A fluorescence-based imaging approach to pharmacokinetic analysis of intracochlear drug delivery

Publication date: Available online 5 April 2018
Source:Hearing Research
Author(s): Andrew M. Ayoob, Marcello Peppi, Vishal Tandon, Robert Langer, Jeffrey T. Borenstein
Advances in microelectromechanical systems (MEMS) technologies are enhancing the development of intracochlear delivery devices for the treatment of hearing loss with emerging pharmacological therapies. Direct intracochlear delivery addresses the limitations of systemic and intratympanic delivery. However, optimization of delivery parameters for these devices requires pharmacokinetic assessment of the spatiotemporal drug distribution inside the cochlea. Robust methods of measuring drug concentration in the perilymph have been developed, but lack spatial resolution along the tonotopic axis or require complex physiological measurements. Here we describe an approach for quantifying distribution of fluorescent drug-surrogate probe along the cochlea's sensory epithelium with high spatial resolution enabled by confocal fluorescence imaging. Fluorescence from FM 1–43 FX, a fixable endocytosis marker, was quantified using confocal fluorescence imaging of whole mount sections of the organ of Corti from cochleae resected and fixed at several time points after intracochlear delivery. Intracochlear delivery of FM 1–43 FX near the base of the cochlea produces a base-apex gradient of fluorescence in the row of inner hair cells after 1 h post-delivery that is consistent with diffusion-limited transport along the scala tympani. By 3 h post-delivery there is approximately an order of magnitude decrease in peak average fluorescence intensity, suggesting FM 1–43 FX clearance from both the perilymph and inner hair cells. The increase in fluorescence intensity at 72 h post-delivery compared to 3 h post-delivery may implicate a potential radial transport pathway into the scala media.

Graphical abstract

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A fluorescence-based imaging approach to pharmacokinetic analysis of intracochlear drug delivery

Publication date: Available online 5 April 2018
Source:Hearing Research
Author(s): Andrew M. Ayoob, Marcello Peppi, Vishal Tandon, Robert Langer, Jeffrey T. Borenstein
Advances in microelectromechanical systems (MEMS) technologies are enhancing the development of intracochlear delivery devices for the treatment of hearing loss with emerging pharmacological therapies. Direct intracochlear delivery addresses the limitations of systemic and intratympanic delivery. However, optimization of delivery parameters for these devices requires pharmacokinetic assessment of the spatiotemporal drug distribution inside the cochlea. Robust methods of measuring drug concentration in the perilymph have been developed, but lack spatial resolution along the tonotopic axis or require complex physiological measurements. Here we describe an approach for quantifying distribution of fluorescent drug-surrogate probe along the cochlea's sensory epithelium with high spatial resolution enabled by confocal fluorescence imaging. Fluorescence from FM 1–43 FX, a fixable endocytosis marker, was quantified using confocal fluorescence imaging of whole mount sections of the organ of Corti from cochleae resected and fixed at several time points after intracochlear delivery. Intracochlear delivery of FM 1–43 FX near the base of the cochlea produces a base-apex gradient of fluorescence in the row of inner hair cells after 1 h post-delivery that is consistent with diffusion-limited transport along the scala tympani. By 3 h post-delivery there is approximately an order of magnitude decrease in peak average fluorescence intensity, suggesting FM 1–43 FX clearance from both the perilymph and inner hair cells. The increase in fluorescence intensity at 72 h post-delivery compared to 3 h post-delivery may implicate a potential radial transport pathway into the scala media.

Graphical abstract

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A fluorescence-based imaging approach to pharmacokinetic analysis of intracochlear drug delivery

Publication date: Available online 5 April 2018
Source:Hearing Research
Author(s): Andrew M. Ayoob, Marcello Peppi, Vishal Tandon, Robert Langer, Jeffrey T. Borenstein
Advances in microelectromechanical systems (MEMS) technologies are enhancing the development of intracochlear delivery devices for the treatment of hearing loss with emerging pharmacological therapies. Direct intracochlear delivery addresses the limitations of systemic and intratympanic delivery. However, optimization of delivery parameters for these devices requires pharmacokinetic assessment of the spatiotemporal drug distribution inside the cochlea. Robust methods of measuring drug concentration in the perilymph have been developed, but lack spatial resolution along the tonotopic axis or require complex physiological measurements. Here we describe an approach for quantifying distribution of fluorescent drug-surrogate probe along the cochlea's sensory epithelium with high spatial resolution enabled by confocal fluorescence imaging. Fluorescence from FM 1–43 FX, a fixable endocytosis marker, was quantified using confocal fluorescence imaging of whole mount sections of the organ of Corti from cochleae resected and fixed at several time points after intracochlear delivery. Intracochlear delivery of FM 1–43 FX near the base of the cochlea produces a base-apex gradient of fluorescence in the row of inner hair cells after 1 h post-delivery that is consistent with diffusion-limited transport along the scala tympani. By 3 h post-delivery there is approximately an order of magnitude decrease in peak average fluorescence intensity, suggesting FM 1–43 FX clearance from both the perilymph and inner hair cells. The increase in fluorescence intensity at 72 h post-delivery compared to 3 h post-delivery may implicate a potential radial transport pathway into the scala media.

