This review highlights advances in inner ear organoids(IEOs)as a novel platform for drug screening and disease modeling,particularly for hearing loss.IEOs,derived from embryonic stem cells,induced pluripotent stem cel...This review highlights advances in inner ear organoids(IEOs)as a novel platform for drug screening and disease modeling,particularly for hearing loss.IEOs,derived from embryonic stem cells,induced pluripotent stem cells,or tissue-specific progenitors,provide a physiologically relevant alternative to traditional animal models.Significant progress has been made in utilizing various cell sources,extracellular matrix materials such as Matrigel and hydrogels,and methods for controlling microenvironments through biochemical and biophysical signals.Applications of IEOs in drug screening,disease modeling,and personalized medicine enable exploration of hearing loss mechanisms and therapeutic testing.However,challenges remain,including the incomplete maturation of cochlear cells and difficulty replicating in vivo environments.Future research should focus on optimizing IEO generation,incorporating microfluidic technologies,and advancing high-throughput screening to enhance drug discovery and clinical translation.展开更多
Objectives:To investigate the imaging characteristics,surgical approaches,and outcomes of cochlear implantation(CI)in patients with special inner ear malformations(IEMs)that show transitional forms between cochlear hy...Objectives:To investigate the imaging characteristics,surgical approaches,and outcomes of cochlear implantation(CI)in patients with special inner ear malformations(IEMs)that show transitional forms between cochlear hypoplasia(CH)and common cavity(CC).Methods:Twelve children(eight males,four females),aged 10 to 43 months,with special IEMs were enrolled,and their inner ear structures were analyzed using detailed segmentation.Two surgical approaches were employed:the transmastoid slot labyrinthotomy approach(TSLA)for cases requiring customized electrodes,and the round window or cochleostomy approach for the remaining cases.Outcomes were evaluated using Categories of Auditory Performance(CAP),Speech Intelligibility Rating(SIR),and Meaningful Auditory Integration Scale(MAIS/IT-MAIS)at 12 months post-implantation.Results:Two main types of malformed cochleae were identified:common cavity-like and primitive CH types.All patients exhibited cochlear nerve deficiency and significant bilateral differences in their inner ear structures.Four patients underwent TSLA with customized electrodes,while the remaining patients received lateral wall electrodes via the round window or cochleostomy approach.Most patients showed improvement in auditory and speech capabilities following implantation.Conclusion:Inner ear malformations with transitional forms between CH and CC present unique challenges,requiring detailed preoperative evaluation and customized surgical plans.Even in severe cases,carefully planned surgery can lead to meaningful auditory rehabilitation.展开更多
Objective:The aims of this study were to investigate the clinical applicability of 3D segmentation in measuring cochlear anatomical parameters,explore factors that influence the insertion angle of cochlear implant ele...Objective:The aims of this study were to investigate the clinical applicability of 3D segmentation in measuring cochlear anatomical parameters,explore factors that influence the insertion angle of cochlear implant electrodes in patients with inner ear malformations,and determine the value of 3D segmentation in predicting cochlear implant electrode insertion depth by simulating electrode implantation in a reconstructed 3D model.Methods:Data from 208 temporal bone CT scans of patients with a variety of inner ear malformations(including the CH,IP-Ⅰ,IP-Ⅱ,and IP-Ⅲtypes)who underwent cochlear implantation at our center were retrospectively analyzed.Preoperative temporal bone CT data were subjected to three-dimensional(3D)segmentation of the cochlea with a 3D slicer.Results:Cochlear malformation types,including IP typesⅠ(42 ears),Ⅱ(278ears),Ⅲ(20 ears),and CH(65 ears),were diagnosed and measured in 208 preoperative CT datasets.Cochlear anatomical parameters and electrode length were correlated,which partially explained the variations in electrode insertion angle.The mean angle of implantation among the enrolled patients was 564.33°,and the mean implantation angle prediction error in the 3D segmentation was|23.74|°.Conclusion:Three-dimensional segmentation from temporal bone CT is valuable for surgeons,especially in treating patients with inner ear malformation.Such insights will help surgeons understand overall anatomical variations,predict electrode implantation depth,and complete preoperative imaging assessments for cochlear implant insertion depth in patients with inner ear malformations.展开更多
ObjectiveTo develop a sustained-release codelivery system for intratympanic administration of dexamethasone(DEX)and lipoic acid(LA).MethodsDEX microcrystals(MCs)were prepared via precipitation,while LA-loaded porous P...ObjectiveTo develop a sustained-release codelivery system for intratympanic administration of dexamethasone(DEX)and lipoic acid(LA).MethodsDEX microcrystals(MCs)were prepared via precipitation,while LA-loaded porous PLGA microspheres(LPMPs)were fabricated using a double emulsion–solvent evaporation method.DEX MCs were physically perfused into LPMPs via negative pressure to form a combined system(DEX MCs+LPMPs).Physicochemical properties,in vitro drug release,pharmacokinetics,and biocompatibility were evaluated.Guinea pigs were used for intratympanic injections of DEX MCs,LPMPs,or DEX MCs+LPMPs.ResultsThe DEX MCs+LPMPs system enabled simultaneous release of both drugs,with DEX exhibiting superior pharmacokinetics(sustained perilymph concentrations up to 7 days)compared to DEX MCs alone.LA release from LPMPs demonstrated prolonged kinetics without burst release.SEM confirmed DEX MCs were localized within/on LPMPs and adhered to the round window membrane(RWM).Histological analysis revealed normal cochlear morphology and no inflammatory response,confirming biocompatibility.ConclusionsThis novel codelivery system combining microcrystals and porous microspheres achieves sustained dual-drug release,enhances therapeutic efficacy,and offers a promising strategy for managing hearing loss via intratympanic administration.展开更多
