NANOCI-Nanotechnology Based Cochlear Implant With Gapless Interface to Auditory Neurons.

: Cochlear implants (CI) restore functional hearing in the majority of deaf patients. Despite the tremendous success of these devices, some limitations remain. The bottleneck for optimal electrical stimulation with CI is caused by the anatomical gap between the electrode array and the auditory neurons in the inner ear. As a consequence, current devices are limited through 1) low frequency resolution, hence sub-optimal sound quality and 2), large stimulation currents, hence high energy consumption (responsible for significant battery costs and for impeding the development of fully implantable systems). A recently completed, multinational and interdisciplinary project called NANOCI aimed at overcoming current limitations by creating a gapless interface between auditory nerve fibers and the cochlear implant electrode array. This ambitious goal was achieved in vivo by neurotrophin-induced attraction of neurites through an intracochlear gel-nanomatrix onto a modified nanoCI electrode array located in the scala tympani of deafened guinea pigs. Functionally, the gapless interface led to lower stimulation thresholds and a larger dynamic range in vivo, and to reduced stimulation energy requirement (up to fivefold) in an in vitro model using auditory neurons cultured on multi-electrode arrays. In conclusion, the NANOCI project yielded proof of concept that a gapless interface between auditory neurons and cochlear implant electrode arrays is feasible. These findings may be of relevance for the development of future CI systems with better sound quality and performance and lower energy consumption. The present overview/review paper summarizes the NANOCI project history and highlights achievements of the individual work packages.

Efficient penetration of ceric ammonium nitrate oxidant-stabilized gamma-maghemite nanoparticles through the oval and round windows into the rat inner ear as demonstrated by MRI.

We aimed to evaluate the magnetic resonance imaging (MRI) contrast effect and delivery efficiency through the middle ear into the inner ear using novel super-paramagnetic maghemite (γ-Fe2 O3 ) nanoparticles (NPs) generated using ceric ammonium nitrate (CAN)-mediated oxidation of Fe3 O4 NPs (CAN-γ-Fe2 O3 NPs). The CAN-γ-Fe2O3 NPs, having hydrodynamic diameters of 50-60 nm and potentials of +55.2 mV, displayed super-paramagnetic behavior characterized by a saturation magnetization Ms of 75.2 emu/g NPs. The r1 and r2* relaxivity (curve slopes) values were 0.0015 and 189 mmol-1  s-1 , respectively, indicating strong T2* relaxation maghemite-based NPs. The CAN-γ-Fe2 O3 NPs were stable in the 7.0 T magnetic field. At 3 h after the tympanic medial wall administration, the NPs had significantly located to the cochlea and vestibule. The signal started to recover at 6 h in the ipsilateral cochlea and by 2 d in the vestibule post-administration. There was no difference in the signal intensity between the left and right ears on the 14th d. Prussian blue staining for iron demonstrated NP distribution in the inner ear tissue. The novel CAN-γ-Fe2 O3 NPs are a strong MRI T2 contrast agent and penetrated the round and oval windows and have potential application in the molecular imaging of the inner ear. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1883-1891, 2017.

Development of Multifunctional Magnetic Nanoparticles for Genetic Engineering and Tracking of Neural Stem Cells.

Genetic modification of cell transplant populations and cell tracking ability are key underpinnings for effective cell therapies. Current strategies to achieve these goals utilize methods which are unsuitable for clinical translation because of related safety issues, and multiple protocol steps adding to cost and complexity. Multifunctional magnetic nanoparticles (MNPs) offering dual mode gene delivery and imaging contrast capacity offer a valuable tool in this context. Despite their key benefits, there is a critical lack of neurocompatible and multifunctional particles described for use with transplant populations for neurological applications. Here, a systematic screen of MNPs (using a core shown to cause contrast in magnetic resonance imaging (MRI)) bearing various surface chemistries (polyethylenimine (PEI) and oxidized PEI and hybrids of oxidized PEI/alginic acid, PEI/chitosan and PEI/polyamidoamine) is performed to test their ability to genetically engineer neural stem cells (NSCs; a cell population of high clinical relevance for central nervous system disorders). It is demonstrated that gene delivery to NSCs can be safely achieved using two of the developed formulations (PEI and oxPEI/alginic acid) when used in conjunction with oscillating magnetofection technology. After transfection, intracellular particles can be detected by histological procedures with labeled cells displaying contrast in MRI (for real time cell tracking).

Acute in vivo toxicity mitigation of PEI-coated maghemite nanoparticles using controlled oxidation and surface modifications toward siRNA delivery.

A ceric ammonium nitrate (CAN)-based doping step was used for the fabrication of core maghemite nanoparticles (NPs) that enabled the obtainment of colloid particles with a view to a high-level nanoparticle (NP) surface doping by Ce(III/IV). Such doping of Ce(III/IV) cations enables one to exploit their quite rich coordination chemistry for ligand coordinative binding. In fact, they were shown to act as powerful Lewis acid centers for attaching any organic (Lewis base) ligand such as a 25 kDa branched PEI polymer. Resulting conPEI25-CAN-γ-Fe2O3 NPs have been fully characterized before a successful implementation of siRNA loading and cell delivery/gene silencing using a well-known dual luciferase system. This attractive result emphasized their significant potential as an NP platform technology toward additional MRI and/or drug delivery (peptide)-relating end applications. However, due to their high positive charge, PEI polymers can cause severe in vivo toxicity due to their interaction with negatively charged red blood cells (RBC), resulting in RBC aggregation and lysis, leading to thrombosis and, finally, to animal death. In order to mitigate these acute toxic effects, two different types of surface modifications were performed. One modification included the controlled oxidation of 0.1-5% of the PEI amines before or after conjugation to the NPs, using hydrogen peroxide or potassium persulfate. The other type of modification was the addition of a second biocompatible polyanionic polymer to the PEI grafted NPs, based on the concept of a layer-by-layer (LbL) technique. This modification is based on the coordination of another polyanionic polymer on the NPs surface in order to create a combined hybrid PEI and polyanionic polymer nanosystem. In both cases, the surface modification successfully mitigated the NP acute in vivo toxicity, without compromising the silencing efficiency.