Lacrimal Diversion Devices (Sinopsys Lacrimal Stent): Sharing our Experience with Patients with Chronic Rhinosinusitis without Polyposis

Introduction: Chronic rhinosinusitis (CRS) is a highly prevalent pathology in our society. Due to the prevalence of this condition and to the persisting symptoms despite an appropriate medical treatment, surgical techniques are often required. Lately, minimal invasive techniques have been described, such as lacrimal diversion devices (LDDs). This technique offers a fast and convenient choice for delivery of sinus irrigation and topical medication. Objective: We aimed to describe our experience with LDDs and evaluate the safety and effectiveness of the procedure in patients with moderate to severe CRS without nasal polyposis (CRSsNP) and persistent symptomatology despite medical therapy. Methods: A total of 7 patients underwent bilateral lacrimal stents placement in the operating room. A retrospective observational study was conducted. The Sino-Nasal Outcome Test-20 (SNOT-20) survey was performed and the score obtained was compared before and 1 month after the procedure. Results: The LDDs were used for an average of 80 days. During the follow-up, only three patients had a mild complication with the device (granuloma in the punctum, obstruction, and early extrusion). The mean baseline SNOT-20 score dropped significantly (p ¼ 0.015) from 25.85 to 11.57 (mean: - 14.29) 1 month after the procedure. Conclusion: According to our experience and results, the use of LDD is a novel, feasible, and less invasive technique to treat refractory CRS. It reduces the risk of mucosal stripping, provides short-term outcomes, and the surgical procedure does not require advanced training in endoscopic sinus surgery. Moreover, it can be performed in-office under local anesthesia or sedation

Correlation between high-resolution computed tomography scan findings and histological findings in human vestibular end organs and surgical implications

Background: Histological study of vestibular end organs has been challenging due to the difficulty in preserving their structures for histological analysis and due to their complex geometry. Recently, radiology advances have allowed to deepen the study of the membranous labyrinth. Summary: A review and analysis of surgical implications related to the anatomy of the vestibular end organ is performed. Radiological advances are key in the advancement of the knowledge of the anatomy and pathology of the vestibule. Thus, application of such knowledge in the development or improvement of surgical procedures may facilitate the development of novel techniques. Key Messages: During the last few decades, the knowledge of the anatomy of the auditory system through histology and radiology had improved. Technological advances in this field may lead to a better diagnosis and therapeutic approach of most common and important diseases affecting the inner ear

Estudio de la farmacocinética coclear por medio de la liberación de fármaco a través de un implante coclear en un modelo experimental animal: Macaca fascicularis

