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PURPOSE: To better characterize the frequency and patterns of hearing dysfunction in patients who have received teprotumumab to treat thyroid eye disease. DESIGN: Noncomparative case series. PARTICIPANTS: Patients who underwent audiology testing before and after completion of teprotumumab infusions. METHODS: A review of patients who underwent audiology testing before and after completion of teprotumumab infusions was carried out. Additional audiogram testing during treatment was included when available. Hearing function was analyzed using audiogram data measuring threshold hearing levels at specific frequencies. Basic demographic data as well as information regarding otologic symptoms also were obtained and analyzed. MAIN OUTCOME MEASURES: Hearing loss demonstrated by a significant change in decibel hearing thresholds or that meets criteria for ototoxicity. RESULTS: Twenty-two patients (44 ears) were included in the study, with baseline and most recent audiology testing after treatment ranging from 84 days before to 496 days after treatment. Fifteen patients (30 ears) also underwent testing during treatment starting after the second infusion up until the day of, but before, the eighth infusion. Hearing loss after treatment met criteria for ototoxicity in 17 of the 44 ears (38.6%), with 11 of the 22 patients (50.0%) meeting criteria in at least 1 ear. The pure-tone average decibel hearing levels (HLs) across all 44 ears demonstrated hearing loss after treatment (P = 0.0029), specifically at high (P = 0.0008) and middle frequencies (P = 0.0042), but not at low frequencies (P = 0.8344). Patients who were older also were more likely to experience hearing loss after treatment (P = 0.0048). CONCLUSIONS: Audiometric data demonstrate that teprotumumab influences hearing function, most significantly at higher frequencies and in older patients. Audiometric testing is critical for counseling patients regarding teprotumumab treatment. A protocol for monitoring hearing during treatment is needed to detect and manage hearing changes associated with teprotumumab use. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
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Pérdida Auditiva , Ototoxicidad , Humanos , Anciano , Umbral Auditivo , Audiometría de Tonos Puros/métodos , Pérdida Auditiva/inducido químicamente , Pérdida Auditiva/diagnóstico , AudiciónRESUMEN
Quantitative analysis of neurite growth and morphology is essential for understanding the determinants of neural development and regeneration, however, it is complicated by the labor-intensive process of measuring diverse parameters of neurite outgrowth. Consequently, automated approaches have been developed to study neurite morphology in a high-throughput and comprehensive manner. These approaches include computer-automated algorithms known as 'convolutional neural networks' (CNNs)-powerful models capable of learning complex tasks without the biases of hand-crafted models. Nevertheless, their complexity often relegates them to functioning as 'black boxes.' Therefore, research in the field of explainable AI is imperative to comprehend the relationship between CNN image analysis output and predefined morphological parameters of neurite growth in order to assess the applicability of these machine learning approaches. In this study, drawing inspiration from the field of automated feature selection, we investigate the correlation between quantified metrics of neurite morphology and the image analysis results from NeuriteNet-a CNN developed to analyze neurite growth. NeuriteNet accurately distinguishes images of neurite growth based on different treatment groups within two separate experimental systems. These systems differentiate between neurons cultured on different substrate conditions and neurons subjected to drug treatment inhibiting neurite outgrowth. By examining the model's function and patterns of activation underlying its classification decisions, we discover that NeuriteNet focuses on aspects of neuron morphology that represent quantifiable metrics distinguishing these groups. Additionally, it incorporates factors that are not encompassed by neuron morphology tracing analyses. NeuriteNet presents a novel tool ideally suited for screening morphological differences in heterogeneous neuron groups while also providing impetus for targeted follow-up studies.
