Magnetic Resonance Imaging Compatibility of the Polymer-based Cochlear Implant

ObjectivesIn this study, we compared the magnetic resonance (MR) image artifacts caused by a conventional metal-based cochlear implant and a newly developed liquid crystal polymer (LCP)-based device.MethodsThe metal-based cochlear implant system (Nurobiosys Co.) was attached to side of the head of a subject and the LCP-based device was attached to opposite side. In both devices, alignment magnets were removed for safety. Magnetic resonance imaging (MRI) was performed on a widely used 3.0 T and an ultra-high 7.0 T MRI machine. 3.0 and 7.0 T MR images were acquired using T1- and T2*-weighted gradient echo sequences, respectively.ResultsIn the 3.0 T images, the metal-based device on the left side generated the significant amount of artifacts. The MR images in the proximity of the metal package were obscured by the artifacts in both axial and sagittal views. On the other hand, the MR images near the LCP-based device were relatively free from the artifacts and clearly showed the brain structures. 7.0 T MR images showed the more severe distortion in the both sides but the metal-based cochlear implant system caused a much larger obscure area than the LCP-based system.ConclusionThe novel LCP-based cochlear implant provides a good MRI compatibility beyond present-day cochlear implants. Thus, MR images can be obtained from the subjects even with the implanted LCP-based neural prosthetic systems providing useful diagnostic information. Furthermore, it will be also useful for functional MRI studies of the auditory perception mechanism after cochlear implantations as well as for positron emission tomography-MRI hybrid imaging

액정폴리머를 기반의 소형, 안구밀착형, 장기안정적인 인공망막장치

학위논문 (박사)-- 서울대학교 대학원 : 전기·컴퓨터공학부, 2015. 8. 김성준.A novel retinal prosthetic device was developed using liquid crystal polymer (LCP) to address the problems associated with conventional metal- and polymer-based devices: the hermetic metal package is bulky, heavy and labor-intensive, whereas a thin, flexible and MEMS-compatible polymer-based system is not durable enough for chronic implantation. Exploiting the advantageous properties of LCP such as a low moisture absorption rate, thermo-bonding and thermo-forming, a small, light-weight, long-term reliable retinal prosthesis was fabricated that can be conformally attached on the eye-surface. A LCP fabrication process using monolithic integration and conformal deformation was established enabling miniaturization and a batch manufacturing process as well as eliminating the need for feed-through technology. The fabricated 16-channels LCP-based retinal implant had 14 mm-diameter with the maximum thickness of 1.4 mm and weight of 0.4 g and could be operated wirelessly up to 16 mm of distance in the air. The long-term reliability of the all-LCP retinal device was evaluated in vitro as well as in vivo. Because an all-polymer implant introduces intrinsic gas permeation for which the traditional helium leak test for metallic packages was not designed to quantify, a new set of reliability tests were designed and carried out specifically for all-polymer implants. Moisture ingress through various pathways were classified into polymer surface, polymer-polymer and polymer-metal adhesions each of which were quantitatively investigated by analytic calculation, in vitro aging test of electrode part and package part, respectively. The functionality and long-term implantation stability of the device was verified through in vivo animal experiments by measuring the cortical potential and monitoring implanted dummy devices for more than a year, respectively. Samples of the LCP electrodes array failed after 114 days in 87°C salin as a result of water penetration through the LCP-metal interface. An eye-confirmable LCP package survived more than 35 