{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T07:47:43Z","timestamp":1789372063492,"version":"build-2803163510"},"reference-count":54,"publisher":"American Chemical Society (ACS)","issue":"10","license":[{"start":{"date-parts":[[2014,10,14]],"date-time":"2014-10-14T00:00:00Z","timestamp":1413244800000},"content-version":"vor","delay-in-days":47,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_ccby_termsofuse.html"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,10,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Overcoming the natural defensive barrier functions of the eye remains one of the greatest challenges of ocular drug delivery. Cornea is a chemical and mechanical barrier preventing the passage of any foreign bodies including drugs into the eye, but the factors limiting penetration of permeants and nanoparticulate drug delivery systems through the cornea are still not fully understood. In this study, we investigate these barrier properties of the cornea using thiolated and PEGylated (750 and 5000 Da) nanoparticles, sodium fluorescein, and two linear polymers (dextran and polyethylene glycol). Experiments used intact bovine cornea in addition to bovine cornea de-epithelialized or tissues pretreated with cyclodextrin. It was shown that corneal epithelium is the major barrier for permeation; pretreatment of the cornea with \u03b2-cyclodextrin provides higher permeation of low molecular weight compounds, such as sodium fluorescein, but does not enhance penetration of nanoparticles and larger molecules. Studying penetration of thiolated and PEGylated (750 and 5000 Da) nanoparticles into the de-epithelialized ocular tissue revealed that interactions between corneal surface and thiol groups of nanoparticles were more significant determinants of penetration than particle size (for the sizes used here). PEGylation with polyethylene glycol of a higher molecular weight (5000 Da) allows penetration of nanoparticles into the stroma, which proceeds gradually, after an initial 1 h lag phase.<\/jats:p>","DOI":"10.1021\/mp500332m","type":"journal-article","created":{"date-parts":[[2014,8,28]],"date-time":"2014-08-28T15:42:27Z","timestamp":1409240547000},"page":"3556-3564","source":"Crossref","is-referenced-by-count":137,"title":["On the Barrier Properties of the Cornea: A Microscopy\nStudy of the Penetration of Fluorescently Labeled Nanoparticles, Polymers,\nand Sodium Fluorescein"],"prefix":"10.1021","volume":"11","author":[{"given":"Ellina A.","family":"Mun","sequence":"first","affiliation":[{"name":"University of Reading , , Whiteknights, , ,","place":["Reading, United Kingdom, RG6 6AD"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter W. J.","family":"Morrison","sequence":"additional","affiliation":[{"name":"University of Reading , , Whiteknights, , ,","place":["Reading, United Kingdom, RG6 6AD"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian C.","family":"Williams","sequence":"additional","affiliation":[{"name":"University of Reading , , Whiteknights, , ,","place":["Reading, United Kingdom, RG6 6AD"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vitaliy V.","family":"Khutoryanskiy","sequence":"additional","affiliation":[{"name":"University of Reading , , Whiteknights, , ,","place":["Reading, United Kingdom, RG6 6AD"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2014,8,28]]},"reference":[{"key":"2026090121195469500_cit1","first-page":"3","article-title":"Ocular Therapeutics","volume-title":"Eye on New Discoveries","author":"Yorio","year":"2008"},{"key":"2026090121195469500_cit2","unstructured":"World Health Organization.\n          \n          http:\/\/www.who.int\/blindness\/history\/en\/]."},{"key":"2026090121195469500_cit3","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.ejpb.2005.01.009","article-title":"Cell culture models of the ocular\nbarriers","volume":"60","author":"Hornof","year":"2005","journal-title":"Eur. 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Eye Res."},{"key":"2026090121195469500_cit5c","doi-asserted-by":"crossref","first-page":"2010","DOI":"10.1016\/j.addr.2005.09.004","article-title":"Topical and systemic\ndrug delivery to the posterior segments","volume":"57","author":"Hughes","year":"2005","journal-title":"Adv.\nDrug Delivery Rev."},{"key":"2026090121195469500_cit6","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1016\/j.jconrel.2012.01.019","article-title":"Liposomes for intravitreal drug delivery: A state of\nthe art","volume":"161","author":"Bochot","year":"2012","journal-title":"J. Controlled Release"},{"key":"2026090121195469500_cit7","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.drudis.2010.12.004","article-title":"Drug delivery\nto the posterior segment of the eye","volume":"16","author":"Thrimawithana","year":"2011","journal-title":"Drug Discovery\nToday"},{"key":"2026090121195469500_cit8","first-page":"961","article-title":"Drug delivery\nfor posterior segment eye disease","volume":"41","author":"Geroski","year":"2000","journal-title":"Invest. Ophthalmol.\nVisual Sci."},{"key":"2026090121195469500_cit9","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1016\/j.addr.2006.07.027","article-title":"Challenges\nand obstacles of ocular pharmacokinetics and drug delivery","volume":"58","author":"Urtti","year":"2006","journal-title":"Adv. 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Sci."