{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T23:59:29Z","timestamp":1773878369231,"version":"3.50.1"},"reference-count":61,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,3,23]],"date-time":"2021-03-23T00:00:00Z","timestamp":1616457600000},"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>The purpose of this study was to evaluate the effectiveness and safety of a novel buffered riboflavin solution approved for corneal cross-linking (CXL) in progressive keratoconus and secondary corneal ectasia. Following the in vivo preclinical study performed on New Zealand rabbits comparing the novel 0.25% riboflavin solution (Safecross\u00ae) containing 1% hydroxypropyl methylcellulose (HPMC) with a 0.1% riboflavin solution containing 0.10% EDTA, accelerated epithelium-off CXL was performed on 10 patients (10 eyes treated, with the contralateral eye used as control) through UV-A at a power setting of 9 mW\/cm2 with a total dose of 5.4 J\/cm2. Re-epithelialization was evaluated in the postoperative 7 days by fluorescein dye test at biomicroscopy; endothelial cell count and morphology (ECD) were analyzed by specular microscopy at the 1st and 6th month of follow-up and demarcation line depth (DLD) measured by anterior segment optical coherence tomography (AS-OCT) one month after the treatment. We observed complete re-epithelization in all eyes between 72 and 96 h after surgery (88 h on average). ECD and morphology remained unchanged in all eyes. DLD was detected at a mean depth of 362 \u00b1 50 \u00b5m, 20% over solutions with equivalent dosage. SafeCross\u00ae riboflavin solution chemically-boosted corneal cross-linking seems to optimize CXL oxidative reaction by higher superoxide anion release, improving DLD by a factor of 20%, without adverse events for corneal endothelium.<\/jats:p>","DOI":"10.3390\/jcm10061324","type":"journal-article","created":{"date-parts":[[2021,3,23]],"date-time":"2021-03-23T14:08:16Z","timestamp":1616508496000},"page":"1324","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Chemically-Boosted Corneal Cross-Linking for the Treatment of Keratoconus through a Riboflavin 0.25% Optimized Solution with High Superoxide Anion Release"],"prefix":"10.3390","volume":"10","author":[{"given":"Cosimo","family":"Mazzotta","sequence":"first","affiliation":[{"name":"Departmental Ophthalmology Unit and USL Toscana Sud-Est, 53100 Siena, Italy"},{"name":"Post Graduate Ophthalmology School, Siena University, 53100 Siena, Italy"},{"name":"Siena Crosslinking Center, Via Sandro Pertini 7, 53100 Siena, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0971-8225","authenticated-orcid":false,"given":"Marco","family":"Ferrise","sequence":"additional","affiliation":[{"name":"Siena Crosslinking Center, Via Sandro Pertini 7, 53100 Siena, Italy"},{"name":"Studio Oculistico Ferrise, 88046 Lamezia Terme, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guido","family":"Gabriele","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, \u201cLe Scotte\u201d Hospital, Viale M. Bracci, 53100 Siena, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paolo","family":"Gennaro","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, \u201cLe Scotte\u201d Hospital, Viale M. Bracci, 53100 Siena, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandro","family":"Meduri","sequence":"additional","affiliation":[{"name":"Unit of Ophthalmology, Department of Biomedical Sciences, Dentistry, Morphological and Functional Imaging, University of Messina, 98100 Messina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/0039-6257(84)90094-8","article-title":"Keratoconus and related noninflammatory corneal thinning disorders","volume":"28","author":"Krachmer","year":"1984","journal-title":"Surv. Ophthalmol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/S0039-6257(97)00119-7","article-title":"Keratoconus","volume":"42","author":"Rabinowitz","year":"1998","journal-title":"Surv Ophthalmol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1016\/S0002-9394(02)02220-1","article-title":"Riboflavin\/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus","volume":"135","author":"Wollensak","year":"2003","journal-title":"Am. J. Ophthalmol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1016\/j.jcrs.2006.01.091","article-title":"Parasurgical therapy for keratoconus by riboflavin-ultraviolet type A rays induced cross-linking of corneal collagen: Preliminary refractive results in an Italian study","volume":"32","author":"Caporossi","year":"2006","journal-title":"J. Cataract. Refract. Surg."},{"key":"ref_5","first-page":"S726","article-title":"Intacs implantation with sequential collagen cross-linking treatment in postoperative LASIK ectasia","volume":"24","author":"Kamburoglu","year":"2008","journal-title":"J. Refract. Surg."