAR BCVA significantly improved at two weeks (0.78) compared to baseline (1.76), remaining stable over time (0.80 at four weeks, 0.77 at three months). Ocular inflammation improved in 14 eyes at 2 weeks, with further slow improvements in all cases. At three months, no patient had signs of corneal inflammation. The presence of corneal scars was first recorded at the two-week follow-up, with an enlargement at the four-week follow-up. At the three-month follow-up, 19 eyes still showed corneal opacities. In conclusion, the tested solution was shown to be effective for the treatment of AK. Furthermore, it might represent a good first-line treatment.

This study aimed to evaluate the protective effect of a topical antioxidant and ultraviolet (UV) shielding action formulation containing riboflavin and D-&alpha, tocopherol polyethylene glycol succinate (TPGS) vitamin E against corneal UV-induced damage in vivo rabbit eyes. In vivo experiments were performed using male albino rabbits, which were divided into four groups. The control group (CG) did not receive any UV irradiation, the first group (IG) was irradiated with a UV-B&minus, UV-A lamp for 30 min, the second (G30) and third (G60) groups received UV irradiation for 30 and 60 min, respectively, and were topically treated with one drop of the antioxidant and shielding formulation every 15 min, starting one hour before irradiation, until the end of UV exposure. The cornea of the IG group showed irregular thickening, detachment of residual fragments of the Descemet membrane, stromal fluid swelling with consequent collagen fiber disorganization and disruption, and inflammation. The cornea of the G30 group showed edema, a mild thickening of the Descemet membrane without fibrillar collagen disruption and focal discoloration, or inflammation. In the G60 group, the cornea showed a more severe thickening, a more abundant fluid accumulation underneath the Descemet membrane with focal detachment, and no signs of severe tissue alterations, as were recorded in the IG group. Our results demonstrate that topical application of eye drops containing riboflavin and TPGS vitamin E counteracts UV corneal injury in exposed rabbits.

This study aimed to test the effectiveness of a solution of chlorhexidine (CHX) and D-α-tocopheryl polyethylene glycol succinate (Vitamin E TPGS or TPGS) in the treatment of Acanthamoeba keratitis (AK) via a prospective, interventional case series study. Twenty-nine consecutive patients with AK were enrolled. At baseline, best-corrected visual acuity (BCVA), slit lamp examination, confocal microscopy, and polymerase chain reaction (PCR) were performed. Topical therapy with CHX 0.02% and VE-TPGS 0.2% was administered hourly/24 h for the first day, hourly in the daytime for the next three days, and finally, every two hours in the daytime up to one month. BCVA and ocular inflammation were recorded after two weeks, four weeks, and three months from baseline. Mean logMAR BCVA significantly improved at two weeks (0.78) compared to baseline (1.76), remaining stable over time (0.80 at four weeks, 0.77 at three months). Ocular inflammation improved in 14 eyes at 2 weeks, with further slow improvements in all cases. At three months, no patient had signs of corneal inflammation. The presence of corneal scars was first recorded at the two-week follow-up, with an enlargement at the four-week follow-up. At the three-month follow-up, 19 eyes still showed corneal opacities. In conclusion, the tested solution was shown to be effective for the treatment of AK. Furthermore, it might represent a good first-line treatment.

Analysis of UV-visible spectra, performed on commercial riboflavin-based eye drops, showed that absorbance is a saturating function of vitamin concentration. This implies a threshold concentration, Ct, such that for riboflavin concentration > Ct the absorbance remains constant and the effectiveness of the eye drops is independent of the dose used. These experimental results were combined with a diffusion-reaction model to elucidate the mechanism of action within the cornea. The model predicts that the eye drops have a low effectiveness on UVB and UVC, while they have a good performance for UVA. Indeed, at the center of the cornea the transmittance is significantly reduced and after 1 h it is reduced by about 70% compared to a cornea devoid of eye drops.

