A short-term study of corneal collagen cross-linking with hypo-osmolar riboflavin solution in keratoconic corneas

AIM: To report the 3mo outcomes of collagen crosslinking(CXL) with a hypo-osmolar riboflavin in thin corneas with the thinnest thickness less than 400 μm without epithelium.METHODS: Eight eyes in 6 patients with age 26.2±4.8y were included in the study. All patients underwent CXL using a hypo-osmolar riboflavin solution after its de-epithelization. Best corrected visual acuity, manifest refraction, the thinnest corneal thickness, and endothelial cell density were evaluated before and 3mo after the procedure.RESULTS: The mean thinnest thickness of the cornea was 408.5 ±29.0 μm before treatment and reduced to369.8 ±24.8 μm after the removal of epithelium. With the application of the hypo-osmolar riboflavin solution, the thickness increased to 445.0 ±26.5 μm before CXL and recover to 412.5 ±22.7 μm at 3mo after treatment, P =0.659). Before surgery, the mean K-value of the apex of the keratoconus corneas was 57.6 ±4.0 diopters, and slightly decreased(54.7±4.9 diopters) after surgery(P =0.085). Mean best-corrected visual acuity was 0.55 ±0.23 logarithm of the minimal angle of resolution, and increased to 0.53±0.26 logarithm after surgery(P =0.879).The endothelial cell density was 2706.4 ±201.6 cells/mm2 before treatment, and slightly decreased( 2641. 2 ±218.2 cells/mm2) at last fellow up(P =0.002).CONCLUSION: Corneal collagen cross-linking with a hypo-osmolar riboflavin in thin corneas seems to be a promising treatment. Further study should be done to evaluate the safety and efficiency of CXL in thin corneas for the long-term.

Experimental study on the treatment of rabbit corneal melting after alkali burn with Collagen cross-linking

AIM: To evaluate the effect of Collagen cross-linking on the prevention of melting in rabbit corneas after alkali burn. METHODS: Twenty New Zealand white rabbits were randomly divided into model control group and collagen cross-linking treatment group. The second group of rabbits received collagen cross linked treatment. Both groups were applied with antibiotic eye drops to prevent infection. The corneas were evaluated for melting, opacity, pathological and immunohistochemistry, record the changes when 28 days after the animals were killed. RESULTS: In the control group, 6 out of 8 rabbits showed corneal melting after injury (14 +/- 4) days, while two corneal perforated. In collagen cross-linking treatment group, one rabbit showed corneal melting after injury 23 days, without corneal perforation; corneal dissolution rate between the two groups was significantly different (P <0.05). Pathological examination suggested that in the treatment group, mild corneal edema, mild damage to collagen fibers, inflammatory cell infiltration was significantly less than the control group. Immunohistochemistry showed that corneal collagen fibers arranged in neat rows in the control group. CONCLUSION: Collagen cross-linking treatment not only can prevent and delay the corneal melting after alkali burn, but also can reduce the destruction of corneal collagen fibers and infiltration of inflammatory cells in the corneal tissue.

Corneal collagen cross-linking and liposomal amphotericin B combination therapy for fungal keratitis in rabbits

AIM： To observe the therapeutic effect of corneal collagen cross-linking（CXL） in combination with liposomal amphotericin B in fungal corneal ulcers.METHODS： New Zealand rabbits were induced fungal corneal ulcers by scratching and randomly divided into 3groups, i.e. control, treated with CXL, and combined therapy of CXL with 0.25% liposomal amphotericin B（n =5 each）. The corneal lesions were documented with slit-lamp and confocal microscopy on 3, 7, 14, 21 and 28 d after treatment. The corneas were examined with transmission electron microscopy（TEM） at 4wk.RESULTS： A rabbit corneal ulcer model of Fusarium was successfully established. The corneal epithelium defect areas in the two treatment groups were smaller than that in the control group on 3, 7, 14 and 21d（P 〈0.05）. The corneal epithelium defect areas of the combined group was smaller than that of the CXL group（P 〈0.05） on 7 and 14 d, but there were no statistical differences on 3, 21 and 28 d. The corneal epithelium defects of the two treatment groups have been healed by day 21. The corneal epithelium defects of the control group were healed on 28 d. The diameters of the corneal collagen fiber bundles（42.960 ±7.383 nm in the CXL group and 37.040±4.160 nm in the combined group） were thicker than that of the control group（24.900±1.868 nm）,but there was no difference between the two treatment groups. Some corneal collagen fiber bundles were distorted and with irregular arrangement, a large number of fibroblasts could be seen among them but no inflammatory cells in both treatment groups. CONCLUSION： CXL combined with liposomal amphotericin B have beneficial effects on fungal corneal ulcers. The combined therapy could alleviate corneal inflammattions, accelerate corneal repair, and shorten the course of disease.

