{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T16:00:48Z","timestamp":1753891248663,"version":"3.41.2"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2020,12,18]],"date-time":"2020-12-18T00:00:00Z","timestamp":1608249600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:p>Middle ear ailments include a broad range of pathological conditions. Otitis media is the leading middle ear disease of childhood, which incurs significant health care resources in developed countries and, in developing countries, causes significant mortality and morbidity. Recurrent and chronic infections of the middle ear lead to the prolonged presence of inflammatory factors and cellular infiltrates resulting in temporary hearing loss. However, long-term alteration of the middle ear space can pose the risk of permanent damage to the delicate ear structures and cause tissue remodeling. While the etiopathogenesis of middle ear diseases is multifactorial, targeting the biological mechanisms and molecular networks that drive disease development is critical. Yet, a pivotal step in realizing the potential of molecular therapies is the development of methods for local drug delivery, since systemic application risks side effects. Utilizing bacteriophage display in the rat, we discovered rare peptides that are able to transit the intact tympanic membrane from the external canal to the middle ear cavity by an active process. An <jats:italic>in vitro<\/jats:italic> assay demonstrated that transport occurs across the tympanic membranes of humans and that the peptides cross the membrane independent of phage. Transport of phage, which is ~900 nm in length, suggests that these peptides could non-invasively deliver drug packages or gene therapy vectors into the middle ear.<\/jats:p>","DOI":"10.3389\/fmed.2020.503819","type":"journal-article","created":{"date-parts":[[2020,12,18]],"date-time":"2020-12-18T05:56:58Z","timestamp":1608271018000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Molecular Screening Strategy to Identify a Non-invasive Delivery Mechanism for the Treatment of Middle Ear Disorders"],"prefix":"10.3389","volume":"7","author":[{"given":"Arwa","family":"Kurabi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Molly","family":"Cooper","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meghan","family":"Spriggs","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuge","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Schaerer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Allen F.","family":"Ryan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2020,12,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"444","DOI":"10.1093\/oxfordjournals.epirev.a036129","article-title":"Otitis media in children: frequency, risk factors, and research avenues","volume":"15","author":"Infante-Rivard","year":"1993","journal-title":"Epidemiol Rev."},{"key":"B2","first-page":"9","article-title":"Socioeconomic impact of otitis media in North America","volume":"27","author":"Elden","year":"1998","journal-title":"J Otolaryngol."},{"unstructured":"Chronic Suppurative Otitis Media: Burden of Illness and Management Options2004","key":"B3"},{"key":"B4","doi-asserted-by":"publisher","first-page":"e0150949","DOI":"10.1371\/journal.pone.0150949","article-title":"Predominant bacteria detected from the middle ear fluid of children experiencing otitis media: a systematic review","volume":"11","author":"Ngo","year":"2016","journal-title":"PLoS ONE"},{"key":"B5","doi-asserted-by":"publisher","first-page":"e964","DOI":"10.1542\/peds.2012-3488","article-title":"The diagnosis and management of acute otitis media","volume":"131","author":"Lieberthal","year":"2013","journal-title":"Pediatrics."},{"key":"B6","doi-asserted-by":"publisher","first-page":"S8","DOI":"10.1016\/S0002-9270(99)00808-4","article-title":"The effects of antibiotic use on gastrointestinal function","volume":"95","author":"Levy","year":"2000","journal-title":"Am J. Gastroenterol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1177\/2042098614554919","article-title":"Antimicrobial resistance: risk associated with antibiotic overuse and initiatives to reduce the problem","volume":"5","author":"Llor","year":"2014","journal-title":"Ther Adv Drug Saf."},{"key":"B8","doi-asserted-by":"publisher","first-page":"243","DOI":"10.2165\/00148581-200911040-00003","article-title":"Variations in amoxicillin pharmacokinetic\/pharmacodynamic parameters may explain treatment failures in acute otitis media","volume":"11","author":"Pichichero","year":"2009","journal-title":"Paediatr Drugs."