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Noninvasive Technique for Monitoring Drug Transport Through the Murine Cochlea using Micro-Computed Tomography

Abstract

Local delivery of drugs to the inner ear has the potential to treat inner ear disorders including permanent hearing loss or deafness. Current mathematical models describing the pharmacokinetics of drug delivery to the inner ear have been based on large rodent studies with invasive measurements of concentration at few locations within the cochlea. Hence, estimates of clearance and diffusion parameters are based on fitting measured data with limited spatial resolution to a model. To overcome these limitations, we developed a noninvasive imaging technique to monitor and characterize drug delivery inside the mouse cochlea using micro-computed tomography (μCT). To increase the measurement accuracy, we performed a subject-atlas image registration to exploit the information readily available in the atlas image of the mouse cochlea and pass segmentation or labeling information from the atlas to our μCT scans. The approach presented here has the potential to quantify concentrations at any point along fluid-filled scalae of the inner ear. This may permit determination of spatially dependent diffusion and clearance parameters for enhanced models.

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Abbreviations

μCT:

Micro-computed tomography

ABR:

Auditory Brainstem Response

AP:

Artificial perilymph

CA:

Cochlear aqueduct

CAP:

Compound Action Potential

CSF:

Cerebrospinal fluid

DPOAE:

Distortion product otoacoustic emissions

IP:

Intraperitoneal injection

MCD:

Mouse cochlea database

MI:

Mutual information

NMI:

Normalized mutual information

OD:

Outer diameter

OPFOS:

Orthogonal plane fluorescence optical sectioning

ROI:

Region of interest

RW:

Round window

SM:

Scala media

SSM:

Statistical shape models

ST:

Scala tympani

SV:

Scala vestibuli

TMPA:

Trimethylphenylammonium

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Acknowledgments

This work was supported in part by NIH Grants from the National Institute on Deafness and other Communication Disorders (K25-DC008291), the National Institute on Aging (P01 AG009524), and the Schmitt Foundation. We thank Dr. Peter Santi for providing access to the mouse cochlea data base. We also thank Mr. Mike Thullen for his technical support in μCT imaging. The help of Dr. Stefan Klein with the elastix software and the help of the AMIRA support team are gratefully acknowledged.

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Correspondence to David A. Borkholder.

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Associate Editor Aleksander S. Popel oversaw the review of this article.

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Haghpanahi, M., Gladstone, M.B., Zhu, X. et al. Noninvasive Technique for Monitoring Drug Transport Through the Murine Cochlea using Micro-Computed Tomography. Ann Biomed Eng 41, 2130–2142 (2013). https://doi.org/10.1007/s10439-013-0816-4

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  • DOI: https://doi.org/10.1007/s10439-013-0816-4

Keywords

  • Computed tomography
  • Image registration
  • Automatic segmentation
  • Drug delivery
  • Pharmacokinetics
  • Inner ear
  • Mouse
  • Cochlea