The feasibility of a novel sensing system for robotic cochlear electrode array feed for hearing preservation

A cochlear implant (CI) was a small electronic device that could provide direct electrical stimulation to the auditory nerve. Unlike a hearing aid, a cochlear implant turned sounds into electrical pulses which were sent directly to the auditory nerve. During a cochlear implant surgery, intracochlear electrode array insertion was considered to be a crucial process. However, the behaviour of the intracochlear electrode array during the insertion remained unclear to surgeons and the behaviour was hardly diagnosed by normal methods. In order to minimize or eliminate the trauma induced by electrode array insertion, we proposed an electrode capacitive sensing method to discriminate among certain signal patterns and notify the surgeons whether the array was placed correctly during the insertion process. In this thesis, we firstly investigated the mechanical behaviour of a CI electrode array during the insertion process. A force model simulating the first contact between the array tip and cochlear inner wall was proposed. Experimental results demonstrated that insertion force was not an effective method for detecting the array behaviours inside of the cochlea. Secondly, we investigated the theory and influencing factors of the capacitive sensing measurements. The relationship between capacitance measured and environmental effect, structural effect and applied force were examined and assessed. Our exploration demonstrated that the measured bipolar capacitive signals were recognised to be sensitive, consistent and reliable. Experiment results revealed that electrode capacitance values were systematically affected by intracochlear forces between the scala tympani wall and the contact electrode. Thirdly, by analysing the bipolar capacitance experimental results, three CI electrode array insertion patterns between the array and the cochlear lateral wall were classified. The possibility of the three patterns which an unknown insertion would fall into could be discriminated by the Principal Component Analysis (PCA) and The Pearson Correlation Coefficient (PCC) analysis. Experiment results showed the overall identification success rate was over 80%. Finally, a multi-channel switch board was proposed to measure multiple electrode pairs at the same time during the array insertion. Measurements and verification based on the board were carried out and shown to be efficient for capacitive signals measuring and recording

Doctor of Philosophy

dissertationFor many with severe-to-profound hearing loss, a condition in which the cochlea is unable to convert sound vibration into neural information to the brain, the cochlear implant has become the standard treatment. The goal of a cochlear-implant system is to bypass the malfunctioned cochlea and directly stimulate the nerves responsible for hearing through an array of electrodes on a silicone-elastomer carrier. However, the insertion of the electrode arrays can often cause intracochlear damage and eliminate residual hearing. With increased focus on hearing preservation in cochlear implantation, methods to minimize intracochlear damage have become a priority in electrode-array insertions. This dissertation explores the application of magnetic manipulation toward improved cochlear-implant electrode-array insertions. We start with initial 3-to-1 proof-of-concept experiments to demonstrate the feasibility of this approach. Then, to achieve relevancy at clinical scale, lateral-wall-type electrode-array models, used in the clinic, are slightly modified at the tip to include a tiny magnet. Next, a scala-tympani phantom is designed with both simulated cochleostomy and round-window openings to mimic both classes of insertions typically conducted. In particular, this is the first phantom to model a round-window opening and can be used reliably to simulate insertion forces in cadaver cochleae. Electrode arrays are then magnetically guided through these phantoms with a statistically significant (p < 0.05) reduction in insertion forces, and by as much as 50% for some electrode-array models. In particular, guiding the electrode-array tip through the cochlear hook and the basal turn, in the same insertion, was demonstrated for the first time using this technology. All existing methods to guide the electrode array can only be accomplished for the basal turn. Analysis is conducted to determine the optimal size and placement of a magnetic dipole-field source for use in the clinic. Its placement is determined to be consistently lateral to and anterior to the patient’s cochlea. Its size depends on numerous factors including the patient, torque requirements, and registration error. Sensitivity curves summarizing these factors are provided. The volume of the magnetic dipole-field source can be reduced by a factor of 5, on average, by moving it from the modiolar configuration originally proposed to this optimal configuration. We verify that magnetic forces do not pose any appreciable risk to the basilar membrane at the optimal configuration. Although patient-specific optimal configurations are characterized, a one-size-fits-all version is described that may be more practical and carries the benefit of substantial robustness to registration error

Beitrag zur Minimierung der Insertionskräfte von Cochlea-Implantat-Elektrodenträgern: Untersuchung gerader, lateral liegender Elektrodenträger sowie deren Funktionalisierung mittels nachgiebiger Aktuatoren