Graphical abstract

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A Computerized Tomography Study of Vocal Tract Setting in Hyperfunctional Dysphonia and in Belting

Publication date: Available online 3 April 2018
Source:Journal of Voice
Author(s): Marcelo Saldias, Marco Guzman, Gonzalo Miranda, Anne-Maria Laukkanen
BackgroundVocal tract setting in hyperfunctional patients is characterized by a high larynx and narrowing of the epilaryngeal and pharyngeal region. Similar observations have been made for various singing styles, eg, belting. The voice quality in belting has been described to be loud, speech like, and high pitched. It is also often described as sounding “pressed” or “tense”. The above mentioned has led to the hypothesis that belting may be strenuous to the vocal folds. However, singers and teachers of belting do not regard belting as particularly strenuous.PurposeThis study investigates possible similarities and differences between hyperfunctional voice production and belting. This study concerns vocal tract setting.MethodsFour male patients with hyperfunctional dysphonia and one male contemporary commercial music singer were registered with computerized tomography while phonating on [a:] in their habitual speaking pitch. Additionally, the singer used the pitch G4 in belting. The scannings were studied in sagittal and transversal dimensions by measuring lengths, widths, and areas.ResultsVarious similarities were found between belting and hyperfunction: high vertical larynx position, small hypopharyngeal width, and epilaryngeal outlet. On the other hand, belting differed from dysphonia (in addition to higher pitch) by a wider lip and jaw opening, and larger volumes of the oral cavity.ConclusionsBelting takes advantage of “megaphone shape” of the vocal tract. Future studies should focus on modeling and simulation to address sound energy transfer. Also, they should consider aerodynamic variables and vocal fold vibration to evaluate the “price of decibels” in these phonation types.



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Does hearing in response to soft-tissue stimulation involve skull vibrations? A within-subject comparison between skull vibration magnitudes and hearing thresholds

Publication date: Available online 3 April 2018
Source:Hearing Research
Author(s): Shai Chordekar, Ronen Perez, Cahtia Adelman, Haim Sohmer, Liat Kishon-Rabin
Hearing can be elicited in response to bone as well as soft-tissue stimulation. However, the underlying mechanism of soft-tissue stimulation is under debate. It has been hypothesized that if skull vibrations were the underlying mechanism of hearing in response to soft-tissue stimulation, then skull vibrations would be associated with hearing thresholds. However, if skull vibrations were not associated with hearing thresholds, an alternative mechanism is involved. In the present study, both skull vibrations and hearing thresholds were assessed in the same participants in response to bone (mastoid) and soft-tissue (neck) stimulation. The experimental group included five hearing-impaired adults in whom a bone-anchored hearing aid was implanted due to conductive or mixed hearing loss. Because the implant is exposed above the skin and has become an integral part of the temporal bone, vibration of the implant represented skull vibrations. To ensure that middle-ear pathologies of the experimental group did not affect overall results, hearing thresholds were also obtained in 10 participants with normal hearing in response to stimulation at the same sites. We found that the magnitude of the bone vibrations initiated by the stimulation at the two sites (neck and mastoid) detected by the laser Doppler vibrometer on the bone-anchored implant were linearly related to stimulus intensity. It was therefore possible to extrapolate the vibration magnitudes at low-intensity stimulation, where poor signal-to-noise ratio limited actual recordings. It was found that the vibration magnitude differences (between soft-tissue and bone stimulation) were not different then the hearing threshold differences at the tested frequencies. Results of the present study suggest that bone vibration magnitude differences can adequately explain hearing threshold differences and are likely to be responsible for the hearing sensation. Thus, the present results support the idea that bone and soft-tissue conduction could share the same underlying mechanism, namely the induction of bone vibrations. Studies with the present methodology should be continued in future work in order to obtain further insight into the underlying mechanism of activation of the hearing system.



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Vestibular and balance function is often impaired in children with profound unilateral sensorineural hearing loss

Publication date: Available online 3 April 2018
Source:Hearing Research
Author(s): Meirav Sokolov, Karen A. Gordon, Melissa Polonenko, Susan I. Blaser, Blake C. Papsin, Sharon L. Cushing
RationaleChildren with unilateral deafness could have concurrent vestibular dysfunction which would be associated with balance deficits and potentially impair overall development. The prevalence of vestibular and balance deficits remains to be defined in these children.MethodsTwenty children with unilateral deafness underwent comprehensive vestibular and balance evaluation.ResultsRetrospective review revealed that more than half of the cohort demonstrated some abnormality of the vestibular end organs (otoliths and horizontal canal), with the prevalence of end organ specific dysfunction ranging from 17 to 48% depending on organ tested and method used. In most children, impairment occurred only on the deaf side. Children with unilateral deafness also displayed significantly poorer balance function than their normal hearing peers.ConclusionsThe prevalence of vestibular dysfunction in children with unilateral deafness is high and similar to that of children with bilateral deafness. Vestibular and balance evaluation should be routine and the functional impact of combined vestibulo-cochlear sensory deficits considered.



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Hearing loss in older adults - From epidemiological insights to national initiatives

Publication date: Available online 3 April 2018
Source:Hearing Research
Author(s): Adele M. Goman, Frank R. Lin
The broader implications of hearing loss for the health and functioning of older adults have begun to be demonstrated in epidemiologic studies. These research findings on the association between hearing loss and poorer health outcomes have formed the foundation for national initiatives on hearing loss and public health. These national initiatives range from the Aging and Cognitive Health Evaluation in Elders (ACHIEVE) clinical trial to the recent passage of the bipartisan Over-The-Counter Hearing Aid Act. Utilizing population health research methodologies to study hearing loss can provide the foundation for initiating top-down approaches to increase the adoption and accessibility of hearing care for older Americans with hearing loss.



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