| 1. |
- Berglin, Cecilia Engmer, et al.
(author)
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Local treatment of the inner ear : A study of three different polymers aimed for middle ear administration
- 2015
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In: Acta Oto-Laryngologica. - : Informa UK Limited. - 0001-6489 .- 1651-2251. ; 135:10, s. 985-994
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Journal article (peer-reviewed)abstract
- Conclusion: A formulation based on sodium hyaluronate (NaHYA) was the most promising candidate vehicle for intra-tympanic drug administration regarding conductive hearing loss, inflammatory reactions, and elimination. Objectives: Recent advances in inner ear research support the idea of using the middle ear cavity for drug administration to target the inner ear. This paper presents rheological and safety assessments of three candidate polymer formulations for intra-tympanic drug administration. Method: The formulations were based on sodium carboxymethyl cellulose (NaCMC), sodium hyaluronate (NaHYA), and poloxamer 407 (POL). Rheological studies were performed with a controlled rate instrument of the couette type. Safety studies were performed in guinea pigs subjected to an intra-tympanic injection of the formulations. Hearing function was explored with ABR before and 1, 2, and 3 weeks after the injection. Elimination of the formulations marked with coal was explored with an endoscopic digital camera 1, 2, and 3 weeks after injection. Middle and inner ear morphology was examined with light microscopy 6 days after injection. Results: The results speak in favor of NaHYA, since it did not cause prolonged hearing threshold elevations. The results of the elimination and morphological investigations support the conclusion of NaHYA being the most promising candidate for intra-tympanic administration.
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| 2. |
- Berglin, Cecilia Engmér, et al.
(author)
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Magnetic Resonance Imaging of the Middle and Inner Ear After Intratympanic Injection of a Gadolinium-Containing Gel
- 2014
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In: Otology and Neurotology. - 1531-7129 .- 1537-4505. ; 35:3, s. 526-532
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Journal article (peer-reviewed)abstract
- OBJECTIVE:To investigate the distribution and elimination of a gadolinium containing high viscosity formulation of sodium hyaluronan (HYA gel) after injection to the middle ear.MATERIALS AND METHODS:The T1 contrast agent gadolinium-diethylenetriamine pentaacetic acid-bis methylamine (Gd-DTPA-BMA) was added to HYA gel and delivered to the middle ear of 13 albino guinea pigs by 3 different ways of injection. Magnetic resonance imaging was performed with a 4.7 T MRI system using a T1-weighted 3-dimentional rapid acquisition with relaxation enhancement sequence.RESULTS:An injection technique where the Gd-DTPA-BMA-containing HYA gel was delivered to the middle ear through a percutaneous injection through the auditory bulla after a small incision had been made in the tympanic membrane gave the best filling of the middle ear, covering the cochlea and the region of the round window niche for 24 hours in a majority of the ears studied. Ears injected without an incision in the tympanic membrane showed an immediate uptake of Gd-DTPA-BMA in the inner ear as a sign of rupture of the round window membrane.CONCLUSION:A percutaneous injection of a HYA gel into the tympanic bulla is distributed in a predictable way and gives a good filling of the middle ear cavity. The HYA gel remains in close vicinity to the RWM for more than 24 hours. Injection should be performed after an incision of the tympanic membrane has been made to prevent rupture of the round window membrane.
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| 3. |
- Berglin, Cecilia Engmer, et al.
