An image-guided robot system for direct cochlear access

The aim of direct cochlear access (DCA) is to replace the standard mastoidectomy with a small diameter tunnel from the lateral bone surface to the cochlea for electrode array insertion. In contrast to previous attempts, the approach described in this work not only achieves an unprecedented high accuracy, but also contains several safety sub-systems. This paper provides a brief description of the system components, and summarizes accuracy results using the system in a cadaver model over the past two years.

Fine control of drug delivery for cochlear implant applications

Cochlear implants are neuroprostheses that are inserted into the inner ear to directly electrically stimulate the auditory nerve, thus replacing lost cochlear receptors, the hair cells. The reduction of the gap between electrodes and nerve cells will contribute to technological solutions simultaneously increasing the frequency resolution, the sound quality and the amplification of the signal. Recent findings indicate that neurotrophins (NTs) such as brain derived neurotrophic factor (BDNF) stimulate the neurite outgrowth of auditory nerve cells by activating Trk receptors on the cellular surface (1–3). Furthermore, small-size TrkB receptor agonists such as di-hydroxyflavone (DHF) are now available, which activate the TrkB receptor with similar efficiency as BDNF, but are much more stable (4). Experimentally, such molecules are currently used to attract nerve cells towards, for example, the electrodes of cochlear implants. This paper analyses the scenarios of low dose aspects of controlled release of small-size Trk receptor agonists from the coated CI electrode array into the inner ear. The control must first ensure a sufficient dose for the onset of neurite growth. Secondly, a gradient in concentration needs to be maintained to allow directive growth of neurites through the perilymph-filled gap towards the electrodes of the implant. We used fluorescein as a test molecule for its molecular size similarity to DHF and investigated two different transport mechanisms of drug dispensing, which both have the potential to fulfil controlled low-throughput drug-deliverable requirements. The first is based on the release of aqueous fluorescein into water through well-defined 60-μm size holes arrays in a membrane by pure osmosis. The release was both simulated using the software COMSOL and observed experimentally. In the second approach, solid fluorescein crystals were encapsulated in a thin layer of parylene (PPX), hence creating random nanometer-sized pinholes. In this approach, the release occurred due to subsequent water diffusion through the pinholes, dissolution of the fluorescein and then release by out-diffusion. Surprisingly, the release rate of solid fluorescein through the nanoscopic scale holes was found to be in the same order of magnitude as for liquid fluorescein release through microscopic holes.

MeV ion beam lithography of biocompatible halogenated Parylenes using aperture masks

Parylenes are poly(p-xylylene) polymers that are widely used as moisture barriers and in biomedicine because of their good biocompatibility. We have investigated MeV ion beam lithography using 16O+ ions for writing defined patterns in Parylene-C, which is evaluated as a coating material for the Cochlear Implant (CI) electrode array, a neuroprosthesis to treat some forms of deafness. Parylene-C and -F on silicon and glass substrates as well as 50 μm thick PTFE were irradiated to different fluences (1×1013-1×10161×1013-1×1016 1 MeV 16O+ ions cm−2) through aperture masks under high vacuum and a low pressure (<10−3 mbar) oxygen atmosphere. Biocompatibility of the irradiated and unirradiated surfaces was tested by cell-counting to determine the proliferation of murine spiral ganglion cells. The results reveal that an oxygen ion beam can be used to pattern Parylene-C and -F without using a liquid solvent developer in a similar manner to PTFE but with a ∼25× smaller removal rate. Biocompatibility tests showed no difference in cell adhesion between irradiated and unirradiated areas or ion fluence dependence. Coating the Parylene surface with an adhesion-promoting protein mixture had a much greater effect on cell proliferation.