days in an accelerated condition at 87°C. The in vivo results confirmed that no adverse effects around the retina were observed after implantation of the device for more than a year.ABSTRACT i Contents iv List of Figures xi List of Tables xxi Chapter 1 : Introduction 1 1.1. Neuroprosthetic devices 1 1.2. Retinal prosthesis 2 1.2.1. Concept 2 1.2.2. Three approaches 3 1.2.3. Camera vs. Photodiode 4 1.3. Conventional devices 5 1.4. Liquid Crystal Polymer (LCP) 7 1.4.1. Low moisture absorption and permeability 9 1.4.2. Thermoplastic property 9 1.4.3. Compatibility with MEMS technologies 10 1.4.4. RF characteristics 10 1.5. LCP-based retinal prosthesis 11 1.6. Long-term reliability 12 1.7. Dissertation outline 14 Chapter 2: Methods 16 2.1. System Overview 16 2.2. Microfabrication on LCP 18 2.2.1. Limitations of the previous microfabrication technique on LCP 19 2.2.2. Improved LCP-based microfabrication 22 2.2.2.1. Electroplated micro-patterning 23 2.2.2.2. Laser-thinning for higher flexibility 24 2.2.2.3. Laser-ablation for site opening 25 2.3. All-LCP Monolithic Fabrication 26 2.3.1. Multilayered integration 29 2.3.1.1. Electrical components 29 2.3.1.2. Thermal lamination 32 2.3.1.3. Layer configuration 34 2.3.2. Thermal deformation 35 2.3.2.1. Deformation process 35 2.3.2.2. Wavy lines for stretchability 36 2.3.2.3. Electrical properties of the deformed coil 40 2.3.3. Circuit Assembly 40 2.3.3.1. Stimulation ASIC 40 2.3.3.2. Surrounding circuitries 41 2.3.4. Packaging 43 2.3.5. Laser Machining 44 2.4. Device characterization 44 2.4.1. Transmitter Circuit and Wireless Operation 45 2.4.1.1. Transmitter circuit 45 2.4.1.2. Transmitter coil 46 2.4.1.3. Wireless operation test 46 2.4.2. Electrochemical measurements 48 2.5. Long-term reliability tests in vitro 49 2.5.1. Failure mechanisms of an all-LCP device 49 2.5.2. Analytic calculation 51 2.5.3. Long-term reliability tests in accelerated environment 55 2.5.3.1. Long-term reliability of electrode array 55 2.5.3.2. Long-term reliability of package 57 2.5.3.3. Long-term reliability of complete device 58 2.5.4. Long-term electrochemical stability 59 2.6. Acute and Chronic Evaluation in vivo 60 2.6.1. Surgical implantation 60 2.6.2. Acute functionality test 62 2.6.3. Long-term implantation stability 63 Chapter 3: Results 64 3.1. Microfabrication on LCP 64 3.1.1. Electroplated micro-patterning 64 3.1.2. Laser-ablation for site opening 67 3.1.3. Laser-thinning for higher flexibility 69 3.2. All-LCP Monolithic fabrication 71 3.2.1. Multilayered integration 71 3.2.2. Thermal deformation 73 3.2.2.1. Deformation results 73 3.2.2.2. Wavy lines for stretchability 74 3.2.2.3. Effect on the electrical properties 74 3.2.3. Circuit assembly 76 3.2.4. Packaging 77 3.2.5. Laser machining 79 3.3. Device Characterization 80 3.3.1. General specifications 81 3.3.2. Transmitter circuit and coil 83 3.3.3. Wireless operation 83 3.3.4. Electrochemical measurements 84 3.4. Long-term reliability tests in vitro 86 3.4.1. Analytic calculation 87 3.4.2. Long-term reliability tests in accelerated condition 90 3.4.2.1. Long-term reliability of electrode arrays 90 3.4.2.2. Long-term reliability of package 92 3.4.2.3. Long-term reliability of complete device 93 3.4.3. Long-term Electrochemical stability 93 3.5. Acute and chronic evaluation in vivo 95 3.5.1. Surgical implantation 95 3.5.2. Acute functionality test 96 3.5.3. Long-term implantation stability 97 Chapter 4: Discussion 100 4.1. Comparison with conventional devices 100 4.2. Potential applications 102 4.3. Opportunities for further improvements 102 4.4. Long-term reliability 104 Chapter 5: Conclusion 108 Reference 110 국문초록 118 감사의 글 121Docto

A Fully Implantable Miniaturized Liquid Crystal Polymer (LCP)-Based Spinal Cord Stimulator for Pain Control

