title: Microperforations significantly enhance diffusion across round window membrane.
abstract: OBJECTIVE
  Introduction of microperforations in round window membrane (RWM) will allow reliable and predictable intracochlear delivery of pharmaceutical, molecular, or cellular therapeutic agents.
  
  
  BACKGROUND
  Reliable delivery of medications into the inner ear remains a formidable challenge. The RWM is an attractive target for intracochlear delivery. However, simple diffusion across intact RWM is limited by what material can be delivered, size of material to be delivered, difficulty with precise dosing, timing, and precision of delivery over time. Further, absence of reliable methods for measuring diffusion across RWM in vitro is a significant experimental impediment.
  
  
  METHODS
  A novel model for measuring diffusion across guinea pig RWM, with and without microperforation, was developed and tested: cochleae, sparing the RWM, were embedded in 3D-printed acrylic holders using hybrid dental composite and light cured to adapt the round window niche to 3 ml Franz diffusion cells. Perforations were created with 12.5-μm-diameter needles and examined with light microscopy. Diffusion of 1 mM Rhodamine B across RWM in static diffusion cells was measured via fluorescence microscopy.
  
  
  RESULTS
  The diffusion cell apparatus provided reliable and replicable measurements of diffusion across RWM. The permeability of Rhodamine B across intact RWM was 5.1 × 10(9-) m/s. Manual application of microperforation with a 12.5-μm-diameter tip produced an elliptical tear removing 0.22 ± 0.07% of the membrane and was associated with a 35× enhancement in diffusion (P < 0.05).
  
  
  CONCLUSIONS
  Diffusion cells can be applied to the study of RWM permeability in vitro. Microperforation in RWM is an effective means of increasing diffusion across the RWM.
authors.affiliation: *Department of Otolaryngology-Head and Neck Surgery, Columbia University College of Physicians and Surgeons; †Department of Mechanical Engineering; and ‡Department of Biomedical Engineering, Columbia University, New York, New York, U.S.A.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Kelso
authors.forename: Hirobumi
authors.initials: H
authors.lastname: Watanabe
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Wazen
authors.forename: Tizian
authors.initials: T
authors.lastname: Bucher
authors.forename: Zhen J
authors.initials: ZJ
authors.lastname: Qian
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Olson
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Kysar
authors.forename: Anil K
authors.initials: AK
authors.lastname: Lalwani
mesh_terms: D000818:Animals; D004058:Diffusion; D004333:Drug Administration Routes; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008962:Models, Theoretical; D010539:Permeability; D012405:Round Window, Ear / Q000737:chemistry*