Optimization of pharmacological interventions in the guinea pig animal model-a new approach to calculate the perilymph volume of the scala tympani.

Objective: The guinea pig serves as a well-established animal model for inner ear research, offering valuable insights into the anatomy, physiology, and therapeutic interventions of the auditory system. However, the heterogeneity of results observed in both in-vivo experiments and clinical studies poses challenges in understanding and optimizing pharmacotherapy outcomes. This heterogeneity may be due to individual differences in the size of the guinea pig cochlea and thus in the volume of the scala tympani (ST), which can lead to different drug concentrations in the ST, a fact that has been largely overlooked thus far. To address this issue, we aimed to develop an approach for calculating the individual volume of perilymph within the ST before and after cochlear implant insertion. Method: In this study, high-resolution µCT images of a total of n = 42 guinea pig temporal bones were used to determine the volume of the ST. We compared fresh, frozen, and fixed tissues from both colored and albino strains to evaluate the potential influence of tissue condition and strain on the results. Results: Our findings demonstrate a variability in mean ST volume with a relative standard deviation (RSD) of 14.7%, comparable to studies conducted with humans (range RSD: 5 to 20%). This indicates that the guinea pig cochlea exhibits similar variability to that of the human cochlea. Consequently, it is crucial to consider this variability when designing and conducting studies utilizing the guinea pig as an animal model. Furthermore, we successfully developed a tool capable of estimating ST volume without the need for manual segmentation, employing two geometric parameters, basal diameter (A) and width (B) of the cochlea, corresponding to the cochlear footprint. The tool is available for free download and use on our website. Conclusion: This novel approach provides researchers with a valuable tool to calculate individual ST volume in guinea pigs, enabling more precise dosing strategies and optimization of drug concentrations for pharmacotherapy studies. Moreover, our study underscores the importance of acknowledging and accounting for inter-individual variability in animal models to enhance the translational relevance and applicability of research outcomes in the field of inner ear investigations.

Local Long-Term Inner Ear Drug Delivery in Normal Hearing Guinea Pig-An Animal Model to Develop Preventive Treatment for Noise-Induced Hearing Loss.

Noise-induced hearing loss (NIHL) is one of the leading causes of sensorineural hearing loss with global importance. The current treatment of choice for patients with hearing problems is a hearing aid or a cochlear implant. However, there is currently no treatment to restore physiological hearing. The development of preventive drugs is currently the focus of hearing research. In order to test the efficacy of a drug, the active ingredient has to be applied at reliable concentrations over a period of time. Osmotic minipumps can provide local drug delivery into the perilymph. Combined with a cochlear implant or a tube, the implantation of the pumps may lead to increased hearing thresholds. Such surgery-related threshold shifts complicate the examination of other factors, such as noise. The aim of the present study was to develop an animal model for the examination of substances that potentially prevent NIHL. For this purpose, six male guinea pigs were unilaterally implanted with a silicon catheter with a hook-shaped microcannula at its tip, attached to an artificial perilymph containing osmotic minipump. One week after surgery, the animals were exposed to four hours of a musical piece, presented at 120 dB SPL, to induce a threshold shift. The implantation of the hook-delivery device caused a moderate threshold shift that allows to detect an additional noise-induced temporary threshold shift. This method enables to investigate drug effects delivered prior to the noise insult in order to establish a preventive strategy against noise-induced temporary threshold shifts. The established drug delivery approach allows the release of drugs into the inner ear in a known concentration and for a known duration. This provides a scientific tool for basic research on drug effects in normal hearing animals.

Prevention of Noise-Induced Hearing Loss In Vivo: Continuous Application of Insulin-like Growth Factor 1 and Its Effect on Inner Ear Synapses, Auditory Function and Perilymph Proteins.

As noise-induced hearing loss (NIHL) is a leading cause of occupational diseases, there is an urgent need for the development of preventive and therapeutic interventions. To avoid user-compliance-based problems occurring with conventional protection devices, the pharmacological prevention is currently in the focus of hearing research. Noise exposure leads to an increase in reactive oxygen species (ROS) in the cochlea. This way antioxidant agents are a promising option for pharmacological interventions. Previous animal studies reported preventive as well as therapeutic effects of Insulin-like growth factor 1 (IGF-1) in the context of NIHL. Unfortunately, in patients the time point of the noise trauma cannot always be predicted, and additive effects may occur. Therefore, continuous prevention seems to be beneficial. The present study aimed to investigate the preventive potential of continuous administration of low concentrations of IGF-1 to the inner ear in an animal model of NIHL. Guinea pigs were unilaterally implanted with an osmotic minipump. One week after surgery they received noise trauma, inducing a temporary threshold shift. Continuous IGF-1 delivery lasted for seven more days. It did not lead to significantly improved hearing thresholds compared to control animals. Quite the contrary, there is a hint for a higher noise susceptibility. Nevertheless, changes in the perilymph proteome indicate a reduced damage and better repair mechanisms through the IGF-1 treatment. Thus, future studies should investigate delivery methods enabling continuous prevention but reducing the risk of an overdosage.

In Situ 3D-Imaging of the Inner Ear Synapses with a Cochlear Implant.

In recent years sensorineural hearing loss was found to affect not exclusively, nor at first, the sensory cells of the inner ear. The sensory cells' synapses and subsequent neurites are initially damaged. Auditory synaptopathies also play an important role in cochlear implant (CI) care, as they can lead to a loss of physiological hearing in patients with residual hearing. These auditory synaptopathies and in general the cascades of hearing pathologies have been in the focus of research in recent years with the aim to develop more targeted and individually tailored therapeutics. In the current study, a method to examine implanted inner ears of guinea pigs was developed to examine the synapse level. For this purpose, the cochlea is made transparent and scanned with the implant in situ using confocal laser scanning microscopy. Three different preparation methods were compared to enable both an overview image of the cochlea for assessing the CI position and images of the synapses on the same specimen. The best results were achieved by dissection of the bony capsule of the cochlea.