Scheimpflug imaged corneal changes on anterior and posterior surfaces after collagen cross-linking

AIM:To compare the anterior and posterior corneal parameters before and after collagen cross-linking therapy for keratoconus.METHODS:Collagen cross-linking was performed in31 eyes of 31 keratoconus patients(mean age 30.6±8.9y).Prior to treatment and an average 7mo after therapy,Scheimpflug analysis was performed using Pentacam HR.In addition to corneal thickness assessments,corneal radius,elevation,and aberrometric measurements were performed both on anterior and posterior corneal surfaces.Data obtained before and after surgery were statistically analyzed.RESULTS:In terms of horizontal and vertical corneal radius,and central corneal thickness no deviations were observed an average 7mo after operation.Corneal higher order aberration showed no difference neither on anterior nor on posterior corneal surfaces.During follow-up period,no significant deviation was detected regarding elevation values obtained by measurement in mm units between the 3.0-8.0 mm-zones.CONCLUSION:Corneal stabilization could be observed in terms of anterior and posterior corneal surfaces,elevation and higher order aberration values 7mo after collagen cross-linking therapy for keratoconus.

Progress of corneal collagen cross-linking combined with refractive surgery

As a photochemical reaction that can stiffen the cornea,corneal collagen cross-linking(CXL) is the only promising method of preventing the progress of keratectasia,such as keratoconus and secondary ectasia following refractive surgery. The aim of CXL is to stabilize the underlying condition,with a small chance of visual improvement. Combining CXL with refractive surgery targeting both stabilization and reshaping of the corneal tissue for visual function improvement is a good treatment option. This review aims to provide a comprehensive and unbiased summary of the published research regarding combined CXL and refractive surgery,including measures and results,to help elucidate the future direction of CXL.

Corneal collagen cross-linking epithelium-on vs. epithelium-off: a systematic review and meta-analysis

Background The purpose of the study was to determine the advantages and disadvantages of epi-on corneal cross-linking(CXL)techniques compared with standard epi-off CXL.Methods We searched MEDLINE and EMBASE for randomized controlled trials(RCTs)and non-randomized studies of interventions(NRSIs)and we evaluated the selected papers according to the Cochrane risk of bias tool.We considered,as primary outcomes,average Kmax flattening,changes in uncorrected and corrected distance visual acuity(UDVA and CDVA);as secondary outcomes,we considered changes in pachymetry values and endothelial cell density(ECD).We also investigated adverse events related to the treatments and treatment failure.Meta-analysis was conducted with a fixed or random-effects model using weighted mean difference(MD)with 95%confidence interval(CI)as the effect size.Results A total of 15 studies were included and among these 15 trials,9 were RCTs and 6 were NRSIs,but only 4 studies showed no high risk of bias and were included in this meta-analysis.Our analysis revealed significant postoperative differences in CDVA(MD=0.07;95%CI 0.04 to 0.10;P<0.001),and no significative differences in UDVA,Kmax,central corneal thickness(CCT)and ECD(P>0.05).Epi-on CXL protocol was found to be significantly less prompt to have risks of delay in epithelial healing(P=0.035)and persistent stromal haze(P=0.026).Conclusion Epi-on CXL is as effective as epi-off CXL.Except for a higher significant improvement in CDVA with current epi-on protocols,our meta-analysis demonstrates that epi-on and epi-off CXL have comparable effects on visual,topographic,pachymetric,and endothelial parameters.Epi-on CXL has clinical advantages in terms of comfort and avoidance of complications as it reduces the risk of developing delay in epithelial healing and persistent stromal haze.

