Inner ear drug delivery via a reciprocating perfusion system in the guinea pig

Chen, Zhiqiang; Kujawa, Sharon G.; McKenna, Michael J.; Fiering, Jason; Mescher, Mark J.; Borenstein, Jeffrey T.; Swan, Erin E. Leary; Sewell, William F.

doi:10.1016/j.jconrel.2005.09.003

Cited by 71 publications

(88 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Considering that respiratory fluctuations are around 0.3 mmHg (∼40 Pa) (Böhmer 1993), each respiratory cycle is calculated to result in a volume displacement of approximately 5.6 nL. A similar reciprocating flow mechanism has been used as the basis of a drug delivery system for the ear (Chen et al 2005;Sewell et al 2009). …”

Section: Discussionmentioning

confidence: 99%

Perilymph Kinetics of FITC-Dextran Reveals Homeostasis Dominated by the Cochlear Aqueduct and Cerebrospinal Fluid

Salt

Gill

Hartsock

2015

JARO

View full text Add to dashboard Cite

Understanding how drugs are distributed in perilymph following local applications is important as local drug therapies are increasingly used to treat disorders of the inner ear. The potential contribution of cerebrospinal fluid (CSF) entry to perilymph homeostasis has been controversial for over half a century, largely due to artifactual contamination of collected perilymph samples with CSF. Measures of perilymph flow and of drug distribution following round window niche applications have both suggested a slow, apically directed flow occurs along scala tympani (ST) in the normal, sealed cochlea. In the p r e s e n t s t u d y , w e h a v e u s e d f l u o r e s c e i n isothiocyanate-dextran as a marker to study perilymph kinetics in guinea pigs. Dextran is lost from perilymph more slowly than other substances so far quantified. Dextran solutions were injected from pipettes sealed into the lateral semicircular canal (SCC), the cochlear apex, or the basal turn of ST. After varying delays, sequential perilymph samples were taken from the cochlear apex or lateral SCC, allowing dextran distribution along the perilymphatic spaces to be quantified. Variability was low and findings were consistent with the injection procedure driving volume flow towards the cochlear aqueduct, and with volume flow during perilymph sampling driven by CSF entry at the aqueduct. The decline of dextran with time in the period between injection and sampling was consistent with both a slow volume influx of CSF (∼30 nL/min) entering the basal turn of ST at the cochlear aqueduct and a CSF-perilymph exchange driven by pressure-driven fluid oscillation across the cochlear aqueduct. Sample data also allowed contributions of other processes, such as communications with adjacent compartments, to be quantified. The study demonstrates that drug kinetics in the basal turn of ST is complex and is influenced by a considerable number of interacting processes.

show abstract

Section: Discussionmentioning

confidence: 99%

Perilymph Kinetics of FITC-Dextran Reveals Homeostasis Dominated by the Cochlear Aqueduct and Cerebrospinal Fluid

Salt

Gill

Hartsock

2015

JARO

View full text Add to dashboard Cite

show abstract

“…Drug delivery into the cochlear base would not be suitable for this purpose because solutions injected in the base spread only slowly towards the apex, predominantly by diffusion (Chen et al 2005). The rate of spread of 3 TTX has been classically used to abolish spike activity and leaves EPSPs unaffected (e.g., see Hille 2001 for review).…”

