Inner ear drug delivery for auditory applications.

Many inner ear disorders cannot be adequately treated by systemic drug delivery. A blood-cochlear barrier exists, similar physiologically to the blood-brain barrier, which limits the concentration and size of molecules able to leave the circulation and gain access to the cells of the inner ear. However, research in novel therapeutics and delivery systems has led to significant progress in the development of local methods of drug delivery to the inner ear. Intratympanic approaches, which deliver therapeutics to the middle ear, rely on permeation through tissue for access to the structures of the inner ear, whereas intracochlear methods are able to directly insert drugs into the inner ear. Innovative drug delivery systems to treat various inner ear ailments such as ototoxicity, sudden sensorineural hearing loss, autoimmune inner ear disease, and for preserving neurons and regenerating sensory cells are being explored.

[1]  R. Labadie,et al.  Intratympanic Dexamethasone for Sudden Sensorineural Hearing Loss After Failure of Systemic Therapy , 2007, The Laryngoscope.

[2]  E. Keithley,et al.  Immunological damage to the inner ear: current and future therapeutic strategies. , 2002, Advances in oto-rhino-laryngology.

[3]  M Maurizi,et al.  The role of antioxidants in protection from ototoxic drugs , 2004, Acta oto-laryngologica.

[4]  M. Holley Application of new biological approaches to stimulate sensory repair and protection. , 2002, British medical bulletin.

[5]  Ryosei Minoda,et al.  Auditory hair cell replacement and hearing improvement by Atoh1 gene therapy in deaf mammals , 2005, Nature Medicine.

[6]  Y. Raphael Cochlear pathology, sensory cell death and regeneration. , 2002, British medical bulletin.

[7]  T. Hoshino,et al.  Protective effect of calcineurin inhibitors on acoustic injury of the cochlea , 2005, Hearing Research.

[8]  K. Pfaller,et al.  Perilymph/Modiolar Communication Routes in the Human Cochlea , 2006, Ear and hearing.

[9]  Toshimitsu Kobayashi,et al.  Transgenic expression of a dominant-negative connexin26 causes degeneration of the organ of Corti and non-syndromic deafness. , 2003, Human molecular genetics.

[10]  Josef M. Miller,et al.  Chronic drug infusion into the scala tympani of the guinea pig cochlea , 1992, Journal of Neuroscience Methods.

[11]  U. Welsch,et al.  Round Window Application of D-Methionine, Sodium Thiosulfate, Brain-Derived Neurotrophic Factor, and Fibroblast Growth Factor-2 in Cisplatin-Induced Ototoxicity , 2004, Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology.

[12]  J. Ito,et al.  Trophic support of mouse inner ear by neural stem cell transplantation , 2003, Neuroreport.

[13]  R. Hata,et al.  Adenovirus-mediated overexpression of a gene prevents hearing loss and progressive inner hair cell loss after transient cochlear ischemia in gerbils , 2003, Gene Therapy.

[14]  R. Kopke,et al.  Pharmacological rescue of noise induced hearing loss using N-acetylcysteine and acetyl-l-carnitine , 2007, Hearing Research.

[15]  A. Bush,et al.  Ototoxic Protection of Sodium Thiosulfate: Daily vs Constant Infusion , 2004, Otolaryngology Head & Neck Surgery.

[16]  E. Borg,et al.  Low-dose, long-term caroverine administration attenuates impulse noise-induced hearing loss in the rat , 2006, Acta oto-laryngologica.

[17]  L. Rybak Mechanisms of cisplatin ototoxicity and progress in otoprotection , 2007, Current opinion in otolaryngology & head and neck surgery.

[18]  R. Clarke,et al.  Advances in genetic manipulations in the treatment of hearing disorders. , 2004, Clinical otolaryngology and allied sciences.

[19]  A. Salt,et al.  Drug delivery to the cochlea after implantation: consideration of the risk factors. , 2005 .

[20]  R. Ruben,et al.  Round window membrane delivery of L-methionine provides protection from cisplatin ototoxicity without compromising chemotherapeutic efficacy. , 2001, Neurotoxicology.