Analysis of the effective dose of ultraviolet light in corneal cross-linking

AIM: To analyze the efficacy of ultraviolet (UV) light initiating corneal cross-linking (CXL). METHODS: The time-dependent absorption of UV light due to the depletion of the initiator (riboflavin) was calculated. The effective dose of CXL with corneal surface covered by a thin layer of riboflavin was derived analytically. The cross linking time was calculated by the depletion level of the riboflavin concentration. A comprehensive method was used to derive analytic formulas. RESULTS: The effective dose of CXL was reduced by a factor (R) which was proportional to the thickness (d) and concentrations (C-0) of the riboflavin surface layer. Our calculations showed that the conventional dose of 5.4 J/cm(2) had a reduced effective dose of 4.3 and 3.45 J/cm(2), for d was 100 and 200 pm, respectively, and C-0=0.1%. The surface cross linking time was calculated to be T*=10.75s, for a depletion level of 0.135 and UV initial intensity of 30 mW/cm(2). The volume T* was exponentially increasing and proportional to exp (bdC(0)), with b being the steady state absorption coefficient. CONCLUSION: The effective dose of CXL is reduced by a factor proportional to the thickness and concentrations of the riboflavin surface layer. The wasted dose should be avoided by washing out the extra riboflavin surface layer prior to the UV light exposure.

Topography versus non-topography-guided photorefractive keratectomy with corneal cross-linking variations in keratoconus

AIM:To compare the visual results of non-topographyguided and topography-guided photorefractive keratectomy(PRK)applying sequential and simultaneous corneal crosslinking(CXL)treatment for keratoconus.METHODS:Interventional and comparative prospective study.Sixty-nine eyes(36 patients)suffering from keratoconus(stages 1 Amsler-Krumeich classification)were divided into four groups:sequential topography-guided photorefractive keratectomy with CXL,simultaneous topography-guided photorefractive keratectomy with CXL,simultaneous nontopography guided photorefractive keratectomy with CXL,and sequential non-topography guided photorefractive keratectomy with CXL.The main outcome measures were pre-and postoperative uncorrected distance visual acuity(UDVA),best corrected distance visual acuity(CDVA),manifest refraction,contrast sensitivity,and keratometry.RESULTS:All analyzed visual,contrast sensitivity,and refractive parameters showed a significant improvement in the four groups(all P<0.05).A noticeable improvement was seen in keratometry in all the groups,and a remarkable difference was observed between topography-guided groups in comparison to non-topography-guided groups(P<0.05).Interestingly,the improvement in all parameters showed a degree of stability to the end of the follow-up.CONCLUSION:The treatment priorities in all four groups are safety,efficacy,and predictability in the correction of the sphero-cylindrical errors in mild and moderate keratoconus.No significant differences among groups in the recorded objective outcomes were found.

Evaluation of corneal endothelium after UVA/riboflavin cross-linking in thin keratoconic corneas

Dear Sir,UVA/riboflavin cross-linking （CXL） has been used clinically applied for the treatment of keratoconus and corneal edema via enhancement of corneal stiffness The safety of the corneal endothelium is of prime importance during CXL treatment. In clinical practice, a corneal thickness （CT） of 400um has traditionally been regarded as the minimum treatable thickness, thereby avoiding damage to the corneal endothelium Although CXL has been applied to thinner corneas, using a hypoosmotic solution onto cornea and inducing edema . CXL safety still needs further evaluation because of lower relative concentration of collagen in the hydrated stroma . This study aims to evaluate the changes of corneal endothelial density （ECD） in cases where the CT is 〈400 um before iatrogenic corneal swelling and CXL treatment.

Riboflavin-UVA collagen cross-linking for the treatment of acanthamoeba keratitis

In this review,recent studies regarding riboflavin-ultraviolet A(UVA)collagen cross-linking for the treatment of acanthamoeba keratitis(AK)were reviewed.English written studies about acanthamoeba,keratitis,riboflavin and collagen cross-linking were retrieved from PubMed search engine(www.ncbi.nlm.nih.gov/pubmed).Although there were significant numbers of cases reporting the effectiveness of riboflavin-UVA collagen cross-linking in AK,experimental studies(in vivo and in vitro)failed to verify amoebicidal or cysticidal effect of riboflavin-UVA collagen cross-linking.In conclusion,the efficacy of riboflavin-UVA collagen cross-linking for the treatment of AK is still debatable.It is necessary to conduct a prospective case-control study for clear guidance for clinicians.