Purpose To evaluate custom fast cross-linking (cfCXL) treatment of keratoconus. Methods "Custom fast cross-linking" or "cfCXL" is a keratoconus treatment algorithm featuring no epithelial disruption, 15 minutes of corneal presoaking with a riboflavin-vitamin E TPGS solution, and a 370-nm ultraviolet A radiation beam centered on the most highly curved corneal region. Ultraviolet A radiation beam fluence, total energy, and exposure time are significantly less than those in the Dresden protocol. In this study, refraction, spectacle-corrected distance visual acuity, Kmax, and corneal hysteresis were monitored in 81 eyes of 81 patients for 7 years with 100% follow-up. Pretreatment Kmax and patient age averaged 53.01 ± 4.87 D and 25.9 ± 4.7 years, respectively. Results Average refractive cylinder magnitude was reduced by 26.1% at 1 month postoperatively and by 44.2% at 7 years postoperatively. Logarithm of the minimum angle of resolution average spectacle-corrected distance visual acuity (best spectacle-corrected distance visual acuity) improved from +0.26 ± 0.34 (20/36.4) to +0.15 ± 0.23 (20/28.25), +0.05 ± 0.20 (20/22.4), and +0.06 ± 0.20 (20/22.96) at 1 month, 1 year, and 7 years postoperatively, respectively. Best spectacle-corrected distance visual acuity improved in 54.3%, 74.1%, 84.0%, 87.7%, 84.0%, 84.0%, and 82.7% of patients at postoperative months 1, 3, 6, 12, 24, 48, and 84, respectively. Kmax did not increase in 96.3% of patients at 1 month, 97.5% at 1 year, and 98.8% at 7 years postoperatively, with average corneal apex flattening at 1 month and 7 years of -2.79 ± 1.70 D and -4.00 ± 2.40 D, respectively. Conclusions Custom fast cross-linking, epi-on, rapid, narrowed beam apex-centered treatment of keratoconus with riboflavin-vitamin E TPGS produced a significant, rapid, and lasting cone progression stoppage, astigmatism reduction, and visual acuity improvement.

Purpose The aim of this study has been to evaluate the protective effect of a topical antioxidant formulation containing riboflavin, d-α-tocopheryl polyethylene glycol (TPGS vitamin E), proline, glycine, lysine, and leucine against UV-B-induced damage in in vivo rabbit retina. Methods Twenty male albino rabbits were used. Animals were divided into four groups of five animals each. Control group did not receive any UV irradiation. The first group (IG) was irradiated with a UV-A lamp for 30 min; the second (IG30) and the third (IG60) groups received UV irradiation for 30 and 60 min, respectively, and were topically treated with 1 drop (approximately 50 µl) of the antioxidant formulation, every 15 min, starting 1 h before irradiation, until the end of the UC exposure. Results The retina of IG group showed extensive destruction of the retinal pigment epithelium (RPE) and of the cones and rods layer. The retina of G30 group showed a lesser destruction of both RPE and cones and rods layer. In the G60 group, retina showed an irregular thickening of the RPE, with massive edema of the inner and outer layer immediately adjacent together with a significant reduction of the photoreceptor number. Conclusion Our results demonstrate that a topical application of eye drops containing riboflavin, d-α-tocopheryl polyethylene glycol (TPGS vitamin E), proline, glycine, lysine, and leucine counteracts UV retinal injury in exposed retina rabbits.

Purpose: To assess the ocular hypotensive effect of 15-keto fluprostenol, the oxidized metabolite of travoprost, on glaucoma patients, through a randomized double-masked placebo-controlled study. Methods: Twelve patients with ocular normal tension glaucoma (NTG) (intraocular pressure [IOP] < 22 mmHg) were enrolled. In order to ensure patient compliance to treatment, all study subjects were hospitalized. In each patient, the eye to be submitted to the treatments was randomly chosen. After hospital admission (day 1), those patients received for 5 days at 8 P.M. either one drop of 15-keto fluprostenol (35 μg/ml) or one drop of placebo. IOP evaluation was performed within 8 A.M. and 8 P.M. for 6 days. Furthermore, we performed a determination of cardiovascular parameters before and after the treatments. Results: Starting with the first IOP measurement after the first treatment (8 A.M. on day 2), IOP was reduced of about 14% in the eyes treated 15-keto fluprostenol, in comparison with baseline IOP values of 15-keto fluprostenol-treated patients. The IOP reduction in the 15-keto fluprostenol-treated group was significantly compared to placebo group (p < 0.05) starting from day 3 till day 6 of the study. Except for mild hyperemia in one 15-keto fluprostenol-treated eye, no other side effects were observed or reported by the enrolled patients. Conclusions: The travoprost metabolite 15-keto fluprostenol was effective in decrease IOP and maintained IOP reduction along 5 days of treatment. The 15-keto fluprostenol can be developed as a good candidate for once-a-day NTG patients’ treatment.

