Nos últimos anos, houve uma tendência na busca por substâncias reguladoras que pudessem otimizar o processo de cicatrização de membranas timpânicas (MTs) perfuradas. Objetivos: Determinar os efeitos da utilização da insulina tópica e da biomembrana de látex natural, de forma isolada e em associação, no processo de cicatrização de perfurações traumáticas de MTs. Materiais e Métodos: MTs de 61 ratos Wistar foram perfuradas nas porções anterior e posterior ao cabo do martelo. Os animais foram divididos em quatro grupos: Controle, Insulina, Látex e Insulina+Látex. No grupo Insulina, as perfurações foram tratadas com uso tópico de insulina regular. No grupo Látex, tratadas com biomembrana de látex natural. No grupo Insulina+Látex, tratadas com associação da insulina e da biomembrana de látex. As MTs foram avaliadas por técnicas histológicas com três, cinco e sete dias após sua perfuração traumática. Foram analisadas as morfometrias das espessuras das camadas epitelial, fibrosa e mucosa; tamanho da perfuração; área de secção transversal da MT; avaliação semiquantitativa e qualitativa da produção de colágeno por microscopia de polarização; e avaliação imuno-histoquímica das células epiteliais, dos miofibroblastos e da vascularização. Resultados: A insulina e a biomembrana de látex anteciparam o fechamento das perfurações traumáticas de MTs (p<0,01); estimularam precocemente o aumento da espessura da camada epitelial externa (p<0,01); promoveram aumento precoce da espessura da camada fibrosa (p<0,01); contribuíram para a maior identificação do anticorpo anti-panqueratina como marcador epitelial (p<0,05); aumentaram a marcação do anticorpo anti-alfa-actina de músculo liso (p<0,05), caracterizando maior proliferação de miofibroblastos. A insulina, isoladamente, provocou maior formação do colágeno tecidual (p<0,05), com fibras colágenas mais espessas e melhor organizadas (p<0,05). Conclusão: A insulina e a biomembrana de látex natural, de forma isolada e em associação, aceleraram o processo de cicatrização de perfurações traumáticas de MTs. / In recent years, there has been a tendency to search for regulatory substances that can optimize the healing process of perforated tympanic membranes (TMs). Objectives: To determine the effects of using topical insulin and natural latex biomembrane, alone or in combination, in the healing process of traumatic perforations of TMs. Methods: TMs of 61 Wistar rats were perforated in two sections, anterior and posterior to the malleus. The rats were divided into 4 groups: Control, Insulin, Latex, and Insulin+Latex. The Insulin group was treated with topical regular insulin. The Latex group was treated with natural latex biomembrane. The Insulin+Latex group was treated with a combination of insulin plus latex biomembrane. The TMs were histologically examined 3, 5, and 7 days post-perforation through morphometric analysis of the thickness of the epithelial, fibrous, and mucosal layers; size of the perforation; cross sectional area of the TM; semiquantitative and qualitative evaluation of the collagen production by polarization microscopy, and immunohistochemical evaluation of epithelial cells, myofibroblasts, and vascularization markers. Results: Insulin and latex biomembrane accelerated the healing process of the perforated TMs (p<0.01); stimulated early thickening of the outer epithelial layer (p<0.01); promoted premature increase in the thickness of the fibrous layer (p<0.01); contributed to a larger identification of anti-pankeratin antibody as epithelial marker (p<0.05); increased labeling of anti-alpha smooth muscle actin antibody (p<0.05), indicating greater proliferation of myofibroblasts. When insulin was used alone, it resulted in greater formation of collagen tissue (p<0.05), with thicker and better-organized collagen fibers (p<0.05). Conclusion: Insulin and natural latex biomembrane, used alone or in combination, accelerated the healing process of traumatic perforations of TMs.