Role of corneal collagen fibrils in corneal disorders and related pathological conditions

The cornea is a soft tissue located at the front of the eye with the principal function of transmitting and refracting light rays to precisely sense visual information. Corneal shape, refraction, and stromal stiffness are to a large part determined by corneal fibrils, the arrangements of which define the corneal cells and their functional behaviour. However, the modality and alignment of native corneal collagen lamellae are altered in various corneal pathological states such as infection, injury, keratoconus, corneal scar formation, and keratoprosthesis. Furthermore, corneal recuperation after corneal pathological change is dependent on the balance of corneal collagen degradation and contraction. A thorough understanding of the characteristics of corneal collagen is thus necessary to develop viable therapies using the outcome of strategies using engineered corneas. In this review, we discuss the composition and distribution of corneal collagens as well as their degradation and contraction, and address the current status of corneal tissue engineering and the progress of corneal cross-linking.

Corneal collagen crosslinking in keratoconus and other eye disease

Keratoconus is a condition characterized by biomechanical instability of the cornea, presenting in a progressive, asymmetric and bilateral way. Corneal collagen crosslinking(CXL) with riboflavin and Ultraviolet-A(UVA) is a new technique of corneal tissue strengthening that combines the use of riboflavin as a photo sensitizer and UVA irradiation. Studies showed that CXL was effective in halting the progression of keratoconus over a period of up to four years. The published studies also revealed a reduction of max K readings by more than 2 D, while the postoperative spherical equivalent(SEQ) was reduced by an average of more than 1 D and refractive cylinder decreased by about1 D. The major indication for the use of CXL is to inhibit the progression of corneal ecstasies, such as keratoconus and pellucid marginal degeneration. CXL may also be effective in the treatment and prophylaxis of iatrogenic keratectasia, resulting from excessively aggressive photo ablation. This treatment has been used to treat infectious corneal ulcers with apparent favorable results. Most recent studies demonstrate the beneficial impact of CXL for iatrogenic ecstasies, pellucid marginal degeneration, infectious keratitis, bullous keratopathy and ulcerative keratitis. Several long-term and short-term complications of CXL have been studied and documented. The possibility of a secondary infection after the procedure exists because the patient is subject to epithelial debridement and the application of a soft contact lens. Formation of temporary corneal haze,permanent scars, endothelial damage, treatment failure,sterile infiltrates, bullous keratopathy and herpes reactivation are the other reported complications of this procedure.

Corneal collagen cross-linking(CXL)in thin corneas

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 400μm is recommended to avoid potential irradiation damage to the corneal endothelium.In advanced keratoconus,however,stromal thickness is often lower than 400μm,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.

5-year follow-up of combined non-topography guided photorefractive keratectomy and corneal collagen cross linking for keratoconus

AIM： To evaluate the visual outcomes of simultaneous non-topography guided photorefractive keratectomy（PRK） and corneal collagen cross-linking（CXL） in eyes with keratoconus 5 y after the procedure.METHODS： Prospective, interventional, non-randomized, and non-controlled case series design was used. Sixty eyes of 30 patients（16 males and 14 females; age： 21-41 y） with mild, non-progressive（stages 1-2） keratoconus were enrolled. Refraction, uncorrected distance visual acuity（UDVA） and corrected distance visual acuity（CDVA）, flat and steep keratometry readings, and adverse events were evaluated preoperatively and postoperatively. Data were collected preoperatively and postoperatively at 3 mo, 1, 2, 3, 4, and 5 y follow-up visits after combined non-topography-guided PRK with CXL was performed. All patients had at least 5 y of follow-up.RESULTS： All study parameters showed a statistically significant improvement at 5 y over baseline values. The mean follow-up time was 68.20±4.71 mo（range： 60-106 mo）. Patients showed a significant improvement in UDVA from 1.24±0.79 log MAR prior to combined non-TG-PRK＋CXL to 0.06±0.15 log MAR postoperatively at the time of their last follow-up visit. CDVA significantly increased from 0.06±0.19 log MAR preoperatively to 0.03±0.12 log MAR postoperatively. A significant decrease in the mean spherical equivalent（SE） refraction was observed from-2.28±1.8 to-0.79±0.93 diopters（D）（P〈0.05）, and the manifest sphere decreased from-1.62±1.23 to-0.27±0.21 D（P=0.001）. The manifest cylinder significantly decreased from-1.73±0.86 to-0.29±0.34 D postoperatively（P=0.001）. The mean steep keratometry was 45.13±1.32 vs 47.28±2.12 D preoperatively（P〈0.05）, and the preoperative mean steepest keratometry（Kmax） 48.6±3.1 was reduced significantly to 46.8±2.9 postoperatively（P〈0.05）. CONCLUSION： Combined non-TG-PRK with 15 min CXL is an effective and safe option for correcting mild refractive error and improving visual acuity in patients with mild stable keratoconus.