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Neuritas , Neurogénesis , Neuronas , Algoritmos , BenchmarkingRESUMEN
BACKGROUND: Cochlear implants (CIs) restore hearing to deafened patients. The foreign body response (FBR) following cochlear implantation (post-CI) comprises an infiltration of macrophages, other immune and non-immune cells, and fibrosis into the scala tympani, a space that is normally devoid of cells. This FBR is associated with negative effects on CI outcomes including increased electrode impedances and loss of residual acoustic hearing. This study investigates the extent to which macrophage depletion by an orally administered CSF-1R specific kinase (c-FMS) inhibitor, PLX-5622, modulates the tissue response to CI and neural health. MAIN TEXT: 10- to 12-week-old CX3CR1 + /GFP Thy1 + /YFP mice on C57BL/6J/B6 background was fed chow containing 1200 mg/kg PLX5622 or control chow for the duration of the study. 7 days after starting the diet, 3-channel cochlear implants were implanted in the ear via the round window. Serial impedance and neural response telemetry (NRT) measurements were acquired throughout the study. Electric stimulation began 7 days post-CI until 28 days post-CI for 5 h/day, 5 days/week, with programming guided by NRT and behavioral responses. Cochleae harvested at 10, 28 or 56 days post-CI were cryosectioned and labeled with an antibody against α-smooth muscle actin (α-SMA) to identify myofibroblasts and quantify the fibrotic response. Using IMARIS image analysis software, the outlines of scala tympani, Rosenthal canal, modiolus, and lateral wall for each turn were traced manually to measure region volume. The density of nuclei, CX3CR1 + macrophages, Thy1 + spiral ganglion neuron (SGN) numbers, and the ratio of the α-SMA + volume/scala tympani volume were calculated. Cochlear implantation in control diet subjects caused infiltration of cells, including macrophages, into the cochlea. Fibrosis was evident in the scala tympani adjacent to the electrode array. Mice fed PLX5622 chow showed reduced macrophage infiltration throughout the implanted cochleae across all time points. However, scala tympani fibrosis was not reduced relative to control diet subjects. Further, mice treated with PLX5622 showed increased electrode impedances compared to controls. Finally, treatment with PLX5622 decreased SGN survival in implanted and contralateral cochleae. CONCLUSION: The data suggest that macrophages play an important role in modulating the intracochlear tissue response following CI and neural survival.
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Implantación Coclear , Humanos , Animales , Ratones , Implantación Coclear/métodos , Ratones Endogámicos C57BL , Cóclea/patología , Cóclea/fisiología , FibrosisRESUMEN
OBJECTIVE: Minimally traumatic surgical techniques and advances in cochlear implant (CI) electrode array designs have allowed acoustic hearing present in a CI candidate prior to surgery to be preserved postoperatively. As a result, these patients benefit from combined electric-acoustic stimulation (EAS) postoperatively. However, 30% to 40% of EAS CI users experience a partial loss of hearing up to 30 dB after surgery. This additional hearing loss is generally not severe enough to preclude use of acoustic amplification; however, it can still impact EAS benefits. The use of electrocochleography (ECoG) measures of peripheral hair cell and neural auditory function have shed insight into the pathophysiology of postimplant loss of residual acoustic hearing. The present study aims to assess the long-term stability of ECoG measures and to establish ECoG as an objective method of monitoring residual hearing over the course of EAS CI use. We hypothesize that repeated measures of ECoG should remain stable over time for EAS CI users with stable postoperative hearing preservation. We also hypothesize that changes in behavioral audiometry for EAS CI users with loss of residual hearing should also be reflected in changes in ECoG measures. DESIGN: A pool of 40 subjects implanted under hearing preservation protocol was included in the study. Subjects were seen at postoperative visits for behavioral audiometry and ECoG recordings. Test sessions occurred 0.5, 1, 3, 6, 12 months, and annually after 12 months postoperatively. Changes in pure-tone behavioral audiometric thresholds relative to baseline were used to classify subjects into two groups: one group with stable acoustic hearing and another group with loss of acoustic hearing. At each test session, ECoG amplitude growth functions for several low-frequency stimuli were obtained. The threshold, slope, and suprathreshold amplitude at a fixed stimulation level was obtained from each growth function at each time point. Longitudinal linear mixed effects models were used to study trends in ECoG thresholds, slopes, and amplitudes for subjects with stable hearing and subjects with hearing loss. RESULTS: Preoperative, behavioral audiometry indicated that subjects had an average low-frequency pure-tone average (125 to 500 Hz) of 40.88 ± 13.12 dB HL. Postoperatively, results showed that ECoG thresholds and amplitudes were stable in EAS CI users with preserved residual hearing. ECoG thresholds increased (worsened) while ECoG amplitudes decreased (worsened) for those with delayed hearing loss. The slope did not distinguish between EAS CI users with stable hearing and subjects with delayed loss of hearing. CONCLUSIONS: These results provide a new application of postoperative ECoG as an objective tool to monitor residual hearing and understand the pathophysiology of delayed hearing loss. While our measures were conducted with custom-designed in-house equipment, CI companies are also designing and implementing hardware and software adaptations to conduct ECoG recordings. Thus, postoperative ECoG recordings can potentially be integrated into clinical practice.
