Round Window Membrane Research Articles

Protective effect of astaxanthin nanoemulsion on mammalian inner ear hair cells.

Aminoglycoside antibiotics are used for treating certain acute infections. However, these drugs cause ototoxicity by inducing inner ear hair cell death. We investigated the protective effect of a nanoemulsion of the carotenoid astaxanthin on mammalian inner ear hair cells against neomycin-induced ototoxicity. Dose-response relationship, quantification of hair cell loss, and reactive oxygen species production were assayed in response to neomycin with and without astaxanthin in cultured utricles of CBA/N mice. In addition, auditory brain response (ABR) and hair cell loss after exposure to the nanoformulation and loud noise were examined in vivo in guinea pigs. Astaxanthin suppressed neomycin-induced reduction of hair cells by reducing the production of hydroxy radicals. Furthermore, hair cell loss in the second rotation of the cochlea was significantly lower in the astaxanthin group than in the noise-only group. The blood-labyrinth barrier limits the successful delivery of drugs for inner ear complications. However, in the nanoemulsion form, astaxanthin can penetrate the round window (fenestra ovale) membrane, enabling topical administration. Thus, astaxanthin nanoemulsion could be useful in treating ototoxicity in individuals with inner ear complications.

Proof of concept of intracochlear drug administration by laser-assisted bioprinting in mice

Transtympanic administration is used clinically for the injection of gentamicin and/or corticosteroids. This atraumatic route is based on passive diffusion through the round window membrane (RWM). The main limitation of this method is related to the clearance through the Eustachian tube, making the concentration of the therapeutic agent at the intracochlear level uncertain and limited. Moreover, this technique remains unsuitable for molecules of high molecular weight or in the case of gene therapies. The purpose was to study a new technique of intracochlear administration in an atraumatic, direct and controlled manner by laser-assisted bioprinting (LAB). LAB was used to deliver dexamethasone phosphate with thermosensitive hydrogel on the mouse RWM. After validation of the regularity and homogeneity of the pattern, the diffusion in vivo of the dexamethasone into the perilymph after LAB has been confirmed by ELISA. Auditory function measurements showed no hearing impairment suggesting that bioprinting does not induce significant cochlear damage. Hence, the present proof of concept study introduces a promising approach for inner ear drug delivery.

Developing the supraparticle technology for round window-mediated drug administration into the cochlea

The semi-permeable round window membrane (RWM) is the gateway to the cochlea. Although the RWM is considered a minimally invasive and clinically accepted route for localised drug delivery to the cochlea, overcoming this barrier is challenging, hindering development of effective therapies for hearing loss. Neurotrophin 3 (NT3) is an emerging treatment option for hearing loss, but its therapeutic effect relies on sustained delivery across the RWM into the cochlea. Silica supraparticles (SPs) are drug delivery carriers capable of providing long-term NT3 delivery, when injected directly into the guinea pig cochlea. However, for clinical translation, a RWM delivery approach is desirable. Here, we aimed to test approaches to improve the longevity and biodistribution of NT3 inside the cochlea after RWM implantation of SPs in guinea pigs and cats. Three approaches were tested (i) coating the SPs to slow drug release (ii) improving the retention of SPs on the RWM using a clinically approved gel formulation and (iii) permeabilising the RWM with hyaluronic acid. A radioactive tracer (iodine 125: 125I) tagged to NT3 (125I NT3) was loaded into the SPs to characterise drug pharmacokinetics in vitro and in vivo. The neurotrophin-loaded SPs were coated using a chitosan and alginate layer-by-layer coating strategy, named as ‘(Chi/Alg)SPs’, to promote long term drug release. The guinea pigs were implanted with 5× 125I NT3 loaded (Chi/Alg) SPs on the RWM, while cats were implanted with 30× (Chi/Alg) SPs. A cohort of animals were also implanted with SPs (controls). We found that the NT3 loaded (Chi/Alg)SPs exhibited a more linear release profile compared to NT3 loaded SPs alone. The 125I NT3 loaded (Chi/Alg)SPs in fibrin sealant had efficient drug loading (~5 μg of NT3 loaded per SP that weights ~50 μg) and elution capacities (~49% over one month) in vitro. Compared to the SPs in fibrin sealant, the (Chi/Alg)SPs in fibrin sealant had a significantly slower 125I NT3 drug release profile over the first 7 days in vitro (~12% for (Chi/Alg) SPs in fibrin sealant vs ~43% for SPs in fibrin sealant). One-month post-implantation of (Chi/Alg) SPs, gamma count measurements revealed an average of 0.3 μg NT3 remained in the guinea pig cochlea, while for the cat, 1.3 μg remained. Histological analysis of cochlear tissue revealed presence of a 125I NT3 signal localised in the basilar membrane of the lower basal turn in some cochleae after 4 weeks in guinea pigs and 8 weeks in cats. Comparatively, and in contrast to the in vitro release data, implantation of the SPs presented better NT3 retention and distribution inside the cochlea in both the guinea pigs and cats. No significant difference in drug entry was observed upon acute treatment of the RWM with hyaluronic acid. Collectively, our findings indicate that SPs and (Chi/Alg)SPs can facilitate drug transfer across the RWM, with detectable levels inside the cat cochlea even after 8 weeks with the intracochlear approach. This is the first study to examine neurotrophin pharmacokinetics in the cochlea for such an extended period of times in these two animal species. Whilst promising, we note that outcomes between animals were variable, and opposing results were found between in vitro and in vivo release studies. These findings have important clinical ramifications, emphasising the need to understand the physical properties and mechanics of this complex barrier in parallel with the development of therapies for hearing loss.