Collagen cross-linking:when and how?A review of the state of the art of the technique and new perspectives

Since the late 1990s corneal crosslinking(CXL)has been proposed as a new possibility to stop progression of keratoconus or secondary corneal ectasia,with the promising aim to prevent progressive visual loss due to the evolution of the pathology and to delay or avoid invasive surgical procedures such as corneal transplantation.The possibility of strengthening corneal tissue by means of a photochemical reaction of corneal collagen by the combined action of Riboflavin and ultraviolet A irradiation(UVA),radically modified the conservative management of progressive corneal ectasia.This is a review of the state of the art of CXL,reporting basic and clinical evidence.The paper describes basic principles,advantages and limits of different CXL techniques and possible future evolution of the procedure.

New techniques to improve classical corneal collagen cross-linking treatment

Objective The aim of this review is to comprehensively and unbiasedly summarize the improvements in the techniques for classical corneal collagen cross-linking （CXL） by covering the reasons for this improvement, measure, and effect to approach the future direction of the CXL. Data sources All articles used in this review were mainly retrieved from the PubMed database. Study selection Original articles and reviews were selected if they were related to the improvement in the technique of classical CXL. Data were mainly extracted from 94 articles, which are listed in the reference section of this review. Results This innovative research involves every step such as instrument preparation, epithelial management, riboflavin instillation, and UVA irradiation. These clinical and experimental results seem promising. Conclusions CXL treatment is the only recent promising method for preventing the progress of keratoconus. The limitations and potential complications that accompany classical CXL such as corneal thickness limitations, ultraviolet-A （UVA） light injury, and the impact of de-epithelialization encourage people to research new improvements in techniques. While this research needs to be further investigated, we hope our review can help related researchers and patients.

AB085.E-beam sterilization of recombinant human collagen-phosphorylcholine corneal implants for transplantation

Background:The sterilization of corneal implants composed of carbodiimide crosslinked recombinant human collagen type III(RHCIII)and phosphorylcholine polymers(RHCIII-MPC)is constrained by the biochemical properties of RHCIII.Early human trials used 1%chloroform in 0.1 M phosphate buffered saline(C-PBS),but require a stringent wash procedure with antibiotics to remove the chloroform.Irradiation with gamma or electron-beam(e-beam)allows a chemical-free sterilization method,but may result in crosslinking or denaturation.Here,electron-beam irradiation is evaluated as a sterilization method for RHCIII-MPC implants.Methods:Dose-finding study:RHCIII-MPC were cast in round,350µm thick,12 mm diameter molds for corneal implants and 0.5 mm thick dumbbell-shaped molds for mechanical testing.The hydrogels received an irradiation dose of 17,19,or 21 kGy and unirradiated controls were stored in C-PBS,n=3 per group.The hydrogels were tested for sterility and endotoxin,optical and mechanical properties,biodegradation,free radicals,and cell compatibility.Clinical evaluation in rabbits:RHCIII-MPC implants were e-beamed at 17 kGy or kept in C-PBS.One implant from each group was implanted into the right cornea of each rabbit by deep anterior lamellar keratoplasty,n=4 animals per group.Animals underwent preoperative and 6-month post-operative in vivo confocal microscopy(IVCM)to check nerve count and ingrowth of keratocytes.Corneal grafts and controls were assessed via histology and immunohistochemistry.Results:Dose finding study:hydrogels were sterile at all irradiation doses with no evidence of free radicals.There were no significant differences in optical or mechanical properties between the treatment groups and controls.All hydrogels supported cell growth.The 19 and 21 kGy implants had high collagenase degradation for 21 hours until they stabilized,whereas the 17 kGy and C-PBS implants had gradual degradation until 48 hours.Clinical results:the rabbits did not experience post-surgical inflammatory reactions and full epithelial coverage of the implants occurred within the first week of surgery for all animals.Mild neovascularization occurred in all animals,but resolved by 6-month follow-up.A mild 0.5-1.0 grade subepithelial haze was observed in all rabbits,but the implanted grafts remained transparent.Re-innervation occurred in all grafts with no significant differences between sterilization methods.All regenerated corneas had mucin production and were positive for cytokeratin 3 and 12.Grafted and control corneas were negative for macrophages and blood vessels.Conclusions:E-beam sterilization is a safe and effective form of sterilization for RHCIII-MPC implants.