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Implantación Coclear , Implantes Cocleares , Sordera , Pérdida Auditiva , Humanos , Estimulación Acústica , Audiometría de Respuesta Evocada/métodos , Implantación Coclear/métodos , Pérdida Auditiva/rehabilitación , Sordera/rehabilitación , Audiometría de Tonos Puros , Umbral Auditivo , Estimulación EléctricaRESUMEN
OBJECTIVES: Understanding speech-in-noise (SiN) is a complex task that recruits multiple cortical subsystems. Individuals vary in their ability to understand SiN. This cannot be explained by simple peripheral hearing profiles, but recent work by our group ( Kim et al. 2021 , Neuroimage ) highlighted central neural factors underlying the variance in SiN ability in normal hearing (NH) subjects. The present study examined neural predictors of SiN ability in a large cohort of cochlear-implant (CI) users. DESIGN: We recorded electroencephalography in 114 postlingually deafened CI users while they completed the California consonant test: a word-in-noise task. In many subjects, data were also collected on two other commonly used clinical measures of speech perception: a word-in-quiet task (consonant-nucleus-consonant) word and a sentence-in-noise task (AzBio sentences). Neural activity was assessed at a vertex electrode (Cz), which could help maximize eventual generalizability to clinical situations. The N1-P2 complex of event-related potentials (ERPs) at this location were included in multiple linear regression analyses, along with several other demographic and hearing factors as predictors of SiN performance. RESULTS: In general, there was a good agreement between the scores on the three speech perception tasks. ERP amplitudes did not predict AzBio performance, which was predicted by the duration of device use, low-frequency hearing thresholds, and age. However, ERP amplitudes were strong predictors for performance for both word recognition tasks: the California consonant test (which was conducted simultaneously with electroencephalography recording) and the consonant-nucleus-consonant (conducted offline). These correlations held even after accounting for known predictors of performance including residual low-frequency hearing thresholds. In CI-users, better performance was predicted by an increased cortical response to the target word, in contrast to previous reports in normal-hearing subjects in whom speech perception ability was accounted for by the ability to suppress noise. CONCLUSIONS: These data indicate a neurophysiological correlate of SiN performance, thereby revealing a richer profile of an individual's hearing performance than shown by psychoacoustic measures alone. These results also highlight important differences between sentence and word recognition measures of performance and suggest that individual differences in these measures may be underwritten by different mechanisms. Finally, the contrast with prior reports of NH listeners in the same task suggests CI-users performance may be explained by a different weighting of neural processes than NH listeners.
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Implantación Coclear , Implantes Cocleares , Percepción del Habla , Humanos , Habla , Individualidad , Ruido , Percepción del Habla/fisiologíaRESUMEN
OBJECTIVE: This report presents a case study of a patient who resumed bilateral hearing aid use after nearly four years of limited progress and subjective dissatisfaction with a hybrid cochlear implant device. DESIGN: Case study. STUDY SAMPLE: One patient. RESULTS: The patient's post-operative objective and subjective abilities with bilateral hearing aids were better than with a hybrid cochlear implant and contralateral hearing aid. CONCLUSIONS: Although the benefits of combined acoustic and electric hearing have been well-documented, this report presents a solution for those with well-preserved hearing and poor hybrid cochlear implant performance: returning to bilateral hearing aid use.
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Implantación Coclear , Implantes Cocleares , Audífonos , Percepción del Habla , Acústica , Estimulación Eléctrica , Audición , Humanos , Percepción del Habla/fisiologíaRESUMEN
The foreign body response (FBR) to implantable materials can negatively impact performance of medical devices such as the cochlear implant. Engineering surfaces that resist the FBR could lead to enhanced functionality including potentially improving outcomes for cochlear implant recipients through reduction in fibrosis. In this work, we coat poly(dimethylsiloxane) (PDMS) surfaces with two zwitterionic polymers, poly(sulfobetaine methacrylate) (pSBMA) and poly(carboxybetaine methacrylate) (pCBMA), using a simultaneous photografting/photo-cross-linking process to produce a robust grafted zwitterionic hydrogel. reduce nonspecific protein adsorption, the first step of the FBR. The coating process uses benzophenone, a photografting agent and type II photoinitiator, to covalently link the cross-linked zwitterionic thin film to the PDMS surface. As the concentration of benzophenone on the surface increases, the adhesive strength of the zwitterionic thin films to PDMS surfaces increases as determined by shear adhesion. Additionally, with increased concentration of the adsorbed benzophenone, failure of the system changes from adhesive delamination to cohesive failure within the hydrogel, demonstrating that durable adhesive bonds are formed from the photografting process. Interestingly, antifouling properties of the zwitterionic polymers are preserved with significantly lower levels of nonspecific protein adsorption on zwitterion hydrogel-coated samples compared to uncoated controls. Fibroblast adhesion is also dramatically reduced on coated substrates. These results show that cross-linked pSBMA and pCBMA hydrogels can be readily photografted to PDMS substrates and show promise in potentially changing the fibrotic response to implanted biomaterials.