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1016\/j.ajo.2014.02.011","article-title":"Same-day intrastromal corneal ring segment and collagen cross-linking for ectasia after laser in situ keratomileusis: Long-term results","volume":"157","author":"Yildirim","year":"2014","journal-title":"Am. J. Ophthalmol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"296","DOI":"10.3928\/1081597X-20180223-01","article-title":"Corneal Allogenic Intrastromal Ring Segments (CAIRS) Combined with Corneal Cross-linking for Keratoconus","volume":"34","author":"Jacob","year":"2018","journal-title":"J. Refract. Surg."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"482","DOI":"10.3928\/1081597X-20101223-02","article-title":"Artiflex phakic intraocular lens implantation after corneal collagen cross-linking in keratoconic eyes","volume":"27","author":"Izquierdo","year":"2011","journal-title":"J. Refract. Surg."},{"key":"ref_9","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_10","first-page":"711","article-title":"Techniques for stiffening the cornea","volume":"15","author":"Spoerl","year":"1999","journal-title":"J. Refract. Surg."},{"key":"ref_11","first-page":"902","article-title":"Erh\u00f6hung der Festigkeit der Hornhaut durch Vernetzung [Increased rigidity of the cornea caused by intrastromal cross-linking]","volume":"94","author":"Huhle","year":"1997","journal-title":"Ophthalmologe"},{"key":"ref_12","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":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1097\/ICO.0b013e3180334f78","article-title":"Safety of UVA-riboflavin cross-linking of the cornea","volume":"26","author":"Spoerl","year":"2007","journal-title":"Cornea"},{"key":"ref_14","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_15","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1016\/j.jcrs.2017.05.030","article-title":"Accelerated 15 mW pulsed-light crosslinking to treat progressive keratoconus: Two-year clinical results","volume":"43","author":"Mazzotta","year":"2017","journal-title":"J. Cataract Refract. Surg."},{"key":"ref_16","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_17","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_18","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1097\/ICO.0000000000001878","article-title":"Comparative Functional Outcomes After Corneal Crosslinking Using Standard, Accelerated, and Accelerated with Higher Total Fluence Protocols","volume":"38","author":"Lang","year":"2019","journal-title":"Cornea"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/s40662-019-0141-6","article-title":"Different accelerated corneal collagen cross-linking treatment modalities in progressive keratoconus","volume":"6","author":"Kirgiz","year":"2019","journal-title":"Eye Vis."},{"key":"ref_20","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_21","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1038\/s41433-018-0323-9","article-title":"Effectiveness and safety of accelerated (9\u2009mW\/cm2) corneal collagen cross-linking for progressive keratoconus: A 24-month follow-up","volume":"33","author":"Ting","year":"2019","journal-title":"Eye"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"438","DOI":"10.3928\/1081597X-20180515-02","article-title":"Enhanced-Fluence Pulsed-Light Iontophoresis Corneal Cross-linking: 1-Year Morphological and Clinical Results","volume":"34","author":"Mazzotta","year":"2018","journal-title":"J. Refract. Surg."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"137","DOI":"10.5005\/jp-journals-10025-1171","article-title":"Pachymetry-based Accelerated Crosslinking: The \u201cM Nomogram\u201d for Standardized Treatment of All-thickness Progressive Ectatic Corneas","volume":"7","author":"Mazzotta","year":"2018","journal-title":"Int. J. Keratoconus Ectatic Corneal Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"286","DOI":"10.3928\/1081597X-20200406-02","article-title":"Iontophoresis Corneal Cross-linking With Enhanced Fluence and Pulsed UV-A Light: 3-Year Clinical Results","volume":"36","author":"Mazzotta","year":"2020","journal-title":"J. Refract. Surg."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1582","DOI":"10.1097\/j.jcrs.0000000000000347","article-title":"Customized corneal crosslinking for treatment of progressive keratoconus: Clinical and OCT outcomes using a transepithelial approach with supplemental oxygen","volume":"46","author":"Mazzotta","year":"2020","journal-title":"J. Cataract Refract. Surg."