Preclinical study to develop fully resorbable PLGA-based intracochlear drug delivery systems

• Applicant: Dr. Arne Liebau
• Subject Area: Otolaryngology, Phoniatrics and Audiology ; Pharmacy
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 531510367

In this project, a new possibility of intracochlear drug delivery to carry out a CI electrode carrier-independent, local drug therapy (avoiding inflammatory processes that occur as a result of the insertion trauma) is to be investigated. The pharmacokinetics of biodegradable drug delivery systems with dexamethasone will be determined under in vivo conditions in animal experiments with guinea pigs. The pharmacokinetics and the distribution of the drug within the scales are reconstructed by measuring the dexamethasone concentration in the perilymph at various time points. In all animals, the drug concentration in the serum should also be determined to give information about the systemic drug concentration. In addition to dexamethasone, drug delivery systems with the more hydrophilic drug triamcinolone are also to be examined. The distribution of triamcinolone in the perilymph is then measured at different time points and compared with the distribution of dexamethasone. In addition to the release kinetics under in vivo conditions, the biocompatibility of the drug delivery system is to be tested. A potential damage caused by the carrier material of the depots and its degradation products on the inner ear should be excluded. A possible damage potential is assessed by means of histological changes in the cochlea and a change in the brainstem potential as well as otoacoustic emissions. Frequency-specific hearing thresholds over the hearing range of the guinea pig as well as the amplitude and latency of wave I are measured. For the histological assessment, the cochlea is examined for fibrosis and ossification. In addition, the spiral ganglion cell density is determined, as well as the amount of hair cells are counted and the dendrite and synapse density on the hair cells is evaluated. The pH value in the perilymph is measured using the fluorescence-based pH indicator SNARFTM-1 in order to observe a possible change in the pH value due to the degradation process of the drug delivery system. The effectiveness of the local glucocorticoid therapy of the insertion trauma using the developed drug delivery systems is to be assessed on the basis of a comparison of an implanted group with drug-loaded depots and an implanted group with drug-free depots. To induce the insertion trauma, self-made CI electrode carrier dummies made of medical soft silicone are implanted in the animals. Histological changes in the cochlea and changes in the brainstem potentials are used to assess the influence of the drug application on the insertion trauma. In addition, the position of the drug delivery systems as well as the CI electrode carrier dummies are examined ex vivo using micro-CT.

• DFG Programme: Research Grants
• International Connection: USA
• Co-Investigators: Eric Lehner; Professor Dr. Karsten Mäder; Professor Dr. Stefan Plontke
• Cooperation Partner: Professor Dr. Alec N. Salt, Ph.D.