Guinea Pig Round Window Membrane Explantation for Ex Vivo Studies.

Efficient and minimally invasive drug delivery to the inner ear is a significant challenge. The round window membrane (RWM), being one of the few entry points to the inner ear, has become a vital focus of investigation. However, due to the complexities of isolating the RWM, our understanding of its pharmacokinetics remains limited. The RWM comprises three distinct layers: the outer epithelium, the middle connective tissue layer, and the inner epithelial layer, each potentially possessing unique delivery properties. Current models for investigating transport across the RWM utilize in vivo animal models or ex vivo RWM models which rely on cell cultures or membrane fragments. Guinea pigs serve as a validated preclinical model for the investigation of drug pharmacokinetics within the inner ear and are an important animal model for the translational development of delivery vehicles to the cochlea. In this study, we describe an approach for explantation of a guinea pig RWM with surrounding cochlear bone for benchtop drug delivery experiments. This method allows for preservation of native RWM architecture and may provide a more realistic representation of barriers to transport than current benchtop models.

A Benchtop Round Window Model for Studying Magnetic Nanoparticle Transport to the Inner Ear.

INTRODUCTION: The round window membrane (RWM) presents a significant barrier to the local application of therapeutics to the inner ear. We demonstrate a benchtop preclinical RWM model and evaluate superparamagnetic iron oxide nanoparticles (SPIONs) as vehicles for magnetically assisted drug delivery. METHODS: Guinea pig RWM explants were inset into a 3D-printed dual chamber benchtop device. Custom-synthesized 7-nm iron core nanoparticles were modified with different polyethylene glycol chains to yield two sizes of SPIONs (NP-PEG600 and NP-PEG3000) and applied to the benchtop model with and without a magnetic field. Histologic analysis of the RWM was performed using transmission electron microscopy (TEM) and confocal microscopy. RESULTS: Over a 4-h period, 19.5 ± 1.9% of NP-PEG3000 and 14.6 ± 1.9% of NP-PEG600 were transported across the guinea pig RWM. The overall transport increased by 1.45× to 28.4 ± 5.8% and 21.0 ± 2.0%, respectively, when a magnetic field was applied. Paraformaldehyde fixation of the RWM decreased transport significantly (NP-PEG3000: 7.6 ± 1.5%; NP-PEG600: 7.0 ± 1.6%). Confocal and electron microscopy analysis demonstrated nanoparticle localization throughout all cellular layers and layer-specific transport characteristics within RWM. CONCLUSION: The guinea pig RWM explant benchtop model allows for targeted and practical investigations of transmembrane transport in the development of nanoparticle drug delivery vehicles. The presence of a magnetic field increases SPION delivery by 45%-50% in a nanoparticle size- and cellular layer-dependent manner. LEVEL OF EVIDENCE: NA Laryngoscope, 134:3355-3362, 2024.

Cochlear Implant Electrode Array Design and Speech Understanding.

OBJECTIVE: Cochlear implant electrode arrays are categorized based on their design as lateral wall (LW) and perimodiolar (PM) electrode arrays. The objective of this study was to investigate the effect of LW versus PM designs on postoperative speech perception across multiple manufacturers and over long follow-up durations. DESIGN: Retrospective cohort study. SETTING: Single academic medical center. PARTICIPANTS: A total of 478 adult cochlear implant recipients, implanted between the years 1992 and 2017. INTERVENTIONSS: PM versus LW cochlear implants. MAIN OUTCOMES AND MEASURES: Postoperative Consonant-Nucleus-Consonant Word (CNC-w) and Hearing in Noise Test (HINT) scores between 6 months and 5 years. RESULTS: Across 478 patients, approximately one-third received LW (n = 176, 36.8%), whereas 302 patients received a PM array (63.2%). The PM group had higher CNC-w scores from 6 months to 2 years (52 [interquartile range, 38-68] versus 48 [31-62], p = 0.036) and from 2 to 5 years (58 [43-72] versus 48 [33-66], p < 0.001). Multivariable analysis of patient-averaged scores indicated that the PM group had greater improvement from preoperative scores at all time points after the initial 6 months for both CNC-w ( ß = 4.4 [95% confidence interval, 0.6-8.3], p = 0.023) and HINT testing ( ß = 4.5 [95% confidence interval, 0.3-8.7], p = 0.038). CONCLUSIONS: This study indicates that PM electrode arrays are associated with small increases in postoperative speech perception scores, relative to LW arrays, when assessed across manufacturers, over long time durations, and using multiple outcome instruments. These findings may help guide surgeon selection and patient counseling of cochlear implant arrays.

Rationally Designed Magnetic Nanoparticles for Cochlear Drug Delivery: Synthesis, Characterization, and In Vitro Biocompatibility in a Murine Model.

Hypothesis: Magnetic nanoparticles (MNPs) for cochlear drug delivery can be precisely engineered for biocompatibility in the cochlea. Background: MNPs are promising drug delivery vehicles that can enhance the penetration of both small and macromolecular therapeutics into the cochlea. However, concerns exist regarding the application of oxidative, metal-based nanomaterials to delicate sensory tissues of the inner ear. Translational development of MNPs for cochlear drug deliver requires specifically tuned nanoparticles that are not cytotoxic to inner ear tissues. We describe the synthesis and characterization of precisely tuned MNP vehicles, and their in vitro biocompatibility in murine organ of Corti organotypic cultures. Methods: MNPs were synthesized via 2-phase ligand transfer process with precise control of nanoparticle size. Core and hydrodynamic sizes of nanoparticles were characterized using electron microscopy and dynamic light scattering, respectively. In vitro biocompatibility was assayed via mouse organ of Corti organotypic cultures with and without an external magnetic field gradient. Imaging was performed using immunohistochemical labeling and confocal microscopy. Outer hair cell, inner hair cell, and spiral ganglion neurites were individually quantified. Results: Monocore PEG-MNPs of 45 and 148 nm (mean hydrodynamic diameter) were synthesized. Organ of Corti cultures demonstrated preserved outer hair cell, inner hair cell, and neurite counts across 2 MNP sizes and doses, and irrespective of external magnetic field gradient. Conclusion: MNPs can be custom-synthesized with precise coating, size, and charge properties specific for cochlear drug delivery while also demonstrating biocompatibility in vitro.