},{"key":"B9","doi-asserted-by":"publisher","first-page":"S1","DOI":"10.1177\/0194599813487302","article-title":"Clinical practice guideline: tympanostomy tubes in children","volume":"149","author":"Rosenfeld","year":"2013","journal-title":"Otolaryngol Head Neck Surg"},{"key":"B10","doi-asserted-by":"publisher","first-page":"16063","DOI":"10.1038\/nrdp.2016.63","article-title":"Otitis media","volume":"2","author":"Schilder","year":"2016","journal-title":"Nat Rev Dis Primers."},{"key":"B11","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1016\/j.jgg.2014.10.003","article-title":"Immunity genes and susceptibility to otitis media: a comprehensive review","volume":"41","author":"Mittal","year":"2014","journal-title":"J Genet Genomics"},{"key":"B12","doi-asserted-by":"publisher","first-page":"854024","DOI":"10.1155\/2015\/854024","article-title":"Updates and knowledge gaps in cholesteatoma research","volume":"2015","author":"Kuo","year":"2015","journal-title":"Biomed Res Int."},{"key":"B13","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1097\/MOO.0b013e3283303688","article-title":"Contemporary assessment and management of congenital cholesteatoma","volume":"17","author":"Richter","year":"2009","journal-title":"Curr Opin Otolaryngol Head Neck Surg."},{"key":"B14","doi-asserted-by":"publisher","first-page":"298","DOI":"10.21053\/ceo.2015.01662","article-title":"Pathogenesis and bone resorption in acquired cholesteatoma: current knowledge and future prospectives","volume":"9","author":"Hamed","year":"2016","journal-title":"Clin Exp Otorhinolaryngol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1002\/lary.24890","article-title":"Etiopathogenesis of acquired cholesteatoma: prominent theories and recent advances in biomolecular research","volume":"125","author":"Kuo","year":"2015","journal-title":"Laryngoscope."},{"key":"B16","doi-asserted-by":"publisher","first-page":"e0132551","DOI":"10.1371\/journal.pone.0132551","article-title":"Predisposition to childhood otitis media and genetic polymorphisms within the toll-like receptor 4 (TLR4) Locus","volume":"10","author":"Hafr\u00e9n","year":"2015","journal-title":"PLoS ONE."},{"key":"B17","doi-asserted-by":"publisher","first-page":"674","DOI":"10.1016\/j.ijporl.2013.01.010","article-title":"Expression of toll-like receptors in chronic otitis media and cholesteatoma","volume":"77","author":"Hirai","year":"2013","journal-title":"Int J Pediatr Otorhinolaryngol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"408169","DOI":"10.1155\/2015\/408169","article-title":"NOD-like receptor signaling in cholesteatoma","volume":"2015","author":"Leichtle","year":"2015","journal-title":"Biomed Res Int"},{"volume-title":"Phage Display: A Laboratory Manual","year":"2004","author":"Barbas","key":"B19"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1315","DOI":"10.1126\/science.4001944","article-title":"Filamentous fusion phage: novel expression vectors that display cloned antigens on the virion surface","volume":"228","author":"Smith","year":"1985","journal-title":"Science."},{"key":"B21","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1038\/380364a0","article-title":"Organ targeting in-vivo using phage display peptide libraries","volume":"380","author":"Pasqualini","year":"1996","journal-title":"Nature."},{"key":"B22","doi-asserted-by":"publisher","first-page":"73","DOI":"10.4161\/mabs.27240","article-title":"Drugs derived from phage display: from candidate identification to clinical practice","volume":"6","author":"Nixon","year":"2014","journal-title":"MAbs."},{"key":"B23","doi-asserted-by":"publisher","first-page":"e00954","DOI":"10.1128\/AAC.00954-17","article-title":"Development and use of personalized bacteriophage-based therapeutic cocktails to treat a patient with a disseminated resistant Acinetobacter baumannii infection","volume":"22","author":"Schooley","year":"2017","journal-title":"Antimicrob Agents Chemother"},{"key":"B24","doi-asserted-by":"publisher","first-page":"1301","DOI":"10.1128\/AAC.47.4.1301-1307.2003","article-title":"Use of genetically engineered phage to deliver antimicrobial agents to bacteria: an alternative therapy for treatment of bacterial infections","volume":"47","author":"Westwater","year":"2003","journal-title":"Antimicrob Agents Chemother."},{"key":"B25","doi-asserted-by":"publisher","first-page":"22663","DOI":"10.1038\/srep22663","article-title":"Discovery of a biological mechanism of active transport through the tympanic membrane to the middle ear","volume":"6","author":"Kurabi","year":"2016","journal-title":"Sci Rep."},{"key":"B26","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1080\/1061186X.2017.1347791","article-title":"Optimisation of peptides that actively cross the tympanic membrane by random amino acid extension: a phage display study","volume":"26","author":"Kurabi","year":"2018","journal-title":"J Drug Target."