Background:Sudden sensorineural hearing loss(SSNHL),often associated with tinnitus,significantly impacts individuals'quality of life.Current treatments,such as free drugs via intravenous or intratympanic(IT)admini...Background:Sudden sensorineural hearing loss(SSNHL),often associated with tinnitus,significantly impacts individuals'quality of life.Current treatments,such as free drugs via intravenous or intratympanic(IT)administration of dexamethasone(DEX)and lidocaine,face limitations like low bioavailability and rapid drug clearance.To address these challenges,we developed a local co-delivery system combining DEX microcrystals(DEX MCs)and lidocaine-loaded poly(lactic-co-glycolic acid)(PLGA)non-spherical microparticles(LPNMs)for sustained drug release in the inner ear.Methods:DEX MCs and LPNMs were prepared using the traditional precipitation technique and double emulsion-solvent evaporation,respectively.After characterizing physicochemical properties and drug release kinetics,they were dispersed in sodium hyaluronate solution for IT injection,then in vivo pharmacokinetics and biocompatibility in guinea pigs were studied.Results:DEX MCs exhibited stable dissolution,while LPNMs provided sustained lidocaine release,reducing potential side effects.In vivo studies in guinea pigs demonstrated prolonged drug retention in the perilymph and improved pharmacokinetics.Histological evaluation confirmed the good biocompatibility of this combined delivery system,with no significant inner ear damage observed.Conclusion:This co-delivery system can be used as a depot for delivering both DEX and lidocaine to the inner ear and offers a promising approach for the synergistic treatment of SSNHL associated with tinnitus.展开更多
Vestibular hair cells(HCs)in the inner ear,crucial for balance and spatial orientation,are classified into type I and type II subtypes,but the mechanisms regulating their differentiation remain unclear.In this study,w...Vestibular hair cells(HCs)in the inner ear,crucial for balance and spatial orientation,are classified into type I and type II subtypes,but the mechanisms regulating their differentiation remain unclear.In this study,we examined the role of Pou4f3,an important transcription factor,in vestibular HC differentiation using Pou4f3^(DTR/DTR)(deficient)and Pou4f3CreER/CreER(knockout)mouse models.In Pou4f3-deficient mice,the HC number decreased,and immature HCs failed to develop type I characteristics,indicating a developmental arrest.While type II HCs differentiated normally,Pou4f3 deficiency disrupted HC bundle formation and cell polarity.Findings from knockout models further confirmed the essential role of Pou4f3 in vestibular HC subtype specification.This study underscores the critical role of Pou4f3 in determining vestibular HC subtypes and offers insights into potential strategies for restoring vestibular function through HC regeneration.展开更多
Objective:To describe the characteristics of the clinical presentation,diagnosis,surgical methods,and outcomes of patients with otogenic cerebrospinal fluid(CSF)leakage secondary to congenital inner ear dysplasia.Meth...Objective:To describe the characteristics of the clinical presentation,diagnosis,surgical methods,and outcomes of patients with otogenic cerebrospinal fluid(CSF)leakage secondary to congenital inner ear dysplasia.Methods:A retrospective review was performed of 18 patients with otogenic CSF leakage secondary to inner ear dysplasia who underwent surgery in our group from 2007 to 2017 and had a follow-up of at least 4 months.The average length of follow-up was three years.The characteristics of the clinical presentations of all patients,such as self-reported symptoms,radiographic findings,surgical approaches and methods of repair,position of the leakage during surgery,and postoperative course,including the success rate of surgery,are presented.Results:The patients presented mostly with typical symptoms of meningitis,severe hearing impairment,and CSF otorrhea or rhinorrhea.All 18 patients had at least one previous episode of meningitis accompanied by a severe hearing impairment.The preoperative audiograms of 17 patients showed profound sensorineural hearing loss,and one patient had conductive hearing loss.Twelve patients presented with an initial onset of otorrhea,and two had accompanying rhinorrhea.Six patients complained of rhinorrhea,two of whom were misdiagnosed with CSF rhinorrhea and underwent transnasal endoscopy at another hospital.High-resolution computed tomography(HRCT)images can reveal developments in the inner ear,such as expansion of a vestibular cyst,unclear structure of the semicircular canal or cochlea,or signs of effusion in the middle ear or mastoid,which strongly suggest the possibility of CSF otorrhea.The children in the study suffered more severe dysplasia than adults.All 18 patients had CSF leakage identified during surgery.The most common defect sites were in the stapes footplates(55.6%),and 38.9%of patients had a leak around the oval window.One patient had a return of CSF otorrhea during the postoperative period,which did not re-occur following a second repair.Conclusions:CSF otorrhea due to congenital inner ear dysplasia is more severe in children than in adults.The most common symptoms were meningitis,hearing impairment,and CSF otorrhea or rhinorrhea.HRCT has high diagnostic accuracy for this disease.The most common fistula site was around the oval window,including the stapes footplates and the annular ligament.展开更多
There are several challenges to inner ear drug delivery and imaging due to the existence of tight biological barriers to the target structure and the dense bone surrounding it. Advances in imaging and nanomedicine may...There are several challenges to inner ear drug delivery and imaging due to the existence of tight biological barriers to the target structure and the dense bone surrounding it. Advances in imaging and nanomedicine may provide knowledge for overcoming the existing limitations to both the diagnosis and treatment of inner ear diseases. Novel techniques have improved the efficacy of drug delivery and targeting to the inner ear, as well as the quality and accuracy of imaging this structure. In this review, we will describe the pathways and biological barriers of the inner ear regarding drug delivery, the beneficial applications and limitations of the imaging techniques available for inner ear research, the behavior of engineered nanomaterials in inner ear applications, and future perspectives for nanomedicine-based inner ear imaging.展开更多