Space Station-like Composite Nanoparticles for Co-Delivery of Multiple Natural Compounds from Chinese Medicine and Hydrogen in Combating Sensorineural Hearing Loss.

Ototoxic drugs such as aminoglycoside antibiotics and cisplatin (CDDP) can cause sensorineural hearing loss (SNHL), which is closely related to oxidative stress and the acidification of the inner ear microenvironment. Effective treatment of SNHL often requires multifaceted approach due to the complex pathology, and drug combination therapy is expected to be at the forefront of modern hearing loss treatment. Here, space-station-like composite nanoparticles (CCC@mPP NPs) with pH/oxidation dual responsiveness and multidrug simultaneous delivery capability were constructed and then loaded with various drugs including panax notoginseng saponins (PNS), tanshinone IIA (TSIIA), and ammonia borane (AB) to provide robust protection against SNHL. Molecular dynamics simulation revealed that carboxymethyl chitosan/calcium carbonate-chitosan (CCC) NPs and monomethoxy poly(ethylene glycol)-PLGA (mPP) NPs can rendezvous and dock primarily by hydrogen bonding, and electrostatic forces may be involved. Moreover, CCC@mPP NPs crossed the round window membrane (RWM) and entered the inner ear through endocytosis and paracellular pathway. The docking state was basically maintained during this process, which created favorable conditions for multidrug delivery. This nanosystem was highly sensitive to pH and reactive oxygen species (ROS) changes, as evidenced by the restricted release of payload at alkaline condition (pH 7.4) without ROS, while significantly promoting the release in acidic condition (pH 5.0 and 6.0) with ROS. TSIIA/PNS/AB-loaded CCC@mPP NPs almost completely preserved the hair cells and remained the hearing threshold shift within normal limits in aminoglycoside- or CDDP-treated guinea pigs. Further experiments demonstrated that the protective mechanisms of TSIIA/PNS/AB-loaded CCC@mPP NPs involved direct and indirect scavenging of excessive ROS, and reduced release of pro-inflammatory cytokines. Both in vitro and in vivo experiments showed the high biocompatibility of the composite NPs, even after long-term administration. Collectively, this work suggests that composite NPs is an ideal multi-drug-delivery vehicle and open new avenues for inner ear disease therapies.

Round-Window Vibroplasty: Systematic Review and Meta-Analysis of Audiological Effectiveness With Different Round-Window Coupling Techniques.