[21]  L. Parnes,et al.  Corticosteroid Pharmacokinetics in the Inner Ear Fluids: An Animal Study Followed by Clinical Application , 1999, The Laryngoscope.

[22]  Y. Sasai,et al.  Fates of mouse embryonic stem cells transplanted into the inner ears of adult mice and embryonic chickens. , 2004, Acta oto-laryngologica. Supplementum.

[23]  Steve D. M. Brown,et al.  Quiet as a mouse: dissecting the molecular and genetic basis of hearing , 2008, Nature Reviews Genetics.

[24]  M. Parker,et al.  Neural stem cells injected into the sound-damaged cochlea migrate throughout the cochlea and express markers of hair cells, supporting cells, and spiral ganglion cells , 2007, Hearing Research.

[25]  L. Gillespie,et al.  Delayed neurotrophin treatment supports auditory neuron survival in deaf guinea pigs , 2004, Neuroreport.

[26]  Ilmari Pyykkö,et al.  Neurotrophic factor intervention restores auditory function in deafened animals , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[27]  M. Seidman,et al.  Glutamate Antagonists, Steroids, and Antioxidants as Therapeutic Options for Hearing Loss and Tinnitus and the Use of an Inner Ear Drug Delivery System. , 1998, The international tinnitus journal.

[28]  J. Scully,et al.  Non-professionals' evaluations of gene therapy ethics. , 2004, Social science & medicine.

[29]  Richard J. H. Smith,et al.  Cochlear expression of a dominant-negative GJB2 R75W construct delivered through the round window membrane in mice , 2007, Neuroscience Research.

[30]  T. Lenarz,et al.  Technical Report: Modification of a Cochlear Implant Electrode for Drug Delivery to the Inner Ear , 2003, Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology.

[31]  Jing Wang,et al.  Local application of sodium thiosulfate prevents cisplatin-induced hearing loss in the guinea pig , 2003, Neuropharmacology.

[32]  J. Ryu,et al.  High resolution two-dimensional electrophoresis: technique and potential applicability to the study of inner ear disease. , 1995, The American journal of otology.

[33]  Harold F. Schuknecht,et al.  Pathology of the Ear , 1974 .

[34]  K. Jahnke,et al.  The fine structure of freeze-fractured intercellular junctions in the guinea pig inner ear. , 1975, Acta oto-laryngologica. Supplementum.

[35]  R. Hartmann,et al.  Application of a Corticosteroid (Triamcinolon) Protects Inner Ear Function after Surgical Intervention , 2007, Ear and hearing.

[36]  M. Woodle,et al.  Harnessing in vivo siRNA delivery for drug discovery and therapeutic development , 2006, Drug Discovery Today.

[37]  Bruce C. Wheeler The Tradition Continues to Improve , 2007 .

[38]  M. Ulfendahl,et al.  Central migration of neuronal tissue and embryonic stem cells following transplantation along the adult auditory nerve , 2004, Brain Research.

[39]  A. Salt,et al.  Perilymph composition in scala tympani of the cochlea: Influence of cerebrospinal fluid , 1989, Hearing Research.

[40]  M Igarashi,et al.  Morphometric comparison of endolymphatic and perilymphatic spaces in human temporal bones. , 1986, Acta oto-laryngologica.

[41]  H P Zenner,et al.  Neurotrophin 3 potentiates glutamatergic responses of IHC afferents in the cochlea in vivo , 2000, The European journal of neuroscience.

[42]  M. Hoffer,et al.  Distribution of PLGA nanoparticles in chinchilla cochleae , 2007, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[43]  R. Altschuler,et al.  Deafferentiation‐associated changes in afferent and efferent processes in the guinea pig cochlea and afferent regeneration with chronic intrascalar brain‐derived neurotrophic factor and acidic fibroblast growth factor , 2008, The Journal of comparative neurology.

[44]  J. Tonndorf,et al.  LXVI Permeability of Intracochlear Membranes to Various Vital Stains , 1962, Transactions of the American Otological Society.

[45]  A. Salt,et al.  Radial communication between the perilymphatic scalae of the cochlea. I: Estimation by tracer perfusion , 1991, Hearing Research.