Auditory function in vertebrates depends on the transduction of sound vibrations into electrical signals by inner ear hair cells.In general,hearing loss resulting from hair cell damage is irreversible because the huma...Auditory function in vertebrates depends on the transduction of sound vibrations into electrical signals by inner ear hair cells.In general,hearing loss resulting from hair cell damage is irreversible because the human ear has been considered to be incapable of regenerating or repairing these sensory elements following severe injury.Therefore,regeneration and protection of inner ear hair cells have become an exciting,rapidly evolving field of research during the last decade.However,mammalian auditory hair cells are few in number,experimentally inaccessible,and barely proliferate postnatally in vitro.Various in vitro primary culture systems of inner ear hair cells have been established by different groups,although many challenges remain unresolved.Here,we briefly explain the structure of the inner ear,summarize the published methods of in vitro hair cell cultures,and propose a feasible protocol for culturing these cells,which gave satisfactory results in our study.A better understanding of in vitro hair cell cultures will substantially facilitate research involving auditory functions,drug development,and the isolation of critical molecules involved in hair cell biology.展开更多
Bone morphogenetic proteins(BMPs)are the largest subfamily of the transforming growth factor-βsuperfamily,and they play important roles in the development of numerous organs,including the inner ear.The inner ear is a...Bone morphogenetic proteins(BMPs)are the largest subfamily of the transforming growth factor-βsuperfamily,and they play important roles in the development of numerous organs,including the inner ear.The inner ear is a relatively small organ but has a highly complex structure and is involved in both hearing and balance.Here,we discuss BMPs and BMP signaling pathways and then focus on the role of BMP signal pathway regulation in the development of the inner ear and the implications this has for the treatment of human hearing loss and balance dysfunction.展开更多
In this study,I focused on finding a mean of protecting against hearing loss.By infusing the cochlea with the neurotrophin factor,NT-3 alone or combined treatment with MK 801,a NMDA receptor antagonist I found hearing...In this study,I focused on finding a mean of protecting against hearing loss.By infusing the cochlea with the neurotrophin factor,NT-3 alone or combined treatment with MK 801,a NMDA receptor antagonist I found hearing loss was attenuated and spiral ganglion neuron loss was nearly totally protected indicating that the importance of the combined treatment of NT-3 and NMDA receptor antagonists in the treatment of hearing disorders.展开更多
K^(+)cycling in the cochlea is critical to maintain hearing.Many sodium-potassium pumps are proved to participate in K^(+)cycling,such as Na/K-ATPase.Theα2-Na/K-ATPase is an important isoform of Na/K-ATPase.The expre...K^(+)cycling in the cochlea is critical to maintain hearing.Many sodium-potassium pumps are proved to participate in K^(+)cycling,such as Na/K-ATPase.Theα2-Na/K-ATPase is an important isoform of Na/K-ATPase.The expression ofα2-Na/K-ATPase in the cochlea is not clear.In this study,we used C57BL/6 mice as a model of presbycusis and implemented immunohistochemistry staining and quantitative real time-PCR,and theα2-Na/K-ATPase expression pattern was confirmed in the inner ear.It was foundα2-Na/K-ATPase was expressed widely in cochlea and its mRNA and protein expression was gradually reduced with aging(4-,14-,26-and 48-weeks old mice).We suspected that,the down-regulation ofα2-Na/K-ATPase expression might be associated with the remodeling of K^(+)cycling,degeneration of morphological structure and decrease of hearing function in aging C57 mice.In conclusion,we speculated that the reduction ofα2-Na/K-ATPase might play an important role in the pathogenesis of age-related hearing loss.展开更多
Congenital hearing loss is a common disorder worldwide.Heterogeneous gene variation accounts for approximately 20-25%of such patients.We investigated a five-generation Chinese family with autosomaldominant nonsyndromi...Congenital hearing loss is a common disorder worldwide.Heterogeneous gene variation accounts for approximately 20-25%of such patients.We investigated a five-generation Chinese family with autosomaldominant nonsyndromic sensorineural hearing loss(SNHL).No wave was detected in the pure-tone audiometry,and the auditory brainstem response was absent in all patients.Computed tomography of the patients,as well as of two sporadic SNHL cases,showed bilateral inner ear anomaly,cochlear maldevelopment,absence of the osseous spiral lamina,and an enlarged vestibular aqueduct.Such findings were absent in nonaffected persons.We used linkage analysis and exome sequencing and uncovered a heterozygous missense mutation in the PI4 KB gene(p.Gln121 Arg)encoding phosphatidylinositol 4-kinaseβ(PI4 KB)from the patients in this family.In addition,3 missense PI4 KB(p.Val434 Gly,p.Glu667 Lys,and p.Met739 Arg)mutations were identified in five patients with nonsyndromic SNHL from 57 sporadic cases.No such mutations were present within 600 Chinese controls,the 1000 genome project,gnom AD,or similar databases.Depleting pi4 kb m RNA expression in zebrafish caused inner ear abnormalities and audiosensory impairment,mimicking the patient phenotypes.Moreover,overexpression of 4 human missense PI4 KB mutant m RNAs in zebrafish embryos resulted in impaired hearing function,suggesting dominant-negative effects.Taken together,our results reveal that PI4 KB mutations can cause SNHL and inner ear malformation.PI4 KB should be included in neonatal deafness screening.展开更多
Postaurical injection of therapeutics was recently applied in clinical practice to treat inner ear diseases based on supposed existence of a direct channel from the postaurical area to the inner ear. Doubting on the a...Postaurical injection of therapeutics was recently applied in clinical practice to treat inner ear diseases based on supposed existence of a direct channel from the postaurical area to the inner ear. Doubting on the associated reports and aiming to provide evidence on the inner ear uptake mechanism, the present study tracked the dynamic distribution of gadolinium-tetra-azacyclo-dodecane-tetra-acetic acid (Gd-DOTA) in rat inner ears after postaurical injection using MRI. A targeted tympanic medial wall delivery was utilized as control. The results showed that, at the early time points after postaurical injection, Gd-DOTA distributed mainly in tissues surrounding the bulla, temporal bone and skull and neck space. In the inner ear, there was gradual uptake of Gd-DOTA on both the ipsilateral and contralateral sides with equal signal intensities. There was no sign of direct channel carrying the agent from the postaurical area to the inner ear. Targeted tympanic medial wall delivery induced significantly greater uptake of Gd-DOTA in the inner ear than did postaurical injection. At 30 min post-administration, targeted tympanic medial wall delivery yielded 4.6-folds higher signal intensity than did postaurical injection. The total dose of Gd-DOTA delivered by the targeted tympanic medial wall approach was only 0.1% of that delivered by postaurical injection. In conclusion, postaurical injection is a systemic administration, which is similar to hypodermic injection, rather than a focal delivery method. By contraries, targeted tympanic medial wall delivery induces fast and abundant uptake of Gd-DOTA in the ipsilateral inner ear without significant distribution in unwanted areas.展开更多