Active middle ear implants can be directly coupled to the round-window (RW) membrane via RW Vibroplasty. The objectives of this systematic review were to summarize data on different RW coupling techniques and to investigate their effect on audiological and safety outcomes using meta-analyses. PubMed (MEDLINE), Cochrane Library, and Embase (DIMDI). All publications reporting on audiological outcomes in human patients after RW Vibroplasty were included. Two independent reviewers carried out screening and data extraction. Meta-analyses and meta-regression were used to evaluate the potential effects of surgical and demographic parameters on primary audiological outcomes. Adverse events were extracted and tabulated for qualitative analysis. Fourteen different combinations of surgical coupling parameters were identified in 61 included publications. Overall, data from 23 publications could be used for meta-analyses. Significantly better aided sound-field thresholds were reported for RW Vibroplasty performed without a dedicated coupler and using fascia as interponate, compared with RW Vibroplasty with an RW coupler or without an interponate. These effects were not found in other outcomes (i.e., functional gain, word recognition score). Reporting of adverse events was relatively heterogeneous, with 32 explicit mentions of revision surgery after the loss of coupling efficacy. There are numerous publications investigating the effectiveness of coupling active middle ear implants to the RW membrane. However, studies are typically undersampled and of low evidence level. Using meta-analyses, weighted means, and qualitative analyses enabled a summary of the existing literature on audiological and safety outcomes after RW Vibroplasty. Individual selection of the most appropriate coupling modality with standardized intraoperative measurement and careful patient follow-up may be considered key factors for achieving effective RW coupling.

Physiologic Effects of Microneedle-Mediated Intracochlear Dexamethasone Injection in the Guinea Pig.

Oral or intratympanic corticosteroids are commonly used to treat sudden sensorineural hearing loss (SSHL), tinnitus, and Meniere disease. Direct intracochlear delivery has been proposed to overcome the variability in bioavailability and efficacy of systemic or middle ear delivery. In this study, we aim to characterize the physiologic consequences of microneedle-mediated direct intracochlear injection of dexamethasone through the round window membrane (RWM). In Hartley guinea pigs (n = 5), a post-auricular incision followed by bullostomy was made to access the round window membrane. Using 100 μm diameter hollow microneedles, 1.0 μl of 10 mg/ml dexamethasone was injected through the RWM over 1 min. Compound action potential (CAP) and distortion product otoacoustic action emissions (DPOAE) were measured before perforation, at 1 h, and at 5 h following injection. CAP hearing thresholds were measured from 0.5 to 40 kHz, and DPOAE f2 frequencies ranged from 1.0 and 32 kHz. Repeated measures ANOVA followed by pairwise t-tests were used for statistical analysis. ANOVA identified significant CAP threshold shifts at four frequencies (4, 16, 36, and 40 kHz) and differences in DPOAE at 1 frequency (6 kHz). Paired t-tests revealed differences between the pre-perforation and 1 h time point. By 5 h post injection, both CAP hearing thresholds and DPOAE recover and are not significantly different from baseline thresholds. Direct intracochlear delivery of dexamethasone via microneedles results in temporary shifts in hearing thresholds that resolve by 5 hours, thus supporting microneedle technology for the treatment of inner ear disorders. NA Laryngoscope, 134:388-392, 2024.

A prestin-targeting peptide-guided drug delivery system rearranging concentration gradient in the inner ear: An improved strategy against hearing loss

Hearing loss is mainly due to outer hair cell (OHC) damage in three cochlear turns. Local administration via the round window membrane (RWM) has considerable otological clinical potential in bypassing the blood–labyrinth barrier. However, insufficient drug distribution in the apical and middle cochlear turns results in unsatisfactory efficacy. We functionalized poly (lactic-co-glycolic acid) nanoparticles (PLGA NPs) with targeting peptide A665, which specifically bound to prestin, a protein uniquely expressed in OHCs. The modification facilitated the cellular uptake and RWM permeability of NPs. Notably, the guide of A665 towards OHCs enabled more NPs perfusion in the apical and middle cochlear turns without decreasing accumulation in the basal cochlear turn. Subsequently, curcumin (CUR), an appealing anti-ototoxic drug, was encapsulated in NPs. In aminoglycoside-treated guinea pigs with the worst hearing level, CUR/A665-PLGA NPs, with superior performance to CUR/PLGA NPs, almost completely preserved the OHCs in three cochlear turns. The lack of increased low-frequencies hearing thresholds further confirmed that the delivery system with prestin affinity mediated cochlear distribution rearrangement. Good inner ear biocompatibility and little or no embryonic zebrafish toxicity were observed throughout the treatment. Overall, A665-PLGA NPs act as desirable tools with sufficient inner ear delivery for improved efficacy against severe hearing loss.