(author)
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Prevention of cisplatin-induced hearing loss by administration of a thiosulfate-containing gel to the middle ear in a guinea pig model
- 2011
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In: Cancer Chemotherapy and Pharmacology. - New York : Springer-Verlag New York. - 0344-5704 .- 1432-0843. ; 68:6, s. 1547-1556
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Journal article (peer-reviewed)abstract
- Thiosulfate may reduce cisplatin-induced ototoxicity, most likely by relieving oxidative stress and by forming inactive platinum complexes. This study aimed to determine the concentration and protective effect of thiosulfate in the cochlea after application of a thiosulfate-containing high viscosity formulation of sodium hyaluronan (HYA gel) to the middle ear prior to i.v. injection of cisplatin in a guinea pig model. The release of thiosulfate (0.1 M) from HYA gel (0.5% w/w) was explored in vitro. Thiosulfate in the scala tympani perilymph of the cochlea 1 and 3 h after application of thiosulfate in HYA gel to the middle ear was quantified with HPLC and fluorescence detection. Thiosulfate in blood and CSF was also explored. The potential otoprotective effect was evaluated by hair cell count after treatment with thiosulfate in HYA gel applied to the middle ear 3 h prior to cisplatin injection (8 mg/kg b.w.). HYA did not impede the release of thiosulfate. Middle ear administration of thiosulfate in HYA gel gave high concentrations in the scala tympani perilymph while maintaining low levels in blood, and it protected against cisplatin-induced hair cell loss. HYA gel is an effective vehicle for administration of thiosulfate to the middle ear. Local application of a thiosulfate-containing HYA gel reduces the ototoxicity of cisplatin most likely without compromising its antineoplastic effect. This provides a minimally invasive protective treatment that can easily be repeated if necessary.
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| 4. |
- Bonnard, Åsa, et al.
(author)
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The risk of cholesteatoma in individuals with first-degree relatives surgically treated for the disease
- 2023
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In: JAMA Otolaryngology - Head and Neck Surgery. - : American Medical Association (AMA). - 2168-6181 .- 2168-619X. ; 149:5
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Journal article (peer-reviewed)abstract
- IMPORTANCE: Cholesteatoma in the middle ear is not regarded as a hereditary disease, but case reports of familial clustering exist in the literature, as well as observed familial cases in the clinical work. However, the knowledge regarding cholesteatoma as a hereditary disease is lacking in the literature. OBJECTIVE To assess the risk of cholesteatoma in individuals with a first-degree relative surgically treated for the same disease.DESIGN, SETTING, AND PARTICIPANTS: In this nested case-control study in the Swedish population between 1987 and 2018 of first-time cholesteatoma surgery identified from the Swedish National Patient Register, 2 controls per case were randomly selected from the population register through incidence density sampling, and all first-degree relatives for cases and controls were identified. Data were received in April 2022, and analyses were conducted between April and September 2022.EXPOSURE: Cholesteatoma surgery in a first-degree relative.MAIN OUTCOMES AND MEASURES: The main outcome was first-time cholesteatoma surgery. The association between having a first-degree relative with cholesteatoma and the risk of cholesteatoma surgery in the index persons was estimated by odds ratios (ORs) and 95% CIs through conditional logistic regression analysis.RESULTS: Between 1987 and 2018, 10 618 individuals with a first-time cholesteatoma surgery (mean [SD] age at surgery, 35.6 [21.5] years; 6302 [59.4%] men) were identified in the Swedish National Patient Register. The risk of having a cholesteatoma surgery was almost 4 times higher in individuals having a first-degree relative surgically treated for the disease (OR, 3.9; 95% CI, 3.1-4.8), but few cases were exposed overall. Among the 10 105 cases with at least 1 control included in the main analysis, 227 (2.2%) had at least 1 first-degree relative treated for cholesteatoma, while the corresponding numbers for controls were 118 of 19 553 control patients (0.6%). The association was stronger for individuals under the age of 20 years at first surgery (OR, 5.2; 95% CI, 3.6-7.6) and for a surgery involving the atticus and/or mastoid region (OR, 4.8; 95% CI, 3.4-6.2). There was no difference in the prevalence of having a partner with cholesteatoma between cases and controls (10 cases [0.3%] and 16 controls [0.3%]; OR, 0.92; 95% CI, 0.41-2.05), which implies that increased awareness does not explain the association.CONCLUSIONS AND RELEVANCE: In this Swedish case-control study using nationwide register data with high coverage and completeness, the findings suggest that the risk of cholesteatoma in the middle ear is strongly associated with a family history of the condition. Family history was nevertheless quite rare and can therefore only explain a limited number of all cases; these families could be an important source for information regarding the genetic background for cholesteatoma disease.
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| 5. |
- Counter, S Allen, et al.