[46]  Robert K. Shepherd,et al.  Neurotrophins and electrical stimulation for protection and repair of spiral ganglion neurons following sensorineural hearing loss , 2008, Hearing Research.

[47]  Edwin W Rubel,et al.  Mechanisms of hair cell death and protection , 2005, Current opinion in otolaryngology & head and neck surgery.

[48]  H. Silverstein,et al.  Chemical perfusion of the inner ear. , 2002, Otolaryngologic clinics of North America.

[49]  L. Rybak,et al.  Ototoxicity: therapeutic opportunities. , 2005, Drug discovery today.

[50]  Zheng-Yi Chen Cell Cycle, Differentiation and Regeneration: Where to Begin? , 2006, Cell cycle.

[51]  Marcos V. Goycoolea,et al.  Round window membrane. Structure function and permeability: A review , 1997, Microscopy research and technique.

[52]  A. Nuttall,et al.  Acute perilymphatic perfusion of the guinea pig cochlea , 1982, Hearing Research.

[53]  M. Ulfendahl,et al.  Glial cell line-derived neurotrophic factor and antioxidants preserve the electrical responsiveness of the spiral ganglion neurons after experimentally induced deafness , 2008, Neurobiology of Disease.

[54]  F. Theeuwes,et al.  Principles of the design and operation of generic osmotic pumps for the delivery of semisolid or liquid drug formulations , 1976, Annals of Biomedical Engineering.

[55]  M. Seidman,et al.  Pharmacologic Manipulation of the Labyrinth with Novel and Traditional Agents Delivered to the Inner Ear , 2003, Ear, nose, & throat journal.

[56]  Zheng-Yi Chen Cell Cycle, Differentiation and Regeneration , 2006 .

[57]  A. Salt,et al.  Radial communication between the perilymphatic scalae of the cochlea. II: Estimation by bolus injection of tracer into the sealed cochlea , 1991, Hearing Research.

[58]  A. Lalwani,et al.  Current Issues in Cochlear Gene Transfer , 2001, Audiology and Neurotology.

[59]  A. Salt,et al.  Local inner-ear drug delivery and pharmacokinetics. , 2005, Drug discovery today.

[60]  C. Klingmann,et al.  Transsynaptic delivery of nanoparticles to the central auditory nervous system , 2007, Acta oto-laryngologica.

[61]  H. Wanamaker Perfusion of the inner ear: basic science considerations , 2001 .

[62]  Jochen Schacht,et al.  Homeostatic Mechanisms in the Cochlea , 1996 .

[63]  K. Kawamoto,et al.  Hearing and hair cells are protected by adenoviral gene therapy with TGF-beta1 and GDNF. , 2003, Molecular therapy : the journal of the American Society of Gene Therapy.

[64]  Kenji Ohyama,et al.  Volume flow rate of perilymph in the guinea-pig cochlea , 1988, Hearing Research.

[65]  M. Knipper,et al.  A Novel Microperfusion System for the Long-Term Local Supply of Drugs to the Inner Ear: Implantation and Function in the Rat Model , 2001, Audiology and Neurotology.

[66]  B. Blakley,et al.  Prevention of aminoglycoside-induced sensorineural hearing loss. , 2006, The Journal of otolaryngology.

[67]  R. Battista Intratympanic dexamethasone for profound idiopathic sudden sensorineural hearing loss , 2004, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[68]  M. Hoffer,et al.  Use of sustained release vehicles in the treatment of Meniere's disease. , 1997, Otolaryngologic clinics of North America.

[69]  P. Plinkert,et al.  Transtympanic endoscopy for drug delivery to the inner ear using a new microendoscope. , 2002, Advances in oto-rhino-laryngology.

[70]  A. Lalwani,et al.  In Vitro and In Vivo Assessment of the Ability of Adeno‐Associated Virus–Brain‐Derived Neurotrophic Factor to Enhance Spiral Ganglion Cell Survival Following Ototoxic Insult , 2002, The Laryngoscope.

[71]  Joseph Santos-Sacchi,et al.  Physiology of the Ear , 1990 .

