title: Ear Cubes for local controlled drug delivery to the inner ear.
abstract: A new type of advanced drug delivery systems is proposed: Miniaturized implants, which can be placed into tiny holes drilled into (or close to) the oval window. They consist of two parts: 1) A cylinder, which is inserted into the hole crossing the oval window. The cylinder (being longer than the depth of the hole) is partly located within the inner ear and surrounded by perilymph. This provides direct access to the target site, and at the same time assures implant fixation. 2) A cuboid, which is located in the middle ear, serving as a drug reservoir. One side of the cuboid is in direct contact with the oval window. Drug release into the cochlea occurs by diffusion through the cylindrical part of the Ear Cubes and by diffusion from the cuboid into and through the oval window. High precision molds were used to prepare two differently sized Ear Cubes by injection molding. The miniaturized implants were based on silicone and loaded with different amounts of dexamethasone (10 to 30 % w/w). The systems were thoroughly characterized before and upon exposure to artificial perilymph at 37°C. Importantly, drug release can effectively be controlled and sustained during long time periods (up to several years). Furthermore, the implants did not swell or erode to a noteworthy extent during the observation period. Drug diffusion through the polymeric matrix, together with limited dexamethasone solubility effects, seem to control the resulting drug release kinetics, which can roughly be estimated using mathematical equations derived from Fick's second law. Importantly, the proposed Ear Cubes are likely to provide much more reliable local long term drug delivery to the inner ear compared to liquid or semi-solid dosage forms administered into the middle ear, due to a more secured fixation. Furthermore, they require less invasive surgeries and can accommodate higher drug amounts compared to intracochlear implants. Thus, they offer the potential to open up new horizons for innovative therapeutic strategies to treat inner ear diseases and disorders.
authors.affiliation: Univ. Lille, F-59000 Lille, France; INSERM U1008, F-59006 Lille, France.
authors.forename: M
authors.initials: M
authors.lastname: Gehrke
authors.affiliation: Univ. Lille, F-59000 Lille, France; INSERM U1008, F-59006 Lille, France; University Hospital of Lille, Otology and Neurotology Department, F-59037 Lille, France.
authors.forename: J
authors.initials: J
authors.lastname: Sircoglou
authors.affiliation: Oticon Medical/Neurelec, R&D, 2720 Chemin Saint-Bernard, F-06224 Vallauris, France.
authors.forename: D
authors.initials: D
authors.lastname: Gnansia
authors.affiliation: Oticon Medical/Neurelec, R&D, 2720 Chemin Saint-Bernard, F-06224 Vallauris, France.
authors.forename: G
authors.initials: G
authors.lastname: Tourrel
authors.affiliation: Univ. Lille, F-59000 Lille, France; UMR CNRS 8207, F-59650 Villeneuve d' Ascq, France.
authors.forename: J-F
authors.initials: JF
authors.lastname: Willart
authors.affiliation: Univ. Lille, F-59000 Lille, France; UMR CNRS 8207, F-59650 Villeneuve d' Ascq, France.
authors.forename: F
authors.initials: F
authors.lastname: Danede
authors.affiliation: Univ. Lille, F-59000 Lille, France; INSERM U1008, F-59006 Lille, France.
authors.forename: E
authors.initials: E
authors.lastname: Lacante
authors.affiliation: Univ. Lille, F-59000 Lille, France; INSERM U1008, F-59006 Lille, France; University Hospital of Lille, Otology and Neurotology Department, F-59037 Lille, France.
authors.forename: C
authors.initials: C
authors.lastname: Vincent
authors.affiliation: Univ. Lille, F-59000 Lille, France; INSERM U1008, F-59006 Lille, France.
authors.forename: F
authors.initials: F
authors.lastname: Siepmann
authors.affiliation: Univ. Lille, F-59000 Lille, France; INSERM U1008, F-59006 Lille, France. Electronic address: juergen.siepmann@univ-lille2.fr.
authors.forename: J
authors.initials: J
authors.lastname: Siepmann
mesh_terms: D003051:Cochlea / Q000187:drug effects*; D003907:Dexamethasone / Q000008:administration & dosage; D004058:Diffusion; D016503:Drug Delivery Systems / Q000295:instrumentation*; D065546:Drug Liberation; D006801:Humans; D007700:Kinetics; D007759:Labyrinth Diseases / Q000188:drug therapy; D010498:Perilymph / Q000187:drug effects*; D004364:Pharmaceutical Preparations / Q000008:administration & dosage*; D019736:Prostheses and Implants; D012828:Silicones; D012995:Solubility
chemical_list: D004364:Pharmaceutical Preparations; D012828:Silicones; D003907:Dexamethasone
keywords: Cochlea; Implant; Local controlled drug delivery; Mathematical modeling; Silicone