The present study was undertaken to evaluate the rat as a model for middle ear re­search. The rat was chosen primarily because the gross structure of its middle ear shows several similarities to that of man. It was considered of great importance to make a thorough structural study of the rat middle ear and to compare the results with those reported for the human middle ear. The thesis therefore includes indepen­dent studies on various aspects of rat middle ear structure and function as well as a review of the literature. The most pertinent findings in the experimental part of this study were the following. The rat Eustachian tube consists of a nasopharyngeal, and a cartilaginous and bony portion. The orifice of the nasopharyngeal portion is composed of two soft tissue lips, which appear to be opened mainly by the action of the salpingopharyngeal mus­cle, but also by the levator and tensor veli palatini muscles. The cartilaginous por­tion appears to be opened solely by the tensor veli palatini muscle. The tensor tympani muscle seems to have no effect on the tube. A ciliated and secretory epithelium lines the inferomedial walls of the tube throughout its length. In the tympanic cavity these thelial cell types extend as two tracts - one anterior and the other inferoposterior to  the promontory - which communicate with the epitympanic/attic compartments. The remaining parts of the tube and the tympanic cavity are covered by a squamous/cuboidal, non-ciliated epithelium. The subepithelial loose connective tissue contains vessels, nerves, and connective tissue cells, among these mast cells. The mast cells are confined to areas covered by the ciliated epithelium, and in the floor of the bulla, in the pars flaccida, and along the manubrial vessels. Glands are restricted to the Eustachian tube. In the clearance/transport of serum-like material, from the epitympanum towards the tube, hydrostatic forces appear to be important. The tympanic membrane is vascularized from meatal and tympanal vessels. Meatal ves­sels branch in the pars flaccida and along the handle of the malleus, where they are localized directly beneath the outer, keratinizing, stratified, squamous epithelium. Furthermore, meatal vessels form a vascular network at the junction between the fi­brocartilaginous annulus and the tympanic sulcus. Tympanal vessels send branches to the periphery of the pars tensa, where they run immediately beneath the tympanal, simple, squamous epithelium. In the major portion of the pars tensa, no blood vessels were found. The rat stapedial artery is a thin-walled vessel with a wide lumen. Without branch­ing, it runs through the tympanic cavity to the extratympanal regions it supplies. In contrast to the corresponding artery in man, the rat stapedial artery persists throughout life. The artery does not seem to be affected by the fluid produced during experimentally induced otitis media with effusion. The middle ear structure in the rat and in man show both similarities and differ­ences. If the differences are kept in mind and considered, it would seem that the rat is indeed a suitable model for experimental middle ear research. / digitalisering@umu

Abstract Patients with orofacial clefts must overcome problems associated with their deformity including multiple surgeries, facial scarring, speech difficulties, dental problems and hearing loss. This study considered dental and hearing problems faced by cleft lip and palate patients in Northern Finland. The research aimed to determine prevalence of dental anomalies in cleft children, assess restorative treatment need and examine dental treatment necessary under general anesthesia. Other aims were to identify middle ear problems, need for ventilation tubes (VTs) among cleft children and examine the