Surgical anatomy of posterior tympanotomy: influence of the retrotympanum on round window exposure.

To describe how the retrotympanic structures could influence the visibility of the round window niche and the round window membrane during cochlear implant surgery, and to investigate if a round window approach is possible even in cases with unfavourable anatomy. Video recordings from 37 patients who underwent cochlear implantation were reviewed. The visibility of the round window niche and round window membrane at different timepoints was assessed according to a modified version of the Saint Thomas Hospital classification. The structures that concealed the round window niche and round window membrane were evaluated. After posterior tympanotomy, 54 per cent of cases had limited exposure (classes IIa, IIb and III) of the round window niche. After remodelling the retrotympanum, round window niche visibility significantly increased, with 100 per cent class I and IIa cases. Following remodelling of the round window niche, visibility of more than 50 per cent of the round window membrane surface was achieved in 100 per cent of cases. Remodelling the retrotympanum and the round window niche significantly increased exposure of the round window niche and round window membrane respectively, allowing round window insertion in all cases.

Micro Injection Molding of Drug-Loaded Round Window Niche Implants for an Animal Model Using 3D-Printed Molds.

A novel approach for the long-term medical treatment of the inner ear is the diffusion of drugs through the round window membrane from a patient-individualized, drug-eluting implant, which is inserted in the middle ear. In this study, drug-loaded (10 wt% Dexamethasone) guinea pig round window niche implants (GP-RNIs, ~1.30 mm × 0.95 mm × 0.60 mm) were manufactured with high precision via micro injection molding (µIM, Tmold = 160 °C, crosslinking time of 120 s). Each implant has a handle (~3.00 mm × 1.00 mm × 0.30 mm) that can be used to hold the implant. A medical-grade silicone elastomer was used as implant material. Molds for µIM were 3D printed from a commercially available resin (TG = 84 °C) via a high-resolution DLP process (xy resolution of 32 µm, z resolution of 10 µm, 3D printing time of about 6 h). Drug release, biocompatibility, and bioefficacy of the GP-RNIs were investigated in vitro. GP-RNIs could be successfully produced. The wear of the molds due to thermal stress was observed. However, the molds are suitable for single use in the µIM process. About 10% of the drug load (8.2 ± 0.6 µg) was released after 6 weeks (medium: isotonic saline). The implants showed high biocompatibility over 28 days (lowest cell viability ~80%). Moreover, we found anti-inflammatory effects over 28 days in a TNF-α-reduction test. These results are promising for the development of long-term drug-releasing implants for human inner ear therapy.

Fluid-solid coupling model and biological features of large vestibular aqueduct syndrome.

Objective: Computed tomography (CT) images of the temporal bone of large vestibular aqueduct syndrome (LVAS) patients were used to establish 3D numerical models based on the structure of the inner ear, which are, in turn, used to construct inner ear fluid-solid coupling models. The physiological features and pathophysiology of LVAS were analyzed from a biomechanical perspective using finite element analysis. Methods: CT images of the temporal bone were collected from five children attending the Second Hospital of Dalian Medical University in 2022. The CT images were used to build 3D models of the inner ear containing the vestibular aqueduct (VA) by Mimics and Geomagic software, and round window membrane models and fluid-solid coupling models were built by ANSYS software to perform fluid-solid coupling analysis. Results: By applying different pressure loads, the deformation of the round window membranes occurred, and their trend was basically the same as that of the load. The deformation and stress of the round window membranes increased with the increase in load. Under the same load, the deformation and stress of the round window membranes increased with the expansion of the midpoint width of the VA. Conclusion: CT images of the temporal bone used clinically could establish a complete 3D numerical model of the inner ear containing VA. Fluctuations in cerebrospinal fluid pressure could affect inner ear pressure, and VA had a limiting effect on the pressure from cerebrospinal fluid. The larger the VA, the smaller the limiting effect on the pressure.

