{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T04:22:16Z","timestamp":1781929336670,"version":"3.54.5"},"reference-count":46,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2021,8,25]],"date-time":"2021-08-25T00:00:00Z","timestamp":1629849600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>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\u2013D-\u03b1-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 \u00b1 0.9 mW\/cm2 for 10 min \u00b1 1.5 min. In both groups, a solution of riboflavin\u2013vitamin 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\u2013VE-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.<\/jats:p>","DOI":"10.3390\/jcm10173799","type":"journal-article","created":{"date-parts":[[2021,8,26]],"date-time":"2021-08-26T00:19:26Z","timestamp":1629937166000},"page":"3799","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Topo-Pachimetric Accelerated Epi-On Cross-Linking Compared to the Dresden Protocol Using Riboflavin with Vitamin E TPGS: Results of a 2-Year Randomized Study"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6023-4277","authenticated-orcid":false,"given":"Ciro","family":"Caruso","sequence":"first","affiliation":[{"name":"Corneal Transplant Center, Pellegrini Hospital, Via Portamedina alla Pignasecca, 41, 80127 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert Leonard","family":"Epstein","sequence":"additional","affiliation":[{"name":"The Center for Corrective Eye Surgery, W. Elm Street, 5400, Mc Henry, IL 60050, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6762-6102","authenticated-orcid":false,"given":"Pasquale","family":"Troiano","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Sacred Family, Fatabenefratelli Hospital, Via Fatebenefratelli, 20, 22036 Erba, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Napolitano","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Pellegrini Hospital, Via Portamedina alla Pignasecca, 41, 80127 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5444-4377","authenticated-orcid":false,"given":"Fabio","family":"Scarinci","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, IRCCS Fondazione, Bietti, Via Livenza, 3, 00198 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8477-6188","authenticated-orcid":false,"given":"Ciro","family":"Costagliola","sequence":"additional","affiliation":[{"name":"Eye Clinic, Department of Medicine and Health Sciences \u201cV. Tiberio\u201d, University of Molise, Via Francesco De Sanctis, 1, 86100 Campobasso, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1159\/000357979","article-title":"Corneal collagen crosslinking: A systematic review","volume":"232","author":"Sorkin","year":"2014","journal-title":"Ophthalmologica"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.ajo.2015.05.019","article-title":"Current protocols of corneal collagen cross-linking: Visual, refractive, and tomographic outcomes","volume":"160","author":"Shetty","year":"2015","journal-title":"Am. J. Ophthalmol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1097\/ICO.0000000000000723","article-title":"Efficacy of corneal collagen cross-linking for the treatment of keratoconus: A systematic review and meta-analysis","volume":"35","author":"Meiri","year":"2016","journal-title":"Cornea"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"9048","DOI":"10.1167\/iovs.11-7818","article-title":"Equivalence of biomechanical changes induced by rapid and standard corneal cross-linking, using riboflavin and ultraviolet radiation","volume":"52","author":"Schumacher","year":"2011","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1097\/ICO.0000000000000460","article-title":"Does corneal collagen cross-linking reduce the need for keratoplasties in patients with keratoconus?","volume":"34","author":"Sandvik","year":"2015","journal-title":"Cornea"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1111\/aos.13095","article-title":"Nationwide reduction in the number of corneal transplantations for keratoconus following the implementation of cross-linking","volume":"94","author":"Godefrooij","year":"2016","journal-title":"Acta Ophthalmol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1670","DOI":"10.1016\/j.jcrs.2019.06.027","article-title":"Corneal crosslinking: Current protocols and clinical approach","volume":"45","author":"Beckman","year":"2019","journal-title":"J. Cataract Refract. Surg."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1097\/ICO.0000000000001912","article-title":"Corneal cross-linking: The science beyond the myths and misconceptions","volume":"38","author":"Rubinfeld","year":"2019","journal-title":"Cornea"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1113\/jphysiol.1952.sp004779","article-title":"The Bunsen-Roscoe law for the human eye at very short durations","volume":"118","author":"Brindley","year":"1952","journal-title":"J. Physiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1097\/ICO.0000000000000809","article-title":"Corneal Cross-Linking: Evaluating the Potential for a Lower Power, Shorter Duration Treatment","volume":"35","author":"Caruso","year":"2016","journal-title":"Cornea"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1097\/ICO.0000000000001160","article-title":"Customized corneal cross-linking-a mathematical model","volume":"36","author":"Caruso","year":"2017","journal-title":"Cornea"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1016\/j.jcrs.2017.04.041","article-title":"Biomechanical stiffening: Slow low-irradiance corneal crosslinking versus the standard Dresden protocol","volume":"43","author":"Kling","year":"2017","journal-title":"J. Cataract Refract. Surg."