액정폴리머기반의 신경 전극의 제작과 성과: 사면 전극과 옵트로드

학위논문 (박사)-- 서울대학교 대학원 공과대학 전기·컴퓨터공학부, 2017. 8. 김성준.A novel liquid-crystal polymer (LCP)-based neural probe with four-sided electrode sites is developed. Ideally, neural probes should have channels with a three-dimensional (3-D) configuration to record 3-D neural circuits. Many types of three-dimensional neural probes have been developedhowever, most of them were formulated as an array of multiple shanks with electrode sites located along one side of the shanks. The proposed LCP-based neural probe has electrode sites on four sides of the shank, i.e., the front, back and two side walls. To generate the suggested configuration of the electrode sites, a thermal lamination process involving LCP films and laser micromachining are used. Using the proposed novel four-sided neural probe, in vivo multichannel neural recording is successfully performed in the mouse primary somatosensory cortex. The multichannel neural recording shows that the proposed four-sided neural probe can record spiking activities from a diverse neuronal population compared to neural probes with single-sided electrodes. This is confirmed by a pair-wise Pearson correlation coefficient (Pearson's r) analysis and a cross- correlation analysis. This study also presents the development of LCP-based depth-type stimulation electrodes with a high charge storage capacity using electrodeposited iridium oxide film (EIROF). On the electrode sites, iridium oxide is electrodeposited to increase the charge storage capacity for facilitating neural stimulation. After electrodeposition using different numbers of rectangular voltage pulses and triangular waveforms, the iridium oxide electrodes are characterized in terms of charge storage capacity and electrochemical impedance. And the surfaces of EIROFs are examined using atomic force microscopy (AFM) and scanning electron microscopy (SEM). In addition, the elementary composition of the EIROF surfaces is quantitatively determined using X-ray photoelectron spectroscopy (XPS). The in vivo neural experiments verified the feasibility of the proposed LCP-based depth-type stimulation electrode. Additionally, LCP-based optrode is suggested for optical stimulation and electrical recording. The suggested neural probes have four contacts at the tip of the electrode shank. After thermally laminating the LCP films, the four tip electrodes are made by cut-exposing the thickness of the electroplated metals. The four tip electrodes have enough contact areas and electrochemical impedance to ensure good quality of neural signal recordings. After the laser cutting process, an optic fiber is integrated to the neural probes. To demonstrate optical stimulation and electrical recording capability of the fabricated LCP-based optrode, in vivo experiments are done. Spontaneous activity and light-evoked activity are successfully recorded from the cortex and the deep brain area.Chapter 1 Introduction 1 1.1 Neural Probes 2 1.1.1 Recording Probes 2 1.1.2 Stimulation Electrodes 3 1.1.3 Optrodes 6 1.2 Proposed Neural Probes 7 1.2.1 Recording Probes 7 1.2.2 Depth-type Stimulation Electrode 8 1.2.3 Optrode 8 1.3 Dissertation Outlines 9 Chapter 2 Materials and Methods 11 2.1 Liquid Crystal Polymer (LCP) 12 2.2 Electrode Configuration 13 2.2.1 Recording Probes 13 2.2.1.1 Four-sided Neural Probe 13 2.2.1.2 Single-sided Neural Probe 15 2.2.1.3 Tetrode 15 2.2.2 Depth-type Stimulation Electrode 16 2.2.3 Optrode 17 2.3 Fabrication Processes 18 2.4 Electrochemical characterization 26 2.5 Electrodeposited Iridium Oxide Film (EIROF) 27 2.5.1 Electrodeposition of Iridium Oxide Film 27 2.5.2 Electrochemical Measurements 29 2.5.3 Surface Morphology and Mechanical Stability 30 2.6 In vivo Experiments 31 2.6.1 In vivo Neural Signal Recording Experiments 31 2.6.2 In vivo Electrical Stimulation Experiments 32 2.6.3 In vivo Optical Stimulation and Electrical Recording Experiment 35 Chapter 3 Results 38 3.1 Neural Probes 39 3.1.1 Recording Probes 39 3.1.1.1 Four-sided Neural Probe 39 3.1.1.2 Single-sided Neural Probe 39 3.1.1.3 Tetrode 41 3.1.2 Depth-type Stimulation Electrode 41 3.1.3 Optrode 42 3.2 Electrochemical Characterization 43 3.3 Electrodeposited Iridium Oxide Film 45 3.3.1 Electrochemical Measurements - 45 3.3.2 Surface Morphology and Mechanical Stability 51 3.4 In vivo Experiments 57 3.4.1 In vivo Neural Signal Recording Experiments 57 3.4.2 In vivo Electrical Stimulation Experiments 62 3.4.3 In vivo Optical Stimulation and Electrical Recording Experiment 64 Chapter 4 Discussion 72 4.1 LCP-based Recording Probes 73 4.2 LCP-based Depth-type Stimulation Electrode 82 4.3 LCP-based Optrode 86 Chapter 5 Conclusion 88 References 92 Abstract in Korean 103Docto