Spinal cord stimulation is a therapy to treat the severe neuropathic pain by suppressing the pain signal via electrical stimulation of the spinal cord. The conventional metal packaged and battery-operated implantable pulse generator (IPG) produces electrical pulses to stimulate the spinal cord. Despite its stable operation after implantation, the implantation site is limited due to its bulky size and heavy weight. Wireless communications including wireless power charging is also restricted, which is mainly attributed to the electromagnetic shielding of the metal package. To overcome these limitations, here, we developed a fully implantable miniaturized spinal cord stimulator based on a biocompatible liquid crystal polymer (LCP). The fabrication of electrode arrays in the LCP substrate and monolithically encapsulating the circuitries using LCP packaging reduces the weight (0.4 g) and the size (the width, length, and thickness are 25.3, 9.3, and 1.9 mm, respectively). An inductive link was utilized to wirelessly transfer the power and the data to implanted circuitries to generate the stimulus pulse. Prior to implantation of the device, operation of the pulse generator was evaluated, and characteristics of stimulation electrode such as an electrochemical impedance spectroscopy (EIS) were measured. The LCP-based spinal cord stimulator was implanted into the spared nerve injury rat model. The degree of pain suppression upon spinal cord stimulation was assessed via the Von Frey test where the mechanical stimulation threshold was evaluated by monitoring the paw withdrawal responses. With no spinal cord stimulation, the mechanical stimulation threshold was observed as 1.47 ± 0.623 g, whereas the stimulation threshold was increased to 12.7 ± 4.00 g after spinal cord stimulation, confirming the efficacy of pain suppression via electrical stimulation of the spinal cord. This LCP-based spinal cord stimulator opens new avenues for the development of a miniaturized but still effective spinal cord stimulator.ope

소형동물의 뇌신경 자극을 위한 완전 이식형 신경자극기

학위논문(박사)--서울대학교 대학원 :공과대학 전기·정보공학부,2020. 2. 김성준.In this study, a fully implantable neural stimulator that is designed to stimulate the brain in the small animal is described. Electrical stimulation of the small animal is applicable to pre-clinical study, and behavior study for neuroscience research, etc. Especially, behavior study of the freely moving animal is useful to observe the modulation of sensory and motor functions by the stimulation. It involves conditioning animal's movement response through directional neural stimulation on the region of interest. The main technique that enables such applications is the development of an implantable neural stimulator. Implantable neural stimulator is used to modulate the behavior of the animal, while it ensures the free movement of the animals. Therefore, stable operation in vivo and device size are important issues in the design of implantable neural stimulators. Conventional neural stimulators for brain stimulation of small animal are comprised of electrodes implanted in the brain and a pulse generation circuit mounted on the back of the animal. The electrical stimulation generated from the circuit is conveyed to the target region by the electrodes wire-connected with the circuit. The devices are powered by a large battery, and controlled by a microcontroller unit. While it represents a simple approach, it is subject to various potential risks including short operation time, infection at the wound, mechanical failure of the device, and animals being hindered to move naturally, etc. A neural stimulator that is miniaturized, fully implantable, low-powered, and capable of wireless communication is required. In this dissertation, a fully implantable stimulator with remote controllability, compact size, and minimal power consumption is suggested for freely moving animal application. The stimulator consists