PURPOSE: There has been a recent explosion in the variety of techniques used to accomplish corneal cross-linking (CXL) for the treatment of ectatic corneal diseases. To understand the success or failure of various techniques, we review the physicochemical basis of corneal CXL and re-evaluate the current principles and long-standing conventional wisdom in the light of recent, compelling, and sometimes contradictory research. METHODS: Two clinicians and a medicinal chemist developed a list of current key topics, controversies, and questions in the field of corneal CXL based on information from current literature, medical conferences, and discussions with international practitioners of CXL. RESULTS: Standard corneal CXL with removal of the corneal epithelium is a safe and efficacious procedure for the treatment of corneal ectasias. However, the necessity of epithelium removal is painful for patients, involves risk and requires significant recovery time. Attempts to move to transepithelial corneal CXL have been hindered by the lack of a coherent understanding of the physicochemistry of corneal CXL. Misconceptions about the applicability of the Bunsen-Roscoe law of reciprocity and the Lambert-Beer law in CXL hamper the ability to predict the effect of ultraviolet A energy during CXL. Improved understanding of CXL may also expand the treatment group for corneal ectasia to those with thinner corneas. Finally, it is essential to understand the role of oxygen in successful CXL. CONCLUSIONS: Improved understanding of the complex interactions of riboflavin, ultraviolet A energy and oxygen in corneal CXL may provide a successful route to transepithelial corneal CXL.

Purpose: To report the clinical outcomes with 24-month follow-up of transepithelial cross-linking using a combination of a D-alpha-tocopheryl polyethylene-glycol 1000 succinate (vitamin E-TPGS)-enhanced riboflavin solution and abbreviated low fluence UV-A treatment. Methods: In a nonrandomized clinical trial, 25 corneas of 19 patients with topographically proven, progressive, mild to moderate keratoconus over the previous 6 months were cross-linked, and all patients were examined at 1, 3, 6, 12, and 24 months. The treatments were performed using a patented solution of riboflavin and vitamin E-TPGS, topically applied for 15 minutes, followed by two 5-minute UV-A treatments with separate doses both at fluence below 3 mW/cm2 that were based on preoperative central pachymetry. Results: During the 6-month pretreatment observation, the average Kmax increased by +1.99 +/- 0.29 D (diopter). Postoperatively, the average Kmax decreased, changing by -0.55 +/- 0.94 D, by -0.88 +/- 1.02 D and by -1.01 +/- 1.22 D at 6, 12, and 24 months. Postoperatively, Kmax decreased in 19, 20, and 20 of the 25 eyes at 6 months, 12 months, and 24 months, respectively. Refractive cylinder was decreased by 3 months postoperatively and afterward, changing by -1.35 +/- 0.69 D at 24 months. Best spectacle-corrected visual acuity (BSCVA) improved at 6, 12, and 24 months, including an improvement of -0.19 +/- 0.13 logarithm of the minimum angle of resolution units at 24 months. There was no reduction in endothelial cell count. No corneal abrasions occurred, and no bandage contact lenses or prescription analgesics were used during postoperative recovery. Conclusions: Transepithelial cross-linking using the riboflavin-vitamin E solution and brief, low-dose, pachymetry-dependent UV-A treatment safely stopped keratoconus progression.