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Betaína/farmacología , Incrustaciones Biológicas/prevención & control , Materiales Biocompatibles Revestidos/farmacología , Dimetilpolisiloxanos/farmacología , Metacrilatos/farmacología , Ácidos Polimetacrílicos/farmacología , Adsorción , Animales , Benzofenonas/química , Benzofenonas/efectos de la radiación , Betaína/síntesis química , Adhesión Celular/efectos de los fármacos , Materiales Biocompatibles Revestidos/síntesis química , Dimetilpolisiloxanos/síntesis química , Fibrinógeno/química , Fibroblastos/metabolismo , Humanos , Hidrogeles/síntesis química , Hidrogeles/química , Metacrilatos/síntesis química , Polimerizacion/efectos de la radiación , Ácidos Polimetacrílicos/síntesis química , RatasRESUMEN
Developing materials that reduce or eliminate fibrosis encapsulation of neural prosthetic implants could significantly enhance implant fidelity by improving the tissue/electrode array interface. Here, we report on the photografting and patterning of two zwitterionic materials, sulfobetaine methacrylate (SBMA) and carboxybetaine methacrylate (CBMA), for controlling the adhesion and directionality of cells relevant to neural prosthetics. CBMA and SBMA polymers were photopolymerized and grafted on glass surfaces then characterized by X-ray photoelectron spectroscopy, water contact angle, and protein adsorption. Micropatterned surfaces were fabricated with alternating zwitterionic and uncoated bands. Fibroblasts, cells prevalent in fibrotic tissue, almost exclusively migrate and grow on uncoated bands with little to no cells present on zwitterionic bands, especially for CBMA-coated surfaces. Astrocytes and Schwann cells showed similarly low levels of cell adhesion and morphology changes when cultured on zwitterionic surfaces. Additionally, Schwann cells and inner ear spiral ganglion neuron neurites aligned well to zwitterionic patterns.
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Metacrilatos/farmacología , Neuronas/metabolismo , Ganglio Espiral de la Cóclea/metabolismo , Animales , Astrocitos/citología , Astrocitos/metabolismo , Adhesión Celular/efectos de los fármacos , Metacrilatos/química , Neuronas/citología , Espectroscopía de Fotoelectrones , Ratas , Células de Schwann/citología , Células de Schwann/metabolismo , Ganglio Espiral de la Cóclea/citologíaRESUMEN
After nerve injury, Schwann cells (SCs) dedifferentiate, proliferate, and support axon regrowth. If axons fail to regenerate, denervated SCs eventually undergo apoptosis due, in part, to increased expression of the low-affinity neurotrophin receptor, p75(NTR). Merlin is the protein product of the NF2 tumor suppressor gene implicated in SC tumorigenesis. Here we explore the contribution of merlin to SC responses to nerve injury. We find that merlin becomes phosphorylated (growth permissive) in SCs following acute axotomy and following gradual neural degeneration in a deafness model, temporally correlated with increased p75(NTR) expression. p75(NTR) levels are elevated in P0SchΔ39-121 transgenic mice that harbor an Nf2 mutation in SCs relative to wild-type mice before axotomy and remain elevated for a longer period of time following injury. Replacement of wild-type, but not phospho-mimetic (S518D), merlin isoforms suppresses p75(NTR) expression in primary human schwannoma cultures which otherwise lack functional merlin. Despite elevated levels of p75(NTR), SC apoptosis following axotomy is blunted in P0SchΔ39-121 mice relative to wild-type mice suggesting that loss of functional merlin contributes to SC resistance to apoptosis. Further, cultured SCs from mice with a tamoxifen-inducible knock-out of Nf2 confirm that SCs lacking functional merlin are less sensitive to p75(NTR)-mediated cell death. Taken together these results point to a model whereby loss of axonal contact following nerve injury results in merlin phosphorylation leading to increased p75(NTR) expression. Further, they demonstrate that merlin facilitates p75(NTR)-mediated apoptosis in SCs helping to explain how neoplastic SCs that lack functional merlin survive long-term in the absence of axonal contact.