Flexible tactile digital feedback for clinical applications

Trauma and damage to the delicate structures of the inner ear frequently occurs during insertion of electrode array into the cochlea. This is strongly related to the excessive manual insertion force of the surgeon without any tool/tissue interaction feedback. The research is examined tool-tissue interaction of large prototype scale (12.5:1) digit embedded with distributive tactile sensor based upon cochlear electrode and large prototype scale (4.5:1) cochlea phantom for simulating the human cochlear which could lead to small scale digit requirements. This flexible digit classified the tactile information from the digit-phantom interaction such as contact status, tip penetration, obstacles, relative shape and location, contact orientation and multiple contacts. The digit, distributive tactile sensors embedded with silicon-substrate is inserted into the cochlea phantom to measure any digit/phantom interaction and position of the digit in order to minimize tissue and trauma damage during the electrode cochlear insertion. The digit is pre-curved in cochlea shape so that the digit better conforms to the shape of the scala tympani to lightly hug the modiolar wall of a scala. The digit have provided information on the characteristics of touch, digit-phantom interaction during the digit insertion. The tests demonstrated that even devices of such a relative simple design with low cost have potential to improve cochlear implants surgery and other lumen mapping applications by providing tactile feedback information by controlling the insertion through sensing and control of the tip of the implant during the insertion. In that approach, the surgeon could minimize the tissue damage and potential damage to the delicate structures within the cochlear caused by current manual electrode insertion of the cochlear implantation. This approach also can be applied diagnosis and path navigation procedures. The digit is a large scale stage and could be miniaturized in future to include more realistic surgical procedures.

Functional Evaluation of Causal Mutations Identified in Human Genetic Studies

Human genetics has been experiencing a wave of genetic discoveries thanks to the development of several technologies, such as genome-wide association studies (GWAS), whole-exome sequencing, and whole genome sequencing. Despite the massive genetic discoveries of new variants associated with human diseases, several key challenges emerge following the genetic discovery. GWAS is known to be good at identifying the locus associated with the patient phenotype. However, the actually causal variants responsible for the phenotype are often elusive. Another challenge in human genetics is that even the causal mutations are already known, the underlying biological effect might remain largely ambiguous. Functional evaluation plays a key role to solve these key challenges in human genetics both to identify causal variants responsible for the phenotype, and to further develop the biological insights from the disease-causing mutations.

We adopted various methods to characterize the effects of variants identified in human genetic studies, including patient genetic and phenotypic data, RNA chemistry, molecular biology, virology, and multi-electrode array and primary neuronal culture systems. Chapter 1 is a broader introduction for the motivation and challenges for functional evaluation in human genetic studies, and the background of several genetics discoveries, such as hepatitis C treatment response, in which we performed functional characterization.

Chapter 2 focuses on the characterization of causal variants following the GWAS study for hepatitis C treatment response. We characterized a non-coding SNP (rs4803217) of IL28B (IFNL3) in high linkage disequilibrium (LD) with the discovery SNP identified in the GWAS. In this chapter, we used inter-disciplinary approaches to characterize rs4803217 on RNA structure, disease association, and protein translation.

Chapter 3 describes another avenue of functional characterization following GWAS focusing on the novel transcripts and proteins identified near the IL28B (IFNL3) locus. It has been recently speculated that this novel protein, which was named IFNL4, may affect the HCV treatment response and clearance. In this chapter, we used molecular biology, virology, and patient genetic and phenotypic data to further characterize and understand the biology of IFNL4. The efforts in chapter 2 and 3 provided new insights to the candidate causal variant(s) responsible for the GWAS for HCV treatment response, however, more evidence is still required to make claims for the exact causal roles of these variants for the GWAS association.

Chapter 4 aims to characterize a mutation already known to cause a disease (seizure) in a mouse model. We demonstrate the potential use of multi-electrode array (MEA) system for the functional characterization and drug testing on mutations found in neurological diseases, such as seizure. Functional characterization in neurological diseases is relatively challenging and available systematic tools are relatively limited. This chapter shows an exploratory research and example to establish a system for the broader use for functional characterization and translational opportunities for mutations found in neurological diseases.

Overall, this dissertation spans a range of challenges of functional evaluations in human genetics. It is expected that the functional characterization to understand human mutations will become more central in human genetics, because there are still many biological questions remaining to be answered after the explosion of human genetic discoveries. The recent advance in several technologies, including genome editing and pluripotent stem cells, is also expected to make new tools available for functional studies in human diseases.

Development of an impedance based biosensor for studies of spheroids formation

Three-dimensional (3D) multicellular spheroids are exceptional in vitro cell models for their ability to accurately mimic real cell-cell interaction processes. However, the challenges in producing well-defined spheroids with controlled size together with the deficiency of techniques to monitor them significantly restrict their use. Herein, a novel device to study spheroid formation in real time is presented. By exploiting electrochemical impedance spectroscopy, a multi-electrode array (MEA) attached to a calcium alginate scaffold is able to monitor the behaviour of 36 different hydrogel wells. The scaffold contains inverted shape pyramidal microwells, which guide the aggregation of cells into spheroids with controlled dimensions. Preliminar studies on calcium alginate, optimisation of fabrication strategy are shown, together with testing of the device in the presence and the absence of the hydrogel. Lastly, the device was tested for its intended aim, i.e. to monitor the formation of a spheroid, proving its potential as an impedance biosensor.