Doctor of Philosophy

dissertationBiomedical implantable devices have been developed for both research and clinical applications, to stimulate and record physiological signals in vivo. Chronic use of biomedical devices with thin-film-based encapsulation in large scale is impeded by their lack of long-term functionality and stability. Biostable, biocompatible, conformal, and electrically insulating coatings that sustain chronic implantation are essential for chip-scale implantable electronic systems. Even though many materials have been studied to for this purpose, to date, no encapsulation method has been thoroughly characterized or qualified as a broadly applicable long-term hermetic encapsulation for biomedical implantable devices. In this work, atomic layer deposited Al2O3 and Parylene C bi-layer was investigated as encapsulation for biomedical devices. The combination of ALD Al2O3 and CVD Parylene C encapsulation extended the lifetime of coated interdigitated electrodes (IDEs) to up to 72 months (to date) with low leakage current of ~ 15 pA. The long lifetime was achieved by significantly reducing moisture permeation due to the ALD Al2O3 layer. Moreover, the bi-layer encapsulation separates the permeated moisture (mostly at the Al2O3 and Parylene interface) from the surface contaminants (mostly at the device and Al2O3 interface), preventing the formation of localized electrolyte through condensation. Al2O3 works as an inner moisture barrier and Parylene works as an external ion barrier, preventing contact of AI2O3 with liquid water, and slowing the kinetics of alumina corrosion. Selective removal of encapsulation materials is required to expose the active sites for interacting with physiological environment. A self-aligned mask process with three steps was developed to expose active sites, composed of laser ablation, oxygen plasma etching, and BOE etching. Al2O3 layer was found to prevent the formation of microcracks in the iridium oxide film during laser ablation. Bi-layer encapsulated iridium oxide had higher charge injection capacity and similar electrochemical impedance compared with Parylene C coated iridium oxide film after deinsulation. The Al2O3 and Parylene C bi-layer encapsulation was applied to Utah electrode array (UEA)-based neural interfaces to study its long-term performance. The median tip impedance of the bi-layer encapsulated wired Utah electrode array increased slowly during the 960 days of equivalent soak testing at 37 °C. Impedance for Parylene coated UEA dropped 50% to 75% within 6 months. In addition, bi-layer coated fully integrated Utah array-based wireless neural interfaces had stable power-up frequencies at ~910 MHz and constant RF signal strength of -50 dBm during the 1044 days of equivalent soaking time at 37 °C. This is much longer than lifetime achieved with Parylene C coating, which was about one year at room temperature

Investigation and development of titanium nitride solid-state potentiometric pH sensor