Columnar outer hair cells of the inner ear form V-shaped bundles, which are arranged in three rows in the cochlea. If the formation of these V-shaped bundles is disturbed, sensorineural hearing loss occurs. To quantif...Columnar outer hair cells of the inner ear form V-shaped bundles, which are arranged in three rows in the cochlea. If the formation of these V-shaped bundles is disturbed, sensorineural hearing loss occurs. To quantify the distribution of V-shaped bundles, the use of a Turing-type reaction-diffusion (RD) system, including anisotropic diffusion, should be considered. We found that a periodic triangle pattern appears based on the anisotropy in the RD system. Then, using the proposed RD system, the image of the V-shaped bundle was examined. The results showed that the correlation between the RD pattern and V-shape bundles not only classifies the experimental result but also significantly differs in the number of directional changes in a set of V-shape bundle. Therefore, this process can help quantify the images of V-shaped bundles.展开更多
Objective:To evaluate the plasma levels of the otoconial proteins,otoconin-90 and otolin-1,in individuals diagnosed with vestibular neuritis(VN)and determine the feasibility of using these proteins as biomarkers for V...Objective:To evaluate the plasma levels of the otoconial proteins,otoconin-90 and otolin-1,in individuals diagnosed with vestibular neuritis(VN)and determine the feasibility of using these proteins as biomarkers for VN.Methods:In this preliminary study,30 patients diagnosed with VN and 70 healthy individuals were recruited and followed to confirm whether they had benign paroxysmal positional vertigo(BPPV)during the following time.The recorded data included measurements of height,weight,and history of diabetes mellitus or hypertension.Additionally,levels of plasma otoconin-90,and otolin-1 were measured and compared.Results:The plasma concentrations of otoconin-90 and otolin-1 may not be significantly different between patients with VN and healthy controls,nor among patients with BPPV secondary to VN and patients with VN without BPPV.Conclusions:Plasma otoconin-90 and otolin-1 levels may not serve as biomarkers of acute VN episodes or predict BPPV occurrence secondary to VN.展开更多
Hair cells in the mammalian inner ear are very fragile and are often injured as a result of acoustic trauma or exposure to ototoxic drugs (cisplatin, aminoglycosides, etc) [1]. In amphibians and birds, spontaneous
1临床资料患儿,女,3岁,主因“发现右耳听力差3年”就诊。家长3年前发现患儿右耳听力差,站于右侧呼唤患儿反应迟钝,说话发声及面部表情正常。体格检查:双侧耳廓及外耳道未见明显异常。声导抗:双耳A型。声反射:左侧90 dB SPL,右侧未引出...1临床资料患儿,女,3岁,主因“发现右耳听力差3年”就诊。家长3年前发现患儿右耳听力差,站于右侧呼唤患儿反应迟钝,说话发声及面部表情正常。体格检查:双侧耳廓及外耳道未见明显异常。声导抗:双耳A型。声反射:左侧90 dB SPL,右侧未引出。行为测听:左侧听力正常,右侧极重度感音神经性听力下降。耳声发射(OAE):左侧正常,右侧全频未引出。展开更多
BACKGROUND Multiple sclerosis(MS)is known to affect many sensory systems,yet most auditory research in MS has focused on the afferent pathways,with relatively few studies examining efferent function.The brainstem is a...BACKGROUND Multiple sclerosis(MS)is known to affect many sensory systems,yet most auditory research in MS has focused on the afferent pathways,with relatively few studies examining efferent function.The brainstem is a common site for MS plaques,and the medial olivocochlear(MOC)system is located in the superior olivary complex(SOC)of the brainstem.The cochlear nuclei are also involved in the MOC reflex arc.Additionally,the temporal cortex can modulate the SOC and cochlear nucleus,so lesions in the brainstem or temporal cortex may affect the MOC reflex in MS.AIM To investigate efferent auditory system activity in patients with multiple sclerosis via the MOC reflex.METHODS The study included 50 patients with MS and 50 healthy controls.Patients with MS were divided into three subgroups according to cranial magnetic resonance imaging findings:Patients with brainstem lesions(Group 1,n=20);patients with temporal cortex lesions without brainstem involvement(Group 2,n=20);and patients without any lesions in the brainstem or temporal cortex(Group 3,n=10).Tympanometry,acoustic stapedial reflex thresholds,pure-tone audiometry,and transientevoked otoacoustic emission(TEOAE)tests(with and without contralateral noise)were performed for all participants.RESULTS There was no significant difference in pure-tone hearing thresholds or baseline TEOAE amplitudes between the MS and control groups,indicating normal cochlear function in patients with MS;however,MOC reflex suppression was significantly reduced in patients with MS compared to controls(P=0.021).In particular,Group 1(MS with brainstem lesions)showed the lowest mean suppression values,which was significantly lower than that of Group 2 and the control group(P=0.002).By contrast,Group 2 and Group 3 did not significantly differ from controls.Additionally,patients with MS exhibited a sex difference in MOC function:Male patients had significantly lower suppression compared to female patients both within Group 1 and in the MS group as a whole.CONCLUSION The findings indicate that the efferent auditory system(specifically the MOC reflex)is affected by MS.MOC reflex activity was most significantly decreased in patients with MS with brainstem lesions,while temporal cortex lesions alone did not appear to notably impair the MOC reflex.Diminished MOC activity may underlie various auditory difficulties in patients with MS(e.g.,hearing in noise),and loss of efferent suppression could contribute to symptoms such as hyperacusis or tinnitus in this population.Further studies are needed to better understand the relationship between MOC dysfunction and auditory symptoms in MS,as well as the potential diagnostic value of MOC testing in MS.展开更多
基金supported by the National Natural Science Foundation of China(82222017 and 82271183)Hubei Province’s Key Research and Development Program(2022BCA046)the Start-up Research Fund of Southeast University(RF1028623028).