Assessment of drug permeability through an ex vivo porcine round window membrane model

Delivery of pharmaceutical therapeutics to the inner ear to treat and prevent hearing loss is challenging. Systemic delivery is not effective as only a small fraction of the therapeutic agent reaches the inner ear. Invasive surgeries to inject through the round window membrane (RWM) or cochleostomy may cause damage to the inner ear. An alternative approach is to administer drugs into the middle ear using an intratympanic injection, with the drugs primarily passing through the RWM to the inner ear. However, the RWM is a barrier, only permeable to a small number of molecules. To study and enhance the RWM permeability, we developed an exvivo porcine RWM model, similar in structure and thickness to the human RWM. The model is viable for days, and drug passage can be measured at multiple time points. This model provides a straightforward approach to developing effective and non-invasive delivery methods to the inner ear.

Microneedles Facilitate Small-Volume Intracochlear Delivery Without Physiologic Injury in Guinea Pigs.

Microneedle-mediated intracochlear injection through the round window membrane (RWM) will facilitate intracochlear delivery, not affect hearing, and allow for full reconstitution of the RWM within 48 hours. We have developed polymeric microneedles that allow for in vivo perforation of the guinea pig RWM and aspiration of perilymph for diagnostic analysis, with full reconstitution of the RWM within 48 to 72 hours. In this study, we investigate the ability of microneedles to deliver precise volumes of therapeutics into the cochlea and assess the subsequent consequences on hearing. Volumes of 1.0, 2.5, or 5.0 μL of artificial perilymph were injected into the cochlea at a rate of 1 μL/min. Compound action potential (CAP) and distortion product otoacoustic emission were performed to assess for hearing loss (HL), and confocal microscopy was used to evaluate the RWM for residual scarring or inflammation. To evaluate the distribution of agents within the cochlea after microneedle-mediated injection, 1.0 μL of FM 1-43 FX was injected into the cochlea, followed by whole mount cochlear dissection and confocal microscopy. Direct intracochlear injection of 1.0 μL of artificial perilymph in vivo , corresponding to about 20% of the scala tympani volume, was safe and did not result in HL. However, injection of 2.5 or 5.0 μL of artificial perilymph into the cochlea produced statistically significant high-frequency HL persisting 48 hours postperforation. Assessment of RWMs 48 hours after perforation revealed no inflammatory changes or residual scarring. FM 1-43 FX injection resulted in distribution of the agent predominantly in the basal and middle turns. Microneedle-mediated intracochlear delivery of small volumes relative to the volume of the scala tympani is feasible, safe, and does not cause HL in guinea pigs; however, injection of large volumes induces high-frequency HL. Injection of small volumes of a fluorescent agent across the RWM resulted in significant distribution within the basal turn, less distribution in the middle turn, and almost none in the apical turn. Microneedle-mediated intracochlear injection, along with our previously developed intracochlear aspiration, opens the pathway for precision inner ear medicine.

Anatomic, physiologic, and proteomic consequences of repeated microneedle-mediated perforations of the round window membrane