En la actualidad, el implante coclear (IC) es uno de los dispositivos más empleados en el tratamiento de la hipoacusia neurosensorial de grado severo-profundo. A pesar de las mejoras en la técnica quirúrgica y en las guías de electrodos empleadas, su colocación genera un daño al oído interno, así como un ambiente proinflamatorio que favorece el aumento de las impedancias eléctricas y el empeoramiento de los niveles auditivos postoperatorios. La reciente experimentación en animales demuestra que la administración de corticoides a nivel intracoclear disminuiría la formación de la capa fibrótica en torno al electrodo tras la implantación, obteniéndose un mayor rendimiento del IC. Dado que la cóclea es un órgano relativamente aislado en el organismo, la administración sistémica de fármacos para el tratamiento de patologías auditivas no ha tenido hasta ahora resultados satisfactorios. A su vez, los tratamientos intratimpánicos presentan un efecto terapéutico limitado a largo plazo. Por esta razón, en las últimas décadas se ha estudiado la posibilidad de emplear un tratamiento basado en la asociación de un IC con fármacos o terapia génica. Para ello, se desarrolló un nuevo dispositivo de IC que cuenta con una bomba de liberación asociada a una cánula, que permitiría tratar las pérdidas de audición por medio de un abordaje combinado de terapia farmacológica y estimulación eléctrica. Sin embargo, a día de hoy aún no se conoce del todo la farmacocinética de los líquidos cocleares. El adecuado conocimiento del comportamiento y distribución de los fármacos en el oído interno permitiría conocer la repercusión exacta que su administración supondría, asegurando un tratamiento a largo plazo, un control eficaz de la dosis y la posibilidad de emplear distintos fármacos. Dados los satisfactorios hallazgos obtenidos en otros animales de experimentación y los estudios recientes que demuestran la similitud existente, tanto a nivel anatómico como fisiológico, entre los primates y el ser humano, el traslado a la experimentación en Macaca fascicularis (Mf) permitiría la futura extrapolación de los resultados obtenidos al ser humano, con el fin de conocer a fondo las características farmacocinéticas de la cóclea humana planteando así dosis y terapias útiles y con menores efectos secundarios en el tratamiento de las distintas patologías auditivas. Así, el objetivo fundamental de esta tesis doctoral es establecer la dinámica de fluidos existente a nivel coclear en un modelo experimental animal: Mf, demostrando la existencia de un flujo en dirección apical, favorecido por distintos factores intracocleares e igualmente condicionado por los mismos. Este estudio se llevó a cabo siguiendo los principios básicos que rigen la farmacocinética: el esquema LADME (Liberación, Absorción, Distribución, Metabolismo y Eliminación). Se realizó un estudio prospectivo, longitudinal, experimental y comparativo entre un total de 15 Mf a los que se les implantó un dispositivo preclínico, CI Electrode Array HL14DD, manufacturado por la compañía Cochlear Ltd., asociado a una bomba de liberación cargada con Isotiocinato de fluoresceína, asociado a dextrano (FITC-Dextran). Se crearon 3 grupos (5 Mf en cada uno), en función del tiempo de liberación programado: Grupo 2 horas, Grupo 24 horas y Grupo 7 días. Se tomaron muestras de perilinfa (10 muestras, de 1 µL cada una) del ápex coclear y se analizaron inmediatamente después por medio de un espectrofluorímetro. Tras la eutanasia del animal, se realizó un análisis histológico detallado del hueso temporal implantado. Los resultados obtenidos fueron analizados, interpretados y comparados entre sí, así como con los hallazgos evidenciados en otros animales de experimentación, en estudios previos. Estos resultados apoyan la viabilidad del Mf como modelo para el estudio de la farmacocinética del oído interno, con la existencia de un flujo coclear en el Mf, en dirección apical, así como la necesidad de un tiempo de infusión de entre 2 y 24 horas para alcanzar concentraciones máximas en el ápex. Pasado este tiempo, una vez transcurrido al menos un periodo de liberación de sustancia comprendido entre 24 horas y 7 días, las concentraciones tienden a disminuir, correspondiéndose con el inicio del periodo de “lavado” de la sustancia administrada a nivel intracoclear. También se sugiere que las variaciones anatómicas del Mf y la existencia de posibles reservorios generados como consecuencia de las comunicaciones existentes entre la escala timpánica, y los espacios extracelulares (espacio modiolar, seno endolinfático) pueden jugar un papel importante en el mantenimiento de las concentraciones a lo largo de la toma de muestras. Los importantes avances en las técnicas de imagen, así como los buenos resultados obtenidos en este estudio, promueven nuevas vías de investigación, aplicando estos hallazgos a otras regiones del oído interno. Técnicas mínimamente invasivas de abordaje al laberinto posterior permitirían no sólo ampliar el conocimiento en