The measurement of pH value is crucial parameter in various fields like, drinking water monitoring, food preparation, biomedical and environmental applications. The most common device for pH sensing is the conventional pH glass electrode. While glass electrodes have several advantages, such as Nernstian sensitivity, superior ion selectivity, excellent stability, and extensive operating range, they have several key disadvantages. pH glass electrodes need to be stored in buffer solutions, they are fragile and have limited size and shape, making them impractical for some applications, such as being potentially used as miniature pH sensors for capsule endoscopy and ambulatory esophageal pH monitoring. To address these issues of limitations of glass electrodes, various metal oxides have been investigated and proposed as potential electrode materials for the development of pH sensors. Solid metal sensors offer unique features such as insolubility, stability, mechanical strength, and possibility of miniaturization. However, the main drawback of the metal oxide pH sensors is the interference caused by oxidizing and reducing agents present in some sample solutions. To reduce the redox interference, metal nitride solid sensors were investigated in this project with the potential for the development of high-sensitivity pH sensing electrodes. Metal nitrides are refractory, have high melting points and interstitial defects, and, at room temperature, they are chemically stable and resist hydrolysis caused by weak acids. There are many reports on different metal nitrides electrodes in literature, of which several have been previously investigated for use as pH sensors. Here, specifically, thin films of titanium nitride (TiN) were manufactured using radio frequency magnetron sputtering. The effect of sputtering parameters (e.g., thickness, sputter power, gas composition) were investigated to optimize the materials for use as pH sensor. Additionally, the underlining mechanism governing the pH sensitivity of these metal nitrides was investigated by examining the pH sensing properties (i.e., sensitivity, hysteresis, and drift) and the effect of redox agents. The successfully optimized material was then used to construct and demonstrate the concept of a solid-state pH sensor using an appropriate reference electrode. The solid-state TiN sensor paves the way for future development of a miniaturised pH sensor capsule for biomedical applications or lab-on-a-chip pH sensor for environmental and industrial applications. Expending the realms of pH monitoring, currently limited by the glass pH electrode

Nano-Micro Tubes & Fibers for Biomedical Applications

Polymer based nanometer to micrometer size fibers and tubes are the bases for a wide range of industrial and medical applications and various research branches. They are capable of guiding light, carrying electricity and liquid or exchanging heat. Two production systems were established and built. These systems enable us to produce a wide range of tiny tubes & fibers. Light, nano-micro tubes & fibers, beads, nanoparticles and biological entities and agents (e.g. cells, antibodies and nerve growth factor) were used in this master work. The main focus in this work is on nerve regenerative implants and neural electrodes

Multimodal Investigation of the Efficiency and Stability of Microstimulation using Electrodes Coated with PEDOT/CNT and Iridium Oxide

Electrical microstimulation is an invaluable tool in neuroscience research to dissect neural circuits, relate brain areas, and identify relationships between brain structure and behavior. In the clinic, electrical microstimulation has enabled partial restoration of vision, movement, sensation and autonomic functions. Recently, novel materials and new fabrication techniques of traditional metals have emerged such as iridium oxide and the conducting polymer PEDOT/CNT. These materials have demonstrated particular promise in the improvement in electrical efficiency. However, the in vivo stimulation efficiency and the in vivo stability of these materials have not been thoroughly characterized. In this dissertation, we use a multimodal approach to study the efficiency and stability of electrode-tissue interface using novel materials in microstimulation

Synthesis and characterization of Titanium Nitride Nanowires for neural-electrode coatings for improving electrode/neuron interface in the brain

