Changes in hearing function and intracochlear morphology after electrode array insertion in minipigs.

BACKGROUND: In temporal bone specimens from long-term cochlear implant users, foreign body response within the cochlea has been demonstrated. However, how hearing changes after implantation and fibrosis progresses within the cochlea is unknown. OBJECTIVES: To investigate the short-term dynamic changes in hearing and cochlear histopathology in minipigs after electrode array insertion. MATERIAL AND METHODS: Twelve minipigs were selected for electrode array insertion (EAI) and the Control. Hearing tests were performed preoperatively and on 0, 7, 14, and 28 day(s) postoperatively, and cochlear histopathology was performed after the hearing tests on 7, 14, and 28 days after surgery. RESULTS: Electrode array insertion had a significant effect for the frequency range tested (1 kHz-20kHz). Exudation was evident one week after electrode array insertion; at four weeks postoperatively, a fibrous sheath formed around the electrode. At each time point, the endolymphatic hydrops was found; no significant changes in the morphology and packing density of the spiral ganglion neurons were observed. CONCLUSIONS AND SIGNIFICANCE: The effect of electrode array insertion on hearing and intracochlear fibrosis was significant. The process of fibrosis and endolymphatic hydrops seemed to not correlate with the degree of hearing loss, nor did it affect spiral ganglion neuron integrity in the 4-week postoperative period.

Analysis of Cochlear Parameters in Paediatric Inner Ears with Enlarged Vestibular Aqueduct and Patent Cochlea.

Is cochlear implant (CI) electrode selection for cochleae with an enlarged vestibular aqueduct (EVA) the same as that for patent cochleae with a normal inner ear structure? Preoperative high-resolution computed tomography (HRCT) images of 247 ears were assessed retrospectively. The A-value, B-value, and H-value were measured with OTOPLAN, and Bell curves were created to show the distribution. All ears with EVA were re-evaluated using a 3D slicer to confirm whether incomplete partition type II (IP II) existed. The Mann-Whitney U-test was applied to determine a statistically significant difference. After adjustment with the Bonferroni correction method, a p-value ≤ 0.006 was considered significant. In total, 157 ears with patent cochlea and 90 ears with EVA were assessed. Seventy (82%) of the EVA ears had an IP II malformation, and 14 (19%) of these were not detected by CT scan but were later seen through the 3D reconstruction. A significant difference was found for the A value and B value between the patent cochleae and EVA-only and between the patent cochleae and EVA with IP II. Most EVA cases had an IP II malformation. The basal turn of the cochlea may be smaller in EVA cases than in the patent cochleae. Electrode selection should be adjusted accordingly.

Combined legumain- and integrin-targeted nanobubbles for molecular ultrasound imaging of breast cancer.

Molecular ultrasound imaging is a promising strategy for non-invasive and precise cancer diagnosis. Previously reported ultrasound contrast agents (UCAs) are mostly microbubbles or nanobubbles (NBs) larger than 200 nm, leading to less efficient tumor delivery. Here we synthesized NBs with a small size (~49 nm) and modified the NB surface with alanine-alanine-asparagine (NB-A) or arginine-glycine-aspartic acid peptide (NB-R) for concurrent active targeting towards legumain in tumor cells and integrin in tumor neovasculature. In vitro, the NB-A and NB-R presented echogenicity comparable with SonoVue MBs and showed specific binding with tumors cells and endothelial cells, respectively. In vivo, the combined NB-A/NB-R accumulated in tumor tissues selectively and provided ultrasound signals with prolonged duration and that were significantly stronger than non-targeted NBs, single-targeted NBs and SonoVue MBs. Overall, the dual targeted NBs served as efficient UCAs for specific imaging of breast cancer, and hold great potential for general cancer diagnosis/monitoring in the future.

Asparagine endopeptidase-targeted Ultrasound-responsive Nanobubbles Alleviate Tau Cleavage and Amyloid-ß Deposition in an Alzheimer's Disease Model.

Inhibition of asparagine endopeptidase (AEP) has been implied to be effective for treating tau- and amyloid-beta-mediated neurodegenerative diseases, although a method for targeted intracerebral delivery of AEP inhibitors has not yet been achieved. Here, we fabricated ultrasound-responsive nanobubbles (NBs) to load AEP inhibitor RR-11a, and modified the NB surface with either AEP recognizable peptide AAN or pro-transendothelial transversal motif RGD, i.e. NB(11a)-A and NB(11a)-R, for AEP-targeted treatment of Alzheimer's disease (AD). The developed NBs were uniform, small in size (50.1 ± 1.5 nm), with strong echogenicity and high drug loading efficiency (∼91.97%). When intravenously co-injected in the APP/PS1 mouse model, NB(11a)-R could adhere to endothelial cells and enhance transient opening of the blood-brain barrier (BBB) upon focused ultrasound oscillations, allowing the rest NBs/localized released RR-11a molecules to enter the brain, and then NB(11a)-A could selectively bind with the impaired neurons and deposit RR-11a molecules at the AD lesion. As a result, co-administration of NB(11a)-A and NB(11a)-R significantly promoted accumulation of RR-11a in the mouse brain, and substantially alleviated both tau cleavage and amyloid plaques deposition in the hippocampus. Most strikingly, the cognitive ability of the AD model mice was dramatically improved, achieving a level close to the normal mice. Overall, this unique AEP-targeted nanobubble design provides an efficient intracerebral drug delivery strategy and significantly enhances treatment efficacy of AD. STATEMENT OF SIGNIFICANCE: Asparagine endopeptidase (AEP) is an innovative therapeutic target simultaneously involved in Aß and tau-mediated Alzheimer's disease (AD) pathology, but targeted delivery of AEP inhibitors has not been achieved yet. Here we developed an efficient strategy to deliver AEP inhibitor RR-11a towards impaired neurons. We fabricated RR-11a-loaded ultrasound-responsive nanobubbles (NBs) and modified the NB surface with RGD peptide to promote BBB crossing upon focused ultrasound oscillations, or with AAN peptide to increase binding of NBs on the neurons. Our results indicated that, co-administration of the NB(11a)-A and NB(11a)-R significantly enhanced accumulation of RR-11a molecules at the AD lesion, alleviated both tau cleavage and amyloid plaques deposition in the hippocampus, and consequently restored cognitive function of the AD model mice.