la administración local de fármacos, directamente a nivel del oído interno, sino también establecer nuevos tratamientos que permitiesen un abordaje completo del conjunto de patologías que pueden comprometer la adecuada funcionalidad de este órgano de los sentidos, tanto a nivel auditivo como vestibular.At present, the cochlear implant (CI) is one of the most widely used devices to treat severe-to-profound sensorineural hearing loss. Despite improvements in surgical technique and electrode arrays, its placement leads to damage to the inner ear, as well as a pro-inflammatory environment that favours increased electrical impedances and worsens postoperative hearing outcomes. Recent animal experimentation reveals that intracochlear corticosteroid administration would decrease the formation of the fibrotic layer around the electrode post-implantation, which would enhance CI performance. Given that the cochlea is a relatively isolated organ in the body, systemic administration of drugs to treat auditory impairment has failed to yield satisfactory results thus far. Furthermore, intratympanic treatments have a limited long-term therapeutic eect. Therefore, the possibility of using a treatment based on the association of a CI with drugs or gene therapy has been explored in recent decades. To this end, a new CI device with a cannula-associated delivery pump was developed that would make it possible to treat hearing loss through a combined approach of drug therapy and electrical stimulation. However, the pharmacokinetics of cochlear fluids have yet to be fully understood. A suitable knowledge of drug behaviour and distribution within the inner ear would provide insight into the precise impact of drug administration, ensuring long-term treatment, eective dosage control, and the possibility of using a variety of drugs. Given the satisfactory findings in other experimental animals and the recent studies that demonstrate the anatomical and physiological similarity between primates and humans, the translation to experimentation in Macaca fascicularis (Mf) would enable the results obtained in the future to be extrapolated to humans, with the aim of gaining in-depth knowledge regarding the pharmacokinetic characteristics of the human cochlea, thereby establishing useful doses and therapies with fewer side eects to treat dierent auditory pathologies. Thus, the main objective of this doctoral thesis is to establish the existing fluid dynamics of the cochlea in an experimental animal model: Mf, evidencing the existence of a flow in the apical direction, assisted by dierent intracochlear factors and also conditioned by them. This study was conducted according to the basic principles governing pharmacokinetics: the LADME (Liberation, Absorption, Distribution, Metabolism, and Elimination) scheme. A prospective, longitudinal, experimental and comparative study was performed in a total of 15 Mf implanted with a preclinical device, CI Electrode Array HL14DD, manufactured by Cochlear Ltd., associated with a release pump loaded with fluorescein isothiocynate, associated with dextran (FITC-Dextran). Three groups (5 Mf each) were formed based on the scheduled release time: Group 2 hours, Group 24 hours and Group 7 days. Perilymph samples (10 samples, 1 µL each) were taken from the cochlear apex and analysed immediately afterwards by spectrofluorimeter. After euthanasia of the animal, a detailed histological analysis of the implanted temporal bone was conducted. The results were analysed, interpreted, and compared with each other, as well as with findings from previous studies in other experimental animals. These results support the viability of the Mf as a model to study inner ear pharmacokinetics, with a cochlear flow in the Mf towards the apex, as well as the need for an infusion time of between 2 and 24 hours to attain peak concentrations in the apex. Then, after a period of at least 24 hours to 7 days of substance release, concentrations tend to decrease, corresponding to the beginning of the “washout” period of the substance administered intracochlearly. Furthermore, it is suggested that the anatomical variations in Mf and the existence of possible reservoirs generated as a result of communications between the scala tympani and the extracellular spaces (modiolar space, endolymphatic sinus) could play an important role in maintaining concentrations throughout the sampling period. Major inroads into imaging techniques, as well as the encouraging results obtained in this study, promote new avenues of research, applying these findings to other regions of the inner ear. Minimally invasive techniques to approach the posterior labyrinth would not only enable us to broaden our knowledge regarding local delivery of drugs directly to the inner ear, but also to establish new treatments that would provide a comprehensive approach to the range of conditions that can compromise the proper functioning of this sensory organ, both at the auditory and vestibular levels