},{"key":"2026090121195469500_cit14","first-page":"684","article-title":"Paracellular permeability of corneal\nand conjunctival epithelia","volume":"30","author":"Huang","year":"1989","journal-title":"Invest. Ophthalmol.\nVisual Sci."},{"key":"2026090121195469500_cit15","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.drudis.2007.10.021","article-title":"Nanotechnology\nin ocular drug delivery","volume":"13","author":"Sahoo","year":"2008","journal-title":"Drug Discovery Today"},{"key":"2026090121195469500_cit16","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.jconrel.2007.11.016","article-title":"Charged nanoparticles delivery to\nthe eye using hydrogel\niontophoresis","volume":"126","author":"Eljarrat-Binstock","year":"2008","journal-title":"J. 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Pharm."},{"key":"2026090121195469500_cit19","doi-asserted-by":"crossref","first-page":"3452","DOI":"10.1021\/bm0604000","article-title":"Carbohydrate-based\nmicelle clusters which enhance hydrophobic drug bioavailability by\nup to 1 order of magnitude","volume":"7","author":"Qu","year":"2006","journal-title":"Biomacromolecules"},{"key":"2026090121195469500_cit20","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/S0378-5173(97)00083-5","article-title":"Evaluation of cationic polymer-coated\nnanocapsules as ocular drug carriers","volume":"153","author":"Calvo","year":"1997","journal-title":"Int. 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J. Pharm. Sci."},{"key":"2026090121195469500_cit25","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/S0939-6411(01)00123-0","article-title":"Reconstruction of an in vitro cornea\nand its use for drug permeation studies from different formulations\ncontaining pilocarpine hydrochloride","volume":"51","author":"Tegtmeyer","year":"2001","journal-title":"Eur. J.\nPharm. Biopharm."},{"key":"2026090121195469500_cit26","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/S0939-6411(03)00036-5","article-title":"Influence of n-octenylsuccinate starch on in vitro\npermeation of sodium diclofenac across excised porcine cornea in comparison\nto Voltaren ophtha","volume":"56","author":"Baydoun","year":"2003","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"2026090121195469500_cit27","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.ejpb.2004.09.016","article-title":"Human cornea\nconstruct HCC\u2500an alternative for in vitro permeation studies?\nA comparison with human donor corneas","volume":"60","author":"Reichl","year":"2005","journal-title":"Eur.\nJ. Pharm. Biopharm."},{"key":"2026090121195469500_cit28","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.ijpharm.2005.09.007","article-title":"Drug release and permeation studies\nof nanosuspensions based on solidified reverse micellar solutions\n(SRMS)","volume":"305","author":"Friedrich","year":"2005","journal-title":"Int. J. Pharm."},{"key":"2026090121195469500_cit29","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1021\/mp3005963","article-title":"Cyclodextrin-Mediated\nEnhancement\nof Riboflavin Solubility and Corneal Permeability","volume":"10","author":"Morrison","year":"2013","journal-title":"Mol. Pharmaceutics"},{"key":"2026090121195469500_cit30","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.ejphar.2013.02.031","article-title":"In vitro evaluation of enhancing\neffect of borneol on transcorneal permeation of compounds with different\nhydrophilicities and molecular sizes","volume":"705","author":"Qi","year":"2013","journal-title":"Eur. J.\nPharmacol."},{"key":"2026090121195469500_cit31","first-page":"1","article-title":"The effects of combined\nmenthol and\nborneol on fluconazole permeation through the cornea ex vivo","volume":"688","author":"Jingjing","year":"2012","journal-title":"Eur. J. Pharmacol."},{"key":"2026090121195469500_cit32","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1016\/j.preteyeres.2010.08.002","article-title":"Applications of nanoparticles in ophthalmology","volume":"29","author":"Diebold","year":"2010","journal-title":"Prog. Retinal Eye Res."},{"key":"2026090121195469500_cit33","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/S0378-5173(01)00761-X","article-title":"Cyclodextrins in topical drug formulations: theory\nand Practice","volume":"225","author":"Loftsson","year":"2001","journal-title":"Int. J. Pharm."},{"key":"2026090121195469500_cit34","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/S0939-6411(00)00108-9","article-title":"Considerations in\nthe use of hydroxypropyl-b-cyclodextrin\nin the formulation of aqueous ophthalmic solutions of hydrocortisone","volume":"50","author":"Bary","year":"2000","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"2026090121195469500_cit35","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1016\/j.exer.2009.08.001","article-title":"Electrically\nassisted delivery of macromolecules into the corneal epithelium","volume":"89","author":"Hao","year":"2009","journal-title":"Exp. Eye Res."},{"key":"2026090121195469500_cit36","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1016\/j.ijbiomac.2011.11.017","article-title":"Carboxymethyl tamarind\nkernel polysaccharide nanoparticles for ophthalmic drug delivery","volume":"50","author":"Kaur","year":"2012","journal-title":"Int. J. Biol. Macromol."