Clinical outcomes at one year following keratoconus treatment with accelerated transepithelial cross-linking

This study evaluated the clinical outcomes in keratoconus corneas following accelerated transepithelial corneal collagen cross-linking（CXL）（Avedro KXL system,Waltham,MA,USA） over one year of follow-up.The mean depth of the demarcation line measured by optical coherence tomography（OCT） was 205.19 μm.One month after surgery,a non-statistically significant change was noted in sphere（P= 0.18） and in spherical equivalent（P= 0.17）,whereas a significant improvement was observed in corrected distance visual acuity（P=0.04）.A significant change was observed in topographic astigmatism（P= 0.03） and posterior corneal a sphericity（P= 0.04）.Accelerated transepithelial CXL may be a useful technique for the management of progressive keratoconus.

Evaluation of corneal cell growth on tissue engineering materials as artificial cornea scaffolds

The keratoprosthesis(KPro;artificial cornea)is a special refractive device to replace human cornea by using heterogeneous forming materials for the implantation into the damaged eyes in order to obtain a certain vision.The main problems of artificial cornea are the biocompatibility and stability of the tissue particularly in penetrating keratoplasty.The current studies of tissue-engineered scaffold materials through comprising composites of natural and synthetic biopolymers together have developed a new way to artificial cornea.Although a wide agreement that the long-term stability of these devices would be greatly improved by the presence of cornea cells,modification of keratoprosthesis to support cornea cells remains elusive.Most of the studies on corneal substrate materials and surface modification of composites have tried to improve the growth and biocompatibility of cornea cells which can not only reduce the stimulus of heterogeneous materials,but also more importantly continuous and stable cornea cells can prevent the destruction of collagenase.The necrosis of stroma and spontaneous extrusion of the device,allow for maintenance of a precorneal tear layer,and play the role of ensuring a good optical surface and resisting bacterial infection.As a result,improvement in corneal cells has been the main aim of several recent investigations;some effort has focused on biomaterial for its well biological properties such as promoting the growth of cornea cells.The purpose of this review is to summary the growth status of the corneal cells after the implantation of several artificial corneas.

Combined corneal CXL and photorefractive keratectomy for treatment of keratoconus: a review

Keratoconus and iatrogenic keratectasia are the corneal ectatic disorders occurring due to biomechanical weakening of the cornea resulting in distorted images,myopia, and irregular astigmatism. Corneal collagen cross-linking(CXL) is performed to arrest keratoconus successfully. The main aim of this review is to discuss the safety and efficacy of the adjuvant therapies, such as the combination of CXL and photorefractive keratectomy(PRK) for the treatment of corneal ectatic disorders. A comprehensive literature search was performed using PubM ed, MEDLINE, and Scopus using keywords ‘collagen’‘keratoconus’,‘keratectasia’,‘collagen cross-linking’,and ‘photorefractive keratectomy’. Search results were restricted to clinical studies published in English. Corneal CXL effectively arrests the progression of keratoconus by enhancing corneal rigidity. However, functional vision is not improved by cross-linking. Combining CXL to refractive surgeries such as topography-guided PRK or transepithelial PRK is found to be a safe and effective method in providing corneal stability as well as significantly improving functional visual acuity with few minor complications. This combined technique also prevents regression of keratoconus and reduce the risk of keratectasia. CXL combined with PRK is a promising therapeutic approach in ophthalmology that can be successfully used to treat progressive keratoconus and other corneal ectatic disorders and to enhance visual acuity.