},{"key":"B27","doi-asserted-by":"publisher","first-page":"e0172158","DOI":"10.1371\/journal.pone.0172158","article-title":"Peptides actively transported across the tympanic membrane: functional and structural properties","volume":"12","author":"Kurabi","year":"2017","journal-title":"PLoS ONE."},{"key":"B28","doi-asserted-by":"publisher","first-page":"11815","DOI":"10.1038\/s41598-018-30031-6","article-title":"Active transport of peptides across the intact human tympanic membrane","volume":"8","author":"Kurabi","year":"2018","journal-title":"Sci Rep"},{"key":"B29","doi-asserted-by":"publisher","first-page":"W498","DOI":"10.1093\/nar\/gkp323","article-title":"PEP-FOLD: an online resource for de novo peptide structure prediction","volume":"37","author":"Maupetit","year":"2009","journal-title":"Nucl Acids Res"},{"key":"B30","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1016\/j.ajhg.2018.09.010","article-title":"FUT2 variants confer susceptibility to familial otitis media","volume":"103","author":"Santos-Cortez","year":"2018","journal-title":"Am J Human Genet"},{"key":"B31","doi-asserted-by":"publisher","first-page":"12496","DOI":"10.1038\/s41598-017-12784-8","article-title":"A mouse-to-man candidate gene study identifies association of chronic otitis media with the loci TGIF1 and FBXO11","volume":"7","author":"Bhutta","year":"2017","journal-title":"Sci Rep"},{"key":"B32","doi-asserted-by":"publisher","first-page":"323","DOI":"10.3389\/fncel.2019.00323","article-title":"Gene therapy for human sensorineural hearing loss","volume":"13","author":"Ren","year":"2019","journal-title":"Front Cell Neurosci."},{"key":"B33","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1016\/j.apsb.2013.02.003","article-title":"Current strategies for drug delivery to the inner ear","volume":"3","author":"Hongzhuo","year":"2013","journal-title":"Acta Pharmaceutica Sinica."},{"key":"B34","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1097\/MAO.0000000000000759","article-title":"Therapeutic effect of dexamethasone for noise-induced hearing loss: systemic versus intratympanic injection in mice","volume":"36","author":"Han","year":"2015","journal-title":"Otol Neurotol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"452","DOI":"10.1177\/0194599811406673","article-title":"Intratympanic dexamethasone to prevent cisplatin ototoxicity: a guinea pig model","volume":"145","author":"Murphy","year":"2011","journal-title":"Otolaryngol Head Neck Surg."},{"key":"B36","doi-asserted-by":"publisher","first-page":"589","DOI":"10.3390\/jcm9020589","article-title":"rAAV-mediated cochlear gene therapy: prospects and challenges for clinical application","volume":"9","author":"Blanc","year":"2020","journal-title":"J Clin Med"},{"key":"B37","doi-asserted-by":"publisher","first-page":"4496","DOI":"10.1073\/pnas.1817537116","article-title":"Dual AAV-mediated gene therapy restores hearing in a DFNB9 mouse model","volume":"116","author":"Akil","year":"2019","journal-title":"Proc Natl Acad Sci USA."},{"key":"B38","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1016\/j.omtm.2019.01.002","article-title":"Targeted gene delivery into the mammalian inner ear using synthetic serotypes of adeno-associated virus vectors","volume":"13","author":"Kim","year":"2019","journal-title":"Mol Ther Methods Clin Devl."},{"key":"B39","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1038\/s41467-019-08716-x","article-title":"Improved TMC1 gene therapy restores hearing and balance in mice with genetic inner ear disorders","volume":"10","author":"Nist-Lund","year":"2019","journal-title":"Nat Commun"},{"key":"B40","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1126\/scitranslmed.aao0935","article-title":"Delivery of therapeutics to the inner ear: the challenge of the blood-labyrinth barrier","volume":"6","author":"Nyberg","year":"2019","journal-title":"Sci Transl Med"}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2020.503819\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,12,18]],"date-time":"2020-12-18T05:57:03Z","timestamp":1608271023000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2020.503819\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,18]]},"references-count":40,"alternative-id":["10.3389\/fmed.2020.503819"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2020.503819","relation":{},"ISSN":["2296-858X"],"issn-type":[{"type":"electronic","value":"2296-858X"}],"subject":[],"published":{"date-parts":[[2020,12,18]]},"article-number":"503819"}}