[72]  Y. Tabata,et al.  Cochlear Protection by Local Insulin‐Like Growth Factor‐1 Application Using Biodegradable Hydrogel , 2006, The Laryngoscope.

[73]  D. Henderson,et al.  The Role of Antioxidants in Protection from Impulse Noise , 1999, Annals of the New York Academy of Sciences.

[74]  S. Juhn,et al.  Barrier systems in the inner ear. , 1988, Acta oto-laryngologica. Supplementum.

[75]  L. Rybak,et al.  Mechanisms of cisplatin-induced ototoxicity and prevention , 2007, Hearing Research.

[76]  G. Gianoli,et al.  Transtympanic Steroids for Treatment of Sudden Hearing Loss , 1999, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[77]  D. Brough,et al.  Pharmacodynamics of adenovector distribution within the inner ear tissues of the mouse , 2007, Hearing Research.

[78]  A. Salt,et al.  Perilymph sampling from the cochlear apex: A reliable method to obtain higher purity perilymph samples from scala tympani , 2006, Journal of Neuroscience Methods.

[79]  S. O'Leary,et al.  Inner Ear Therapy for Neural Preservation , 2006, Audiology and Neurotology.

[80]  L. Bruschini,et al.  Transtympanic Steroids as a Salvage Therapy in Sudden Hearing Loss: Preliminary Results , 2006, ORL.

[81]  A. Salt Pharmacokinetics of Drug Entry into Cochlear Fluids. , 2005, The Volta review.

[82]  K. Kawamoto,et al.  Antioxidant gene therapy can protect hearing and hair cells from ototoxicity. , 2004, Molecular therapy : the journal of the American Society of Gene Therapy.

[83]  J. R. Holt,et al.  Gene Transfer in Human Vestibular Epithelia and the Prospects for Inner Ear Gene Therapy , 2008, The Laryngoscope.

[84]  R. Miyamoto,et al.  Enhanced Survival of Bone–Marrow‐Derived Pluripotent Stem Cells in an Animal Model of Auditory Neuropathy , 2007, The Laryngoscope.

[85]  A. Wise,et al.  Resprouting and survival of guinea pig cochlear neurons in response to the administration of the neurotrophins brain‐derived neurotrophic factor and neurotrophin‐3 , 2005, The Journal of comparative neurology.

[86]  Stephen O'Leary,et al.  Delivery of Neurotrophin-3 to the Cochlea using Alginate Beads , 2005, Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology.

[87]  M. Ulfendahl,et al.  Protection and treatment of sensorineural hearing disorders caused by exogenous factors: experimental findings and potential clinical application , 2002, Hearing Research.

[88]  Thomas R. Van De Water,et al.  Brain-derived neurotrophic factor gene therapy prevents spiral ganglion degeneration after hair cell loss , 1998, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[89]  F. E. Offeciers,et al.  Long-Term Evaluation of the Effect of Intracochlear Steroid Deposition on Electrode Impedance in Cochlear Implant Patients , 2003, Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology.

[90]  A. Lalwani,et al.  Cationic liposome mediated transgene expression in the guinea pig cochlea , 1999, Hearing Research.

[91]  T. Yamasoba,et al.  Differential protective effects of neurotrophins in the attenuation of noise-induced hair cell loss , 2000, Hearing Research.

[92]  H. Silverstein,et al.  Transtympanic perfusion: indications and limitations , 2004, Current opinion in otolaryngology & head and neck surgery.

[93]  B. Mccabe Autoimmune inner ear disease: therapy. , 1989, The American journal of otology.

[94]  Adrien A Eshraghi,et al.  Cochlear implantation trauma and noise-induced hearing loss: Apoptosis and therapeutic strategies. , 2006, The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology.

[95]  A. Eshraghi,et al.  Local Dexamethasone Therapy Conserves Hearing in an Animal Model of Electrode Insertion Trauma-Induced Hearing Loss , 2007, Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology.

[96]  H. Silverstein,et al.  Use of a New Device, the MicroWick™, to Deliver Medication to the Inner Ear , 1999, Ear, nose, & throat journal.

