title: Searching for a rat model of chronic tympanic membrane perforation: Healing delayed by mitomycin C/dexamethasone but not paper implantation or iterative myringotomy.
abstract: OBJECTIVE
  Surgical intervention such as myringoplasty or tympanoplasty is an option in the current clinical management of chronic tympanic membrane perforation (TMP). Animal models of chronic TMP are needed for pre-clinical testing of new materials and to improve existing techniques. We evaluated several reported animal model techniques from the literature for the creation of chronic TMPs. The aim of this study was to evaluate production of chronic TMPs in a rat model using topical mitomycin C/dexamethasone, paper insertion into middle ear cavity (MEC) or re-myringotomy.
  
  
  METHODS
  Forty male Sprague-Dawley rats underwent myringotomy of the right tympanic membrane (TM) and were randomly divided into 3 experimental groups: application of topical mitomycin C/dexamethasone, paper insertion into middle ear cavity, or re-myringotomy. Control perforations were allowed to close spontaneously. TMs were assessed regularly with otoscopy for 8 weeks. At the end of 8 weeks, animals were sacrificed for histology.
  
  
  RESULTS
  The closure of TMPs was significantly delayed by mitomycin C/dexamethasone (mean patency, 18.9 days; P≤0.01) compared with the control (mean patency, 7 days), but was not significantly delayed in the paper insertion group (mean patency, 9.4 days; P=0.74). Repeated myringotomy of closed perforations (mean number of myringotomies, 8.9 per ear) stimulated acceleration of closure rather than delay. Histologically, the mitomycin C/dexamethasone group had almost normal TM morphology, while the paper insertion group revealed inflammatory and granulomatous responses. The re-myringotomy group had a thickened TM fibrous layer with collagen deposition.
  
  
  CONCLUSIONS
  Mitomycin C/dexamethasone delayed TMP closure in rats but the effect was not sufficiently long-lasting to be defined as a chronic TMP. Neither paper insertion into middle ear cavity nor re-myringotomy created chronic TMP in rats.
authors.affiliation: Ear Sciences Centre, School of Surgery, The University of Western Australia, Perth, WA, Australia; Ear Science Institute Australia, Perth, WA, Australia; Department of Otolaryngology, Head and Neck, Skull Base Surgery, Sir Charles Gairdner Hospital, Perth, WA, Australia. Electronic address: allen.wang@earscience.org.au.
authors.forename: Allen Y
authors.initials: AY
authors.lastname: Wang
authors.affiliation: Ear Sciences Centre, School of Surgery, The University of Western Australia, Perth, WA, Australia; Ear Science Institute Australia, Perth, WA, Australia; Department of Otolaryngology, Head and Neck Surgery, Ningbo Lihuili Hospital (Ningbo Medical Centre), Ningbo, Zhejiang, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Ear Sciences Centre, School of Surgery, The University of Western Australia, Perth, WA, Australia; Ear Science Institute Australia, Perth, WA, Australia.
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Liew
authors.affiliation: Ear Sciences Centre, School of Surgery, The University of Western Australia, Perth, WA, Australia.
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Wang
authors.affiliation: Akershus University Hospital, Lørenskog, Norway; University of Oslo, Oslo, Norway; Center for Clinical Research Västerås, University of Uppsala, Uppsala, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: von Unge
authors.affiliation: Ear Sciences Centre, School of Surgery, The University of Western Australia, Perth, WA, Australia; Ear Science Institute Australia, Perth, WA, Australia; Department of Otolaryngology, Head and Neck, Skull Base Surgery, Sir Charles Gairdner Hospital, Perth, WA, Australia.
authors.forename: Marcus D
authors.initials: MD
authors.lastname: Atlas
authors.affiliation: Ear Sciences Centre, School of Surgery, The University of Western Australia, Perth, WA, Australia; Ear Science Institute Australia, Perth, WA, Australia.
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Dilley
mesh_terms: D000477:Alkylating Agents / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002908:Chronic Disease; D003907:Dexamethasone / Q000494:pharmacology*; D004195:Disease Models, Animal; D008297:Male; D016685:Mitomycin / Q000494:pharmacology*; D010209:Paper; D019736:Prostheses and Implants; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014432:Tympanic Membrane / Q000601:surgery*; D018058:Tympanic Membrane Perforation / Q000473:pathology; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D000477:Alkylating Agents; D000893:Anti-Inflammatory Agents; D016685:Mitomycin; D003907:Dexamethasone
keywords: Animal model; Chronic; Mitomycin C; Otology; Tympanic membrane; Tympanic membrane perforation