Individualized, Additively Manufactured Drug-Releasing External Ear Canal Implant for Prevention of Postoperative Restenosis: Development, In Vitro Testing, and Proof of Concept in an Individual Curative Trial

Abstract

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.

Micro Injection Molding of Drug-Loaded Round Window Niche Implants for an Animal Model Using 3D-Printed Molds

“…A TNF-α-reduction test was performed for the investigation of the anti-inflammatory effect of the µIM-manufactured GP-RNI samples containing 10 wt% DEX as shown before [ 40 ]. It is assumed that the GP-RNI should release DEX into the supernatant (see Section 2.5 .…”

“…A TNF-α-reduction test was performed for the investigation of the anti-inflammatory effect of the µIM-manufactured GP-RNI samples containing 10 wt% DEX as shown before [40]. It is assumed that the GP-RNI should release DEX into the supernatant (see Section 2.5. for supernatant sampling), and to be bioeffective, the released DEX should reduce the TNF-α-production of cells being stressed with lipopolysaccharide (LPS, Sigma-Aldrich, St. Louis, MO, USA).…”

Micro Injection Molding of Drug-Loaded Round Window Niche Implants for an Animal Model using 3D Printed Molds

“…Cells of the DC2.4 mouse dendritic cell line (DCs) (Sigma-Aldrich, St. Louis, MO, USA, LOT:3093896) were maintained in RPMI 1640 medium (Sigma-Aldrich, St. Louis, MO, USA) supplemented with non-essential amino acids (1 mmol/L, Sigma-Aldrich, St Louis, MO, USA) and 10% FCS (Bio & Sell GmbH, Feucht, Germany). The cells (passages 3 to 10) were cultured in a humidified atmosphere of 5% CO2/95% air at 37 °C, as shown before [35]. DCs were seeded at a 1.5 × 105 cells/mL density in 48-well plates (Eppendorf, Hamburg, Germany) containing 200 µL of the medium per well.…”

Stability of Dexamethasone during Hot-Melt Extrusion of Filaments based on Eudragit® RS, Ethyl Cellulose and Polyethylene Oxide

“…For example, DEX is incorporated in the extruded intravitreal implant Ozurdex® approved by the FDA and EMA ( U.S. Food and Drug Administration, 2024 ; European Medicines Agency, n.d. ), as well as DEX-containing dosage forms such as implants were already developed by HME or FDM 3D printing in the past ( dos Santos et al, 2021 ; Kelley et al, 2020 ; Lehner et al, 2019 ; Farto-Vaamonde et al, 2019 ; Stein et al, 2018 ; Li et al, 2018 ; Costa et al, 2015 ; Li et al, 2013a ; Li et al, 2013b ). Moreover, non-thermal 3D printing techniques were already used to produce individually-shaped external ear canal implants or round window niche implant prototypes containing DEX ( Matin-Mann et al, 2022 ; Mau et al, 2022 ). However, a general processability of DEX by HME or 3D printing including the stability of the drug is not transferable to further developments of hot-melt or 3D printed implants since the used techniques, materials or processing parameters might differ from the intended ones or the stability of the drug has not been analyzed so far.…”