Dexamethasone is widely used in preclinical studies and clinical trials to treat inner ear disorders. The results of those studies vary widely, maybe due to the different dexamethasone formulations used. Laboratory (lab) and medical grade (med) dexamethasone (DEX, C₂₂H₂₉FO₅) and dexamethasone dihydrogen phosphate-disodium (DPS, C₂₂H₂₈FNa₂O₈P) were investigated for biocompatibility and bio-efficacy in vitro. The biocompatibility of each dexamethasone formulation in concentrations from 0.03 to 10,000 µM was evaluated using an MTT assay. The concentrations resulting in the highest cell viability were selected to perform a bio-efficiency test using a TNFα-reduction assay. All dexamethasone formulations up to 900 µM are biocompatible in vitro. DPS-lab becomes toxic at 1000 µM and DPS-med at 2000 µM, while DEX-lab and DEX-med become toxic at 4000 µM. Bio-efficacy was evaluated for DEX-lab and DPS-med at 300 µM, for DEX-med at 60 µM, and DPS-lab at 150 µM, resulting in significantly reduced expression of TNFα, with DPS-lab having the highest effect. Different dexamethasone formulations need to be applied in different concentration ranges to be biocompatible. The concentration to be applied in future studies should carefully be chosen based on the respective dexamethasone form, application route and duration to ensure biocompatibility and bio-efficacy.

The local treatment of diseases by drug-eluting implants is a promising tool to enable successful therapy under potentially reduced systemic side effects. Especially, the highly flexible manufacturing technique of 3D printing provides the opportunity for the individualization of implant shapes adapted to the patient-specific anatomy. It can be assumed that variations in shape can strongly affect the released amounts of drug per time. This influence was investigated by performing drug release studies with model implants of different dimensions. For this purpose, bilayered model implants in a simplified geometrical shape in form of bilayered hollow cylinders were developed. The drug-loaded abluminal part consisted of a suitable polymer ratio of Eudragit^® RS and RL, while the drug-free luminal part composed of polylactic acid served as a diffusion barrier. Implants with different heights and wall thicknesses were produced using an optimized 3D printing process, and drug release was determined in vitro. The area-to-volume ratio was identified as an important parameter influencing the fractional drug release from the implants. Based on the obtained results drug release from 3D printed implants with individual shapes exemplarily adapted to the frontal neo-ostial anatomy of three different patients was predicted and also tested in an independent set of experiments. The similarity of predicted and tested release profiles indicates the predictability of drug release from individualized implants for this particular drug-eluting system and could possibly facilitate the estimation of the performance of customized implants independent of individual in vitro testing of each implant geometry.

Modern therapy of inner ear disorders is increasingly shifting to local drug delivery using a growing number of pharmaceuticals. Access to the inner ear is usually made via the round window membrane (RWM), located in the bony round window niche (RWN). We hypothesize that the individual shape and size of the RWN have to be taken into account for safe reliable and controlled drug delivery. Therefore, we investigated the anatomy and its variations. Cone beam computed tomography (CBCT) images of 50 patients were analyzed. Based on the reconstructed 3D volumes, individual anatomies of the RWN, RWM, and bony overhang were determined by segmentation using 3D Slicer^TM with a custom build plug-in. A large individual anatomical variability of the RWN with a mean volume of 4.54 mm³ (min 2.28 mm³, max 6.64 mm³) was measured. The area of the RWM ranged from 1.30 to 4.39 mm² (mean: 2.93 mm²). The bony overhang had a mean length of 0.56 mm (min 0.04 mm, max 1.24 mm) and the shape was individually very different. Our data suggest that there is a potential for individually designed and additively manufactured RWN implants due to large differences in the volume and shape of the RWN.