(author)
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Experimental Fusion of Contrast Enhanced High-Field Magnetic Resonance Imaging and High-Resolution Micro-Computed Tomography in Imaging the Mouse Inner Ear
- 2015
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In: The Open Neuroimaging Journal. - : Bentham Science Publishers Ltd.. - 1874-4400. ; 9, s. 7-12
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Journal article (peer-reviewed)abstract
- OBJECTIVE: Imaging cochlear, vestibular, and 8th cranial nerve abnormalities remains a challenge. In this study, the membranous and osseous labyrinths of the wild type mouse inner ear were examined using volumetric data from ultra high-field magnetic resonance imaging (MRI) with gadolinium contrast at 9.4 Tesla and high-resolution micro-computed tomography (µCT) to visualize the scalae and vestibular apparatus, and to establish imaging protocols and parameters for comparative analysis of the normal and mutant mouse inner ear.METHODS: For in vivo MRI acquisition, animals were placed in a Milleped coil situated in the isocenter of a horizontal 9.4 T Varian magnet. For µCT examination, cone beam scans were performed ex vivo following MRI using the µCT component of a nanoScan PET/CT in vivo scanner.RESULTS: The fusion of Gd enhanced high field MRI and high-resolution µCT scans revealed the dynamic membranous labyrinth of the perilymphatic fluid filled scala tympani and scala vestibule of the cochlea, and semicircular canals of the vestibular apparatus, within the µCT visualized contours of the contiguous osseous labyrinth. The ex vivo µCT segmentation revealed the surface contours and structural morphology of each cochlea turn and the semicircular canals in 3 planes.CONCLUSIONS: The fusion of ultra high-field MRI and high-resolution µCT imaging techniques were complementary, and provided high-resolution dynamic and static visualization of the complex morphological features of the normal mouse inner ear structures, which may offer a valuable approach for the investigation of cochlear and vestibular abnormalities that are associated with birth defects related to genetic inner ear disorders in humans.
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| 6. |
- Counter, S Allen, et al.
(author)
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MRI evidence of endolymphatic impermeability to the gadolinium molecule in the in vivo mouse inner ear at 9.4 tesla
- 2013
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In: The Open Neuroimaging Journal. - : Bentham Science Publishers Ltd.. - 1874-4400. ; 7, s. 27-31
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Journal article (peer-reviewed)abstract
- OBJECTIVE:Previous in vivo experimental magnetic resonance imaging (MRI) investigations of the mammalian inner ear at 4.7 Tesla have indicated that intravenously injected gadolinium (Gd) penetrates the perilymphatic labyrinth, but not the endolymphatic membranous labyrinth. In the present study, high field MRI at 9.4T was used to visualize the in vivo mouse vestibulo-cochlea system, and to determine whether the endolymphatic system is permeable to a Gd complex.METHODS:A 9.4 T Varian magnet equipped with a 12 cm inner diameter gradient system with maximum gradient strength of 600 mT/m, a millipede coil (Varian design) and a Gd contrast agent were used for image acquisition in the normal C57 BL-6 mouse.RESULTS:High-resolution 2D and 3D images of the mouse cochlea were acquired within 80 minutes following intravenous injection of Gd. Gd initially permeated the perilymphatic scala tympani and scala vestibuli, and permitted visualization of both cochlear turns from base to apex. The superior, inferior and lateral semicircular canals were subsequently visualized in 3 planes. The membranous endolymphatic labyrinth was impermeable to intravenously injected Gd, and thus showed no apparent uptake of Gd at 9.4T.CONCLUSION:The 9.4T field strength MRI permitted acquisition of high resolution images of anatomical and physiological features of the normal, wild type mouse perilymphatic inner ear in vivo, and provided further evidence that the endolymphatic system is impermeable to intravenously injected Gd.
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| 7. |
- Counter, S. Allen, et al.