of modular units of surface-type and depth-type arrays for accessing target brain area, package for accommodating the stimulating electronics all of which are assembled after independent fabrication and implantation using customized flat cables and connectors. The electronics in the package contains ZigBee telemetry for low-power wireless communication, inductive link for recharging lithium battery, and an ASIC that generates biphasic pulse for neural stimulation. A dual-mode power-saving scheme with a duty cycling was applied to minimize the power consumption. All modules were packaged using liquid crystal polymer (LCP) to avoid any chemical reaction after implantation. To evaluate the fabricated stimulator, wireless operation test was conducted. Signal-to-Noise Ratio (SNR) of the ZigBee telemetry were measured, and its communication range and data streaming capacity were tested. The amount of power delivered during the charging session depending on the coil distance was measured. After the evaluation of the device functionality, the stimulator was implanted into rats to train the animals to turn to the left (or right) following a directional cue applied to the barrel cortex. Functionality of the device was also demonstrated in a three-dimensional maze structure, by guiding the rats to navigate better in the maze. Finally, several aspects of the fabricated device were discussed further.본 연구에서는 소형 동물의 두뇌를 자극하기 위한 완전 이식형 신경자극기가 개발되었다. 소형 동물의 전기자극은 전임상 연구, 신경과학 연구를 위한 행동연구 등에 활용된다. 특히, 자유롭게 움직이는 동물을 대상으로 한 행동 연구는 자극에 의한 감각 및 운동 기능의 조절을 관찰하는 데 유용하게 활용된다. 행동 연구는 두뇌의 특정 관심 영역을 직접적으로 자극하여 동물의 행동반응을 조건화하는 방식으로 수행된다. 이러한 적용을 가능케 하는 핵심기술은 이식형 신경자극기의 개발이다. 이식형 신경자극기는 동물의 움직임을 방해하지 않으면서도 그 행동을 조절하기 위해 사용된다. 따라서 동물 내에서의 안정적인 동작과 장치의 크기가 이식형 신경자극기를 설계함에 있어 중요한 문제이다. 기존의 신경자극기는 두뇌에 이식되는 전극 부분과, 동물의 등 부분에 위치한 회로부분으로 구성된다. 회로에서 생산된 전기자극은 회로와 전선으로 연결된 전극을 통해 목표 지점으로 전달된다. 장치는 배터리에 의해 구동되며, 내장된 마이크로 컨트롤러에 의해 제어된다. 이는 쉽고 간단한 접근방식이지만, 짧은 동작시간, 이식부위의 감염이나 장치의 기계적 결함, 그리고 동물의 자연스러운 움직임 방해 등 여러 문제점을 야기할 수 있다. 이러한 문제의 개선을 위해 무선통신이 가능하고, 저전력, 소형화된 완전 이식형 신경자극기의 설계가 필요하다. 본 연구에서는 자유롭게 움직이는 동물에 적용하기 위하여 원격 제어가 가능하며, 크기가 작고, 소모전력이 최소화된 완전이식형 자극기를 제시한다. 설계된 신경자극기는 목표로 하는 두뇌 영역에 접근할 수 있는 표면형 전극과 탐침형 전극, 그리고 자극 펄스 생성 회로를 포함하는 패키지 등의 모듈들로 구성되며, 각각의 모듈은 독립적으로 제작되어 동물에 이식된 뒤 케이블과 커넥터로 연결된다. 패키지 내부의 회로는 저전력 무선통신을 위한 지그비 트랜시버, 리튬 배터리의 재충전을 위한 인덕티브 링크, 그리고 신경자극을 위한 이상성 자극파형을 생성하는 ASIC으로 구성된다. 전력 절감을 위해 두 개의 모드를 통해 사용률을 조절하는 방식이 장치에 적용된다. 모든 모듈들은 이식 후의 생물학적, 화학적 안정성을 위해 액정 폴리머로 패키징되었다. 제작된 신경자극기를 평가하기 위해 무선 동작 테스트가 수행되었다. 지그비 통신의 신호 대 잡음비가 측정되었으며, 해당 통신의 동작거리 및 데이터 스트리밍 성능이 검사되었고, 장치의 충전이 수행될 때 코일간의 거리에 따라 전송되는 전력의 크기가 측정되었다. 장치의 평가 이후, 신경자극기는 쥐에 이식되었으며, 해당 동물은 이식된 장치를 이용해 방향 신호에 따라 좌우로 이동하도록 훈련되었다. 또한, 3차원 미로 구조에서 쥐의 이동방향을 유도하는 실험을 통하여 장치의 기능성을 추가적으로 검증하였다. 마지막으로, 제작된 장치의 특징이 여러 측면에서 심층적으로 논의되었다.Chapter 1 : Introduction 1 1.1. Neural Interface 2 1.1.1. Concept 2 1.1.2. Major Approaches 3 1.2. Neural Stimulator for Animal Brain Stimulation 5 1.2.1. Concept 5 1.2.2. Neural Stimulator for Freely Moving Small Animal 7 1.3. Suggested Approaches 8 1.3.1. Wireless Communication 8 1.3.2. Power Management 9 1.3.2.1. Wireless Power Transmission 10 1.3.2.2. Energy Harvesting 11 1.3.3. Full implantation 14 1.3.3.1. Polymer Packaging 14 1.3.3.2. Modular Configuration 16 1.4. Objectives of This Dissertation 16 Chapter 2 : Methods 18 2.1. Overview 19 2.1.1. Circuit Description 20 2.1.1.1. Pulse Generator ASIC 21 2.1.1.2. ZigBee Transceiver 23 2.1.1.3. Inductive Link 24 2.1.1.4. Energy Harvester 25 2.1.1.5. Surrounding Circuitries 26 2.1.2. Software Description 27 2.2. Antenna Design 29 2.2.1. RF Antenna 30 2.2.1.1. Design of Monopole Antenna 31 2.2.1.2. FEM Simulation 31 2.2.2. Inductive Link 36 2.2.2.1. Design of Coil Antenna 36 2.2.2.2. FEM Simulation 38 2.3. Device Fabrication 41 2.3.1. Circuit Assembly 41 2.3.2. Packaging 42 