Anatomy and Physiology of the Ear

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Diseases of the inner ear

Current strategies to treat inner ear diseases aim at the treatment of Noise Induced and Sudden Sensorineural Hearing Loss (NIHL and SSHL respectively), of Autoimmune Inner Ear Disease (AIED), Tinnitus or Meniere’s Disease and the protection of the inner ear, e.g., during aminoglycoside or anti-cancer therapy. In this introduction a major focus will be on Hearing Loss. Additionally, a short overview on other illnesses will be given here.
Autoimmune Inner Ear Disease causes bilateral, generally asymmetric, progressive or fluctuating hearing loss that is often combined with a systemic autoimmune disease of the patient as well as vestibular symptoms and responds to immunosuppressive therapy (42,43). Researchers assume that the etiology of the disease includes inflammation, vascular and cochlear tissue damage (e.g., Stria vascularis, Spiral ganglion, Organ of Corti) due to a disproportionate Th1 immune response (42). Therapy includes systemic and intratympanic administration of corticosteroids for a prolonged period. Sometimes other immunosuppressive agents like methotrexate or cyclophosphamide seem to be beneficial for the patient by reducing the dose of steroids. Recent research focuses on fusion proteins and monoclonal antibodies to block the inflammatory reaction. A second promising approach might be the application of stem cell and gene therapy to repair damaged inner ear tissues (43).
Tinnitus is defined as the perception of sound without an external acoustic stimulation (44,45). The cause of the disease is unclear, researchers discuss not only a peripheral but also a central neural origin (46). This disease can occur following to excessive noise exposure or during the normal process of aging and can be associated with additional symptoms like hearing loss, sleep disturbance, hearing loss, anxiety and depression (45). Therapy aims at interrupting or masking the “phantom” sound via sound therapy (47) but also includes an appropriate treatment of the additional symptoms. This treatment might involve supply with hearing aids, education, psychological support, relaxation and cognitive behavioral therapy for the patient (44,45). Research on drugs that might be promising for the treatment of Tinnitus focuses on corticosteroids, e.g., dexamethasone, local anesthetics, e.g., lidocaine, and n-Methyl-d-aspartate receptor antagonists (18).
Patients suffering from Meniere’s disease report intermittently occurring episodes of vertigo, often associated with hearing loss, tinnitus or an aural pressure (48). This illness has an enormous impact on patient’s lives and researchers still discuss about its origin. Autoimmune reactions or viral infections might cause endolymphatic hydrops as well as fibrosis and tissue degeneration leading to the major symptoms of Meniere’s disease (48). The treatment with intratympanic Aminoglycoside antibiotics, e.g., gentamicin, seems to reduce vertigo but increases the risk to suffer from hearing loss (49). Also transtympanic injection of steroids seems to have a beneficial effect on vertigo attacks but further studies should be performed to proof those promising results (50).
Otoprotective actions should be taken to prevent hearing loss due to Cisplatin or Aminoglycoside related toxicity. Both groups of drugs cause similar damage to the inner ear hair cells. Mainly outer hair cells inside the cochlea are degraded, while the damage is increasing from the apex to the base of the cochlea (51). Therefore, an increasing hearing impairment at the correspondent frequencies can be observed. Hearing Loss due to Cisplatin administration during anti-cancer therapy is not only age- (very young and the elder patients are more affected) but also dose-dependent (25): Administration of the ototoxic drug via an osmotic pump with concentrations from 0 to 300 µg/mL respectively resulted in greater and faster hearing loss when a higher concentration is administered (52). Spiral ganglion cells can also be affected. Additionally to this hearing loss, during aminoglycoside administration vestibular toxicity can be observed. The mechanism behind seems to be an excessive level of reactive oxygen species damaging especially outer hair cells (25). Local administration of antioxidants seems to be promising but systemically administered methionine or sodium thiosulfate decreases the effectiveness of the cisplatin therapy (25). Furthermore, the use of cytoprotective agents, e.g., amifostine, has not been proven to prevent hearing loss due to cisplatin therapy in children (53). During aminoglycoside therapy, otoprotection can be achieved by the administration of antioxidants as well as steroids (25).
Hearing loss can be related to all of the inner ear illnesses described above and, thus, will be discussed in detail in the following chapter.