relationship between cleft severity, palatoplasty technique and hearing outcomes in cleft children aged between 3 and 9-years. The material comprised 214 cleft patients treated at Oulu University Hospital. In the dental study 26.6% had at least one dental anomaly while 17.9% had 2 or 3, most commonly missing or supernumerary teeth. In the general anesthesia study 11.5% had a syndrome and 52.4% of those with a syndrome aged 6-years-old needed restorative treatment. General anesthesia was required for dental treatment in 17.5% of cleft patients, mostly in those with a syndrome. In the middle ear study 79% had secretions in the middle ear during the study period. On average 3 VTs were placed in each patient. The prevalence of tympanic perforation was 35.9% and cholesteatoma occurred in 3.3%. In the hearing study pure tone average did not significantly differ between right and left ears and was unrelated to cleft severity or palatoplasty technique. Based on the dental study the severity of clefting increased with the prevalence of dental anomalies. The general anesthesia study found that need for restorations increased with cleft severity. The presence of a syndrome increased the need for dental treatment under general anesthesia. The middle ear study found that patients with cleft lip and palate and isolated cleft palate had more extensive clefts affecting Eustachian tube function with more frequent middle ear problems requiring more VTs than isolated cleft lip patients. Continuous presence of VTs increased the prevalence of tympanic perforation and cholesteatoma. The hearing study concluded that most of the 3 to 9 year-old cleft patients had normal hearing thresholds unaffected by cleft severity or palatoplasty technique. / Tiivistelmä Huuli- ja suulakihalkioihin liittyy monia haasteita kuten useita leikkauksia, näkyviä arpia, puheongelmia, hampaiston ongelmia ja kuulonalenemaa. Tässä tutkimuksessa perehdyttiin halkiolasten hampaiden ja kuulon ongelmiin Pohjois-Suomessa. Tutkimus selvitti halkiopotilaiden hampaiden anomalioiden esiintyvyyttä, hampaiden korjaavan hoidon tarvetta sekä hampaiden hoidon tarvetta yleisanestesiassa. Lisäksi selvitettiin välikorvaongelmia, ilmastointiputkien tarvetta sekä kuulontutkimustulosten yhteyttä halkion vakavuuden ja suulaen leikkaustekniikan välillä 3-9-vuotiailla halkiolapsilla. Aineisto koostui 214 halkiopotilaasta jotka hoidettiin Oulun yliopistollisessa sairaalassa. Potilaista 26,6%:lla oli vähintään yksi ja 17,9%:lla kaksi tai kolme hammasanomaliaa. Yleisin anomalia oli puuttuvat tai ylilukuiset hampaat. Yleisanestesiassa hoidetuista potilaista 11,5%:lla oli syndrooma eli oireyhtymä, kaikkiaan yleisanestesiaa tarvitsi 17,5%. 6-vuotiaista syndroomapotilaista 52,4% tarvitsi hampaiden korjaavaa hoitoa. Korvien tutkimuksessa 79%:lla potilaista oli eritettä välikorvissa tutkimusjakson aikana. Jokaiselle potilaalle laitettiin ilmastointiputket keskimäärin 3 kertaa. Tärykalvon perforaatio havaittiin 35,9%:lla ja kolesteatooma todettiin 3,3%:lla. Oikean ja vasemman korvan välillä ei ollut merkittävää eroa kuulontutkimustuloksissa eikä niillä havaittu yhteyttä halkion vakavuuden tai suulaen leikkaustekniikan kanssa. Halkion vakavuus lisäsi hammasanomalioiden esiintyvyyttä sekä korjaavan hoidon tarvetta yleisanestesiassa. Syndrooma lisäsi myös korjaavan hoidon tarvetta yleisanestesiassa. Huuli- ja suulakihalkiopotilailla sekä suulakihalkiopotilailla laaja halkio vaikutti voimakkaasti korvatorven toimintaan ja näin ollen se lisäsi putkituksia vaativia korvaongelmia toisin kuin huulihalkiopotilailla joilla suulaki oli ehjä. Jatkuva ilmastointiputkien läsnäolo lisäsi tärykalvon perforaatioita ja kolesteatoomia. Kuitenkin enemmistöllä 3-9-vuotiaista halkiopotilaista kuulotutkimustulokset olivat normaalit.

