Adjuvant agents enhance round window membrane permeability to dexamethasone and modulate basal to apical cochlear gradients

Creber, Nathan; Eastwood, Hayden; Hampson, Amy; Tan, Justin; O’Leary, Stephen

doi:10.1016/j.ejps.2018.08.013

Cited by 15 publications

(19 citation statements)

References 33 publications

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“…To overcome the short residence times for contact with the RWM, several delivery devices, such as the MicroWick, microcathers, and osmotic pumps, have been developed to prolong the duration of medication contact with the RWM. Delivery materials and agents such as gelfoam, hyaluronic acid hydrogels, histamine, nanoparticles, and nanovesicles can also provide a sustained inner ear delivery via the RWM (El Kechai et al, 2015;Mäder et al, 2018;Creber et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Ultrastructural Changes Associated With the Enhanced Permeability of the Round Window Membrane Mediated by Ultrasound Microbubbles

Lin

Chen

et al. 2020

Front. Pharmacol.

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The round window membrane (RWM) is the most common entryway for local drug and gene delivery into the inner ear, but its permeability can change the treatment outcome. We previously demonstrated a feasible and highly efficient approach using ultrasound-aided microbubble (USMB) cavitation to enhance the permeability of the RWM. Here, we investigated the safety of USMB exposure and the association between temporal changes in RWM permeability and ultrastructure. Experimental guinea pigs were divided into two treatment groups: a control group receiving round window soaking (RWS) with MBs and treatment (USM) groups undergoing 3 (USM-3) or 5 (USM-5) consecutive USMB exposures (1 min/exposure) at an acoustic intensity of 3 W/cm 2 and 1 MHz frequency. The trans-RWM delivery efficiency of biotin-fluorescein isothiocyanate conjugates, used as permeability tracers, revealed a greater than 7-fold higher delivery efficiency for the USM groups immediately after 3 or 5 exposures than for the RWS group. After 24 h, the delivery efficiency was 2.4-fold higher for the USM-3 group but was 6.6-fold higher for the USM-5 group (and 3.7-fold higher after 48 h), when compared to the RWS group. Scanning electron microscopy images of the RWM ultrastructure revealed USMB-induced sonoporation effects that could include the formation of heterogeneous pore-like openings with perforation diameters from 100 nm to several micrometers, disruption of the continuity of the outer epithelial surface layer, and loss of microvilli. These ultrastructural features were associated with differential permeability changes that depended on the USMB exposure course. Fourteen days after treatment, the pore-like openings had significantly decreased in number and the epithelial defects were healed either by cell expansion or by repair by newly migrated epithelial cells. The auditory brainstem response recordings of the animals following the 5-exposure USMB treatment indicated no deterioration in the hearing thresholds at a 2-month follow-up and no significant hair cell damage or apoptosis, based on scanning electron microscopy, surface preparations, and TUNEL assays. USMBs therefore appear to be safe and effective for inner ear drug delivery. The mechanism of enhanced permeability may involve a disruption of the continuity of the outer RWM epithelial layer, which controls transmembrane transport of various substances.

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Section: Introductionmentioning

confidence: 99%

Ultrastructural Changes Associated With the Enhanced Permeability of the Round Window Membrane Mediated by Ultrasound Microbubbles

Lin

Chen

et al. 2020

Front. Pharmacol.

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“…Some agents such as collagenase (6), histamine and local anesthetic phenols (7), and hyaluronic acid (8) have been applied to the RWM to destroy its outer epithelial cells and thereby enhance drug delivery without resorting to surgery. However, these approaches may cause infection in the middle ear cavity and damage the RWM -or even the inner ear, itself (9).…”

Section: Introductionmentioning

confidence: 99%

Ultrasound-induced microbubble cavitation via a transcanal or transcranial approach facilitates inner ear drug delivery

Liao¹,

Wang²,

Weng³

et al. 2020

JCI Insight

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“…Anatomical variations, varying permeability of the round window membrane and poor diffusion patterns within the cochlea might result in an insufficient dose accumulation of the steroids with lack of effect (14). Attempts to enhance absorption and distribution of dexamethasone to the inner ear after transtympanic application at the round window levels have been successfully demonstrated in an animal model by the use of hyaluronic acid and histamine (17). Another approach to increase steroid concentrations in the inner ear is the direct intracochlear application.…”

Section: Introductionmentioning

confidence: 99%

Dose-Dependent Transient Decrease of Impedances by Deep Intracochlear Injection of Triamcinolone With a Cochlear Catheter Prior to Cochlear Implantation–1 Year Data

et al. 2020

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Administration of low-dose steroids via a catheter inserted into the cochlea to apply pharmaceuticals to more apical regions was previously shown not to be sufficient for long-term reduction of electrode impedances. The aim of the present study was to investigate the effect of intra-cochlear high-dose triamcinolone application on impedances in cochlear implant recipients. Patients received low-dose (4 mg/ml; n = 5) or high-dose (20 mg/ml; n = 5) triamcinolone via a cochlear catheter just prior to the insertion of a Med-El Flex28 electrode. Impedances were measured at defined time points from intra-operatively up to 12 months after first fitting and retrospectively compared with a control group (no steroid application). Patients who received a high-dose application of crystalloid triamcinolone showed significantly reduced impedances in the first fitting measurements compared to the control group. This effect was no longer detectable in patients of the low-dose group at that time. Looking at the different regions of the electrode, the impedance values were lowered significantly only at the basal and medial contacts. At later time points, there were no significant differences between any of the groups. This is the first study to demonstrate a dose-dependent reduction of impedances by deep intra-cochlear injection of triamcinolone in cochlear implant patients. With a high-dose, single application of triamcinolone using a cochlear catheter prior to insertion of a Flex28 electrode, the impedances can be significantly reduced up to and including the first fitting. Although the effect was longer lasting than when compared to low-dose triamcinolone, it was also not permanent.

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Adjuvant agents enhance round window membrane permeability to dexamethasone and modulate basal to apical cochlear gradients

Cited by 15 publications

References 33 publications

Ultrastructural Changes Associated With the Enhanced Permeability of the Round Window Membrane Mediated by Ultrasound Microbubbles

Ultrastructural Changes Associated With the Enhanced Permeability of the Round Window Membrane Mediated by Ultrasound Microbubbles

Ultrasound-induced microbubble cavitation via a transcanal or transcranial approach facilitates inner ear drug delivery

Dose-Dependent Transient Decrease of Impedances by Deep Intracochlear Injection of Triamcinolone With a Cochlear Catheter Prior to Cochlear Implantation–1 Year Data

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