[97]  J. Ito,et al.  Drug Delivery to the Cochlea Using PLGA Nanoparticles , 2005, The Laryngoscope.

[98]  K. Ehrenberger,et al.  New approaches for inner ear therapy with glutamate antagonists. , 1999, Acta oto-laryngologica.

[99]  K. Dietz,et al.  Outcomes research analysis of continuous intratympanic glucocorticoid delivery in patients with acute severe to profound hearing loss: Basis for planning randomized controlled trials , 2005, Acta oto-laryngologica.

[100]  M. Seidman,et al.  Auditory research involving antioxidants , 2007, Current opinion in otolaryngology & head and neck surgery.

[101]  T. Konishi,et al.  Effect of Calcium Deficiency on Cochlear Potentials , 1967 .

[102]  S. Rauch Intratympanic steroids for sensorineural hearing loss. , 2004, Otolaryngologic clinics of North America.

[103]  S. Juhn,et al.  Labyrinthine barriers and cochlear homeostasis. , 1981, Acta oto-laryngologica.

[104]  Jing Wang,et al.  A novel dual inhibitor of calpains and lipid peroxidation (BN82270) rescues the cochlea from sound trauma , 2007, Neuropharmacology.

[105]  S. Chandrasekhar Intratympanic Dexamethasone for Sudden Sensorineural Hearing Loss: Clinical and Laboratory Evaluation , 2001, Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology.

[106]  A. Salt,et al.  Marker retention in the cochlea following injections through the round window membrane , 2007, Hearing Research.

[107]  Andrew K. Wise,et al.  Neurotrophic Factors and Neural Prostheses: Potential Clinical Applications Based Upon Findings in the Auditory System , 2007, IEEE Transactions on Biomedical Engineering.

[108]  D. Brough,et al.  Drug delivery to the inner ear using gene therapy. , 2004, Otolaryngologic clinics of North America.

[109]  M. Behlke,et al.  Advances in Molecular and Cellular Therapies for Hearing Loss. , 2008, Molecular therapy : the journal of the American Society of Gene Therapy.

[110]  R. Orecchia,et al.  Radiotherapy-induced ear toxicity. , 2003, Cancer treatment reviews.

[111]  I. Hochmair,et al.  Cochlear Implants : State of the Art and a Glimpse Into the Future , 2006 .

[112]  E. Keithley,et al.  Glial Cell Line‐Derived Neurotrophic Factor: Potential for Otoprotection , 1999, Annals of the New York Academy of Sciences.

[113]  S. Merchant,et al.  Anatomy of the normal human cochlear aqueduct with functional implications , 1997, Hearing Research.

[114]  A. Salt,et al.  Analysis of Gentamicin Kinetics in Fluids of the Inner Ear with Round Window Administration , 2002, Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology.

[115]  Ilmari Pyykkö,et al.  In Vivo Observation of Dynamic Perilymph Formation Using 4.7 T MRI with Gadolinium as a Tracer , 2003, Acta oto-laryngologica.

[116]  M V Goycoolea,et al.  The round window membrane under normal and pathological conditions. , 1992, Acta oto-laryngologica. Supplementum.

[117]  Thomas Meyer,et al.  AM-111 protects against permanent hearing loss from impulse noise trauma , 2007, Hearing Research.

[118]  D. Fabry,et al.  Autoimmune inner ear disease: diagnostic and therapeutic approaches in a multidisciplinary setting. , 2003, Journal of the American Academy of Audiology.

[119]  Jeffrey T Borenstein,et al.  Inner ear drug delivery via a reciprocating perfusion system in the guinea pig. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[120]  E. Lynch,et al.  Compounds for the prevention and treatment of noise-induced hearing loss. , 2005, Drug discovery today.

[121]  L. Hughes,et al.  Prevention of noise- and drug-induced hearing loss with d-methionine , 2007, Hearing Research.

[122]  R. Shepherd,et al.  Survival of Partially Differentiated Mouse Embryonic Stem Cells in the Scala Media of the Guinea Pig Cochlea , 2005, Journal of the Association for Research in Otolaryngology.