Although the Vibrant Soundbridge is one of the most frequently used active middle ear implants, data regarding how middle ear ventilation disorders may affect the transmission behavior of its floating mass transducer are still insufficient. Studies involving coupling the floating mass transducer to the stapes head are particularly lacking. This temporal bone study evaluated the influence of simulated middle ear ventilation disorders on the middle ear transfer function in the reconstructed middle ear. The middle ear transfer function was measured using Laser Doppler Vibrometry after vibroplasty onto the stapes head, with or without tympanic membrane reconstruction. Middle ear ventilation disorders were simulated through changes in static pressure via the external ear channel with a maximum pressure of þ3 kPa. Slice thickness of tympanic membrane reconstruction material was measured using micro-CT. When the reconstructed ossicular chain and the reconstructed tympanic membrane were mechanically excited by the floating mass transducer under conditions of ambient static pressure, the transmission behavior was found to be independent of the type of tissue used. Increase in static pressure up to þ3 kPa caused maximum low frequency transmission loss of 15 dB when elastic grafts were used and 5 dB when stiff tissue was inserted. At high frequencies, measured loss of up to 5 dB was relatively independent of the tissue stiffness. Increase in static pressure led to displacement of the tissues towards the vestibulum and caused stiffening, especially of the annular ligament. Stiffening-induced transmission losses were mainly found at low frequencies and could not be compensated by the floating mass transducer in this range. Above 1300 Hz, the continuous force spectrum of the actuator sufficiently protected against loss of amplitude. To minimize postoperative transmission loss due to persisting ventilation disorders, choosing a very stiff tympanic membrane reconstruction material seems to be appropriate.:Inhaltsverzeichnis Abkürzungsverzeichnis V 1 Einleitung 1 1.1 Einführung 1 1.2 Operationen zur Hörverbesserung 2 1.3 Mittelohrimplantate 6 1.4 Belüftungsstörungen des Mittelohres 12 1.5 Fragestellungen, Forschungshypothesen und Zielstellung der Arbeit 18 2 Material und Methoden 20 2.1 Laserdopplervibrometrische Messungen am Felsenbeinpräparat 20 2.2 Untersuchung der Trommelfellersatzmaterialien mittels optischer Messverfahren 3 Ergebnisse 42 3.1 Ermittelung der Trommelfellersatzmaterialdicken und -steifigkeiten mittels optischer Messverfahren 42 3.2 Messung der Mittelohrübertragungsfunktion am Felsenbeinpräparat 62 4 Diskussion 104 4.1 Bestimmung der Trommelfellersatzmaterialdicken und -steifigkeiten mittels optischer Messverfahren 104 4.2 Messung der Mittelohrübertragungsfunktion am Felsenbeinpräparat 110 4.3 Ausblick und Konsequenzen der Untersuchungen zur Paukenminderbelüftung auf die Vibroplastik und die Tympanoplastik Typ III 131 4.4 Funktionelles Hörergebnis nach Implantation einer VSB beim Vorliegen einer Schallleitungsschwerhörigkeit oder kombinierten Schwerhörigkeit 133 4.5 Schlussfolgerung 134

In order to get a better insight into the function of the human middle ear it is necessary to simulate its dynamic behaviour by means of the finite-element method. Three-dimensional measurements of the surfaces of the tympanic membrane and of the auditory ossicles malleus, incus and stapes are carried out and geometrical models are created. On the basis of these data, finite-element models are constructed and the dynamic behaviour of the combinations tympanic membrane with malleus in its elastic suspensions and stapes with annular ligament is simulated. Natural frequencies and mode shapes are computed by modal analysis. These investigations showed that the ossicles can be treated as rigid bodies only in a restricted frequency range from 0 to 3.5 kHz. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Recently, optical coherence tomography (OCT) was utilized in multiple studies for structural and functional imaging of the middle ear and the tympanic membrane. Since Doppler OCT allows both, the spatially resolved measurement of the tympanic membrane oscillation and high-resolution imaging, it is regarded as a promising tool for future in vivo applications. In this study, Doppler OCT is utilized for the visualization of the tympanic membrane oscillation in temporal bones with simulated Eustachian catarrh, which was realized by generating a depression in the tympanic cavity. The transfer function, meaning the oscillation amplitude normalized to the applied sound pressure, is measured frequency resolved in the range from 0.5 kHz to 6 kHz and with a lateral spatial resolution of 0.4 mm. Typical oscillation patterns could be observed in case of ambient pressure in the tympanic cavity. Under depression the characteristic oscillation patterns were observed with widely congruent appearance but at higher frequencies.

