Murine intracochlear drug delivery: Reducing concentration gradients within the cochlea

Department of Electrical and Microelectronic Engineering, Rochester Institute of Technology, Rochester, NY 14623, USA.
Hearing research (Impact Factor: 2.97). 05/2010; 268(1-2):2-11. DOI: 10.1016/j.heares.2010.04.014
Source: PubMed


Direct delivery of compounds to the mammalian inner ear is most commonly achieved by absorption or direct injection through the round window membrane (RWM), or infusion through a basal turn cochleostomy. These methods provide direct access to cochlear structures, but with a strong basal-to-apical concentration gradient consistent with a diffusion-driven distribution. This gradient limits the efficacy of therapeutic approaches for apical structures, and puts constraints on practical therapeutic dose ranges. A surgical approach involving both a basal turn cochleostomy and a posterior semicircular canal canalostomy provides opportunities for facilitated perfusion of cochlear structures to reduce concentration gradients. Infusion of fixed volumes of artificial perilymph (AP) and sodium salicylate were used to evaluate two surgical approaches in the mouse: cochleostomy-only (CO), or cochleostomy-plus-canalostomy (C+C). Cochlear function was evaluated via closed-system distortion product otoacoustic emissions (DPOAE) threshold level measurements from 8 to 49 kHz. AP infusion confirmed no surgical impact to auditory function, while shifts in DPOAE thresholds were measured during infusion of salicylate and AP (washout). Frequency dependent shifts were compared for the CO and C+C approaches. Computer simulations modeling diffusion, volume flow, interscala transport, and clearance mechanisms provided estimates of drug concentration as a function of cochlear position. Simulated concentration profiles were compared to frequency-dependent shifts in measured auditory responses using a cochlear tonotopic map. The impact of flow rate on frequency dependent DPOAE threshold shifts was also evaluated for both surgical approaches. Both the C+C approach and a flow rate increase were found to provide enhanced response for lower frequencies, with evidence suggesting the C+C approach reduces concentration gradients within the cochlea.

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Available from: David A Borkholder, Oct 08, 2015
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    • "Will increasing the expression of these ion channels/pumps improve hearing in old mice, as relations have been observed between hearing thresholds, strial function, and endocochlear potential levels in aging mammals (Gratton, Schmiedt, & Schulte, 1996; Lang et al., 2010; Marcus, Wu, Wangemann, & Kofuji, 2002)? Can novel microelectromechanical cochlear drug delivery systems be utilized to deliver therapeutic compounds to the mammalian cochlea (Borkholder et al., 2010; Johnson, Frisina, & Borkholder, 2011; Johnson, Waldron, Frisina, & Borkholder, 2010), circumventing problems of unstable dosage levels and systemic side effects? "
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    • "Progress toward safe and efficacious inner ear delivery systems will benefit from microsystems-based approaches, where multiple therapeutic compounds can be introduced in a highly controlled and timesequenced manner over periods of months to years, enabling precise control over the drug concentration, kinetics and molecular and cellular targeting of therapies for hearing restoration. Microsystems-based drug delivery systems are emerging for a range of clinical applications, and these capabilities have been leveraged toward the inner ear [5] [6] [7] [8] [9]. As noted in these investigations, there are several aspects of inner ear delivery that present specific technological challenges. "
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    • "A similar strategy was used for fluid delivery into the perilymph compartment of the adult mouse cochlea.52, 53 Infusion of an artificial perilymph solution into the scala tympani at a rate of 16–32 nl/min resulted in good preservation of hearing function. "
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