2.3.3. Electrode, Feedthrough, Cable, and Connector 43 2.4. Evaluations 45 2.4.1. Wireless Operation Test 46 2.4.1.1. Signal-to-Noise Ratio (SNR) Measurement 46 2.4.1.2. Communication Range Test 47 2.4.1.3. Device Operation Monitoring Test 48 2.4.2. Wireless Power Transmission 49 2.4.3. Electrochemical Measurements In Vitro 50 2.4.4. Animal Testing In Vivo 52 Chapter 3 : Results 57 3.1. Fabricated System 58 3.2. Wireless Operation Test 59 3.2.1. Signal-to-Noise Ratio Measurement 59 3.2.2. Communication Range Test 61 3.2.3. Device Operation Monitoring Test 62 3.3. Wireless Power Transmission 64 3.4. Electrochemical Measurements In Vitro 65 3.5. Animal Testing In Vivo 67 Chapter 4 : Discussion 73 4.1. Comparison with Conventional Devices 74 4.2. Safety of Device Operation 76 4.2.1. Safe Electrical Stimulation 76 4.2.2. Safe Wireless Power Transmission 80 4.3. Potential Applications 84 4.4. Opportunities for Further Improvements 86 4.4.1. Weight and Size 86 4.4.2. Long-Term Reliability 93 Chapter 5 : Conclusion 96 Reference 98 Appendix - Liquid Crystal Polymer (LCP) -Based Spinal Cord Stimulator 107 국문 초록 138 감사의 글 140Docto

완전 이식형 시각 보철 시스템을 위한 연구

학위논문(박사)--서울대학교 대학원 :공과대학 전기·정보공학부,2020. 2. 김성준.A visual prosthetic system typically consists of a neural stimulator, which is a surgically implantable device for electrical stimulation intended to restore the partial vision of blind patients, and peripheral external devices including an image sensor, a controller, and a processor. Although several visual prosthetic systems, such as retinal prostheses or retinal implants, have already been commercialized, there are still many issues on them (e.g., substrate materials for implantable units, electrode configurations, the use of external hardware, power supply and data transmission methods, design and fabrication approaches, etc.) to be dealt with for an improved visual prosthetic system. In this dissertation, a totally implantable visual prosthetic system is suggested with four motivations, which are thought to be important, as in the following: 1) simple fabrication of implantable parts, such as micro-sized electrodes and a case, for a neural stimulator based on polymer without semiconductor techniques, 2) multi-polar stimulation for virtual channel generation to overcome a limited number of physical electrodes in a confined space, 3) a new image acquisition strategy using an implantable camera, and 4) power supply as well as data transmission to a neural stimulator without hindering patients various activities. First, polymer materials have been widely used to develop various implantable devices for visual prosthetic systems because of their outstanding advantages including flexibility and applicability to microfabrication, compared with metal, silicon, or ceramic. Most polymer-based implantable devices have been fabricated by the semiconductor technology based on metal deposition and photolithography. This technology provides high accuracy and precision for metal patterning on a polymer substrate. However, the technology is also complicated and time-consuming as it requires masks for photolithography and vacuum for metal deposition as well as huge fabrication facilities. This is the reason why biocompatible cyclic olefin polymer (COP) with low water absorption (<0.01 %) and high light transmission (92 %) was chosen as a new substrate material of an implantable device in this study. Based on COP, simple fabrication process of an implantable device was developed without masks, vacuum, and huge fabrication facilities. COP is characterized by strong adhesion to gold and high ultraviolet (UV) transparency as well. Because of such adhesion and UV transparency, a gold thin film can be thermally laminated on a COP substrate with no adhesion layer and micromachined by a UV laser without damaging the substrate. Using the developed