BackgroundWe have developed 3D-printed microneedle technology for diagnostic aspiration of perilymph and intracochlear delivery of therapeutic agents. Single microneedle-mediated round window membrane (RWM) perforation does not cause hearing loss, heals within 48–72 h, and yields sufficient perilymph for proteomic analysis. In this study, we investigate the anatomic, physiologic, and proteomic consequences of repeated microneedle-mediated perforations of the same RWM at different timepoints. Methods100-μm-diameter hollow microneedles were fabricated using two-photon polymerization (2PP) lithography. The tympanic bullae of Hartley guinea pigs (n = 8) were opened with adequate exposure of the RWM. Distortion product otoacoustic emissions (DPOAE) and compound action potential (CAP) were recorded to assess hearing. The hollow microneedle was introduced into the bulla and the RWM was perforated; 1 μL of perilymph was aspirated from the cochlea over the course of 45 s. 72 h later, the above procedure was repeated with aspiration of an additional 1 μL of perilymph. 72 h after the second perforation, RWMs were harvested for confocal imaging. Perilymph proteomic analysis was completed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). ResultsTwo perforations and aspirations were performed in 8 guinea pigs. In six, CAP, DPOAE, and proteomic analysis were obtained; in one, only CAP and DPOAE results were obtained; and in one, only proteomics results were obtained. Hearing tests demonstrated mild hearing loss at 1–4 kHz and 28 kHz, most consistent with conductive hearing loss. Confocal microscopy demonstrated complete healing of all perforations with full reconstitution of the RWM. Perilymph proteomic analysis identified 1855 proteins across 14 samples. The inner ear protein cochlin was observed in all samples, indicating successful aspiration of perilymph. Non-adjusted paired t-tests with p < 0.01 revealed significant changes in 13 of 1855 identified proteins (0.7%) between the first and second aspirations. ConclusionsWe demonstrate that repeated microneedle perforation of the RWM is feasible, allows for complete healing of the RWM, and minimally changes the proteomic expression profile. Thus, microneedle-mediated repeated aspirations in a single animal can be used to monitor the response to inner ear treatments over time.

Investigation of inner ear drug delivery with a cochlear catheter in piglets as a representative model for human cochlear pharmacokinetics.

Hearing impairment is the most common sensory disorder in humans, and yet hardly any medications are licensed for the treatment of inner ear pathologies. Intricate pharmacokinetic examinations to better understand drug distribution within this complex organ could facilitate the development of novel therapeutics. For such translational research projects, animal models are indispensable, but differences in inner ear dimensions and other anatomical features complicate the transfer of experimental results to the clinic. The gap between rodents and humans may be bridged using larger animal models such as non-human primates. However, their use is challenging and impeded by administrative, regulatory, and financial hurdles. Other large animal models with more human-like inner ear dimensions are scarce. In this study, we analyzed the inner ears of piglets as a potential representative model for the human inner ear and established a surgical approach for intracochlear drug application and subsequent apical sampling. Further, controlled intracochlear delivery of fluorescein isothiocyanate-dextran (FITC-d) was carried out after the insertion of a novel, clinically applicable CE-marked cochlear catheter through the round window membrane. Two, six, and 24hours after a single injection with this device, the intracochlear FITC-d distribution was determined in sequential perilymph samples. The fluorometrically assessed concentrations two hours after injection were compared to the FITC-d content in control groups, which either had been injected with a simple needle puncture through the round window membrane or the cochlear catheter in combination with a stapes vent hole. Our findings demonstrate not only significantly increased apical FITC-d concentrations when using the cochlear catheter but also higher total concentrations in all perilymph samples. Additionally, the concentration decreased after six and 24hours and showed a more homogenous distribution compared to shorter observation times.

The effect of cochlear size on electrically evoked auditory brainstem responses in deaf children.

To investigate the relationship between auditory pathway function and cochlear size in deaf children with a radiologically normal inner ear or Mondini malformation. Thirty-five deaf children without inner ear malformations (IEMs) and forty cases with Mondini malformation were included in this study. The electrically evoked auditory brainstem responses (EABRs) evoked by electrical stimulation at the round window niche (RWN) and round window membrane (RWM) were recorded during cochlear implantation (CI) surgery. The anatomical parameters of the cochlea were assessed by high-resolution computed tomography and OTOPLAN 3-D construction software. Correlations between EABRs and cochlear sizes were analyzed. The EABR thresholds and/or latencies were negatively correlated with the basal cochlear diameter, cochlear width and/or cochlear duct length in both patients without IEMs and those with Mondini malformation. The physiological function of the peripheral auditory system depends on the anatomical structure of the cochlea to an extent. A larger cochlear size appears to be associated with better auditory conduction function. Our findings may be beneficial to selection of the proper electrode type and prediction of postoperative auditory rehabilitation. Level 4.