Sensorineurale Hörstörungen können mit einem Cochlea-Implantat behandelt werden. Dazu wird ein Elektrodenträger (ET) vom Chirurgen in die Cochlea inseriert, um dort die geschädigten Haarzellen zu ersetzen. Die vorliegende Arbeit befasst sich mit dem ET und dessen Insertionsprozess in die Cochlea. Dazu werden digitale und anschließend physikalische, planare Modelle der humanen Cochlea erstellt. Es werden Einflussfaktoren auf den Insertionsprozess systematisiert. Mit dem Ziel einer Reduktion der Insertionskräfte werden drei ausgewählte Einflussfaktoren mit eigens hergestellten Labormustern untersucht: Die Geometrie der Cochleamodelle, die Insertionsgeschwindigkeit des ETs und eine Alginat-Beschichtung des ETs. Abschließend wird ein fluidisch-aktuierter, nachgiebiger Mechanismus zur Funktionalisierung des ETs betrachtet. Die Skalierbarkeit dieses Mechanismus wird analytisch und numerisch gezeigt. Die Synthese des fluidmechanischen Aktuators liefert dessen geometrische Maße, um unter Druckbeaufschlagung mit definiertem Druck einer vorgegebenen Form zu entsprechen

Endoscopy

Endoscopy is a fast moving field, and new techniques are continuously emerging. In recent decades, endoscopy has evolved and branched out from a diagnostic modality to enhanced video and computer assisting imaging with impressive interventional capabilities. The modern endoscopy has seen advances not only in types of endoscopes available, but also in types of interventions amenable to the endoscopic approach. To date, there are a lot more developments that are being trialed. Modern endoscopic equipment provides physicians with the benefit of many technical advances. Endoscopy is an effective and safe procedure even in special populations including pediatric patients and renal transplant patients. It serves as the tool for diagnosis and therapeutic interventions of many organs including gastrointestinal tract, head and neck, urinary tract and others

TARGETING MAGNETIC NANOCARRIERS IN THE HEAD FOR DRUG DELIVERY AND BIOSENSING APPLICATIONS

Magnetic nanocarriers have proven to be effective vehicles for transporting therapeutic and diagnostic agents in the body. Their main advantage is their ability to be manipulated by external magnets to direct them to specific targets in the body. In this dissertation, I study the transport, safety and efficacy of moving drug coated magnetic nanocarriers in different types of tissue. Movement of magnetic nanocarriers of sizes ranging from 100 nm to 1µm with different biocompatible coatings (Starch, PEG, Lipid and Chitosan) was quantified in different tissue types using an automated cryostat system. The safety of moving magnetic nanocarriers in live rodent brain tissue was assessed using electrophysiology, calcium imaging and immunohistochemistry. Moving magnetic nanocarriers in brain tissue did not significantly affect the firing ability of single neurons, synaptic connectivity and the overall functioning of the neuron network. As part of efficacy studies, steroid-eluting magnetic nanoparticles were targeted using external magnets to the inner ear of mice to counter hearing loss caused by cisplatin chemotherapeutics. This targeted steroid delivery to the cochlea significantly reduced the change in hearing threshold at 32 KHz caused by cisplatin injections and protected the hair cells from significant damage. Finally, I explore the potential of spin-transfer torque nano-oscillators, which are multi-layered ferromagnetic nanocarriers, as high-resolution in vivo wireless biosensors. These nanocarriers have been shown to detect action potentials from crayfish lateral giant neurons and that the microwave magnetic signals from these devices can be detected wirelessly by near field induction

Development of in vitro and in vivo models to underpin advances in human radiotherapy