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Apoptosis/fisiología , Neurofibromina 2/metabolismo , Traumatismos de los Nervios Periféricos/metabolismo , Receptor de Factor de Crecimiento Nervioso/metabolismo , Células de Schwann/metabolismo , Transducción de Señal/fisiología , Animales , Axones/metabolismo , Axones/patología , Axotomía , Desdiferenciación Celular/fisiología , Proliferación Celular , Células Cultivadas , Humanos , Ratones , Ratones Transgénicos , Regeneración Nerviosa/fisiología , Neuroma Acústico/metabolismo , Neuroma Acústico/patología , Traumatismos de los Nervios Periféricos/patología , Ratas Sprague-Dawley , Células de Schwann/patologíaRESUMEN
OBJECTIVES: To model the contribution of implant material and insertion trauma on loss of acoustic hearing after cochlear implantation in an appropriate animal model. METHODS: Sixty-five C57Bl/6J mice underwent unilateral implantation with implant grade materials: 2 implant grade silicones and a third uncoated platinum wire. A sham surgery group was included as a control. Serial auditory brainstem response (ABR) thresholds and distortion product otoacoustic emissions (DPOAEs) were used to discern effects on hearing over 22 weeks. Histologic measurements of damage to the organ of Corti and spiral ganglion were correlated with degree of hearing loss and material type. RESULTS: Organ of Corti damage correlated with rate of hearing loss soon after implantation (0-2 weeks) but not subsequently (2-22 weeks). Organ of Corti damage did not depend on implant type and was present even in sham surgery subjects when hearing was severely damaged. Spiral ganglia appeared unaffected. There was no evidence of an inflammatory or toxic effect of the materials beyond the site of implant insertion. CONCLUSIONS: Hearing loss and cochlear damage appear to be related to insertion trauma, with minimal effect on delayed hearing loss caused by different materials. In the C57Bl/6J mouse model, the sensory epithelium appears to be the location of damage after cochlear implantation.
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Implantación Coclear/efectos adversos , Implantes Cocleares , Pérdida Auditiva Unilateral/etiología , Órgano Espiral/patología , Ganglio Espiral de la Cóclea/patología , Animales , Umbral Auditivo , Potenciales Evocados Auditivos del Tronco Encefálico , Fibrosis , Ratones Endogámicos C57BL , Modelos Animales , Órgano Espiral/lesiones , Emisiones Otoacústicas Espontáneas , Diseño de Prótesis , Factores de TiempoRESUMEN
Vestibular schwannomas (VSs) arise from Schwann cells (SCs) and result from the loss of function of merlin, the protein product of the NF2 tumor suppressor gene. In contrast to non-neoplastic SCs, VS cells survive long-term in the absence of axons. We find that p75(NTR) is overexpressed in VSs compared with normal nerves, both at the transcript and protein level, similar to the response of non-neoplastic SCs following axotomy. Despite elevated p75(NTR) expression, VS cells are resistant to apoptosis due to treatment with proNGF, a high affinity ligand for p75(NTR) . Furthermore, treatment with proNGF protects VS cells from apoptosis due to c-Jun N-terminal kinase (JNK) inhibition indicating that p75(NTR) promotes VS cell survival. Treatment of VS cells with proNGF activated NF-κB while inhibition of JNK with SP600125 or siRNA-mediated knockdown reduced NF-κB activity. Significantly, proNGF also activated NF-κB in cultures treated with JNK inhibitors. Thus, JNK activity appears to be required for basal levels of NF-κB activity but not for proNGF-induced NF-κB activity. To confirm that the increase in NF-κB activity contributes to the prosurvival effect of proNGF, we infected VS cultures with Ad.IκB.SerS32/36A virus, which inhibits NF-κB activation. Compared with control virus, Ad.IκB.SerS32/36A significantly increased apoptosis including in VS cells treated with proNGF. Thus, in contrast to non-neoplastic SCs, p75(NTR) signaling provides a prosurvival response in VS cells by activating NF-κB independent of JNK. Such differences may contribute to the ability of VS cells to survive long-term in the absence of axons.