COP-based process, a depth-type microprobe was fabricated first, and its electrochemical and mechanical properties as well as functionality were evaluated by impedance measurements, buckling tests, and in vivo neural signal recording, respectively. Furthermore, the long-term reliability of COP encapsulation formed by the developed process was estimated through leakage current measurements during accelerated aging in saline solution, to show the feasibility of the encapsulation using COP as well. Second, even if stimulation electrodes become sufficiently small, it is demanding to arrange them for precise stimulation on individual neurons due to electrical crosstalk, which is the spatial superposition of electric fields generated by simultaneous stimuli. Hence, an adequate spacing between adjacent electrodes is required, and this causes a limited number of physical electrodes in a confined space such as in the brain or in the retina. To overcome this limitation, many researchers have proposed stimulation strategies using virtual channels, which are intermediate areas with large magnitudes of electric fields between physical electrodes. Such virtual channels can be created by multi-polar stimulation that can combine stimuli output from two or more electrodes at the same time. To produce more delicate stimulation patterns using virtual channels herein, penta-polar stimulation with a grid-shaped arrangement of electrodes was leveraged specially to generate them in two dimensions. This penta-polar stimulation was realized using a custom-designed integrated circuit with five different current sources and surface-type electrodes fabricated by the developed COP-based process. The effectiveness of the penta-polar stimulation was firstly evaluated by focusing electric fields in comparison to mono-polar stimulation. In addition, the distribution of electric fields changed by the penta-polar stimulation, which indicated virtual channel generation, was estimated in accordance with an amplitude ratio between stimuli of the two adjacent electrodes and a distance from them, through both finite element analysis and in vitro evaluation. Third, an implantable camera is herein proposed as a new image acquisition approach capturing real-time images while implanted in the eye, to construct a totally implantable visual prosthetic system. This implantable camera has distinct advantages in that it can provide blind patients with benefits to perform several ordinary activities, such as sleep, shower, or running, while focusing on objects in accordance with natural eye movements. These advantages are impossible to be achieved using a wearing unit such as a glasses-mounted camera used in a conventional partially implantable visual prosthetic system. Moreover, the implantable camera also has a merit of garnering a variety of image information using the complete structure of a camera, compared with a micro-photodiode array of a retinal implant. To fulfill these advantageous features, after having been coated with a biocompatible epoxy to prevent moisture penetration and sealed using a medical-grade silicone elastomer to gain biocompatibility as well as flexibility, the implantable camera was fabricated enough to be inserted into the eye. Its operation was assessed by wireless image acquisition that displayed a processed black and white image. In addition, to estimate reliable wireless communication ranges of the implantable camera in the body, signal-to-noise ratio measurements were conducted while it was covered by an 8-mm-thick biological medium that mimicked an in vivo environment. Lastly, external hardware attached on the body has been generally used in conventional visual prosthetic systems to stably deliver power and data to implanted units and to acquire image signals outside the body. However, there are common