文摘This review highlights advances in inner ear organoids(IEOs)as a novel platform for drug screening and disease modeling,particularly for hearing loss.IEOs,derived from embryonic stem cells,induced pluripotent stem cells,or tissue-specific progenitors,provide a physiologically relevant alternative to traditional animal models.Significant progress has been made in utilizing various cell sources,extracellular matrix materials such as Matrigel and hydrogels,and methods for controlling microenvironments through biochemical and biophysical signals.Applications of IEOs in drug screening,disease modeling,and personalized medicine enable exploration of hearing loss mechanisms and therapeutic testing.However,challenges remain,including the incomplete maturation of cochlear cells and difficulty replicating in vivo environments.Future research should focus on optimizing IEO generation,incorporating microfluidic technologies,and advancing high-throughput screening to enhance drug discovery and clinical translation.
基金supported by the National Key Research and Development Program of China(grant no.2022YFC2402705)National Municipal Natural Science Foundation(grant no.82471161)Beijing Municipal Natural Science Foundation(grant no.7244308).
文摘Objectives:To investigate the imaging characteristics,surgical approaches,and outcomes of cochlear implantation(CI)in patients with special inner ear malformations(IEMs)that show transitional forms between cochlear hypoplasia(CH)and common cavity(CC).Methods:Twelve children(eight males,four females),aged 10 to 43 months,with special IEMs were enrolled,and their inner ear structures were analyzed using detailed segmentation.Two surgical approaches were employed:the transmastoid slot labyrinthotomy approach(TSLA)for cases requiring customized electrodes,and the round window or cochleostomy approach for the remaining cases.Outcomes were evaluated using Categories of Auditory Performance(CAP),Speech Intelligibility Rating(SIR),and Meaningful Auditory Integration Scale(MAIS/IT-MAIS)at 12 months post-implantation.Results:Two main types of malformed cochleae were identified:common cavity-like and primitive CH types.All patients exhibited cochlear nerve deficiency and significant bilateral differences in their inner ear structures.Four patients underwent TSLA with customized electrodes,while the remaining patients received lateral wall electrodes via the round window or cochleostomy approach.Most patients showed improvement in auditory and speech capabilities following implantation.Conclusion:Inner ear malformations with transitional forms between CH and CC present unique challenges,requiring detailed preoperative evaluation and customized surgical plans.Even in severe cases,carefully planned surgery can lead to meaningful auditory rehabilitation.
基金supported by the National Key Research and Development Program of China(grant no.2022YFC2402705)National Municipal Natural Science Foundation(grant no.82471161)Beijing Municipal Natural Science Foundation(grant no.7244308)。
文摘Objective:The aims of this study were to investigate the clinical applicability of 3D segmentation in measuring cochlear anatomical parameters,explore factors that influence the insertion angle of cochlear implant electrodes in patients with inner ear malformations,and determine the value of 3D segmentation in predicting cochlear implant electrode insertion depth by simulating electrode implantation in a reconstructed 3D model.Methods:Data from 208 temporal bone CT scans of patients with a variety of inner ear malformations(including the CH,IP-Ⅰ,IP-Ⅱ,and IP-Ⅲtypes)who underwent cochlear implantation at our center were retrospectively analyzed.Preoperative temporal bone CT data were subjected to three-dimensional(3D)segmentation of the cochlea with a 3D slicer.Results:Cochlear malformation types,including IP typesⅠ(42 ears),Ⅱ(278ears),Ⅲ(20 ears),and CH(65 ears),were diagnosed and measured in 208 preoperative CT datasets.Cochlear anatomical parameters and electrode length were correlated,which partially explained the variations in electrode insertion angle.The mean angle of implantation among the enrolled patients was 564.33°,and the mean implantation angle prediction error in the 3D segmentation was|23.74|°.Conclusion:Three-dimensional segmentation from temporal bone CT is valuable for surgeons,especially in treating patients with inner ear malformation.Such insights will help surgeons understand overall anatomical variations,predict electrode implantation depth,and complete preoperative imaging assessments for cochlear implant insertion depth in patients with inner ear malformations.
基金supported by Capital’s Funds for Health Improvement and Research(CFH:2022-2-5072)the Tianjin Natural Science Foundation for Jingjinji Collaboration(23JCZXJC00240)+1 种基金Beijing Natural Science Foundation(J230006)the CAMS Innovation Fund for Medical Science(2021-I2M-1-052).
文摘ObjectiveTo develop a sustained-release codelivery system for intratympanic administration of dexamethasone(DEX)and lipoic acid(LA).MethodsDEX microcrystals(MCs)were prepared via precipitation,while LA-loaded porous PLGA microspheres(LPMPs)were fabricated using a double emulsion–solvent evaporation method.DEX MCs were physically perfused into LPMPs via negative pressure to form a combined system(DEX MCs+LPMPs).Physicochemical properties,in vitro drug release,pharmacokinetics,and biocompatibility were evaluated.Guinea pigs were used for intratympanic injections of DEX MCs,LPMPs,or DEX MCs+LPMPs.ResultsThe DEX MCs+LPMPs system enabled simultaneous release of both drugs,with DEX exhibiting superior pharmacokinetics(sustained perilymph concentrations up to 7 days)compared to DEX MCs alone.LA release from LPMPs demonstrated prolonged kinetics without burst release.SEM confirmed DEX MCs were localized within/on LPMPs and adhered to the round window membrane(RWM).Histological analysis revealed normal cochlear morphology and no inflammatory response,confirming biocompatibility.ConclusionsThis novel codelivery system combining microcrystals and porous microspheres achieves sustained dual-drug release,enhances therapeutic efficacy,and offers a promising strategy for managing hearing loss via intratympanic administration.