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FN-kappa B/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Neuroma Acústico/fisiopatología , Receptores de Factor de Crecimiento Nervioso/metabolismo , Animales , Apoptosis/fisiología , Supervivencia Celular/fisiología , Células Cultivadas , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Ratones , FN-kappa B/agonistas , FN-kappa B/antagonistas & inhibidores , Factor de Crecimiento Nervioso/metabolismo , Precursores de Proteínas/metabolismo , Ratas , Receptores de Factores de Crecimiento , Células de Schwann/fisiología , Nervio Ciático/fisiologíaRESUMEN
The ability to direct neurite growth into a close proximity of stimulating elements of a neural prosthesis, such as a retinal or cochlear implant (CI), may enhance device performance and overcome current spatial signal resolution barriers. In this work, spiral ganglion neurons (SGNs), which are the target neurons to be stimulated by CIs, were cultured on photopolymerized micropatterns with varied matrix stiffnesses to determine the effect of rigidity on neurite alignment to physical cues. Micropatterns were generated on methacrylate thin film surfaces in a simple, rapid photopolymerization step by photomasking the prepolymer formulation with parallel line-space gratings. Two methacrylate series, a nonpolar HMA-co-HDDMA series and a polar PEGDMA-co-EGDMA series, with significantly different surface wetting properties were evaluated. Equivalent pattern periodicity was maintained across each methacrylate series based on photomask band spacing, and the feature amplitude was tuned to a depth of 2 µm amplitude for all compositions using the temporal control afforded by the UV curing methodology. The surface morphology was characterized by scanning electron microscopy and white light interferometry. All micropatterned films adsorb similar amounts of laminin from solution, and no significant difference in SGN survival was observed when the substrate compositions were compared. SGN neurite alignment significantly increases with increasing material modulus for both methacrylate series. Interestingly, SGN neurites respond to material stiffness cues that are orders of magnitude higher (GPa) than what is typically ascribed to neural environments (kPa). The ability to understand neurite response to engineered physical cues and mechanical properties such as matrix stiffness will allow the development of advanced biomaterials that direct de novo neurite growth to address the spatial signal resolution limitations of current neural prosthetics.
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Neuritas/metabolismo , Animales , Materiales Biocompatibles/metabolismo , Células Cultivadas , Laminina/metabolismo , Neuronas/metabolismo , Polimerizacion , Polímeros/metabolismo , Ratas , Ganglio Espiral de la Cóclea/metabolismo , Propiedades de Superficie , Ingeniería de Tejidos/métodosRESUMEN
Cochlear implants (CI) represent incredible devices that restore hearing perception for those with moderate to profound sensorineural hearing loss. However, the ability of a CI to restore complex auditory function is limited by the number of perceptually independent spectral channels provided. A major contributor to this limitation is the physical gap between the CI electrodes and the target spiral ganglion neurons (SGNs). In order for CI electrodes to stimulate SGNs more precisely, and thus better approximate natural hearing, new methodologies need to be developed to decrease this gap, (i.e., transitioning CIs from a far-field to near-field device). In this review, strategies aimed at improving the neural-electrode interface are discussed in terms of the magnitude of impact they could have and the work needed to implement them. Ongoing research suggests current clinical efforts to limit the CI-related immune response holds great potential for improving device performance. This could eradicate the dense, fibrous capsule surrounding the electrode and enhance preservation of natural cochlear architecture, including SGNs. In the long term, however, optimized future devices will likely need to induce and guide the outgrowth of the peripheral process of SGNs to be in closer proximity to the CI electrode in order to better approximate natural hearing. This research is in its infancy; it remains to be seen which strategies (surface patterning, small molecule release, hydrogel coating, etc.) will be enable this approach. Additionally, these efforts aimed at optimizing CI function will likely translate to other neural prostheses, which face similar issues.
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Micro and nanoscale patterning of surface features and biochemical cues have emerged as tools to precisely direct neurite growth into close proximity with next generation neural prosthesis electrodes. Biophysical cues can exert greater influence on neurite pathfinding compared to the more well studied biochemical cues; yet the signaling events underlying the ability of growth cones to respond to these microfeatures remain obscure. Intracellular Ca2+ signaling plays a critical role in how a growth cone senses and grows in response to various cues (biophysical features, repulsive peptides, chemo-attractive gradients). Here, we investigate the role of inositol triphosphate (IP3) and ryanodine-sensitive receptor (RyR) signaling as sensory neurons (spiral ganglion neurons, SGNs, and dorsal root ganglion neurons, DRGNs) pathfind in response to micropatterned substrates of varied geometries. We find that IP3 and RyR signaling act in the growth cone as they navigate biophysical cues and enable proper guidance to biophysical, chemo-permissive, and chemo-repulsive micropatterns. In response to complex micropatterned geometries, RyR signaling appears to halt growth in response to both topographical features and chemo-repulsive cues. IP3 signaling appears to play a more complex role, as growth cones appear to sense the microfeatures in the presence of xestospongin C but are unable to coordinate turning in response to them. Overall, key Ca2+ signaling elements, IP3 and RyR, are found to be essential for SGNs to pathfind in response to engineered biophysical and biochemical cues. These findings inform efforts to precisely guide neurite regeneration for improved neural prosthesis function, including cochlear implants.