Section: Discussionmentioning

confidence: 99%

The Auditory Nerve Overlapped Waveform (ANOW) Originates in the Cochlear Apex

Lichtenhan¹,

Hartsock²,

Gill³

et al. 2014

JARO

View full text Add to dashboard Cite

Measurements of cochlear function with compound action potentials (CAPs), auditory brainstem responses, and otoacoustic emissions work well with high-frequency sounds but are problematic at low frequencies. We have recently shown that the auditory nerve overlapped waveform (ANOW) can objectively quantify low-frequency (G1 kHz) auditory sensitivity, as thresholds for ANOW at low frequencies and for CAP at high frequencies relate similarly to single auditory nerve fiber thresholds. This favorable relationship, however, does not necessarily mean that ANOW originates from auditory nerve fibers innervating low-frequency regions of the cochlear apex. In the present study, we recorded the cochlear response to tone bursts of low frequency (353, 500, and 707 Hz) and high frequency (2 to 16 kHz) during administration of tetrodotoxin (TTX) to block neural function. TTX was injected using a novel method of slow administration from a pipette sealed into the cochlear apex, allowing real-time measurements of systematic neural blocking from apex to base. The amplitude of phase-locked (ANOW) and onset (CAP) neural firing to moderate-level, low-frequency sounds were markedly suppressed before thresholds and responses to moderate-level, high-frequency sounds were affected. These results demonstrate that the ANOW originates from responses of auditory nerve fibers innervating cochlear apex, confirming that ANOW provides a valid physiological measure of low-frequency auditory nerve function.

show abstract

“…The existence of longitudinal gradients of drugs along the cochlea have been suggested based on morphological studies (Saijo and Kimura 1984;Imamura and Adams 2003;Stover et al 1999;Wagner et al 2005), physiological measures (Chen et al 2005;Salt and Ma 2001;, and computer simulations (Plontke et al 2002;Plontke and Salt 2003). Previously, however, there has not been a methodology capable of documenting or quantifying longitudinal drug gradients.…”

Section: Figmentioning

confidence: 99%

Demonstration of a Longitudinal Concentration Gradient Along Scala Tympani by Sequential Sampling of Perilymph from the Cochlear Apex

Mynatt

Hale

Gill

et al. 2006

JARO

View full text Add to dashboard Cite

Local applications of drugs to the inner ear are increasingly being used to treat patients' inner ear disorders. Knowledge of the pharmacokinetics of drugs in the inner ear fluids is essential for a scientific basis for such treatments. When auditory function is of primary interest, the drug's kinetics in scala tympani (ST) must be established. Measurement of drug levels in ST is technically difficult because of the known contamination of perilymph samples taken from the basal cochlear turn with cerebrospinal fluid (CSF). Recently, we reported a technique in which perilymph was sampled from the cochlear apex to minimize the influence of CSF contamination (J. Neurosci. Methods, doi: 10.1016/j.jneumeth.2005.10.008). This technique has now been extended by taking smaller fluid samples sequentially from the cochlear apex, which can be used to quantify drug gradients along ST. The sampling and analysis methods were evaluated using an ionic marker, trimethylphenylammonium (TMPA), that was applied to the round window membrane. After loading perilymph with TMPA, 10 1-mL samples were taken from the cochlear apex. The TMPA content of the samples was consistent with the first sample containing perilymph from apical regions and the fourth or fifth sample containing perilymph from the basal turn. TMPA concentration decreased in subsequent samples, as they increasingly contained CSF that had passed through ST. Sample concentration curves were interpreted quantitatively by simulation of the experiment with a finite element model and by an automated curve-fitting method by which the apical-basal gradient was estimated. The study demonstrates that sequential apical sampling provides drug gradient data for ST perilymph while avoiding the major distortions of sample composition associated with basal turn sampling. The method can be used for any substance for which a sensitive assay is available and is therefore of high relevance for the development of preclinical and clinical strategies for local drug delivery to the inner ear.

show abstract

Inner ear drug delivery via a reciprocating perfusion system in the guinea pig

Cited by 71 publications

References 69 publications

Perilymph Kinetics of FITC-Dextran Reveals Homeostasis Dominated by the Cochlear Aqueduct and Cerebrospinal Fluid

Perilymph Kinetics of FITC-Dextran Reveals Homeostasis Dominated by the Cochlear Aqueduct and Cerebrospinal Fluid

The Auditory Nerve Overlapped Waveform (ANOW) Originates in the Cochlear Apex

Demonstration of a Longitudinal Concentration Gradient Along Scala Tympani by Sequential Sampling of Perilymph from the Cochlear Apex

Contact Info

Product

Resources

About