Development and In-Silico and Ex-Vivo Validation of a Software for a Semi-Automated Segmentation of the Round Window Niche to Design a Patient Specific Implant to Treat Inner Ear Disorders.

The aim of this study was to develop and validate a semi-automated segmentation approach that identifies the round window niche (RWN) and round window membrane (RWM) for use in the development of patient individualized round window niche implants (RNI) to treat inner ear disorders. Twenty cone beam computed tomography (CBCT) datasets of unilateral temporal bones of patients were included in the study. Defined anatomical landmarks such as the RWM were used to develop a customized 3D Slicer™ plugin for semi-automated segmentation of the RWN. Two otolaryngologists (User 1 and User 2) segmented the datasets manually and semi-automatically using the developed software. Both methods were compared in-silico regarding the resulting RWM area and RWN volume. Finally, the developed software was validated ex-vivo in N = 3 body donor implantation tests with additively manufactured RNI. The independently segmented temporal bones of the different Users showed a strong consistency in the volume of the RWN and the area of the RWM. The volume of the semi-automated RWN segmentations were 48 ± 11% smaller on average than the manual segmentations and the area of the RWM of the semi-automated segmentations was 21 ± 17% smaller on average than the manual segmentation. All additively manufactured implants, based on the semi-automated segmentation method could be implanted successfully in a pressure-tight fit into the RWN. The implants based on the manual segmentations failed to fit into the RWN and this suggests that the larger manual segmentations were over-segmentations. This study presents a semi-automated approach for segmenting the RWN and RWM in temporal bone CBCT scans that is efficient, fast, accurate, and not dependent on trained users. In addition, the manual segmentation, often positioned as the gold-standard, actually failed to pass the implantation validation.

Human cochlear microstructures at risk of electrode insertion trauma, elucidated in 3D with contrast-enhanced microCT

Cochlear implant restores hearing loss through electrical stimulation of the hearing nerve from within the cochlea. Unfortunately, surgical implantation of this neuroprosthesis often traumatizes delicate intracochlear structures, resulting in loss of residual hearing and compromising hearing in noisy environments and appreciation of music. To avoid cochlear trauma, insertion techniques and devices have to be adjusted to the cochlear microanatomy. However, existing techniques were unable to achieve a representative visualization of the human cochlea: classical histology damages the tissues and lacks 3D perspective; standard microCT fails to resolve the cochlear soft tissues; and previously used X-ray contrast-enhancing staining agents are destructive. In this study, we overcame these limitations by performing contrast-enhanced microCT imaging (CECT) with a novel polyoxometalate staining agent Hf-WD POM. With Hf-WD POM-based CECT, we achieved nondestructive, high-resolution, simultaneous, 3D visualization of the mineralized and soft microstructures in fresh-frozen human cochleae. This enabled quantitative analysis of the true intracochlear dimensions and led to anatomical discoveries, concerning surgically-relevant microstructures: the round window membrane, the Rosenthal’s canal and the secondary spiral lamina. Furthermore, we demonstrated that Hf-WD POM-based CECT enables quantitative assessment of these structures as well as their trauma.

Intratympanic microcrystals of dexamethasone and lipoic acid for the treatment of cisplatin-induced inner ear injury

Steroids (anti-inflammatory drugs) combined with antioxidants are frequently prescribed to treat cisplatin (CP)-induced hearing loss in the clinic. Compared to systemic administration of free drugs, local drug delivery systems offer better therapeutic qualities and patient compliance since they not only can bypass the blood-labyrinth barrier but also can perform sustained release. In this work, dexamethasone (DEX) and lipoic acid (LA) non-spherical microcrystals (MCs) were prepared without complicated chemical modification. Following a series of physical characterizations, including morphology, stability and injectability, dissolution and round window membrane distribution of MCs, DEX MCs, LA MCs and the simple mixture of DEX MCs + LA MCs (combination group) were administered in guinea pigs by intratympanic injection. We found that LA MCs enabled improvement of DEX absorption in the combination group compared to a single dose. In addition, no significant morphological changes or inflammatory responses were observed in cochlear tissue, indicating good biocompatibility. Finally, the combination group also demonstrated synergistic therapeutic effect for protecting hair cells against CP-induced damage. The local co delivery of DEX MCs and LA MCs offers a new strategy for the treatment of CP-induced inner ear injury since they provide sustained anti-inflammatory and antioxidant effects simultaneously.