Hearing Loss

Especially when it occurs suddenly, hearing loss is a frightening disorder for the patient.
In addition to the hearing loss patients may report tinnitus (“ringing” of the ears), dizziness or fullness of the ear (54).
According to the World Health Organization there are five grades of hearing impairment (Table 1.2.): no, slight, moderate, severe and profound impairment (Grades 0 to 4 respectively). Following this classification, disabling hearing impairment occurs when the patient has at least a hearing loss of Grade 2. This moderate impairment with a loss of 41 dB or more on the better hearing ear means that words can still be understood and repeated at 1 m distance with a raised voice (55).
The causes of hearing loss are various. In general, they can be classified as congenital or acquired (1). Congenital hearing loss refers to causes occurring during or shortly after birth, e.g., rubella, toxoplasmosis or other infections of the mother as well as treatment with inappropriate drugs during pregnancy, asphyxia and low weight of the newborn (56). Importantly, genetic factors also play a major role in 25 % of the cases, over 400 gene related syndromes have been identified (4,56). Unfortunately, in 57 % of the cases the cause of congenital hearing loss still remains unknown (4). Acquired hearing loss refers to cases occurring at every age of the patient and can develop suddenly or over a long period. Hearing loss can develop due to infections, e.g. meningitis, measles, mumps or otitis media, as well as traumata of the head or the ear following an accident or surgery (1,55,57). Other causes can be autoimmune diseases, e.g. systemic lupus erythematosus, tumor growth and treatment, neurologic diseases, e.g. Multiple sclerosis, or vascular events (58–61). Additionally, certain drugs can have a toxic effect on the ear, e.g. aminoglycoside antibiotics as well as several chemotherapeutic agents and anti-malaria drugs (51,62,63). Importantly, also acute or long term noise exposure can cause noise-induced hearing loss (NIHL), e.g. recreational noise during a sport event or from a MP3-Player and noise from machines or explosions. Also, a certain degree of hearing loss is age-related (64) and can be considered as a normal process: It was estimated that 30 % of the men and 20 % of the women over 70 suffer from hearing loss (threshold shift of at least 30 dB) in Europe (65). Frequently, patients are also diagnosed with hearing loss due to excessive ear wax stuck in the ear canal (66). Nevertheless, only in 7 to 45 % of patients with Sudden Sensorineural Hearing Loss (SSNHL with a threshold shift of at least 30 dB over three continuous frequencies during 72 h) the cause can be identified, a major part of cases remains idiopathic (57).
Depending on the region, there are several types of hearing loss (Table 1.3.) (15). Conductive loss occurs when the stiffness of the outer or middle ear is changed, e.g. when the ear canal is stuck with ear wax or in case that the ossicular chain is damaged because of otosclerosis (67). Sensorineural hearing loss (SNHL) occurs when the cochlea or the nerve is damaged, e.g. this is the case when hair cells of the organ of Corti are damaged due to gentamicin administration (37). A combination of conductive and sensorineural is a so called mixed hearing loss. When the auditory system is damaged in higher regions than the auditory nerve a central hearing loss occurs. Nevertheless, the cause of hearing loss is unknown in most of the cases and therapy still remains challenging. Ongoing research on different strategies to treat hearing loss is discussed in the following chapter.

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Drug delivery to the inner ear

Current strategies used in clinic focus mainly at treating Sudden Sensorineural Hearing Loss and autoimmune diseases as well as at a protection of the inner ear (25). Besides the strategy of providing the patient with appropriate medical devices, e.g., hearing aids or cochlear implants to cure persistent hearing loss, different drug delivery tools are a major topic in research.
Since the rate of spontaneous recovery from Sudden Sensorineural Hearing Loss is relatively high (32 to 65 %) and the etiology of Hearing Loss is not fully understood yet, clinicians discuss about the appropriate treatment of hearing loss. Nevertheless, in case that the cause is known, the patient should be treated accordingly (57,66). In the case of Idiopathic Hearing Loss, current therapeutic strategies often include systemic or local administration of steroids but also antivirals, diuretics, vasodilators, antioxidants, hyperbaric oxygen treatment, middle ear surgery and bedrest are used to treat hearing loss (57,66).
Systemic drug delivery (described in section 1.3.1.) is still used to treat inner ear diseases but is progressively replaced by local drug delivery (described in section 1.3.2.) to avoid adverse events caused by high systemic blood concentrations of the drug.