In neurophysiological measurements, a neural-electrode interface material plays a critical role in delivering adequate charge to elicit action potentials without damaging the tissue of interest. However, the need to minimise electrode dimensions to reduce invasiveness and increase selectivity, demands the use of materials that are able to handle larger current and charge densities than traditional noble electrodes such as platinum. Since charge density is directly affected by the surface area of the electrode, nanoscale materials have shown a great deal of potential for not just improving the electrochemical properties, but the biocompatibility at reduced electrode dimensions. Titanium Nitride thin film (TiN) has been implemented previously in neural-electrode application due to its apposite properties. The work described here is aimed towards the synthesis of a novel TiN Nanowire interface (TiN-NW) as a potential neural-electrode material. The synthesis of the nanowires involved a three-step approach: (1) sputter of TiN thin film onto a substrate to act as a seed layer for the growth of NWs, (2) the growth of titanium dioxide nanowires (TiO2-NWs) of high aspect ratio and crystallinity followed by (3) a novel plasma nitridation step using Plasma Enhanced Chemical Vapour Deposition (PECVD) which offered a lower synthesis temperature than the conventional processing temperature reported in the literature. An optimised TiN thin film, grown through Radio Frequency (RF) non-reactive magnetron sputtering, was used as a seeding layer for the growth of NWs. The properties of the seed layer and the grown NWs were studied by scanning electron microscopy (SEM), atomic force microscopy (AFM), X-Ray diffraction (XRD), Raman spectroscopy, X-Ray photoelectron spectroscopy (XPS), and transmission electron microscopy (TEM) while the suitability of the grown TiN-NWs as an electrode material was tested by studying their electrochemical performance through cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). In addition, the biocompatibility of both structures were tested by culturing glioblastoma cells (GBM) in vitro, and cell viability and behaviour were studied and compared to that on TiN thin film. xv XPS and TEM results showed that TiO2-NWs were converted to TiN-NWs at a temperature of 600 °C. Electrochemical results showed 5-fold of capacitance enhancement of the synthesised TiN-NWs as compared to that of the optimised TiN film. Additionally, TiN-NWs have shown greater cyclic stability, with capacitance retention of almost 99%, and lowered susceptibility to oxidation compared to TiN thin films. The impedance of TiN-NWs electrode at low frequencies, corresponding to ion diffusion, was noticeably lower than that of the film electrode. The in vitro test showed that cells were viable and attached to both structures and the cells on NWs formed dense 3D structures and had a greater spatial distribution than those cultured on the thin film layer. These findings not only highlighted the potential use of TiN-NWs as a neural-electrode interface material but also suggested a way of reducing the nitridation temperature to obtain TiN through PECVD process, which can improve existing electrodes or be integrated into next-generation neural-electrode structures.Royal Embassy of Saudi Arabia Cultural Bureau

Sensitivity and packaging improvement of an LCP pressure sensor for intracranial pressure measurement via FEM simulation

A biocompatible liquid crystal polymer (LCP) pressure sensor is proposed for measuring intracranial pressure (ICP) in Traumatic Brain Injury (TBI) patients. Finite element method using COMSOL multiphysics is employed to study the mechanical behavior of the packaged LCP pressure sensor in order to optimize the sensor design. A 3D model of the 8x8x0.2 mm LCP pressure sensor is simulated to investigate the parameters that significantly influence the sensor characteristics under the uniform pressure range of 0 to 50 mmHg. The simulation results of the new design are compared to the experimental results from a previous design. The result shows that reducing the thickness of the sensing membrane can increase the sensitivity up to six times of that previously reported. An improvement of fabrication methodology is proposed to complete the LCP packaging

Exploration of carbon nanotube composites and piezoelectric materials for implantable devices

This thesis describes an exploration of carbon nanotube (CNT) nanocomposites for application in implantable medical devices. The focus here is on materials and structures of interest as components of devices incorporating electrodes. Electrodes for implantable devices are commonly required to interface between an electrical system, where the charge carriers are electrons presented through a metal, and human tissue, where the charge carriers are ions as well as electrons not in a metal. These interfaces are found to be prone to issues such as fibrosis and rejection. The properties of carbon nanomaterials, piezoelectric peptides/polymers and their composites suggest them as promising candidate materials that could resolve these issues. The superior conductivity, mechanical properties and chemical stability of carbon nanotubes have been explored in recent years for potential application in biomedical sensors and devices. This work has explored piezoelectric materials, carbon nanotubes, polymers and nanocomposites of these as potential components of implantable devices. Diphenylalanine is a chiral, amphiphilic dipeptide molecule which has the ability to self-assemble into piezoelectric microtubules. The self-assembly process of diphenylalanine microtubules has been explored and its properties have been compared to the properties of poly[vinylidenefluoride-co-trifluoroethylene] (P[VDF-TrFE]) electrospun nanofibres. Later parts of this work considered the deposition of electrodes by printing. The development of CNT-polymer nanocomposites as printable inks for the fabrication of electrodes was explored. The structure and properties of the piezoelectric nano/ micro-materials, CNT-peptide complex and conductive CNT-polymer printable inks were characterised by a range of microscopic and spectroscopic techniques. The viability of neural cells on the developed functional materials and electrodes were tested by metabolic activity measurements and immunochemical staining microscopy. A CNT-polymer ink demonstrated good conductivity and dimensional stability when printed by 3D printer. Good biocompatibility of all the functional materials developed have been demonstrated in vitro, showing promise for further development of soft electrodes and applications in nanostructure piezoelectric sensors and implantable devices