Sonoporation of the Round Window Membrane on a Sheep Model: A Safety Study.

Sonoporation using microbubble-assisted ultrasound increases the permeability of a biological barrier to therapeutic molecules. Application of this method to the round window membrane could improve the delivery of therapeutics to the inner ear. The aim of this study was to assess the safety of sonoporation of the round window membrane in a sheep model. To achieve this objective, we assessed auditory function and cochlear heating, and analysed the metabolomics profiles of perilymph collected after sonoporation, comparing them with those of the control ear in the same animal. Six normal-hearing ewes were studied, with one sonoporation ear and one control ear for each. A mastoidectomy was performed on both ears. On the sonoporation side, Vevo MicroMarker® microbubbles (MBs; VisualSonics-Fujifilm, Amsterdam, The Netherlands) at a concentration of 2 × 108 MB/mL were locally injected into the middle ear and exposed to 1.1 MHz sinusoidal ultrasonic waves at 0.3 MPa negative peak pressure with 40% duty cycle and 100 μs interpulse period for 1 min; this was repeated three times with 1 min between applications. The sonoporation protocol did not induce any hearing impairment or toxic overheating compared with the control condition. The metabolomic analysis did not reveal any significant metabolic difference between perilymph samples from the sonoporation and control ears. The results suggest that sonoporation of the round window membrane does not cause damage to the inner ear in a sheep model.

Imaging Study &amp; Surgical Perspective Of Cochlear Implantees

Introduction: A cross-sectional prospective clinical study was done to evaluate the inner ear anomalies in candidates undergoing cochlear implantation. Materials and Methods: Study was carried out over a period of 07 years (Jan 2013 to Dec 2019) at Cochlear Implant Centre, Combined Military Hospital Dhaka. A total 206 deaf candidates, both pre and post lingual, were included in convenient sampling method. Result: The sample consisted of 206 candidates, of whom 117 (56.80%) were female and 89 (43.20%) were male. All candidates had severe to profound bilateral deafness. 182 (88.35%) of them were pre and 24 (11.65%) were in post lingual group. All patients diagnosed audiologically as profound deafness underwent HRCT scan of temporal bone with 3D reconstruction of cochlea and MRI of internal auditory canal &amp; brain. Radiological examination revealed that 36 (17.47%) candidates had ear anomalies. Mondini deformity 14 (06.80%), cochlear ossification 11 (5.34%), large vestibular aqueduct 04 (1.94%), high jugular bulb 04 (1.94%) and anteriorly placed sigmoid sinus 03 (1.45%) were noted. During intervention, 42 (20.39%) candidates had anomalous intra operative findings. Among them CSF gusher 19 (9.23%), ossification of basal turn 12 (5.83%), isolated rotated Cochlea 02 (0.97%), high jugular bulb 04 (1.94%), anteriorly placed sigmoid sinus 03 (1.45%), and very high facial nerve 02 (0.97%) were observed. During surgery, electrode insertion difficulty due to high CSF gusher was experienced in19 (9.23%) cases, full length of electrode insertion was not possible due to ossified basal turn 12 (5.83%), difficult to find out round window membrane due to rotated cochlea 02 (0.97%), prevented direct visualization of the round window due to high jugular bulb 04 (1.94%), difficult to approach round window due to very high facial nerve 02 (0.97%). and approach to round window membrane was compromised due to anteriorly placed sigmoid sinus 03 (1.45%). Most of these difficulties were effectively managed during surgery. Conclusions: This study highlights the importance of preoperative radiological scanning in the assessment of patients undergoing cochlear implantation. It provides vital information on cochlear status and in ruling out non cochlear causes where cochlear implantation is not feasible. Detection of anatomical abnormalities with appropriate evaluation, specially imaging should be mandatory in every patient undergoing cochlear implantation. J Dhaka Med Coll. 2021; 30(2) : 167-175