Postoperative restenosis in patients with external ear canal (EEC) atresia or stenosis is a common complication following canaloplasty. Our aim in this study was to explore the feasibility of using a three dimensionally (3D)-printed, patient-individualized, drug ((dexamethasone (DEX)), and ciprofloxacin (cipro))-releasing external ear canal implant (EECI) as a postoperative stent after canaloplasty. We designed and pre-clinically tested this novel implant for drug release (by high-performance liquid chromatography), biocompatibility (by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay), bio-efficacy (by the TNF-α (tumor necrosis factor-alpha)-reduction test (DEX) and inhibition zone test (for cipro)), and microbial contamination (formation of turbidity or sediments in culture medium). The EECI was implanted for the first time to one patient with a history of congenital EEC atresia and state after three canaloplasties due to EEC restenosis. The preclinical tests revealed no cytotoxic effect of the used materials; an antibacterial effect was verified against the bacteria Staphylococcus aureus and Pseudomonas aeruginosa, and the tested UV-irradiated EECI showed no microbiological contamination. Based on the test results, the combination of silicone with 1% DEX and 0.3% cipro was chosen to treat the patient. The EECI was implantable into the EEC; the postoperative follow-up visits revealed no otogenic symptoms or infections and the EECI was explanted three months postoperatively. Even at 12 months postoperatively, the EEC showed good epithelialization and patency. Here, we report the first ever clinical application of an individualized, drug-releasing, mechanically flexible implant and suggest that our novel EECI represents a safe and effective method for postoperatively stenting the reconstructed EEC.

A novel approach for the long-term medical treatment of the inner ear is the diffusion of drugs through the round window membrane from a patient-individualized, drug-eluting implant, which is inserted in the middle ear. In this study, drug-loaded (10 wt% Dexamethasone) guinea pig round window niche implants (GP-RNIs, ~1.30 mm × 0.95 mm × 0.60 mm) were manufactured with high precision via micro injection molding (µIM, T_mold = 160 °C, crosslinking time of 120 s). Each implant has a handle (~3.00 mm × 1.00 mm × 0.30 mm) that can be used to hold the implant. A medical-grade silicone elastomer was used as implant material. Molds for µIM were 3D printed from a commercially available resin (T_G = 84 °C) via a high-resolution DLP process (xy resolution of 32 µm, z resolution of 10 µm, 3D printing time of about 6 h). Drug release, biocompatibility, and bioefficacy of the GP-RNIs were investigated in vitro. GP-RNIs could be successfully produced. The wear of the molds due to thermal stress was observed. However, the molds are suitable for single use in the µIM process. About 10% of the drug load (8.2 ± 0.6 µg) was released after 6 weeks (medium: isotonic saline). The implants showed high biocompatibility over 28 days (lowest cell viability ~80%). Moreover, we found anti-inflammatory effects over 28 days in a TNF-α-reduction test. These results are promising for the development of long-term drug-releasing implants for human inner ear therapy.

Background: Preserving residual hearing after cochlear implant (CI) surgery remains a crucial challenge. The application of dexamethasone (DEX) has been proven to positively affect residual hearing. To deliver DEX in a localized and controlled way, a round window niche implant (RNI), allowing drug diffusion via the round window membrane into the cochlea, may be used. To prove this concept, an RNI for guinea pigs as a CI-trauma model was manufactured by molding and tested for its drug release in vitro and biological effects in vivo. Methods: The RNIs were molded using silicone containing 10% DEX. Release was analyzed over time using high-performance liquid chromatography (HPLC). Fourteen adult guinea pigs were randomly assigned to two groups (CI or CI + RNI group). All animals received a unilateral CI electrode insertion trauma followed by CI insertion. The CI + RNI group was additionally implanted with an RNI containing 10% DEX. Animals were followed up for 4 weeks. Acoustically evoked auditory brainstem response and impedance measurement, micro-computed tomography (µCT) imaging, and histology were performed for evaluation. Results: DEX was released for more than 250 days in vitro, with an initial burst followed by a slower release over time. Comparing the hearing threshold shift (from day 0 to day 28) of the CI and CI + RNI groups, significant differences were observed at 32 and 40 kHz. The impedance shift at basal contacts was lower in the CI + RNI group than in the CI group. Moreover, the fibrosis in the lower basal turn was reduced in the CI + RNI group in contrast to the CI group. Conclusions: The RNI containing 10% DEX has anti-inflammatory potential concerning fibrosis inhibition and has beneficial effects on hearing preservation at high frequencies.