Estudio de la farmacocinética coclear por medio de la liberación de fármaco a través de un implante coclear en un modelo experimental animal: Macaca fascicularis

En la actualidad, el implante coclear (IC) es uno de los dispositivos más empleados en el tratamiento de la hipoacusia neurosensorial de grado severo-profundo. A pesar de las mejoras en la técnica quirúrgica y en las guías de electrodos empleadas, su colocación genera un daño al oído interno, así como un ambiente proinflamatorio que favorece el aumento de las impedancias eléctricas y el empeoramiento de los niveles auditivos postoperatorios. La reciente experimentación en animales demuestra que la administración de corticoides a nivel intracoclear disminuiría la formación de la capa fibrótica en torno al electrodo tras la implantación, obteniéndose un mayor rendimiento del IC. Dado que la cóclea es un órgano relativamente aislado en el organismo, la administración sistémica de fármacos para el tratamiento de patologías auditivas no ha tenido hasta ahora resultados satisfactorios. A su vez, los tratamientos intratimpánicos presentan un efecto terapéutico limitado a largo plazo. Por esta razón, en las últimas décadas se ha estudiado la posibilidad de emplear un tratamiento basado en la asociación de un IC con fármacos o terapia génica. Para ello, se desarrolló un nuevo dispositivo de IC que cuenta con una bomba de liberación asociada a una cánula, que permitiría tratar las pérdidas de audición por medio de un abordaje combinado de terapia farmacológica y estimulación eléctrica. Sin embargo, a día de hoy aún no se conoce del todo la farmacocinética de los líquidos cocleares. El adecuado conocimiento del comportamiento y distribución de los fármacos en el oído interno permitiría conocer la repercusión exacta que su administración supondría, asegurando un tratamiento a largo plazo, un control eficaz de la dosis y la posibilidad de emplear distintos fármacos. Dados los satisfactorios hallazgos obtenidos en otros animales de experimentación y los estudios recientes que demuestran la similitud existente, tanto a nivel anatómico como fisiológico, entre los primates y el ser humano, el traslado a la experimentación en Macaca fascicularis (Mf) permitiría la futura extrapolación de los resultados obtenidos al ser humano, con el fin de conocer a fondo las características farmacocinéticas de la cóclea humana planteando así dosis y terapias útiles y con menores efectos secundarios en el tratamiento de las distintas patologías auditivas. Así, el objetivo fundamental de esta tesis doctoral es establecer la dinámica de fluidos existente a nivel coclear en un modelo experimental animal: Mf, demostrando la existencia de un flujo en dirección apical, favorecido por distintos factores intracocleares e igualmente condicionado por los mismos. Este estudio se llevó a cabo siguiendo los principios básicos que rigen la farmacocinética: el esquema LADME (Liberación, Absorción, Distribución, Metabolismo y Eliminación). Se realizó un estudio prospectivo, longitudinal, experimental y comparativo entre un total de 15 Mf a los que se les implantó un dispositivo preclínico, CI Electrode Array HL14DD, manufacturado por la compañía Cochlear Ltd., asociado a una bomba de liberación cargada con Isotiocinato de fluoresceína, asociado a dextrano (FITC-Dextran). Se crearon 3 grupos (5 Mf en cada uno), en función del tiempo de liberación programado: Grupo 2 horas, Grupo 24 horas y Grupo 7 días. Se tomaron muestras de perilinfa (10 muestras, de 1 µL cada una) del ápex coclear y se analizaron inmediatamente después por medio de un espectrofluorímetro. Tras la eutanasia del animal, se realizó un análisis histológico detallado del hueso temporal implantado. Los resultados obtenidos fueron analizados, interpretados y comparados entre sí, así como con los hallazgos evidenciados en otros animales de experimentación, en estudios previos. Estos resultados apoyan la viabilidad del Mf como modelo para el estudio de la farmacocinética del oído interno, con la existencia de un flujo coclear en el Mf, en dirección apical, así como la necesidad de un tiempo de infusión de entre 2 y 24 horas para alcanzar concentraciones máximas en el ápex. Pasado este tiempo, una vez transcurrido al menos un periodo de liberación de sustancia comprendido entre 24 horas y 7 días, las concentraciones tienden a disminuir, correspondiéndose con el inicio del periodo de “lavado” de la sustancia administrada a nivel intracoclear. También se sugiere que las variaciones anatómicas del Mf y la existencia de posibles reservorios generados como consecuencia de las comunicaciones existentes entre la escala timpánica, y los espacios extracelulares (espacio modiolar, seno endolinfático) pueden jugar un papel importante en el mantenimiento de las concentraciones a lo largo de la toma de muestras. Los importantes avances en las técnicas de imagen, así como los buenos resultados obtenidos en este estudio, promueven nuevas vías de investigación, aplicando estos hallazgos a otras regiones del oído interno. Técnicas mínimamente invasivas