Systemic drug delivery

Unfortunately, the systemic administration of both, steroids, optionally combined with antivirals, and vasodilators did not show a significant improvement in Cochrane Reviews (54,68,69). This may be partially due to insufficient patient numbers and inconsistent inclusion criteria or study designs. However, oral steroids may be useful in the treatment of sudden sensorineural hearing loss but their influence on hearing recovery remains uncertain. Only one of three studies included in the Cochrane Review showed a significant effect of oral steroids on hearing recovery with a hearing improvement of 61 % compared to 32 % in the placebo/untreated group (70). In two other studies no improvement of hearing loss can be seen when oral steroids are administered (71,72).
The systemic administration of antivirals to treat idiopathic sudden sensorineural hearing loss neither shows improvement: Two studies included in a Cochrane review showed no improvement when aciclovir was administered additionally to prednisolone (73,74). Accordingly, patients treated with valaciclovir in addition to prednisone, or aciclovir administered additionally to hydrocortisone, showed no hearing improvement (75,76). Nevertheless, animal studies support the assumption that an early treatment of patients with antivirals could be beneficial. Unfortunately, in clinical practice most patients present very late so the impact of the treatment with antivirals may be difficult to prove (54).
The administration of vasodilators or vasoactive substances could be beneficial for the treatment of hearing loss but due to the small number of patients included in the studies the benefit remains unproven (68). A significant hearing improvement has been reported for patients receiving carbogen additionally to several other drugs compared to no inhalation of carbogen (77). In a study where patients received Prostglandin E1 additionally to hydrocortisone only the hearing in higher frequencies was improved (78). The hearing in lower frequencies was improved by the administration of low molecular weight Dextran with additional Naftidrofuryl (79). Those results are promising clinicians should be aware of potential side effects of drugs whose benefit for the patient is not yet approved in clinical practice (66).
In addition to the unknown cause of the disease in most of the cases, during systemic administration of drugs side effects are more likely to occur. The patient often needs an elevated dose to enhance absorption of the drug into the inner ear to reach therapeutic drug concentrations. This is due to the barriers protecting the highly sensitive inner ear as described before (chapter 1.1.1. Barriers of the Inner Ear). Additionally, the small volume of the inner ear fluids and its complicated anatomical access make local drug delivery very difficult.
Nevertheless, local drug delivery seems to be a promising approach to limit adverse events during the treatment of hearing loss and will be discussed in the following chapter.

Table of contents :

1. Introduction
1.1. Anatomy and Physiology of the Ear
1.1.1. Barriers of the Inner Ear
1.1.2. Auditory perception
1.1.3. Sense of balance
1.2. Diseases of the Inner Ear
1.2.1. Hearing Loss
1.3. Drug delivery to the Inner Ear
1.3.1. Systemic drug delivery
1.3.2. Local drug delivery
1.3.2.1. Intratympanic drug delivery
1.3.2.2. Intracochlear drug delivery
1.4. Drug release from silicone matrices
1.5. Objectives
2. Materials and Methods
2.1. Dexamethasone mobility in thin films
2.1.1. Materials
2.1.2. Preparation of drug loaded films
2.1.3. Preparation of drug loaded extrudates
2.1.4. Drug release measurements
2.1.5. Scanning electron microscopy
2.2. Ear Cube implants for Controlled Drug Delivery to the Inner Ear
2.2.1. Materials
2.2.2. Preparation of drug-loaded silicone matrices
2.2.3. Drug release measurements
2.2.4. Side-by-side diffusion cells
2.2.5. Swelling kinetics of Ear Cubes
2.2.6. Scanning electron microscopy
2.2.7. Thermal analysis (DSC)
2.2.8. X-ray diffraction
2.3. Trans-Oval-Window Implants: Extended Dexamethasone Release
2.3.1. Materials
2.3.2. Preparation of drug-loaded Matrices
2.3.3. Drug Release Measurements
2.3.4. Gerbil Study
2.3.5. Implantation Procedure
2.3.6. Cochleae Preparation for Further Analysis
2.3.7. Immunohistochemistry
3. Results and Discussion
3.1. Dexamethasone mobility in thin films
3.1.1. Effects of PEG addition
3.1.2. Effects of the type of silicone
3.1.3. Impact of the initial drug loading
3.1.4. Theoretical predictions for cylindrical extrudates
3.2. Ear Cube implants for Controlled Drug Delivery to the Inner Ear
3.2.1. Physico-chemical key properties of the Ear Cubes
3.2.2. Characterization of thin films of identical composition
3.2.3. Drug release from Ear Cubes
3.2.4. Absence of Ear Cube swelling
3.3. Trans-Oval-Window Implants: Extended Dexamethasone Release
3.3.1. Results
3.3.1.1. In vitro studies
3.3.1.2. In vivo studies
3.3.2. Discussion
4. Conclusion
References
Résumé
List of Publications
Curriculum Vitae

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