Objectifs Aucun agent n’a été approuvé pour prévenir l’ototoxicité secondaire au cisplatin. Nos objectifs consistaient à évaluer la protection auditive offerte par le lactate et le N-acétylcystéine (NAC) intra-tympaniques après injection de cisplatin, ainsi que l’absorption systémique du NAC intra-tympanique. Méthodes Seize cochons d’inde formaient 2 groupes ayant reçu une solution de lactate et de NAC à 20% dans l’oreille testée. L’oreille contro-latérale a reçu une solution saline contrôle. Après 30 minutes, une injection intrapéritonéale de 3 mg/kg de cisplatin a été effectuée et répétée une fois par semaine jusqu’à une dose finale de 24 mg/kg. Les potentiels évoqués auditifs du tronc cérébral (PEATC) ont été mesurés avant les injections, après 9 mg/kg et 24 mg/kg de cisplatin. Les cochlées ont été analysées au microscope électronique à balayage. La diffusion systémique du NAC a été évaluée par chromatographie en phase liquide. Résultats Pour les oreilles contrôles, les seuils auditifs des PEATC ont augmenté uniformément sur toutes les fréquences (28,4 dB en moyenne). Le groupe lactate montrait une augmentation moins importante (17,0 dB). Les basses fréquences étaient nettement moins affectées. Le groupe NAC a subi une augmentation des seuils de 89 dB. La microscopie électronique a démontré une préservation partielle des cellules ciliées externes des cochlées traitées au lactate et une destruction complète de celles traitées au NAC. La chromatographie n’a démontré aucune diffusion de NAC. Conclusions Le lactate offre une protection partielle significative contre l’ototoxicité induite par le cisplatin. Les injections de NAC n’offrent pas de protection lorsque administrées en concentrations élevée. Le NAC intra-tympanique ne se diffuse pas systémiquement. / Objectives There is no approved agent to prevent cisplatin-induced ototoxicity. Our objectives are to identify and compare the protective effect of intratympanic injections of lactate or N-acetylcysteine (NAC) in the prevention of cisplatin-induced ototoxicity and to study systemic diffusion of intratympanic NAC. Methods Sixteen guinea pigs, forming two groups, received respectively intratympanic lactate and 20% NAC in one ear. The contra-lateral ears received a control saline solution. After 30 minutes, an intra-peritoneal cisplatin injection of 3 mg/kg was performed and repeated once a week to achieve a final dose of 24mg/kg. Auditory brainstem responses (ABR) were recorded before any injection, after 9mg/kg and after 24mg/kg of cisplatin for the frequencies 2, 4, 6 and 8kHz. Cochleas were analyzed under scanning electron microscope. Systemic diffusion of NAC was studied using high performance liquid chromatography. Results For the control ears, ABR thresholds increased uniformly by an average of 28.4dB. The lactate group showed a lower threshold increase by an average of 17.0dB. The NAC showed an important threshold increase of 89.0dB. Lactate showed a significant hearing protection at 2000Hz (p<0.01). Electron microscopy revealed partial preservation of cochlear outer hair cells stereocilia for the ears treated with lactate and severe disruption for NAC group. No systemic diffusion of NAC was observed with chromatography. Conclusion Lactate offers significant partial protection against cisplatin-induced ototoxicity. NAC does not offer any protection when administered in high concentrations. Intratympanic NAC does not diffuse systemically.

