title: Round window membrane intracochlear drug delivery enhanced by induced advection.
abstract: Delivery of therapeutic compounds to the inner ear via absorption through the round window membrane (RWM) has advantages over direct intracochlear infusions; specifically, minimizing impact upon functional hearing measures. However, previous reports show that significant basal-to-apical concentration gradients occur, with the potential to impact treatment efficacy. Here we present a new approach to inner ear drug delivery with induced advection aiding distribution of compounds throughout the inner ear in the murine cochlea. Polyimide microtubing was placed near the RWM niche through a bullaostomy into the middle ear cavity allowing directed delivery of compounds to the RWM. We hypothesized that a posterior semicircular canalostomy would induce apical flow from the patent cochlear aqueduct to the canalostomy due to influx of cerebral spinal fluid. To test this hypothesis, young adult CBA/CaJ mice were divided into two groups: bullaostomy approach only (BA) and bullaostomy+canalostomy (B+C). Cochlear function was evaluated by distortion product otoacoustic emission (DPOAE) and auditory brainstem response (ABR) thresholds during and after middle ear infusion of salicylate in artificial perilymph (AP), applied near the RWM. The mice recovered for 1week, and were re-tested. The results demonstrate there was no significant impact on auditory function utilizing the RWM surgical procedure with or without the canalostomy, and DPOAE thresholds were elevated reversibly during the salicylate infusion. Comparing the threshold shifts for both methods, the B+C approach had more of a physiological effect than the BA approach, including at lower frequencies representing more apical cochlear locations. Unlike mouse cochleostomies, there was no deleterious auditory functional impact after 1week recovery from surgery. The B+C approach had more drug efficacy at lower frequencies, underscoring potential benefits for more precise control of delivery of inner ear therapeutic compounds.
authors.affiliation: Department of Electrical and Microelectronic Engineering, Rochester Institute of Technology, Rochester 14623, USA; Department of Microsystems Engineering, Rochester Institute of Technology, Rochester 14623, USA; Department of Otolaryngology, University of Rochester Medical School, Rochester 14642, USA; Department of Biomedical Engineering, University of Rochester Medical School, Rochester 14642, USA. Electronic address: david.borkholder@rit.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Borkholder
authors.affiliation: Department of Otolaryngology, University of Rochester Medical School, Rochester 14642, USA; International Center for Hearing & Speech Research, National Technical Institute for the Deaf, Rochester Institute of Technology, Rochester 14623, USA. Electronic address: xiaoxiazhu@usf.edu.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Otolaryngology, University of Rochester Medical School, Rochester 14642, USA; Department of Biomedical Engineering, University of Rochester Medical School, Rochester 14642, USA; Department of Neurobiology & Anatomy, University of Rochester Medical School, Rochester 14642, USA; International Center for Hearing & Speech Research, National Technical Institute for the Deaf, Rochester Institute of Technology, Rochester 14623, USA. Electronic address: rfrisina@usf.edu.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Frisina
mesh_terms: D000818:Animals; D004333:Drug Administration Routes; D016503:Drug Delivery Systems; D016057:Evoked Potentials, Auditory, Brain Stem; D006309:Hearing; D051379:Mice; D008808:Mice, Inbred CBA; D012405:Round Window, Ear / Q000378:metabolism* / Q000502:physiology; D012980:Sodium Salicylate / Q000008:administration & dosage
chemical_list: D012980:Sodium Salicylate
keywords: Cochlea; Concentration gradient; Drug delivery; Infusion; Inner ear; Mouse