Ultraviolet-radiation exerts a well-known role in the development of various ocular diseases and may contribute to the progress of age-related macular degeneration. Therefore, the use of compounds able to protect the eyes from UV-induced cellular damage is challenging. The aim of this study has been to test the protective effects of an antioxidant topical formulation against UV-induced damage in rabbit eyes. Twelve male rabbits were used. Animals were divided into 4 groups of 3 animals each. Control group (CG) did not receive any irradiation and/or eye drop. The other three experimental groups were treated as follows: the first group received only UVR irradiation for 30 min, without eye drop supplementation (Irradiation group, IG), the second (G30) and the third (G60) groups received UV irradiation for 30’ and 60’, respectively, and eye drop supplementation (riboflavin, d-α-tocopheryl polyethylene glycol, proline, glycine, lysine and leucine solution) every 15 min for three hours. In the IG group a significant increase of oxidized glutathione (GSSG) and hydrogen peroxide (H2O2) was recorded in the aqueous humor, whereas ascorbic acid levels were significantly lower when compared to control eyes. In the groups exposed to UVR rays for 30 min, and treated with the topical antioxidant formulation, the GSSG, H2O2 and ascorbic acid levels were similar to those recorded in controls, whereas in the G60 group the three markers significantly differ from control group. In the lens, a significant decrease of alpha tocopherol and total antioxidant capacity (TAC) was recorded in IG-animals as compared to control group, whereas malondialdehyde (MDA) levels were significantly higher in UV-induced eye than in control eyes. In the G30 groups the alpha tocopherol, MDA and TAC levels do not significantly differ from those recorded in controls, whereas in the G60 group these three markers significantly differ from control group. Present findings demonstrate that topical treatment with the antioxidant formulation used herein protects ocular structures from oxidative stress induced by UV exposure in in vivo animal model.

Purpose: To improve the safety, reproducibility, and depth of effect of corneal cross-linking with the ultraviolet A (UV-A) exposure time and fluence customized according to the corneal thickness. Methods: Twelve human corneas were used for the experimental protocol. They were soaked using a transepithelial (EPI-ON) technique using riboflavin with the permeation enhancer vitamin E-tocopheryl polyethylene glycol succinate. The corneas were then placed on microscope slides and irradiated at 3 mW/cm2 for 30 minutes. The UV-A output parameters were measured to build a new equation describing the time-dependent loss of endothelial protection induced by riboflavin during cross-linking, as well as a pachymetry-dependent and exposure time-dependent prescription for input UV-A fluence. The proposed equation was used to establish graphs prescribing the maximum UV-A fluence input versus exposure time that always maintains corneal endothelium exposure below toxicity limits. Results: Analysis modifying the Lambert-Beer law for riboflavin oxidation leads to graphs of the maximum safe level of UV-A radiation fluence versus the time applied and thickness of the treated cornea. These graphs prescribe UV-A fluence levels below 1.8 mW/cm2 for corneas of thickness 540 [mu]m down to 1.2 mW/cm2 for corneas of thickness 350 [mu]m. Irradiation times are typically below 15 minutes. Conclusions: The experimental and mathematical analyses establish the basis for graphs that prescribe maximum safe fluence and UV-A exposure time for corneas of different thicknesses. Because this clinically tested protocol specifies a corneal surface clear of shielding riboflavin on the corneal surface during UV-A irradiation, it allows for shorter UV-A irradiation time and lower fluence than in the Dresden protocol.

Corneal collagen cross-linking (CXL) as introduced in the Dresden protocol1,2 has succeeded in reducing visual loss in an increasing number of people worldwide. The Bunsen–Roscoe Law suggests that the same cross-linking effect could be completed in a shorter time as long as the total ultraviolet (UV) irradiation energy is the same. Higher intensity, shorter duration treatments have been tried, but there have been safety and effectiveness questions with these variations. Kymionis et al3 recently demonstrated that the 30-minute, 3-mW/cm2 UV-A intensity Dresden protocol CXL yielded a deeper corneal effect than a shorter, more intense treatment of a 10-minute, 9-mW/cm2 CXL protocol, casting some doubt on the application of the Bunsen–Roscoe Law to cross-linking. Studies on porcine eyes have shown toxicity to the endothelium at irradiation levels of 0.35 mW/cm2 for 30 minutes.4 Based on the Lambert–Beer law of exponential decline in UV transmission as a function of corneal depth, a recommendation was derived, and it is now standard, that cross-linking at 3 mW/cm2 should not be performed on corneas thinner than 400 μm. Furthermore, to prevent endothelial damage, there was a recommendation that a riboflavin layer be renewed on the cornea during UV-A irradiation, but variations in the thickness of the riboflavin covering layer over the treatment time and over different treatments is a potential cause of variation in the degree of cross-linking effect. Two laboratory experiments, reported here, were conducted to determine if it was possible to produce a shorter duration, lower energy, time-variable UV intensity cross-linking treatment that would accomplish the goal of adequately increasing corneal stiffness while lowering the risk of endothelial cell damage.