Objectifs Aucun agent n’a été approuvé pour prévenir l’ototoxicité secondaire au cisplatin. Nos objectifs consistaient à évaluer la protection auditive offerte par le lactate et le N-acétylcystéine (NAC) intra-tympaniques après injection de cisplatin, ainsi que l’absorption systémique du NAC intra-tympanique. Méthodes Seize cochons d’inde formaient 2 groupes ayant reçu une solution de lactate et de NAC à 20% dans l’oreille testée. L’oreille contro-latérale a reçu une solution saline contrôle. Après 30 minutes, une injection intrapéritonéale de 3 mg/kg de cisplatin a été effectuée et répétée une fois par semaine jusqu’à une dose finale de 24 mg/kg. Les potentiels évoqués auditifs du tronc cérébral (PEATC) ont été mesurés avant les injections, après 9 mg/kg et 24 mg/kg de cisplatin. Les cochlées ont été analysées au microscope électronique à balayage. La diffusion systémique du NAC a été évaluée par chromatographie en phase liquide. Résultats Pour les oreilles contrôles, les seuils auditifs des PEATC ont augmenté uniformément sur toutes les fréquences (28,4 dB en moyenne). Le groupe lactate montrait une augmentation moins importante (17,0 dB). Les basses fréquences étaient nettement moins affectées. Le groupe NAC a subi une augmentation des seuils de 89 dB. La microscopie électronique a démontré une préservation partielle des cellules ciliées externes des cochlées traitées au lactate et une destruction complète de celles traitées au NAC. La chromatographie n’a démontré aucune diffusion de NAC. Conclusions Le lactate offre une protection partielle significative contre l’ototoxicité induite par le cisplatin. Les injections de NAC n’offrent pas de protection lorsque administrées en concentrations élevée. Le NAC intra-tympanique ne se diffuse pas systémiquement. / Objectives There is no approved agent to prevent cisplatin-induced ototoxicity. Our objectives are to identify and compare the protective effect of intratympanic injections of lactate or N-acetylcysteine (NAC) in the prevention of cisplatin-induced ototoxicity and to study systemic diffusion of intratympanic NAC. Methods Sixteen guinea pigs, forming two groups, received respectively intratympanic lactate and 20% NAC in one ear. The contra-lateral ears received a control saline solution. After 30 minutes, an intra-peritoneal cisplatin injection of 3 mg/kg was performed and repeated once a week to achieve a final dose of 24mg/kg. Auditory brainstem responses (ABR) were recorded before any injection, after 9mg/kg and after 24mg/kg of cisplatin for the frequencies 2, 4, 6 and 8kHz. Cochleas were analyzed under scanning electron microscope. Systemic diffusion of NAC was studied using high performance liquid chromatography. Results For the control ears, ABR thresholds increased uniformly by an average of 28.4dB. The lactate group showed a lower threshold increase by an average of 17.0dB. The NAC showed an important threshold increase of 89.0dB. Lactate showed a significant hearing protection at 2000Hz (p<0.01). Electron microscopy revealed partial preservation of cochlear outer hair cells stereocilia for the ears treated with lactate and severe disruption for NAC group. No systemic diffusion of NAC was observed with chromatography. Conclusion Lactate offers significant partial protection against cisplatin-induced ototoxicity. NAC does not offer any protection when administered in high concentrations. Intratympanic NAC does not diffuse systemically.

The presented thesis concerns the biomechanics of hearing. The main aim of this work is the determination of so called corrections which allow for the comparison of synthetic audiograms and measured audiograms. With these corrections we attempt to overcome the discrepancy that exists between the computational modelling and audiological measurement. The discrepancy lies in a fact that the computational modelling usually simulates the sound coming from a free eld to the external auditory canal, while audiological measurement is realized by audiological headphones, whether the auditory system is healthy or injured. Then corrections adjust the computational model so that the obtained result is comparable to audiological measurement. In this work is also addressed the influence of stapes kinematics to the excitation of basilar membrane. The movement of stapes consists of piston-like movement and rocking movement. The computational simulation shows which movement is more signicant for the excitation of basilar membrane and how this effect can be used in otosurgery, in particular, for type IV of tympanoplasty.

This paper presents a method of parameter identification for a finite-element model of the human middle ear. The parameter values are estimated using a characterization of the difference in natural frequencies and mode shapes of the tympanic membrane between the model and the specimens. Experimental results were obtained from temporal bone specimens under sound excitation (300–3,000 Hz). The first 3 modes of the tympanic membrane could be observed with a laser scanning vibrometer and were used to estimate the stiffness parameters for the orthotropic finite-element model of the eardrum. A further point of discussion is the parameter sensitivity and its implication for the identification process. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.