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1156","DOI":"10.1016\/j.ajo.2014.02.042","article-title":"Intraoperative corneal thickness measurement by optical coherence tomography in keratoconic patients undergoing corneal collagen cross-linking","volume":"157","author":"Mazzotta","year":"2014","journal-title":"Am. J. Ophthalmol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1517\/21678707.2013.765799","article-title":"Riboflavin 0.1% for the treatment of keratoconus","volume":"3","author":"Mazzotta","year":"2013","journal-title":"Expert Opinion Orphan Drugs"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1310","DOI":"10.3109\/02713683.2015.1118130","article-title":"Intraoperative OCT Pachymetry in Patients Undergoing Dextran-Free Riboflavin UVA Accelerated Corneal Collagen Crosslinking","volume":"41","author":"Rechichi","year":"2016","journal-title":"Curr. Eye Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1016\/j.ajo.2013.11.018","article-title":"Corneal cross-linking: Intrastromal riboflavin concentration in iontophoresis-assisted imbibition versus traditional and transepithelial techniques","volume":"157","author":"Mastropasqua","year":"2014","journal-title":"Am. J. Ophthalmol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"794256","DOI":"10.1155\/2015\/794256","article-title":"Evaluation of Intrastromal Riboflavin Concentration in Human Corneas after Three Corneal Cross-Linking Imbibition Procedures: A Pilot Study","volume":"2015","author":"Franch","year":"2015","journal-title":"J. Ophthalmol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1016\/j.jcrs.2009.01.009","article-title":"Corneal crosslinking: Riboflavin concentration in corneal stroma exposed with and without epithelium","volume":"35","author":"Baiocchi","year":"2009","journal-title":"J. Cataract Refract. Surg."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3269","DOI":"10.1007\/s10792-020-01512-3","article-title":"Complications of accelerated corneal collagen cross-linking: Review of 2025 eyes","volume":"40","author":"Sucu","year":"2020","journal-title":"Int. Ophthalmol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.1016\/j.jcrs.2009.03.035","article-title":"Complication and failure rates after corneal crosslinking","volume":"35","author":"Koller","year":"2009","journal-title":"J. Cataract Refract. Surg."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1111\/j.1442-9071.2007.01536.x","article-title":"Stromal haze after combined riboflavin-UVA corneal collagen cross-linking in keratoconus: In vivo confocal microscopic evaluation","volume":"35","author":"Mazzotta","year":"2007","journal-title":"Clin. Exp. Ophthalmol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1167\/iovs.13-12595","article-title":"Iontophoresis Transcorneal Delivery Technique for Transepithelial Corneal Collagen Crosslinking With Riboflavin in a Rabbit Model","volume":"57","author":"Cassagne","year":"2016","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e600","DOI":"10.1111\/aos.13032","article-title":"Standard corneal collagen crosslinking versus transepithelial iontophoresis-assisted corneal crosslinking, 24 months follow-up: Randomized control trial","volume":"94","author":"Bikbova","year":"2016","journal-title":"Acta Ophthalmol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2526","DOI":"10.1167\/iovs.13-13363","article-title":"Structural modifications and tissue response after standard epi-off and iontophoretic corneal crosslinking with different irradiation procedures","volume":"55","author":"Mastropasqua","year":"2014","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"488","DOI":"10.3928\/1081597X-20170504-03","article-title":"Medium- to Long-Term Results of Corneal Cross-Linking for Keratoconus Using Phototherapeutic Keratectomy for Epithelial Removal and Partial Stromal Ablation","volume":"33","author":"Chen","year":"2017","journal-title":"J. Refract. Surg."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"626","DOI":"10.3928\/1081597X-20160531-02","article-title":"Epithelial Thickness Profile Change After Combined Topography-Guided Transepithelial Photorefractive Keratectomy and Corneal Cross-linking in Treatment of Keratoconus","volume":"32","author":"Chen","year":"2016","journal-title":"J. Refract. Surg."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"478","DOI":"10.3928\/1081597X-20190627-01","article-title":"Ten-Year Outcomes of Progressive Keratoconus Management with the Athens Protocol (Topography-Guided Partial-Refraction PRK Combined With CXL)","volume":"35","author":"Kanellopoulos","year":"2019","journal-title":"J. Refract. Surg."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1016\/j.jcrs.2017.06.047","article-title":"Combined transepithelial phototherapeutic keratectomy and conventional photorefractive keratectomy followed simultaneously by corneal crosslinking for keratoconus: Cretan protocol plus","volume":"43","author":"Grentzelos","year":"2017","journal-title":"J. Cataract Refract. Surg."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/0003-2697(71)90370-8","article-title":"Superoxide dismutase: Improved assays and an assay applicable to acrylamide gels","volume":"44","author":"Beauchamp","year":"1971","journal-title":"Anal Biochem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/0009-2509(93)80291-W","article-title":"The estimation of gas solubilities in salt solutions","volume":"48","author":"Shumpe","year":"1993","journal-title":"Chem. Eng. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1021\/j150168a003","article-title":"Solubility of Oxygen in Salt Solutions and the Hydrates of These Salts","volume":"20","author":"MacArtur","year":"1916","journal-title":"J. Phys. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1006\/jcis.1996.0651","article-title":"Surface Tension of Aqueous Solutions of Electrolytes: Relationship with Ion Hydration, Oxygen Solubility, and Bubble Coalescence","volume":"184","author":"Weissenborn","year":"1996","journal-title":"J. Colloid Interface Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3310","DOI":"10.1002\/app.31854","article-title":"Gas permeation related to the moisture sorption in films of glassy hydrophilic polymers","volume":"116","author":"Laksmana","year":"2010","journal-title":"J. Appl. Polym. Sci."},{"key":"ref_47","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_48","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1358\/dot.2016.52.6.2494140","article-title":"Riboflavin for corneal cross-linking","volume":"52","year":"2016","journal-title":"Drugs Today"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1167\/iovs.11-8059","article-title":"Optimization model for UV-riboflavin corneal cross-linking","volume":"53","author":"Schumacher","year":"2012","journal-title":"Investig. Ophthalmol Vis. Sci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/S0378-5173(01)00907-3","article-title":"Increased corneal hydration induced by potential ocular penetration enhancers: Assessment by differential scanning calorimetry (DSC) and by desiccation","volume":"232","author":"Monti","year":"2002","journal-title":"Int. J. Pharm."},{"key":"ref_51","first-page":"268","article-title":"Visco-elastic material in keratoplasty","volume":"103","author":"Steele","year":"1983","journal-title":"Trans Ophthalmol Soc UK"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1016\/S0002-9394(14)78301-1","article-title":"The effects of sodium hyaluronate, chondroitin sulfate, and methylcellulose on the corneal endothelium and intraocular pressure","volume":"95","author":"Edelhauser","year":"1983","journal-title":"Am. J. Ophthalmol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1001\/archopht.1986.01050240093047","article-title":"A comparison of the efficacy and toxicity of and intraocular pressure response to viscous solutions in the anterior chamber","volume":"104","author":"Glaser","year":"1986","journal-title":"Arch. Ophthalmol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1016\/S0886-3350(13)80420-8","article-title":"2% hydroxypropyl methylcellulose as a viscous surgical adjunct","volume":"17","author":"Smith","year":"1991","journal-title":"J. Cataract. Refract. Surg."},{"key":"ref_55","unstructured":"Brightbill, F.S., McDonnell, P.J., McGhee, C.N.J., Farjo, A.A., and Serdarevic, O. (2009). Corneal Surgery: Theory Technique and Tissue, Elsevier Inc. [4th ed.]."},{"key":"ref_56","first-page":"966","article-title":"Effects of hydroxypropyl methylcellulose and polyvinyl alcohol on intraocular penetration of topical fluorescein in man","volume":"9","author":"Waltman","year":"1970","journal-title":"Investig. Ophthalmol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1002\/jbm.820291108","article-title":"Physical crosslinking of collagen fibers: Comparison of ultraviolet irradiation and dehydrothermal treatment","volume":"29","author":"Weadock","year":"1995","journal-title":"J. Biomed. Mater. Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"293","DOI":"10.3109\/10731198309118815","article-title":"Evaluation of collagen crosslinking techniques","volume":"11","author":"Weadock","year":"1983","journal-title":"Biomater. Med. Devices. Artif. Organs."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Mazzotta, C., Wollensak, G., Raiskup, F., and Pandolfi, A.M. (2019). Eberhard Spoerl. The meaning of the demarcation line after riboflavin-UVA corneal collagen crosslinking. Expert Rev. Ophthalmol.","DOI":"10.1080\/17469899.2019.1611425"},{"key":"ref_60","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_61","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/s40662-019-0165-y","article-title":"Central corneal regularization (CCR): An alternative approach in keratoconus treatment","volume":"6","author":"Chen","year":"2019","journal-title":"Eye Vis."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/6\/1324\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:39:45Z","timestamp":1760161185000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/6\/1324"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,23]]},"references-count":61,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,3]]}},"alternative-id":["jcm10061324"],"URL":"https:\/\/doi.org\/10.3390\/jcm10061324","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,23]]}}}