de abordaje al laberinto posterior permitirían no sólo ampliar el conocimiento en la administración local de fármacos, directamente a nivel del oído interno, sino también establecer nuevos tratamientos que permitiesen un abordaje completo del conjunto de patologías que pueden comprometer la adecuada funcionalidad de este órgano de los sentidos, tanto a nivel auditivo como vestibular.At present, the cochlear implant (CI) is one of the most widely used devices to treat severe-to-profound sensorineural hearing loss. Despite improvements in surgical technique and electrode arrays, its placement leads to damage to the inner ear, as well as a pro-inflammatory environment that favours increased electrical impedances and worsens postoperative hearing outcomes. Recent animal experimentation reveals that intracochlear corticosteroid administration would decrease the formation of the fibrotic layer around the electrode post-implantation, which would enhance CI performance. Given that the cochlea is a relatively isolated organ in the body, systemic administration of drugs to treat auditory impairment has failed to yield satisfactory results thus far. Furthermore, intratympanic treatments have a limited long-term therapeutic eect. Therefore, the possibility of using a treatment based on the association of a CI with drugs or gene therapy has been explored in recent decades. To this end, a new CI device with a cannula-associated delivery pump was developed that would make it possible to treat hearing loss through a combined approach of drug therapy and electrical stimulation. However, the pharmacokinetics of cochlear fluids have yet to be fully understood. A suitable knowledge of drug behaviour and distribution within the inner ear would provide insight into the precise impact of drug administration, ensuring long-term treatment, eective dosage control, and the possibility of using a variety of drugs. Given the satisfactory findings in other experimental animals and the recent studies that demonstrate the anatomical and physiological similarity between primates and humans, the translation to experimentation in Macaca fascicularis (Mf) would enable the results obtained in the future to be extrapolated to humans, with the aim of gaining in-depth knowledge regarding the pharmacokinetic characteristics of the human cochlea, thereby establishing useful doses and therapies with fewer side eects to treat dierent auditory pathologies. Thus, the main objective of this doctoral thesis is to establish the existing fluid dynamics of the cochlea in an experimental animal model: Mf, evidencing the existence of a flow in the apical direction, assisted by dierent intracochlear factors and also conditioned by them. This study was conducted according to the basic principles governing pharmacokinetics: the LADME (Liberation, Absorption, Distribution, Metabolism, and Elimination) scheme. A prospective, longitudinal, experimental and comparative study was performed in a total of 15 Mf implanted with a preclinical device, CI Electrode Array HL14DD, manufactured by Cochlear Ltd., associated with a release pump loaded with fluorescein isothiocynate, associated with dextran (FITC-Dextran). Three groups (5 Mf each) were formed based on the scheduled release time: Group 2 hours, Group 24 hours and Group 7 days. Perilymph samples (10 samples, 1 µL each) were taken from the cochlear apex and analysed immediately afterwards by spectrofluorimeter. After euthanasia of the animal, a detailed histological analysis of the implanted temporal bone was conducted. The results were analysed, interpreted, and compared with each other, as well as with findings from previous studies in other experimental animals. These results support the viability of the Mf as a model to study inner ear pharmacokinetics, with a cochlear flow in the Mf towards the apex, as well as the need for an infusion time of between 2 and 24 hours to attain peak concentrations in the apex. Then, after a period of at least 24 hours to 7 days of substance release, concentrations tend to decrease, corresponding to the beginning of the “washout” period of the substance administered intracochlearly. Furthermore, it is suggested that the anatomical variations in Mf and the existence of possible reservoirs generated as a result of communications between the scala tympani and the extracellular spaces (modiolar space, endolymphatic sinus) could play an important role in maintaining concentrations throughout the sampling period. Major inroads into imaging techniques, as well as the encouraging results obtained in this study, promote new avenues of research, applying these findings to other regions of the inner ear. Minimally invasive techniques to approach the posterior labyrinth would not only enable us to broaden our knowledge regarding local delivery of drugs directly to the inner ear, but also to establish new treatments that would provide a comprehensive approach to the range of conditions that can compromise the proper functioning of this sensory organ, both at the auditory and vestibular levels