基金Tianjin Natural Science Foundation for Jingjinji Collaboration,Grant/Award Number:23JCZXJC00240Hebei Natural Science Foundation,Grant/Award Number:H2023201903+2 种基金Beijing Natural Science Foundation,Grant/Award Number:J230006Capital's Funds for Health Improvement and Research,Grant/Award Number:CFH:2022-2-5072CAMS Innovation Fund for Medical Sciences,Grant/Award Number:2021-I2M-1-052。
文摘Background:Sudden sensorineural hearing loss(SSNHL),often associated with tinnitus,significantly impacts individuals'quality of life.Current treatments,such as free drugs via intravenous or intratympanic(IT)administration of dexamethasone(DEX)and lidocaine,face limitations like low bioavailability and rapid drug clearance.To address these challenges,we developed a local co-delivery system combining DEX microcrystals(DEX MCs)and lidocaine-loaded poly(lactic-co-glycolic acid)(PLGA)non-spherical microparticles(LPNMs)for sustained drug release in the inner ear.Methods:DEX MCs and LPNMs were prepared using the traditional precipitation technique and double emulsion-solvent evaporation,respectively.After characterizing physicochemical properties and drug release kinetics,they were dispersed in sodium hyaluronate solution for IT injection,then in vivo pharmacokinetics and biocompatibility in guinea pigs were studied.Results:DEX MCs exhibited stable dissolution,while LPNMs provided sustained lidocaine release,reducing potential side effects.In vivo studies in guinea pigs demonstrated prolonged drug retention in the perilymph and improved pharmacokinetics.Histological evaluation confirmed the good biocompatibility of this combined delivery system,with no significant inner ear damage observed.Conclusion:This co-delivery system can be used as a depot for delivering both DEX and lidocaine to the inner ear and offers a promising approach for the synergistic treatment of SSNHL associated with tinnitus.
基金supported by the National Natural Science Foundation of China(82271159,82071049,82425018,and 82101219)the STI2030-Major Projects(2022ZD0205400).
文摘Vestibular hair cells(HCs)in the inner ear,crucial for balance and spatial orientation,are classified into type I and type II subtypes,but the mechanisms regulating their differentiation remain unclear.In this study,we examined the role of Pou4f3,an important transcription factor,in vestibular HC differentiation using Pou4f3^(DTR/DTR)(deficient)and Pou4f3CreER/CreER(knockout)mouse models.In Pou4f3-deficient mice,the HC number decreased,and immature HCs failed to develop type I characteristics,indicating a developmental arrest.While type II HCs differentiated normally,Pou4f3 deficiency disrupted HC bundle formation and cell polarity.Findings from knockout models further confirmed the essential role of Pou4f3 in vestibular HC subtype specification.This study underscores the critical role of Pou4f3 in determining vestibular HC subtypes and offers insights into potential strategies for restoring vestibular function through HC regeneration.
基金Project supported by the National Natural Science Foundation of China(Nos.81570914 and 81700925)
文摘Objective:To describe the characteristics of the clinical presentation,diagnosis,surgical methods,and outcomes of patients with otogenic cerebrospinal fluid(CSF)leakage secondary to congenital inner ear dysplasia.Methods:A retrospective review was performed of 18 patients with otogenic CSF leakage secondary to inner ear dysplasia who underwent surgery in our group from 2007 to 2017 and had a follow-up of at least 4 months.The average length of follow-up was three years.The characteristics of the clinical presentations of all patients,such as self-reported symptoms,radiographic findings,surgical approaches and methods of repair,position of the leakage during surgery,and postoperative course,including the success rate of surgery,are presented.Results:The patients presented mostly with typical symptoms of meningitis,severe hearing impairment,and CSF otorrhea or rhinorrhea.All 18 patients had at least one previous episode of meningitis accompanied by a severe hearing impairment.The preoperative audiograms of 17 patients showed profound sensorineural hearing loss,and one patient had conductive hearing loss.Twelve patients presented with an initial onset of otorrhea,and two had accompanying rhinorrhea.Six patients complained of rhinorrhea,two of whom were misdiagnosed with CSF rhinorrhea and underwent transnasal endoscopy at another hospital.High-resolution computed tomography(HRCT)images can reveal developments in the inner ear,such as expansion of a vestibular cyst,unclear structure of the semicircular canal or cochlea,or signs of effusion in the middle ear or mastoid,which strongly suggest the possibility of CSF otorrhea.The children in the study suffered more severe dysplasia than adults.All 18 patients had CSF leakage identified during surgery.The most common defect sites were in the stapes footplates(55.6%),and 38.9%of patients had a leak around the oval window.One patient had a return of CSF otorrhea during the postoperative period,which did not re-occur following a second repair.Conclusions:CSF otorrhea due to congenital inner ear dysplasia is more severe in children than in adults.The most common symptoms were meningitis,hearing impairment,and CSF otorrhea or rhinorrhea.HRCT has high diagnostic accuracy for this disease.The most common fistula site was around the oval window,including the stapes footplates and the annular ligament.
基金supported by the National Natural Science Foundation of China(grant number:81170914/H1304)
文摘There are several challenges to inner ear drug delivery and imaging due to the existence of tight biological barriers to the target structure and the dense bone surrounding it. Advances in imaging and nanomedicine may provide knowledge for overcoming the existing limitations to both the diagnosis and treatment of inner ear diseases. Novel techniques have improved the efficacy of drug delivery and targeting to the inner ear, as well as the quality and accuracy of imaging this structure. In this review, we will describe the pathways and biological barriers of the inner ear regarding drug delivery, the beneficial applications and limitations of the imaging techniques available for inner ear research, the behavior of engineered nanomaterials in inner ear applications, and future perspectives for nanomedicine-based inner ear imaging.