[123]  A Totally Implantable Drug Delivery System for Local Therapy of the Middle and Inner Ear , 1997, Ear, nose, & throat journal.

[124]  Jing Wang,et al.  Caspase Inhibitors, but not c-Jun NH2-Terminal Kinase Inhibitor Treatment, Prevent Cisplatin-Induced Hearing Loss , 2004, Cancer Research.

[125]  Richard J. H. Smith,et al.  In vitro and in vivo suppression of GJB2 expression by RNA interference. , 2005, Human molecular genetics.

[126]  J. R. Holt,et al.  Differential Distribution of Stem Cells in the Auditory and Vestibular Organs of the Inner Ear , 2007, Journal of the Association for Research in Otolaryngology.

[127]  Carvalho Gj,et al.  The effect of cochleostomy and intracochlear infusion on auditory brain stem response threshold in the guinea pig. , 1999 .

[128]  M. Leinung,et al.  Substance distribution in a cochlea model using different pump rates for cochlear implant drug delivery electrode prototypes , 2006, Hearing Research.

[129]  M. Arriaga,et al.  Intratympanic steroids: Do they acutely improve hearing in cases of cochlear hydrops? , 2003, The Laryngoscope.

[130]  L. Parnes,et al.  The biology of intratympanic drug administration and pharmacodynamics of round window drug absorption. , 2004, Otolaryngologic clinics of North America.

[131]  C. Herraiz,et al.  Intratympanic Steroids for Treatment of Sudden Hearing Loss after Failure of Intravenous Therapy , 2007, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[132]  Thomas Lenarz,et al.  Changes of Postoperative Impedances in Cochlear Implant Patients: The Short-Term Effects of Modified Electrode Surfaces and Intracochlear Corticosteroids , 2006, Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology.

[133]  B. Blakley Update on Intratympanic Gentamicin for Meniere's Disease , 2000, The Laryngoscope.

[134]  W. Mendenhall,et al.  Ototoxicity after radiotherapy for head and neck tumors. , 2007, International journal of radiation oncology, biology, physics.

[135]  W. Arnold,et al.  Novel Slow- and Fast-Type Drug Release Round-Window Microimplants for Local Drug Application to the Cochlea: An Experimental Study in Guinea Pigs , 2004, Audiology and Neurotology.

[136]  M. McKenna,et al.  A method for intracochlear drug delivery in the mouse , 2006, Journal of Neuroscience Methods.

[137]  F. Scheibe,et al.  Biochemical differences between perilymph, cerebrospinal fluid and blood plasma in the guinea pig , 1985, Hearing Research.

[138]  I. Thalmann,et al.  Protein profiles of perilymph and endolymph of the guinea pig , 1992, Hearing Research.

[139]  Juichi Ito,et al.  Novel Strategy for Treatment of Inner Ears using a Biodegradable Gel , 2005, The Laryngoscope.

[140]  Robert K Shepherd,et al.  A multichannel scala tympani electrode array incorporating a drug delivery system for chronic intracochlear infusion , 2002, Hearing Research.

[141]  H. Schuknecht,et al.  LII Experimental Observations on the Fluid Physiology of the Inner Ear , 1963, The Annals of otology, rhinology, and laryngology.

[142]  T. Lenarz,et al.  Development of a drug delivery device: using the femtosecond laser to modify cochlear implant electrodes , 2007, Cochlear implants international.

[143]  F. Linthicum,et al.  Extraneous round Window Membranes and Plugs: Possible Effect on Intratympanic Therapy , 2000, The Annals of otology, rhinology, and laryngology.

[144]  H. Schuknecht Ablation therapy in the management of Menière's disease. , 1957, Acta oto-laryngologica. Supplementum.

[145]  Ito,et al.  Clinical Experiences of Steroid Targeting Therapy to Inner Ear for Control of Tinnitus. , 1997, The international tinnitus journal.

[146]  T. Yamashita,et al.  Direct inner ear infusion of dexamethasone attenuates noise-induced trauma in guinea pig , 2004, Hearing Research.

[147]  Y. Raphael,et al.  Cochlear gene transfer: round window versus cochleostomy inoculation , 1999, Hearing Research.