},{"key":"2026090121195469500_cit37","doi-asserted-by":"crossref","first-page":"1606","DOI":"10.1016\/j.carbpol.2011.09.065","article-title":"Thiolated pectin nanoparticles: Preparation,\ncharacterization and ex vivo corneal permeation study","volume":"87","author":"Sharma","year":"2012","journal-title":"Carbohydr. Polym."},{"key":"2026090121195469500_cit38a","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/S0168-3659(96)01503-9","article-title":"Ex-vivo permeation study of indomethacin\nfrom a submicron emulsion through albino rabbit cornea","volume":"44","author":"Muchtar","year":"1997","journal-title":"J. Controlled Release"},{"key":"2026090121195469500_cit38b","first-page":"150","article-title":"Effect of circulation on the disposition\nand ocular tissue distribution of 20 nm nanoparticles after periocular\nadministration","volume":"14","author":"Amrite","year":"2008","journal-title":"Mol. Vision"},{"key":"2026090121195469500_cit39","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1002\/mabi.201000388","article-title":"Advances\nin Mucoadhesion and Mucoadhesive Polymers","volume":"11","author":"Khutoryanskiy","year":"2011","journal-title":"Macromol.\nBiosci."},{"key":"2026090121195469500_cit40","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1038\/eye.1993.96","article-title":"Comparison of tear film thickness\nin three species determined by the glass fibre method and confocal\nmicroscopy","volume":"7","author":"Prydal","year":"1993","journal-title":"Eye"},{"key":"2026090121195469500_cit41","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1016\/j.addr.2005.07.002","article-title":"Thiomers:\nA new generation of mucoadhesive polymers","volume":"57","author":"Bernkop-Schnurch","year":"2005","journal-title":"Adv.\nDrug Delivery Rev."},{"key":"2026090121195469500_cit42","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1021\/bm700916h","article-title":"Novel Insulin\nThiomer Nanoparticles: In Vivo Evaluation of an Oral Drug Delivery\nSystem","volume":"9","author":"Deutel","year":"2008","journal-title":"Biomacromolecules"},{"key":"2026090121195469500_cit43","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1016\/S0002-9394(02)02220-1","article-title":"Riboflavin\/Ultraviolet-A-induced\nCollagen Crosslinking for the Treatment of Keratoconus","volume":"135","author":"Wollensak","year":"2003","journal-title":"Am. J. Ophthalmol."},{"key":"2026090121195469500_cit44","first-page":"376","article-title":"Human corneal stroma contains three\ndistinct collagens","volume":"22","author":"Newsome","year":"1982","journal-title":"Invest. Ophthalmol. Visual\nSci."},{"key":"2026090121195469500_cit45","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/S0968-4328(00)00041-X","article-title":"Corneal and scleral\ncollagens\u2500a microscopist\u2019s\nperspective","volume":"32","author":"Meek","year":"2001","journal-title":"Micron"},{"key":"2026090121195469500_cit46","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1016\/j.exer.2003.07.003","article-title":"The organization of collagen in the\ncorneal stroma","volume":"78","author":"Meek","year":"2004","journal-title":"Exp. Eye Res."},{"key":"2026090121195469500_cit47","first-page":"303","article-title":"Collagen types\nin healing alkali-burned corneal stroma in rabbits","volume":"40","author":"Saika","year":"1996","journal-title":"Jpn. J. Ophthalmol."},{"key":"2026090121195469500_cit48","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.addr.2008.11.002","article-title":"Mucus-penetrating nanoparticles for\ndrug and gene delivery to mucosal tissues","volume":"61","author":"Lai","year":"2009","journal-title":"Adv.\nDrug Delivery Rev."},{"key":"2026090121195469500_cit49","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.jconrel.2013.05.035","article-title":"Scalable method to\nproduce biodegradable nanoparticles that rapidly\npenetrate human mucus","volume":"170","author":"Xu","year":"2013","journal-title":"J. Controlled Release"},{"key":"2026090121195469500_cit50","first-page":"735","article-title":"PEGylation\nof nanoparticles improves\ntheir cytoplasmic transport","volume":"2","author":"Suh","year":"2007","journal-title":"Int. J. Nanomed."},{"key":"2026090121195469500_cit51","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.jconrel.2013.01.018","article-title":"Nanoparticle diffusion\nin, and microrheology of, the bovine vitreous\nex vivo","volume":"167","author":"Xu","year":"2013","journal-title":"J. Controlled Release"}],"container-title":["Molecular Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/mp500332m","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/mpohbp\/article-pdf\/11\/10\/3556\/14379612\/mp500332m.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/mpohbp\/article-pdf\/11\/10\/3556\/14379612\/mp500332m.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T01:20:05Z","timestamp":1788312005000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/mpohbp\/article\/11\/10\/3556\/1380162\/On-the-Barrier-Properties-of-the-Cornea-A"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,8,28]]},"references-count":54,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2014,8,28]]},"published-print":{"date-parts":[[2014,10,6]]}},"URL":"https:\/\/doi.org\/10.1021\/mp500332m","relation":{},"ISSN":["1543-8384","1543-8392"],"issn-type":[{"value":"1543-8384","type":"print"},{"value":"1543-8392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,8,28]]}}}