(author)
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Ultra-high-field (9.4 T) MRI Analysis of Contrast Agent Transport Across the Blood-Perilymph Barrier and Intrastrial Fluid-Blood Barrier in the Mouse Inner Ear
- 2017
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In: Otology and Neurotology. - 1531-7129 .- 1537-4505. ; 38:7, s. 1052-1059
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Journal article (peer-reviewed)abstract
- Hypothesis: Effective paramagnetic contrast agent for the penetration of the perilymphatic spaces of the scala tympani, scala vestibuli, and scala media of the mouse inner ear can be determined using intravenous injection of various gadolinium (Gd) complexes and ultra-high-field magnetic resonance imaging (MRI) at 9.4 Tesla.Background: A number of contrast agents have been explored in experimental high-field MRI to determine the most effective Gd complex for ideal signal-to-noise ratio and maximal visualization of the in vivo mammalian inner ear in analyzing the temporal and spatial parameters involved in drug penetration of the blood-perilymph barrier and intrastrial fluid-blood barrier in the mouse model using MRI.Methods: Gadoteric acid (Dotarem), Gadobutrol (Gadovist), Gadodiamide (Omniscan), Gadopent acid (Magnevist), and Mangafodipir (Teslascan) were administered intravenously using the tail vein of 60 Balb/C mice. High-resolution T1 images of drug penetration were acquired with a horizontal 9.4 T Agilent magnet after intravenously injection. Signal intensity was used as a metric of temporal and spatial parameters of drug delivery and penetration of the perilymphatic and endolymphatic spaces.Results: ANOVA analysis of the area under the curve of intensity enhancement in perilymph revealed a significant difference (p < 0.05) in the scalae uptake using different contrast agents (F (3,25) = 3.54, p = 0.029). The Gadoteric acid complex Dotarem was found to be the most effective Gd compound in terms of rapid, morphological enhancement for analysis of the temporal, and spatial distribution in the perilymphatic space of the inner ear.Conclusion: Gadoteric acid (Dotarem) demonstrated efficacy as a contrast agent for enhanced visualization of the perilymphatic spaces of the inner ear labyrinthine in the mouse, including the scala tympani and scala vestibuli of the cochlea, and the semicircular canals of the vestibular apparatus. These findings may inform the clinical application of Gd compounds in patients with inner ear fluid disorders and vertigo.
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| 8. |
- Engmér Berglin, Cecilia
(author)
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Local pharmacological treatment of inner ear disorders
- 2011
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Doctoral thesis (other academic/artistic)abstract
- Hearing disorders are among the top 10 in terms of burden of disease in middle- and high-income countries, affecting 250 million people worldwide. During the last few decades researchers have made significant advances in understanding the basic mechanisms and molecular biology of inner ear diseases. The principal challenge in treatment of the inner ear is that the targets for pharmacological therapy are inaccessible due to the various barrier systems of the inner ear, and that the inner ear is embedded in the base of the skull. New technologies to provide safe and efficacious delivery of drugs to the inner ear are of great clinical interest. Local administration of medication to the inner ear would solve some of the problems associated with systemic delivery, such as drug interaction and systemic side effects. The aim of the research presented in this thesis was to elucidate different aspects of drug delivery to the inner ear using a local application technique. The round window membrane (RWM) is believed to be the main route for drug delivery to the inner ear when a drug is administered to the middle ear i.e. by an intratympanic injection. A morphological study of the round window performed on cynomolgus monkey described in Paper I showed the existence of a local defense system housed within the rim of the RWM. Previously undescribed gland-like structures were identified in the loose connective tissue of the mucosal layer near the bony insertion of the RWM. These findings could explain why labyrinthitis is rare despite the close proximity of the infection-prone middle ear. A local immunodefense system would also most likely affect the transport of drugs from the middle ear cavity to the inner ear and needs to be taken into consideration when developing new strategies for local drug administration in the middle ear. In the studies on which Paper II is based, the rheological and safety aspects of three candidate vehicles for intratympanic drug administration were investigated. The results speak in favor of sodium hyaluronate (HYA gel) which, in contrast to carboxymethyl cellulose and poloxamer 407, did not cause lasting or significant increases in hearing threshold after intratympanic injection in 8 the guinea pig. Studies of vehicle