Radiotherapy (RT) is commonly used for the local control of many cancer types. Unfortunately, not all patients will achieve a therapeutic benefit, and some will develop loco-regional recurrences and/or metastatic disease. The hypoxic nature of the tumour microenvironment and the development of radioresistant cancer cells can contribute to these treatment failures. Understanding the mechanisms involved in acquired radioresistance and the development of techniques to identify and target hypoxic tumour areas has the potential to improve RT response rates. The first aim of this project was to investigate the development of acquired radioresistance and identify radiation-induced secreted biomarkers which could be used as indicators of a radiation response or radiosensitivity. Human radioresistant (RR) breast cancer cell lines were developed from parental MCF-7, ZR-751 and MDA-MB-231 cells. Parental and RR cells underwent genotypic, phenotypic and functional characterisation. RR cells exhibited enhanced migration and invasion, with evidence of epithelial-to-mesenchymal transition. MCF-7 RR and ZR-751 RR cell lines exhibited significant phenotypic changes, including loss of ERα and PgR expression and increased EGFR expression, which were associated with the down-regulation of ER signalling genes and up-regulation of genes associated with PI3K, MAPK and WNT pathway activation. A change in subtype classification from luminal A to HER2-overexpressing (MCF-7 RR) and normal-like (ZR-751 RR) subtypes was also observed, consistent with radiation and endocrine therapy resistance and a more aggressive phenotype. To identify biomarkers secreted in response to radiation, human and canine breast and ovine lung cancer cell lines were radiated. Secretome samples were analysed by liquid chromatography-mass spectrometry. Using results from the MCF- 7 cell line, 33 radiation-induced secreted biomarkers were identified which had higher (up to 12-fold) secretion levels compared to untreated controls. Based on secretion profiles and functional analysis 9 candidate biomarkers were selected (YBX3, TK1, SEC24C, EIF3G, EIF4EBP2, NAP1L4, VPS29, GNPNAT1 and DKK1) of which the first 4 underwent in-lab validation. To identify biomarkers related to radiosensitivity transcriptomic analysis identified higher expression of genes encoding 7 of the candidate biomarkers in the MCF-7 cell line compared to its radioresistant derivative. WB analysis identified increased levels of the 4 biomarkers in the conditioned media of parental cells 24 h post-radiation which was not seen in the RR cell lines. These biomarkers, which had differential gene expression and secretion profiles between parental and RR cell lines, may be useful for both predicting and monitoring a tumour’s response to RT. A further aim was to investigate the biocompatibility and functionality of an implantable electrochemical sensor, developed within the Engineering and Physical Sciences Research Council funded IMPACT project. This sensor was designed to measure tissue O2 tension (ptO2) within a tumour, enabling the identification and monitoring of radioresistant hypoxic tumour areas. This study developed a novel in vivo tumour xenograft model to evaluate the potential of 6 materials (silicon dioxide, silicon nitride, Parylene-C, Nafion, biocompatible EPOTEK epoxy resin and platinum) used in the construction of the sensor, to trigger a foreign body response (FBR) when implanted into a solid tumour. Following implantation none of the materials affected tumour growth and all mice remained healthy. Immunohistochemistry performed on the tumour showed no significant changes in necrosis, hypoxic cell number, proliferation, apoptosis, immune cell infiltration or collagen deposition around the implant site. The absence of a FBR supports their use in the construction of implantable medical devices. In vivo validation of the O2 sensor to provide real-time measurements on intra-tumoural ptO2 was performed using a novel large animal ovine model. To achieve this aim, we developed a novel computed tomography (CT) guided transthoracic percutaneous implantation technique for the delivery of sensors into naturally occurring ovine pulmonary adenocarcinoma (OPA) tumours. This model successfully integrated techniques such as ultrasound, general anaesthesia, CT and surgery into the OPA model, all of which are techniques commonly used in the treatment of human lung cancer patients. This methodology resulted in the accurate implantation of sensors into OPA tumours with minimal complications and demonstrated the sensor’s ability to detect changes in intra-tumoural ptO2 following manipulation of the inspired fractional O2 concentration (FiO2). To investigate other possible clinical applications, sensors were validated for measuring intestinal ptO2 using a novel rat model. These experiments assessed the potential of the sensor to monitor intestinal perfusion following an intestinal resection and anastomosis. The sensor was placed onto the serosal surface of the small intestine of anaesthetised rats that were subsequently exposed to ischaemic, hypoxaemic and haemorrhagic insults. Decreases in intestinal ptO2 were observed following superior mesenteric artery occlusion and reductions in FiO2; these changes were reversible after reinstating blood flow or increasing FiO2. These results provided evidence that the sensors could detect changes in intestinal perfusion which could be utilised in a clinical setting to monitor peri-anastomotic intestinal ptO2. Overall this PhD project has conducted both in vitro and in vivo work aimed at the investigation of mechanisms of radioresistance, identifying secreted biomarkers of radiosensitivity and validating the ability of an implantable sensor to measure real-time intra-tumoural and visceral surface O2 tension. Identification of factors contributing to poor RT responses, such as radioresistance development and hypoxic tumour areas could provide a means by which RT could become personalised. Patients identified as having radioresistant tumours or those not responding to RT based on radiation-induced secreted biomarkers, could be given higher dose of radiation or radiosensitising agents to improve patient outcomes

Proceedings of the 19th Sound and Music Computing Conference

Proceedings of the 19th Sound and Music Computing Conference - June 5-12, 2022 - Saint-Étienne (France). https://smc22.grame.f