Correlation between high-resolution computed tomography scan findings and histological findings in human vestibular end organs and surgical implications

Background: Histological study of vestibular end organs has been challenging due to the difficulty in preserving their structures for histological analysis and due to their complex geometry. Recently, radiology advances have allowed to deepen the study of the membranous labyrinth. Summary: A review and analysis of surgical implications related to the anatomy of the vestibular end organ is performed. Radiological advances are key in the advancement of the knowledge of the anatomy and pathology of the vestibule. Thus, application of such knowledge in the development or improvement of surgical procedures may facilitate the development of novel techniques. Key Messages: During the last few decades, the knowledge of the anatomy of the auditory system through histology and radiology had improved. Technological advances in this field may lead to a better diagnosis and therapeutic approach of most common and important diseases affecting the inner ear

Inner ear drug delivery through a cochlear implant: pharmacokinetics in a macaque experimental model

Objectives: The method of drug delivery directly into the cochlea with an implantable pump connected to a CI electrode array ensures long-term delivery and effective dose control, and also provides the pos- sibility to use different drugs. The objective is to develop a model of inner ear pharmacokinetics of an implanted cochlea, with the delivery of FITC-Dextran, in the non-human primate model. Design: A preclinical cochlear electrode array (CI Electrode Array HL14DD, manufactured by Cochlear Ltd.) attached to an implantable peristaltic pump filled with FITC-Dextran was implanted unilaterally in a total of 15 Macaca fascicularis (Mf). Three groups were created (5 Mf in each group), according to three differ- ent drug delivery times: 2 hours, 24 hours and 7 days. Perilymph (10 samples, 1μL each) was sampled from the apex of the cochlea and measured immediately after extraction with a spectrofluorometer. After scarifying the specimens, x-Rays and histological analysis were performed. Results: Surgery, sampling and histological analysis were performed successfully in all specimens. FITC- Dextran quantification showed different patterns, depending on the delivery group. In the 2 hours injec- tion experiment, an increase in FITC-Dextran concentrations over the sample collection time was seen, reaching maximum concentration peaks (420-964μM) between samples 5 and 7, decreasing in successive samples, without returning to baseline. The 24-hours and 7-days injection experiments showed even be- haviour throughout the 10 samples obtained, reaching a plateau with mean concentrations ranging from 2144 to 2564 μM and from 1409 to 2502μM, respectively. Statistically significant differences between the 2 hours and 24 hours groups (p = 0.001) and between the 2 hours and 7 days groups (p = 0.037) were observed, while between the 24 hours and 7 days groups no statistical differences were found. Conclusions: This experimental study shows that a model of drug delivery and pharmacokinetics using an active pump connected to an electrode array is feasible in Mf. An infusion time ranging from 2 to 24 hours is required to reach a maximum concentration peak at the apex. It establishes then an even concentration profile from base to apex that is maintained throughout the infusion time in Mf. Flow mechanisms during injection and during sampling that may explain such findings may involve cochlear aqueduct flow as well as the possible existence of substance exchange from scala tympani to extracel- lular spaces, such as the modiolar space or the endolymphatic sinus, acting as a substance reservoir to maintain a relatively flat concentration profile from base to apex during sampling. Leveraging the learnings achieved by experimentation in rodent models, we can move to experiment in non-human primate with the aim of achieving a useful model that provides transferrable data to hu- man pharmacokinetics. Thus, it may broaden clinical and therapeutic approaches to inner ear diseases

Inner ear drug delivery through a cochlear implant: pharmacokinetics in a macaque experimental model

Objectives: The method of drug delivery directly into the cochlea with an implantable pump connected to a CI electrode array ensures long-term delivery and effective dose control, and also provides the pos- sibility to use different drugs. The objective is to develop a model of inner ear pharmacokinetics of an implanted cochlea, with the delivery of FITC-Dextran, in the non-human primate model. Design: A preclinical cochlear electrode array (CI Electrode Array HL14DD, manufactured by Cochlear Ltd.) attached to an implantable peristaltic pump filled with FITC-Dextran was implanted unilaterally in a total of 15 Macaca fascicularis (Mf). Three groups were created (5 Mf in each group), according to three differ- ent drug delivery times: 2 hours, 24 hours and 7 days. Perilymph (10 samples, 1μL each) was sampled from the apex of the cochlea and measured immediately after extraction with a spectrofluorometer. After scarifying the specimens, x-Rays and histological analysis were performed. Results: Surgery, sampling and histological analysis were performed successfully in all specimens. FITC- Dextran quantification showed different patterns, depending on the delivery group. In the 2 hours injec- tion experiment, an increase in FITC-Dextran concentrations over the sample collection time was seen, reaching maximum concentration peaks (420-964μM) between samples 5 and 7, decreasing in successive samples, without returning to baseline. The 24-hours and 7-days injection experiments showed even be- haviour throughout the 10 samples obtained, reaching a plateau with mean concentrations ranging from 2144 to 2564 μM and from 1409 to 2502μM, respectively. Statistically significant differences between the 2 hours and 24 hours groups (p = 0.001) and between the 2 hours and 7 days groups (p = 0.037) were observed, while between the 24 hours and 7 days groups no statistical differences were found. Conclusions: This experimental study shows that a model of drug delivery and pharmacokinetics using an active pump connected to an electrode array is feasible in Mf. An infusion time ranging from 2 to 24 hours is required to reach a maximum concentration peak at the apex. It establishes then an even concentration profile from base to apex that is maintained throughout the infusion time in Mf. Flow mechanisms during injection and during sampling that may explain such findings may involve cochlear aqueduct flow as well as the possible existence of substance exchange from scala tympani to extracel- lular spaces, such as the modiolar space or the endolymphatic sinus, acting as a substance reservoir to maintain a relatively flat concentration profile from base to apex during sampling. Leveraging the learnings achieved by experimentation in rodent models, we can move to experiment in non-human primate with the aim of achieving a useful model that provides transferrable data to hu- man pharmacokinetics. Thus, it may broaden clinical and therapeutic approaches to inner ear diseases