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Neuritas , Canal Liberador de Calcio Receptor de Rianodina , Transducción de Señal , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Neuritas/metabolismo , Animales , Ganglios Espinales/metabolismo , Ganglios Espinales/citología , Conos de Crecimiento/metabolismo , Conos de Crecimiento/efectos de los fármacos , Señalización del Calcio , Ratas , Propiedades de Superficie , Células Cultivadas , Oxazoles , Compuestos MacrocíclicosRESUMEN
Objective. Cochlear implants provide auditory perception to those with severe to profound sensorineural hearing loss: however, the quality of sound perceived by users does not approximate natural hearing. This limitation is due in part to the large physical gap between the stimulating electrodes and their target neurons. Therefore, directing the controlled outgrowth of processes from spiral ganglion neurons (SGNs) into close proximity to the electrode array could provide significantly increased hearing function.Approach.For this objective to be properly designed and implemented, the ability and limits of SGN neurites to be guided must first be determined. In this work, we engineer precise topographical microfeatures with angle turn challenges of various geometries to study SGN pathfinding and use live imaging to better understand how neurite growth is guided by these cues.Main Results.We find that the geometry of the angled microfeatures determines the ability of neurites to navigate the angled microfeature turns. SGN neurite pathfinding fidelity is increased by 20%-70% through minor increases in microfeature amplitude (depth) and by 25% if the angle of the patterned turn is made obtuse. Further, we see that dorsal root ganglion neuron growth cones change their morphology and migration to become more elongated within microfeatures. Our observations also indicate complexities in studying neurite turning. First, as the growth cone pathfinds in response to the various cues, the associated neurite often reorients across the angle topographical microfeatures. Additionally, neurite branching is observed in response to topographical guidance cues, most frequently when turning decisions are most uncertain.Significance.Overall, the multi-angle channel micropatterned substrate is a versatile and efficient system to assess neurite turning and pathfinding in response to topographical cues. These findings represent fundamental principles of neurite pathfinding that will be essential to consider for the design of 3D systems aiming to guide neurite growthin vivo.
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Implantes Cocleares , Neuritas , Conos de Crecimiento , Células Cultivadas , Neuronas , Ganglio Espiral de la CócleaRESUMEN
Cochlear implants (CI) have revolutionized the treatment of patients with severe to profound sensory hearing loss by providing a method of bypassing normal hearing to directly stimulate the auditory nerve. A further advance in the field has been the introduction of "hearing preservation" surgery, whereby the CI electrode array (EA) is carefully inserted to spare damage to the delicate anatomy and function of the cochlea. Preserving residual function of the inner ear allows patients to receive maximal benefit from the CI and to combine CI electric stimulation with acoustic hearing, offering improved postoperative speech, hearing, and quality of life outcomes. However, under the current paradigm of implant surgery, where EAs are inserted by hand, the cochlea cannot be reliably spared from damage. Robotics-assisted EA insertion is an emerging technology that may overcome fundamental human kinetic limitations that prevent consistency in achieving steady and slow EA insertion. This review begins by describing the relationship between EA insertion speed and generation of intracochlear forces and pressures. The various mechanisms by which these intracochlear forces can damage the cochlea and lead to worsened postoperative outcomes are discussed. The constraints of manual insertion technique are compared to robotics-assisted methods, followed by an overview of the current and future state of robotics-assisted EA insertion.
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The durability of photografted zwitterionic hydrogel coatings on cochlear implant biomaterials was examined to determine the viability of these antifouling surfaces during insertion and long-term implant usage. Tribometry was used to determine the effect of zwitterionic coatings on the lubricity of surfaces with varying hydration levels, applied normal force, and time frame. Additionally, flexural resistance was investigated using mandrel bending. Ex vivo durability was assessed by determining the coefficient of friction between tissues and treated surfaces. Furthermore, cochlear implantation force was measured using cadaveric human cochleae. Hydrated zwitterionic hydrogel coatings reduced frictional resistance approximately 20-fold compared to uncoated PDMS, which led to significantly lower mean force experienced by coated cochlear implants during insertion compared to uncoated systems. Under flexural force, zwitterionic films resisted failure for up to 60 min of desiccation. The large increase in lubricity was maintained for 20 h under continual force while hydrated. For loosely cross-linked systems, films remained stable and lubricious even after rehydration following complete drying. All coatings remained hydrated and functional under frictional force for at least 30 min in ambient conditions allowing drying, with lower cross-link densities showing the greatest longevity. Moreover, photografted zwitterionic hydrogel samples showed no evidence of degradation and nearly identical lubricity before and after implantation. This work demonstrates that photografted zwitterionic hydrogel coatings are sufficiently durable to maintain viability before, during, and after implantation. Mechanical properties, including greatly increased lubricity, are preserved after complete drying and rehydration for various applied forces. Additionally, this significantly enhanced lubricity translates to significantly decreased force during insertion of implants which should result in less trauma and scarring.