基金Project supported by the National Basic Research Priorities Program of China(Nos.2014CB541702 and 2014CB541704)the National Natural Science Foundation of China(No.31671305)
文摘Auditory function in vertebrates depends on the transduction of sound vibrations into electrical signals by inner ear hair cells.In general,hearing loss resulting from hair cell damage is irreversible because the human ear has been considered to be incapable of regenerating or repairing these sensory elements following severe injury.Therefore,regeneration and protection of inner ear hair cells have become an exciting,rapidly evolving field of research during the last decade.However,mammalian auditory hair cells are few in number,experimentally inaccessible,and barely proliferate postnatally in vitro.Various in vitro primary culture systems of inner ear hair cells have been established by different groups,although many challenges remain unresolved.Here,we briefly explain the structure of the inner ear,summarize the published methods of in vitro hair cell cultures,and propose a feasible protocol for culturing these cells,which gave satisfactory results in our study.A better understanding of in vitro hair cell cultures will substantially facilitate research involving auditory functions,drug development,and the isolation of critical molecules involved in hair cell biology.
基金Project Project supported by the National Key Technologies R&D Program of China(Nos.2017YFA0103900 and 2016YFC0905200)the National Natural Science Foundation of China(Nos.81620108005,8177040802,and 81622013)the Shanghaigng Talents Plan(No.18PJ1401700),China
文摘Bone morphogenetic proteins(BMPs)are the largest subfamily of the transforming growth factor-βsuperfamily,and they play important roles in the development of numerous organs,including the inner ear.The inner ear is a relatively small organ but has a highly complex structure and is involved in both hearing and balance.Here,we discuss BMPs and BMP signaling pathways and then focus on the role of BMP signal pathway regulation in the development of the inner ear and the implications this has for the treatment of human hearing loss and balance dysfunction.
文摘In this study,I focused on finding a mean of protecting against hearing loss.By infusing the cochlea with the neurotrophin factor,NT-3 alone or combined treatment with MK 801,a NMDA receptor antagonist I found hearing loss was attenuated and spiral ganglion neuron loss was nearly totally protected indicating that the importance of the combined treatment of NT-3 and NMDA receptor antagonists in the treatment of hearing disorders.
基金National Natural Science Foundation of China(Nos.81771004,81271078,81500791,81500794 and 81300827).
文摘K^(+)cycling in the cochlea is critical to maintain hearing.Many sodium-potassium pumps are proved to participate in K^(+)cycling,such as Na/K-ATPase.Theα2-Na/K-ATPase is an important isoform of Na/K-ATPase.The expression ofα2-Na/K-ATPase in the cochlea is not clear.In this study,we used C57BL/6 mice as a model of presbycusis and implemented immunohistochemistry staining and quantitative real time-PCR,and theα2-Na/K-ATPase expression pattern was confirmed in the inner ear.It was foundα2-Na/K-ATPase was expressed widely in cochlea and its mRNA and protein expression was gradually reduced with aging(4-,14-,26-and 48-weeks old mice).We suspected that,the down-regulation ofα2-Na/K-ATPase expression might be associated with the remodeling of K^(+)cycling,degeneration of morphological structure and decrease of hearing function in aging C57 mice.In conclusion,we speculated that the reduction ofα2-Na/K-ATPase might play an important role in the pathogenesis of age-related hearing loss.
基金supported by the grants from the National Key R&D Program of China(2018YFA0801200)the National Natural Science Foundation of China(31970777,31771628,and 31601165)+1 种基金Guangdong Natural Science Fund for Distinguished Young Scholars(2017A030306024)to J.Z.the Deutsche Forschungsgemeinschaft(DFG:GO 1990/1-1)to M.G
文摘Congenital hearing loss is a common disorder worldwide.Heterogeneous gene variation accounts for approximately 20-25%of such patients.We investigated a five-generation Chinese family with autosomaldominant nonsyndromic sensorineural hearing loss(SNHL).No wave was detected in the pure-tone audiometry,and the auditory brainstem response was absent in all patients.Computed tomography of the patients,as well as of two sporadic SNHL cases,showed bilateral inner ear anomaly,cochlear maldevelopment,absence of the osseous spiral lamina,and an enlarged vestibular aqueduct.Such findings were absent in nonaffected persons.We used linkage analysis and exome sequencing and uncovered a heterozygous missense mutation in the PI4 KB gene(p.Gln121 Arg)encoding phosphatidylinositol 4-kinaseβ(PI4 KB)from the patients in this family.In addition,3 missense PI4 KB(p.Val434 Gly,p.Glu667 Lys,and p.Met739 Arg)mutations were identified in five patients with nonsyndromic SNHL from 57 sporadic cases.No such mutations were present within 600 Chinese controls,the 1000 genome project,gnom AD,or similar databases.Depleting pi4 kb m RNA expression in zebrafish caused inner ear abnormalities and audiosensory impairment,mimicking the patient phenotypes.Moreover,overexpression of 4 human missense PI4 KB mutant m RNAs in zebrafish embryos resulted in impaired hearing function,suggesting dominant-negative effects.Taken together,our results reveal that PI4 KB mutations can cause SNHL and inner ear malformation.PI4 KB should be included in neonatal deafness screening.
基金supported by the 1255 project of Changhai HospitalSecond Military Medical University,Shanghai,China
文摘Postaurical injection of therapeutics was recently applied in clinical practice to treat inner ear diseases based on supposed existence of a direct channel from the postaurical area to the inner ear. Doubting on the associated reports and aiming to provide evidence on the inner ear uptake mechanism, the present study tracked the dynamic distribution of gadolinium-tetra-azacyclo-dodecane-tetra-acetic acid (Gd-DOTA) in rat inner ears after postaurical injection using MRI. A targeted tympanic medial wall delivery was utilized as control. The results showed that, at the early time points after postaurical injection, Gd-DOTA distributed mainly in tissues surrounding the bulla, temporal bone and skull and neck space. In the inner ear, there was gradual uptake of Gd-DOTA on both the ipsilateral and contralateral sides with equal signal intensities. There was no sign of direct channel carrying the agent from the postaurical area to the inner ear. Targeted tympanic medial wall delivery induced significantly greater uptake of Gd-DOTA in the inner ear than did postaurical injection. At 30 min post-administration, targeted tympanic medial wall delivery yielded 4.6-folds higher signal intensity than did postaurical injection. The total dose of Gd-DOTA delivered by the targeted tympanic medial wall approach was only 0.1% of that delivered by postaurical injection. In conclusion, postaurical injection is a systemic administration, which is similar to hypodermic injection, rather than a focal delivery method. By contraries, targeted tympanic medial wall delivery induces fast and abundant uptake of Gd-DOTA in the ipsilateral inner ear without significant distribution in unwanted areas.