Neural response telemetry in patients with the double-array cochlear implant

This study aimed to evaluate the neural response in double-array cochlear implant as well as to describe the refractory recovery and the spread of excitation functions. In a prospective study 11 patients were implanted with the double-array cochlear implant. Neural response telemetry (NRT) was performed intra-operatively. NRT threshold could be registered in 6 of the 11 patients, at least in one electrode. The remaining five patients did not show measurable neural response intra-operatively. It was noted that although recovery and spread of excitation functions could be recorded in all the tested electrodes with measurable neural responses, the responses were shown to be different from the usual register in patients with other etiologies.

Vertical CNT-Si Photodiode Array

Agências financiadoras: National Natural Science Foundation of China - 61204077; Shenzhen Science and Technology Innovation Commission - JCYJ20120614150521967

Investigations on Ultrasonic Transducer Array Systems for NDE of Underwater Pipelines

The main objective of carrying out this investigation is to develop suitable transducer array systems so that underwater pipeline inspection could be carried out in a much better way, a focused beam and electronic steering can reduce inspection time as well. Better results are obtained by optimizing the array parameters. The spacing between the elements is assumed to be half the wavelength so that the interelement interaction is minimum. For NDT applications these arrays are operated at MHz range. The wavelengths become very small in these frequency ranges. Then the size of the array elements becomes very small, requiring hybrid construction techniques for their fabrication. Transducer elements have been fabricated using PVDF as the active, mild steel as the backing and conducting silver preparation as the bonding materials. The transducer is operated in the (3,3) mode. The construction of a high frequency array is comparatively complicated. The interelement spacing between the transducer elements becomes considerably small when high frequencies are considered. It becomes very difficult to construct the transducer manually. The electrode connections to the elements can produce significant loading effect. The array has to be fabricated using hybrid construction techniques. The active materials has to be deposited on a proper substrate and etching techniques are required to fabricate the array. The annular ring, annular cylindrical or other similar structural forms of arrays may also find applications in the near future in treatments were curved contours of the human body are affected.

Sensor array made with nanostructured films to detect a phenothiazine compound

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Toxicity assessment and degradation of disperse azo dyes by photoelectrocatalytic oxidation on Ti/TiO2 nanotubular array electrodes

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Removal of sunscreen compounds from swimming pool water using self-organized TiO2 nanotubular array electrodes

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

The Determination of Methanol Using an Electrolytically Fabricated Nickel Microparticle Modified Boron Doped Diamond Electrode

A nickel modified boron doped diamond (Ni-BDD) electrode and nickel foil electrode were used in the determination of methanol in alkaline solutions. The Ni-BDD electrode was electrodeposited from a 1 mM Ni(NO(3))(2) solution (pH 5), followed by repeat cycling in KOH. Subsequent analysis utilised the Ni(OH)(2)/NiOOH redox couple to electrocatalyse the oxidation of methanol. Methanol was determined to limits of 0.3 mM with a sensitivity of 110 nA/mM at the Ni-BDD electrode. The foil electrode was less sensitive achieving a limit of 1.6 mM and sensitivity of 27 nA/mM. SEM analysis of the electrodes found the Ni-BDD to be modified by a quasi-random microparticle array.

Amperometric differential determination of ascorbic acid in beverages and vitamin C tablets using a flow cell containing an array of gold microelectrodes modified with palladium

A simple and attractive method for quantification of ascorbic acid (AA) in beers, soda, natural juices and commercial vitamin C tablets was achieved by combining Bow injection analysis and amperometric detection. An array of gold microelectrodes electrochemically modified by deposition of palladium was employed as working electrode which was almost unaffected by fouling effects. Ascorbic acid was quantified in beverages and vitamin tablets using amperometric differential measurements. This method is based on three steps involving the flow injection of: 1) the sample plus a standard addition of AA, 2) the pure sample, and 3) the enzymatically-treated sample. The enzymatic treatment was carried out with Cucumis sativus tissue, which is a rich source of ascorbate oxidase, at pH 7. The calibration plots for freshly prepared ascorbic acid standards were very linear in the concentration range of 0.18-1.8 mg L-1 with a relative standard deviation (RSD) < 1%, while for real samples the deviations were between 2.7% to 8.9%.