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Materiales Biocompatibles Revestidos , Implantes Cocleares , Hidrogeles , Ensayo de Materiales , Hidrogeles/química , Humanos , Materiales Biocompatibles Revestidos/química , Materiales Biocompatibles Revestidos/farmacología , Propiedades de Superficie , Tamaño de la PartículaRESUMEN
Analyzing confocal microscopic data of biological samples using the Imaris software poses challenges due to its time-consuming nature involving tedious multiple steps and possibility of human errors. Here, we developed a supervised automation protocol to minimize manual input in cell and spot counting on confocal images obtained from mouse cochlear sections. The protocol increases efficiency by incorporating image recognition and object-oriented macros. Moreover, the protocol being adaptable allows scientists in diverse other fields to customize it for their specific needs.
RESUMEN
Delayed loss of residual acoustic hearing after cochlear implantation is a common but poorly understood phenomenon due to the scarcity of relevant temporal bone tissues. Prior histopathological analysis of one case of post-implantation hearing loss suggested there were no interaural differences in hair cell or neural degeneration to explain the profound loss of low-frequency hearing on the implanted side (Quesnel et al., 2016) and attributed the threshold elevation to neo-ossification and fibrosis around the implant. Here we re-evaluated the histopathology in this case, applying immunostaining and improved microscopic techniques for differentiating surviving hair cells from supporting cells. The new analysis revealed dramatic interaural differences, with a > 80 % loss of inner hair cells in the cochlear apex on the implanted side, which can account for the post-implantation loss of residual hearing. Apical degeneration of the stria further contributed to threshold elevation on the implanted side. In contrast, spiral ganglion cell survival was reduced in the region of the electrode on the implanted side, but apical counts in the two ears were similar to that seen in age-matched unimplanted control ears. Almost none of the surviving auditory neurons retained peripheral axons throughout the basal half of the cochlea. Relevance to cochlear implant performance is discussed.
Asunto(s)
Umbral Auditivo , Implantación Coclear , Implantes Cocleares , Ganglio Espiral de la Cóclea , Implantación Coclear/instrumentación , Implantación Coclear/efectos adversos , Humanos , Ganglio Espiral de la Cóclea/patología , Ganglio Espiral de la Cóclea/fisiopatología , Células Ciliadas Auditivas Internas/patología , Factores de Tiempo , Supervivencia Celular , Masculino , Audición , Pérdida Auditiva/fisiopatología , Pérdida Auditiva/patología , Pérdida Auditiva/cirugía , Pérdida Auditiva/etiología , Femenino , Células Ciliadas Auditivas/patología , Anciano , Degeneración Nerviosa , Persona de Mediana Edad , Hueso Temporal/patología , Hueso Temporal/cirugíaRESUMEN
OBJECTIVE: To describe the use of robotics-assisted electrode array (EA) insertion combined with intraoperative electrocochleography (ECochG) in hearing preservation cochlear implant surgery. STUDY DESIGN: Prospective, single-arm, open-label study. SETTING: All procedures and data collection were performed at a single tertiary referral center. PATIENTS: Twenty-one postlingually deaf adult subjects meeting Food and Drug Administration indication criteria for cochlear implantation with residual acoustic hearing defined as thresholds no worse than 65 dB at 125, 250, and 500 Hz. INTERVENTION: All patients underwent standard-of-care unilateral cochlear implant surgery using a single-use robotics-assisted EA insertion device and concurrent intraoperative ECochG. MAIN OUTCOME MEASURES: Postoperative pure-tone average over 125, 250, and 500 Hz measured at initial activation and subsequent intervals up to 1 year afterward. RESULTS: Twenty-two EAs were implanted with a single-use robotics-assisted insertion device and simultaneous intraoperative ECochG. Fine control over robotic insertion kinetics could be applied in response to changes in ECochG signal. Patients had stable pure-tone averages after activation with normal impedance and neural telemetry responses. CONCLUSIONS: Combining robotics-assisted EA insertion with intraoperative ECochG is a feasible technique when performing hearing preservation implant surgery. This combined approach may provide the surgeon a means to overcome the limitations of manual insertion and respond to cochlear feedback in real-time.