文摘Columnar outer hair cells of the inner ear form V-shaped bundles, which are arranged in three rows in the cochlea. If the formation of these V-shaped bundles is disturbed, sensorineural hearing loss occurs. To quantify the distribution of V-shaped bundles, the use of a Turing-type reaction-diffusion (RD) system, including anisotropic diffusion, should be considered. We found that a periodic triangle pattern appears based on the anisotropy in the RD system. Then, using the proposed RD system, the image of the V-shaped bundle was examined. The results showed that the correlation between the RD pattern and V-shape bundles not only classifies the experimental result but also significantly differs in the number of directional changes in a set of V-shape bundle. Therefore, this process can help quantify the images of V-shaped bundles.
基金supported by the Ningbo Leading Medical&Health Discipline(Grant No.2022-B12)Ningbo Natural Science Foundation(Grant No.202003N4240)+1 种基金Hwa Mei Foundation(Grant No.2021HMZY102,Grant No.2022HMKY45)Medical Scientific Research Foundation of Zhejiang Province(Grant No.2023KY1085).
文摘Objective:To evaluate the plasma levels of the otoconial proteins,otoconin-90 and otolin-1,in individuals diagnosed with vestibular neuritis(VN)and determine the feasibility of using these proteins as biomarkers for VN.Methods:In this preliminary study,30 patients diagnosed with VN and 70 healthy individuals were recruited and followed to confirm whether they had benign paroxysmal positional vertigo(BPPV)during the following time.The recorded data included measurements of height,weight,and history of diabetes mellitus or hypertension.Additionally,levels of plasma otoconin-90,and otolin-1 were measured and compared.Results:The plasma concentrations of otoconin-90 and otolin-1 may not be significantly different between patients with VN and healthy controls,nor among patients with BPPV secondary to VN and patients with VN without BPPV.Conclusions:Plasma otoconin-90 and otolin-1 levels may not serve as biomarkers of acute VN episodes or predict BPPV occurrence secondary to VN.
基金supported by the follow grants:1. The StateKey Program of National Natural Science of China (Grant No. 30730040)2. The National High Technology Research and Development Program of China (Grant No.2007AA02Z150)+2 种基金3. The National Natural Science Foundation of China (30871398)Key Projects in the National Science & Technology Supporting Program during the Eleventh Five-Year Plan Period (2008BAI50B08 2007 BAI18B12, 2007BAI18B14)
文摘Hair cells in the mammalian inner ear are very fragile and are often injured as a result of acoustic trauma or exposure to ototoxic drugs (cisplatin, aminoglycosides, etc) [1]. In amphibians and birds, spontaneous
文摘1临床资料患儿,女,3岁,主因“发现右耳听力差3年”就诊。家长3年前发现患儿右耳听力差,站于右侧呼唤患儿反应迟钝,说话发声及面部表情正常。体格检查:双侧耳廓及外耳道未见明显异常。声导抗:双耳A型。声反射:左侧90 dB SPL,右侧未引出。行为测听:左侧听力正常,右侧极重度感音神经性听力下降。耳声发射(OAE):左侧正常,右侧全频未引出。
文摘BACKGROUND Multiple sclerosis(MS)is known to affect many sensory systems,yet most auditory research in MS has focused on the afferent pathways,with relatively few studies examining efferent function.The brainstem is a common site for MS plaques,and the medial olivocochlear(MOC)system is located in the superior olivary complex(SOC)of the brainstem.The cochlear nuclei are also involved in the MOC reflex arc.Additionally,the temporal cortex can modulate the SOC and cochlear nucleus,so lesions in the brainstem or temporal cortex may affect the MOC reflex in MS.AIM To investigate efferent auditory system activity in patients with multiple sclerosis via the MOC reflex.METHODS The study included 50 patients with MS and 50 healthy controls.Patients with MS were divided into three subgroups according to cranial magnetic resonance imaging findings:Patients with brainstem lesions(Group 1,n=20);patients with temporal cortex lesions without brainstem involvement(Group 2,n=20);and patients without any lesions in the brainstem or temporal cortex(Group 3,n=10).Tympanometry,acoustic stapedial reflex thresholds,pure-tone audiometry,and transientevoked otoacoustic emission(TEOAE)tests(with and without contralateral noise)were performed for all participants.RESULTS There was no significant difference in pure-tone hearing thresholds or baseline TEOAE amplitudes between the MS and control groups,indicating normal cochlear function in patients with MS;however,MOC reflex suppression was significantly reduced in patients with MS compared to controls(P=0.021).In particular,Group 1(MS with brainstem lesions)showed the lowest mean suppression values,which was significantly lower than that of Group 2 and the control group(P=0.002).By contrast,Group 2 and Group 3 did not significantly differ from controls.Additionally,patients with MS exhibited a sex difference in MOC function:Male patients had significantly lower suppression compared to female patients both within Group 1 and in the MS group as a whole.CONCLUSION The findings indicate that the efferent auditory system(specifically the MOC reflex)is affected by MS.MOC reflex activity was most significantly decreased in patients with MS with brainstem lesions,while temporal cortex lesions alone did not appear to notably impair the MOC reflex.Diminished MOC activity may underlie various auditory difficulties in patients with MS(e.g.,hearing in noise),and loss of efferent suppression could contribute to symptoms such as hyperacusis or tinnitus in this population.Further studies are needed to better understand the relationship between MOC dysfunction and auditory symptoms in MS,as well as the potential diagnostic value of MOC testing in MS.