[148]  I. Thalmann,et al.  Amino acid profiles in inner ear fluids and cerebrospinal fluid , 1982, The Laryngoscope.

[149]  S. Juhn,et al.  Review of round window membrane permeability. , 1989, Acta oto-laryngologica. Supplementum.

[150]  K. J. Lee,et al.  Steroid use in idiopathic sudden sensorineural hearing loss , 1984, The Laryngoscope.

[151]  Rachael T. Richardson,et al.  Tracing neurotrophin-3 diffusion and uptake in the guinea pig cochlea , 2004, Hearing Research.

[152]  Tatsuo Nakamura,et al.  Transplantation of bone marrow stromal cells into the cochlea of chinchillas , 2004, Neuroreport.

[153]  H. Gladstone,et al.  Enhanced preservation of the auditory nerve following cochlear perfusion with nerve growth factors. , 1995, The American journal of otology.

[154]  James M. Roberts,et al.  Gene disruption of p27(Kip1) allows cell proliferation in the postnatal and adult organ of corti. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[155]  F. de Ribaupierre,et al.  A Peptide Inhibitor of C-jun N-terminal Kinase Protects against Both Aminoglycoside and Acoustic Trauma-induced Auditory Hair Cell Death and Hearing Loss , 2022 .

[156]  Kimura Rs,et al.  Ultrastructure of toe cochlear blood vessels. , 1974 .

[157]  H. Silverstein,et al.  Inner ear perfusion: indications and applications , 2003, Current Opinion in Otolaryngology & Head and Neck Surgery.

[158]  R. Kimura,et al.  Volumetric and Dimensional Analysis of the Guinea Pig Inner Ear , 2001, The Annals of otology, rhinology, and laryngology.

[159]  R. Altschuler,et al.  Delayed neurotrophin treatment following deafness rescues spiral ganglion cells from death and promotes regrowth of auditory nerve peripheral processes: Effects of brain‐derived neurotrophic factor and fibroblast growth factor , 2007, Journal of neuroscience research.

[160]  G. Laurell,et al.  Intracochlear administration of thiourea protects against cisplatin-induced outer hair cell loss in the guinea pig , 2003, Hearing Research.

[161]  I. Lopez,et al.  The protective effect of brain-derived neurotrophic factor after gentamicin ototoxicity. , 1999, The American journal of otology.

[162]  P. Sellick,et al.  A method for introducing non-silencing siRNA into the guinea pig cochlea in vivo , 2008, Journal of Neuroscience Methods.

[163]  R. Shepherd,et al.  Surface microstructure of the perilymphatic space: implications for cochlear implants and cell- or drug-based therapies. , 2004, Archives of otolaryngology--head & neck surgery.

[164]  E. Rubel,et al.  Rapid changes in cochlear nucleus cell size following blockade of auditory nerve electrical activity in gerbils , 1989, The Journal of comparative neurology.

[165]  Y. Won,et al.  Polymer-based siRNA delivery: perspectives on the fundamental and phenomenological distinctions from polymer-based DNA delivery. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[166]  Josef M. Miller,et al.  Technical report: chronic and acute intracochlear infusion in rodents , 2000, Hearing Research.

[167]  E. Keithley,et al.  Immune-mediated Hearing Loss: Basic Mechanisms and Options for Therapy , 2002, Acta oto-laryngologica. Supplementum.

[168]  Huawei Li,et al.  Stem cells as therapy for hearing loss. , 2004, Trends in molecular medicine.

[169]  P. E. Stopp,et al.  The effect of cerebrospinal fluid pressure on perilymphatic flow in the opened cochlea. , 1979, Acta oto-laryngologica.

[170]  R. Frisina,et al.  Neurotrophin-3 transduction attenuates cisplatin spiral ganglion neuron ototoxicity in the cochlea. , 2002, Molecular therapy : the journal of the American Society of Gene Therapy.

[171]  E. Ferrary,et al.  Production of inner ear fluids. , 1988, Physiological reviews.

[172]  Alfred L. Nuttall,et al.  Osmotic pump implant for chronic infusion of drugs into the inner ear , 1993, Hearing Research.

