Initial Method for Characterization of Tympanic Membrane Drug Permeability in Human Temporal Bones In Situ

Abstract

Background and Introduction: Acute otitis media is the most common reason for a visit to the pediatrician, often requiring systemic administration of oral antibiotics. Local drug therapy applied to the middle ear could avoid side effects associated with systemic antibiotic administration, however in the majority of patients this would require drugs to diffuse across an intact tympanic membrane. Experimental methods for testing trans-tympanic drug flux in human tissues in situ would be highly valuable to guide drug therapy development for local drug delivery to the middle ear.Materials and Methods: A total of 30 cadaveric human temporal bones were characterized by trans-tympanic impedance testing to determine how steps in tissue processing and storage might impact intactness of the tympanic membrane and thus suitability for use in studies of trans-tympanic drug flux. Ciprofloxacin drug solutions of varying concentrations were then applied to the lateral surface of the tympanic membrane in eight samples, and middle ear aspirate was collected over the following 48 h to evaluate trans-tympanic flux to the middle ear.Results: Tissue processing steps that involved extensive tissue manipulation were consistently associated with evidence of microperforations in the tympanic membrane tissue. Maintaining the tympanic membrane in situ within the temporal bone, while using an otologic drill to obtain transmastoid access to the middle ear, was demonstrated as a reliable, non-damaging technique for accessing both lateral and medial surfaces for trans-tympanic flux testing. Results in these bones demonstrated trans-tympanic flux of ciprofloxacin when administered at sufficiently high concentration.Discussion and Conclusion: The study describes key techniques and best practices, as well as pitfalls to avoid, in the development of a model for studying trans-tympanic drug flux in human temporal bones in situ. This model can be a valuable research tool in advancing progress toward eventual clinical studies for trans-tympanic drug delivery to the middle ear.

Mortui vivos docent: a modern revival of temporal bone plug harvests

“…Furosemide, another known ototoxic agent, was shown to cause edema and cystic changes in the stria vascularis, collapse of the Reissner’s and tectorial membranes, and diffuse loss of hair cells ( Santos and Nadol, 2017 ). HTBs have also served as effective models for evaluating therapeutic drug delivery to the middle and inner ear ( Early et al, 2021 ; Veit et al, 2022 ). Multifunctional nanoparticles have been shown to cross the round window membrane and penetrate into the sensory hair cells and nerve fibers of the cochlea ( Roy et al, 2012 ).…”

“…Furosemide, another known ototoxic agent, was shown to cause edema and cystic changes in the stria vascularis, collapse of the Reissner's and tectorial membranes, and diffuse loss of hair cells (Santos and Nadol, 2017). HTBs have also served as effective models for evaluating therapeutic drug delivery to the middle and inner ear (Early et al, 2021;Veit et al, 2022).…”

Overcoming barriers: a review on innovations in drug delivery to the middle and inner ear

“…Topical treatments such as ciprofloxacin/dexamethasone ear drops or Otiprio ® are efficacious for OM, however they are indicated exclusively for OM with perforated TM (e.g., post tympanostomy or CSOM) ( van Dongen et al, 2014 ). While animal and human cadaveric studies have showed that intact TMs are readily permeable to ciprofloxacin ( Yang et al, 2016 ; Yang et al, 2018b ; Early et al, 2021 ), it remains unclear whether such results can be achieved in a clinical setting. Apart from this physical barrier, bacterial biofilm formed during OM creates a second physical-chemical barrier that hinders treatment ( Silva and Sillankorva, 2019 ).…”

Ex vivo transtympanic permeation of the liposome encapsulated S. pneumoniae endolysin MSlys

“…Porcine skin is often used as an alternative to human skin in transdermal permeation studies since they are histologically similar, have comparable stratum corneum thicknesses and have identical permeability ( Abd et al, 2016 ; Supe and Takudage, 2021 ). For the transtympanic studies, ex vivo TMs from different animal species as well as animal temporal bones, including rabbit auditory bullae positioned in beakers ( Abdelbary et al, 2019 ; Al-mahallawi et al, 2017 ; Al-Mahallawi et al, 2014 ), chinchilla auditory bullae placed in transwell membrane inserts ( Khoo et al, 2013 ; Yang et al, 2019 , 2018a , 2018b , 2016 ), and more recently, human temporal bones mounted in paraffin ( Early et al, 2021 ) have been used.…”