elimination and morphological investigations support HYA gel as the most promising candidate for intratympanic administration. An important factor for local administration of drugs to the middle ear aimed for inner ear treatment is the adherence of the vehicle to the RWM. The distribution and elimination of HYA gel after intratympanic injection to the auditory bulla in guinea pig were investigated by magnetic resonance imaging in Paper III. HYA gel was distributed in a predictable way and filled the middle ear cavity well. The HYA gel remained close to the RWM for more than 24 hours. A myringotomy was needed before middle ear administration to allow air to escape and prevent trauma to the RWM. The hypothesis that higher concentrations of a drug in the inner ear could be achieved by local administration than through systemic administration was investigated in Paper IV and V using the antioxidant thiosulfate, which has previously been identified as a promising otoprotector against cisplatin-induced ototoxicity. The concentration of thiosulfate in scala tympani perilymph was much higher after intratympanic delivery to the guinea pig using an injection of a thiosulfate-containing HYA gel than after i.v. administration of a thiosulfate solution. The levels of thiosulfate in blood remained low after intratympanic administration, confirming that this delivery system will not risk decreased antitumoral effect due to cisplatin inactivation in tumor tissue. The final study, Paper V, demonstrated that ototoxicity in guinea pigs treated with the antineoplastic drug cisplatin was reduced by injection of thiosulfate-containing HYA gel three hours prior to the systemic cisplatin injection. This confirms the hypothesis of thiosulfate being a promising otoprotector for cisplatin induced hearing loss and also shows that drugs can be delivered locally to the inner ear by intratympanic injection using HYA gel as a vehicle.
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| 9. |
- Engmér, Cecilia, et al.
(author)
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Immunodefense of the round window
- 2008
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In: The Laryngoscope. - Philadelphia : Lippincott Williams & Wilkins. - 0023-852X .- 1531-4995. ; 118:6, s. 1057-62
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Journal article (peer-reviewed)abstract
- A systematic analysis using serial sectioning of the round window membrane (RWM) in the cynomolgus monkey was performed. Light and transmission electron microscopy (LM and TEM) revealed that the RWM rim may be endowed with gland-like structures with glyco-protein material secernated into the window niche. This was detected in one third of the specimens. The secreted material displayed waste material and scavenger cells. There was also a rich network of capillaries, lymph channels, and sinusoidal veins containing leukocytes. Their abluminal surfaces displayed mature plasma cells and monocytes. These findings suggest that in certain primates the middle ear may have developed specific immunoprotective means for disposal of foreign and noxious substances before they reach the inner ear.
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| 10. |
- Modée Borgström, Agnes, et al.
(author)
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Occurrence of mucosa-affecting diseases of the upper airways in middle ear cholesteatoma patients : a nationwide case-control study
- 2024
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In: European Archives of Oto-Rhino-Laryngology. - : Springer. - 0937-4477 .- 1434-4726.
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Journal article (peer-reviewed)abstract
- PURPOSE: Exploring a possible link between upper airway inflammation and the development of cholesteatoma by studying the association between mucosa-affecting diseases of the upper airways and cholesteatoma surgery.METHODS: This is a nationwide case-control study of 10,618 patients who underwent surgery for cholesteatoma in Sweden between 1987 and 2018. The cases were identified in the National Patient Register and 21,235 controls matched by age, sex and place of residency were included from national population registers. Odds ratios (OR) and corresponding 95% confidence intervals were used to assess the association between six types of mucosa-affecting diseases of the upper airways and cholesteatoma surgery.RESULTS: Chronic rhinitis, chronic sinusitis and nasal polyposis were more common in cholesteatoma patients than in controls (OR 1.5 to 2.5) as were both adenoid and tonsil surgery (OR > 4) where the strongest association was seen for adenoid surgery. No association was seen between allergic rhinitis and cholesteatoma.CONCLUSION: This study supports an association between mucosa-affecting diseases of the upper airways and cholesteatoma. Future studies should aim to investigate the mechanisms connecting mucosa-affecting diseases of the upper airways and cholesteatoma formation regarding genetic, anatomical, inflammatory and mucosa properties.
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