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1786","DOI":"10.1016\/S0886-3350(03)00343-2","article-title":"Endothelial cell damage after riboflavin-ultraviolet-A treatment in the rabbit","volume":"29","author":"Wollensak","year":"2003","journal-title":"J. Cataract Refract. Surg."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.jcrs.2009.07.044","article-title":"Significance of the riboflavin film in corneal collagen crosslinking","volume":"36","author":"Wollensak","year":"2010","journal-title":"J. Cataract Refract. Surg."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"181","DOI":"10.2174\/1874364101812010181","article-title":"A review of corneal collagen cross-linking\u2014Current trends in practice applications","volume":"12","author":"Lim","year":"2018","journal-title":"Open Ophthalmol. J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1097\/ICO.0000000000002092","article-title":"Accelerated versus standard corneal cross-linking for progressive keratoconus: A meta-analysis of randomized controlled trials","volume":"39","author":"Kobashi","year":"2020","journal-title":"Cornea"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"97","DOI":"10.2147\/OPTH.S27170","article-title":"Long term results of a prospective randomized bilateral eye comparison trial of higher fluence, shorter duration ultraviolet A radiation, and riboflavin collagen cross linking for progressive keratoconus","volume":"6","author":"Kanellopoulos","year":"2012","journal-title":"Clin. Ophthalmol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"218","DOI":"10.3109\/15569527.2013.834497","article-title":"Comparison of accelerated and conventional corneal collagen cross-linking for progressive keratoconus","volume":"33","author":"Yuksel","year":"2014","journal-title":"Cutan. Ocul. Toxicol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"837","DOI":"10.3928\/1081597X-20141117-02","article-title":"Evaluation of corneal changes after conventional versus accelerated corneal cross-linking: A randomized controlled trial","volume":"30","author":"Hashemian","year":"2014","journal-title":"J. Refract. Surg."},{"key":"ref_20","first-page":"4238","article-title":"Conventional vs. pulsed-light accelerated corneal collagen cross-linking for the treatment of progressive keratoconus: 12-month results from a prospective study","volume":"14","author":"Jiang","year":"2017","journal-title":"Exp. Ther. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"8371","DOI":"10.1167\/iovs.14-15444","article-title":"Corneal cross-linking in keratoconus using the standard and rapid treatment protocol: Differences in demarcation line and 12-month outcomes","volume":"55","author":"Brittingham","year":"2014","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1111\/ceo.12571","article-title":"Conventional versus accelerated corneal collagen cross-linking in the treatment of keratoconus","volume":"44","author":"Ng","year":"2016","journal-title":"Clin. Exp. Ophthalmol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"14425","DOI":"10.1038\/srep14425","article-title":"One-year outcomes of conventional and accelerated collagen crosslinking in progressive keratoconus","volume":"5","author":"Chow","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.ijpharm.2012.09.051","article-title":"Enhancement of corneal permeation of riboflavin-5\u2019-phosphate through vitamin E TPGS: A promising approach in corneal trans-epithelial cross linking treatment","volume":"440","author":"Ostacolo","year":"2013","journal-title":"Int. J. Pharm."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1080\/02713680600899655","article-title":"Identification and functional expression of a carrier-mediated riboflavin transport system on rabbit corneal epithelium","volume":"31","author":"Hariharan","year":"2006","journal-title":"Curr. Eye Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1089\/jop.2005.21.275","article-title":"Identification and functional characterization of riboflavin transporter in human-derived retinoblastoma cell line (Y-79): Mechanisms of cellular uptake and translocation","volume":"21","author":"Kansara","year":"2005","journal-title":"J. Ocul. Pharmacol. Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/0378-5173(96)04663-7","article-title":"Evaluation of ocular permeation enhancers: In vitro effects on corneal transport of four \u03b2-blockers, and in vitro\/in vivo toxic activity","volume":"142","author":"Saettone","year":"1996","journal-title":"Int. J. Pharm."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1007\/s11095-005-9262-9","article-title":"Advances in the use of tocols as drug delivery vehicles","volume":"23","author":"Constantinides","year":"2006","journal-title":"Pharm. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1016\/j.ophtha.2017.01.040","article-title":"Randomized controlled trial comparing transepithelial corneal cross-linking using iontophoresis with the dresden protocol in progressive keratoconus","volume":"124","author":"Lombardo","year":"2017","journal-title":"Ophthalmology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2881","DOI":"10.1167\/iovs.13-13748","article-title":"Corneal biomechanical properties at different corneal cross-linking (CXL) irradiances","volume":"55","author":"Hammer","year":"2014","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1167\/tvst.2.7.6","article-title":"The biomechanical effect of corneal collagen cross-linking (CXL) with riboflavin and UV-A is oxygen dependent","volume":"2","author":"Richoz","year":"2013","journal-title":"Transl. Vis. Sci. Technol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2360","DOI":"10.1167\/iovs.11-9385","article-title":"Photochemical kinetics of corneal cross-linking with riboflavin","volume":"53","author":"Kamaev","year":"2012","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1097\/ICO.0000000000002088","article-title":"Topography and pachymetry guided, rapid Epi-on corneal cross-linking for keratoconus: 7-year study results","volume":"39","author":"Caruso","year":"2020","journal-title":"Cornea"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1097\/ICO.0000000000000699","article-title":"Transepithelial corneal cross-linking with vitamin E-enhanced riboflavin solution and abbreviated, low-dose UV-A: 24-month clinical outcomes","volume":"35","author":"Caruso","year":"2016","journal-title":"Cornea"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1097\/ICO.0b013e318190734d","article-title":"Can we measure corneal biomechanical changes after collagen cross-linking in eyes with keratoconus?\u2014A pilot study","volume":"28","author":"Goldich","year":"2009","journal-title":"Cornea"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.jcrs.2004.10.044","article-title":"Determining in vivo biomechanical properties of the cornea with an ocular response analyzer","volume":"31","author":"Luce","year":"2005","journal-title":"J. Cataract Refract. Surg."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1728","DOI":"10.1016\/j.jcrs.2010.06.056","article-title":"Biomechanical parameters of the cornea after collagen crosslinking measured by waveform analysis","volume":"36","author":"Sedaghat","year":"2010","journal-title":"J. Cataract Refract. Surg."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"452","DOI":"10.3928\/1081597X-20110106-01","article-title":"Detection of biomechanical changes after corneal cross-linking using Ocular Response Analyzer software","volume":"27","author":"Spoerl","year":"2011","journal-title":"J. Refract. Surg."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1007\/s00417-011-1674-0","article-title":"Biomechanical property analysis after corneal collagen cross-linking in relation to ultraviolet A irradiation time","volume":"249","author":"Lanchares","year":"2011","journal-title":"Graefes Arch. Clin. Exp. Ophthalmol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1111\/j.1755-3768.2008.01190.x","article-title":"Long-term biomechanical properties of rabbit cornea after photodynamic collagen crosslinking","volume":"87","author":"Wollensak","year":"2009","journal-title":"Acta Ophthalmol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1097\/ICO.0b013e31820143d1","article-title":"Limitation of collagen cross-linking with hypoosmolar riboflavin solution: Failure in an extremely thin cornea","volume":"30","author":"Hafezi","year":"2011","journal-title":"Cornea"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"571","DOI":"10.3928\/1081597X-20080601-05","article-title":"Epithelial thickness in the normal cornea: Three-dimensional display with Artemis very high-frequency digital ultrasound","volume":"24","author":"Reinstein","year":"2008","journal-title":"J. Refract. Surg."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.ajo.2020.12.011","article-title":"Individualized corneal cross-linking with riboflavin and UV-A in ultrathin corneas: The Sub400 protocol","volume":"224","author":"Hafezi","year":"2021","journal-title":"Am. J. Ophthalmol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3403","DOI":"10.1007\/s10792-020-01526-x","article-title":"Epi-off-lenticule-on corneal collagen cross-linking in thin keratoconic corneas","volume":"40","author":"Cagini","year":"2020","journal-title":"Int. Ophthalmol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2773","DOI":"10.4103\/ijo.IJO_2138_20","article-title":"Contact lens assisted corneal cross linking in thin ectatic corneas\u2014A review","volume":"68","author":"Jacob","year":"2020","journal-title":"Indian J. Ophthalmol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"12345","DOI":"10.1038\/s41598-018-30173-7","article-title":"Improving precision for detecting change in the shape of the cornea in patients with keratoconus","volume":"8","author":"Brunner","year":"2018","journal-title":"Sci. Rep."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/17\/3799\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:51:22Z","timestamp":1760165482000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/17\/3799"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,25]]},"references-count":46,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["jcm10173799"],"URL":"https:\/\/doi.org\/10.3390\/jcm10173799","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,25]]}}}