Introduction: Abdominal angina occurs in patients affected by mesenteric artery obstruction, causing postprandial episodes of visceral pain. The conventional treatment consists of vessels revascularization, but sometimes this is not applicable. Case Report: The authors report a case of a patient with severe abdominal angina caused by mesenteric ischemia, not treatable with surgery and few-responder to pharmacological therapy (opioids and epidural infusion of local anesthetics). After a successful screening test, the patient underwent implantation of a spinal cord stimulation (SCS) device. Results: The stimulation provided a reduction in pain episodes (number and intensity) and in oral analgesics consumption. Results obtained support the clinical efficacy and durability of the SCS in the management of abdominal angina due to not treatable mesenteric ischemia. Conclusions: Spinal cord stimulation may be considered for abdominal angina, although there is still no evidence provided by controlled studies.

Corneal accumulation of riboflavin-5’-phosphate (Riboflavin) is an essential step in the so called collagen cross-linking (CXL), the elective therapeutic approach for the treatment of keratoconus, also adopted in the treatment of corneal ectasia and irregular astigmatism. Since corneal epithelium impedes the passage of riboflavin, which, therefore, is unable to penetrate deep into the corneal stroma in a relatively short time, CXLis usually performed aftersurgicaldebridement of corneal epithelium. D-alpha-tocopheryl poly(ethylene glycol) 1000 succinate (VE-TPGS) is a really effective permeation enhancer used to increase adsorption of drugs trough different biological barriers. Moreover, belonging to the group of tocopherols pro-drugs, VE-TPGS exerts a protective effect on biological membrane against free-radical damage. The aim of this work is the evaluation of VE-TPGS effects on intact cornea permeability ofriboflavin, and the potential protective effect against free-radicals generated in CXL procedures. Different solutions containing riboflavin (0.125% w/w), dextran(20.0% w/w) and increasing concentration of VE-TPGS were prepared. Corneal permeation was evaluated in vitroby the use of modified Franz-cell type diffusion cells and freshly excised porcine corneas as barrier. The effect of VE-TPGS on Riboflavin corneal penetration was compared with standard commercial solution of riboflavinin dextran at different times. Accumulation experiments were conducted both on normal and disepithelized corneas.Moreover, intact porcine corneas,treated with the new proposed solutions, were subjected toan in vitro CXL procedure and compared with disephitelized corneas, treated withcommercial solution of riboflavin. Differences were measured by meansoffirmnessof treated corneas using Young’s modulus. The photo-protective effect of proposed solutions on corneal epithelium was, finally, evaluated. CXL protocol was applied, in vitro, on human explanted corneas and resulting morphology of corneal epithelium was investigated by scanning electron microscopy.

Corneal accumulation of riboflavin-5'-phosphate (riboflavin) is an essential step in the so called corneal cross-linking (CXL), an elective therapy for the treatment of progressive keratoconus, corneal ectasia and irregular astigmatism. CXL is usually performed after surgical debridement of corneal epithelium, since it impedes the stromal penetration of riboflavin in a relatively short time. d-Alpha-tocopheryl poly(ethylene glycol) 1000 succinate (VE-TPGS) is an effective permeation enhancer used to increase adsorption of drugs trough different biological barriers. Moreover, belonging to the group of tocopherol pro-drugs, VE-TPGS exerts a protective effect on biological membrane against free-radical damage. The aim of this work is the evaluation of VE-TPGS effects on riboflavin corneal permeability, and the assessment of its protective effect against free-radicals generated during CXL procedures. Different solutions containing riboflavin (0.125% w/w), dextran (20.0% w/w) and increasing concentration of VE-TPGS were tested. Corneal permeation was evaluated in vitro by the use of modified Franz-cell type diffusion cells and freshly excised porcine corneas as barrier. The effect of VE-TPGS on riboflavin corneal penetration was compared with a standard commercial solution of riboflavin in dextran at different times. Accumulation experiments were conducted both on epithelized and non-epithelized corneas. Moreover, epithelized porcine corneas, treated with the tested solutions, were subjected to an in vitro CXL procedure versus non-epithelized corneas, treated with a commercial solution of riboflavin. Differences were measured by means of corneal rigidity using Young's modulus. The photo-protective effect of tested solutions on corneal epithelium was, finally, evaluated. CXL treatment was applied, in vitro, on human explanted corneas and resulting morphology of corneal epithelium was investigated by scanning electron microscopy.