[173]  D. Bouccara,et al.  Management of Idiopathic Sudden Sensorineural Hearing Loss , 1999, Oto-Rhino-Laryngologia Nova.

[174]  Stephanie B. Epp,et al.  Chronic depolarization enhances the trophic effects of brain‐derived neurotrophic factor in rescuing auditory neurons following a sensorineural hearing loss , 2005, The Journal of comparative neurology.

[175]  Lisa N Gillespie,et al.  BDNF‐induced survival of auditory neurons in vivo: Cessation of treatment leads to accelerated loss of survival effects , 2003, Journal of neuroscience research.

[176]  J. Ryu,et al.  Protein Profile of Human Perilymph: In Search of Markers for the Diagnosis of Perilymph Fistula and other Inner Ear Disease , 1994, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[177]  S. Heller,et al.  The potential role of endogenous stem cells in regeneration of the inner ear , 2007, Hearing Research.

[178]  K. Kawamoto,et al.  Math1 Gene Transfer Generates New Cochlear Hair Cells in Mature Guinea Pigs In Vivo , 2003, The Journal of Neuroscience.

[179]  D. Clarençon,et al.  Therapeutic efficacy of intra-cochlear administration of methylprednisolone after acoustic trauma caused by gunshot noise in guinea pigs , 2006, Hearing Research.

[180]  T. Wienker,et al.  The Contribution of GJB2 (Connexin 26) 35delG to Age-Related Hearing Impairment and Noise-Induced Hearing Loss , 2007, Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology.

[181]  Donald L. Swiderski,et al.  Cochlear implants and ex vivo BDNF gene therapy protect spiral ganglion neurons , 2007, Hearing Research.

[182]  E. Keithley,et al.  Intratympanic immunosuppressives for prevention of immune-mediated sensorineural hearing loss. , 2000, The American journal of otology.

[183]  Stephanie B. Epp,et al.  Fate of Embryonic Stem Cells Transplanted into the Deafened Mammalian Cochlea , 2006, Cell transplantation.

[184]  T. Yamashita,et al.  Intra-cochlear administration of dexamethasone attenuates aminoglycoside ototoxicity in the guinea pig , 2002, Hearing Research.

[185]  A. Salt,et al.  Quantification of solute entry into cochlear perilymph through the round window membrane , 2001, Hearing Research.

[186]  A. Salt,et al.  Simulation of methods for drug delivery to the cochlear fluids. , 2002, Advances in oto-rhino-laryngology.

[187]  Huawei Li,et al.  Generation of hair cells by stepwise differentiation of embryonic stem cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[188]  H. Schuknecht Ablation therapy for the relief of meniere's disease , 1956, The Laryngoscope.

[189]  F. Byl,et al.  The efficacy of steroids in the treatment of idiopathic sudden hearing loss. A double-blind clinical study. , 1980, Archives of otolaryngology.

[190]  K. Kawamoto,et al.  Glial cell line‐derived neurotrophic factor and chronic electrical stimulation prevent VIII cranial nerve degeneration following denervation , 2002, The Journal of comparative neurology.

[191]  H. Staecker,et al.  Steroid Perfusion of the Inner Ear for Sudden Sensorineural Hearing Loss after Failure of Conventional Therapy: A Pilot Study , 2002, Acta oto-laryngologica.

[192]  K. Willecke,et al.  Targeted Ablation of Connexin26 in the Inner Ear Epithelial Gap Junction Network Causes Hearing Impairment and Cell Death , 2002, Current Biology.

[193]  D. Henderson,et al.  Prevention of noise-induced hearing loss with Src-PTK inhibitors , 2005, Hearing Research.

[194]  J. Ito,et al.  A New Method for Drug Application to the Inner Ear , 2005, ORL.

[195]  M. Hoffer,et al.  Targeted Topical Steroid Therapy in Sudden Sensorineural Hearing Loss , 2001, Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology.

[196]  D. G. Drescher,et al.  The amino-acid content of perilymph and cerebrospinal fluid from guinea-pigs and the effect of noise on the amino-acid composition of perilymph , 1981, Neuroscience.