problems caused by this external hardware, including functional failure due to external damages, unavailability during sleep, in the shower, or while running or swimming, and cosmetic issues. Especially, an external coil for power and data transmission in a conventional visual prosthetic system is connected to a controller and processor through a wire, which makes the coil more vulnerable to the problems. To solve this issue, a totally implantable neural stimulation system controlled by a handheld remote controller is presented. This handheld remote controller can control a totally implantable stimulator powered by a rechargeable battery through low-power but relatively long-range ZigBee wireless communication. Moreover, two more functions can be performed by the handheld controller for expanded applications; one is percutaneous stimulation, and the other is inductive charging of the rechargeable battery. Additionally, simple switches on the handheld controller enable users to modulate parameters of stimuli like a gamepad. These handheld and user-friendly interfaces can make it easy to use the controller under various circumstances. The functionality of the controller was evaluated in vivo, through percutaneous stimulation and remote control especially for avian navigation, as well as in vitro. Results of both in vivo experiments were compared in order to verify the feasibility of remote control of neural stimulation using the controller. In conclusion, several discussions on results of this study, including the COP-based simple fabrication process, the penta-polar stimulation, the implantable camera, and the multi-functional handheld remote controller, are addressed. Based on these findings and discussions, how the researches in this thesis can be applied to the realization of a totally implantable visual prosthetic system is elucidated at the end of this dissertation.시각 보철 시스템은 일반적으로 실명 환자들의 부분 시력을 전기 자극으로 회복시키기 위하여 수술적으로 이식될 수 있는 장치인 신경 자극기와 이미지 센서 또는 컨트롤러, 프로세서를 포함하는 외부의 주변 장치들로 구성된다. 망막 보철 장치 또는 망막 임플란트와 같이 몇몇 시각 보철 시스템은 이미 상용화 되었지만, 여전히 더 나은 시각 보철 시스템을 위하여 다뤄져야 할 많은 이슈들 (예를 들어, 이식형 장치의 기판 물질, 전극의 배열, 외부 하드웨어의 사용, 전력 공급 및 데이터 전송 방법, 설계 및 제작 방식 등)이 있다. 본 학위논문은 완전 이식형 시각 보철 시스템을 제안하며, 이를 위하여 다음과 같이 중요하다고 생각되는 총 네 가지의 이슈들과 관련된 연구 내용을 다룬다. 1) 폴리머를 기반으로 한 신경 자극기의 미세 전극 및 패키지와 같은 이식 가능한 부분을 반도체 기술 없이 간단하게 제작하는 방법과 2) 제한된 공간에서 전극 개수의 물리적인 한계를 극복하기 위하여 가상 채널을 형성하는 다극성 자극 방식, 3) 이식형 카메라를 사용하는 새로운 이미지 획득 전략, 4) 환자의 다양한 활동을 방해하지 않으면서 신경 자극기에 전력을 공급하고 데이터를 전송하는 방법. 첫째로, 금속이나 실리콘, 세라믹에 비하여 폴리머는 유연성 및 미세 제작에의 적용 가능성을 포함하는 두드러진 이점들이 있기 때문에 시각 보철 시스템을 구성하는 다양한 이식 가능한 부분들에 널리 이용되었다. 대부분의 폴리머 기반 이식형 장치들은 금속 증착과 사진 식각을 기반으로 하는 반도체 공정으로 제작되었다. 이 공정은 폴리머 기판 위에 금속을 패터닝 하는 데에 있어서 높은 정확성과 정밀도를 제공한다. 하지만 그 공정은 또한, 사진 식각에 쓰이는 마스크와 금속 증착을 위한 진공뿐만 아니라 아주 큰 공정 설비를 요구하기 때문에 시간 소모가 심하고 복잡하다. 이는 본 연구에서 낮은 수분 흡수 (<0.01 %)와 높은 빛 투과 (92 %)를 특징으로 하는 생체적합한 고리형 올레핀 폴리머 (cyclic olefin polymer, COP)가 이식형 장치를 위한 새로운 기판 물질로써 선택된 이유이다. COP를 기반으로 하여, 마스크와 진공, 큰 공정 설비가 필요 없이 이식 가능한 장치를 간단하게 제작하는 공정이 개발되었다. COP는 금과의 강한 접합과 자외선에 대한 높은 투명성을 또 다른 특징으로 한다. 이와 같은 접합 특성과 자외선 투명성 덕분에, 금박은 COP 기판에 별도의 접합층 없이 열로 접합될 수 있을 뿐만 아니라 그 기판에 손상을 주지 않으면서 자외선 레이저를 통하여 미세하게 가공될 수 있다. 개발된 COP 기반의 공정을 처음으로 사용하여 침습형 미세 프로브가 제작되었고, 그 전기화학적, 기계적 특성과 기능성이 각각 임피던스 측정과 버클링 테스트, 생체 내 신경신호 기록으로 평가되었다. 그리고 COP를 사용한 밀봉의 가능성도 알아보기 위하여, 개발된 공정을 사용하여 형성된 COP 밀봉의 장기 안정성이 생리식염수에서의 가속 노화 중 누설 전류 측정을 통하여 추정되었다. 둘째로, 자극 전극의 크기가 충분히 작아진다고 하더라도, 동시에 출력되는 자극에 의해 형성되는 전기장의 중첩인 크로스 토크 때문에 개개의 신경세포를 정밀하게 자극하기 위하여 전극을 배열하는 것은 아주 어렵다. 따라서 인접한 전극 사이에 적당한 간격이 필요하게 되고, 이는 특히 뇌 또는 망막과 같은 제한된 공간에서 전극 개수의 물리적인 한계를 야기한다. 이 한계를 극복하기 위하여, 많은 연구자들은 실제 전극 사이에서 큰 전기장 세기를 갖는 중간 영역을 나타내는 가상 채널을 이용한 자극 전략을 제안하였다. 이러한 가상 채널은 둘 이상의 전극에서 동시에 출력되는 자극 파형을 합칠 수 있는 다극성 자극에 의하여 형성이 가능하다. 본 연구에서는 가상 채널을 이용하여 더 정교한 자극 패턴을 만들기 위하여, 특히 2차원에서의 가상 채널을 생성하고자 격자형 배열의 전극과 함께 5극성 자극이 사용되었다. 이 5극성 자극은 다섯 개의 서로 다른 전류원을 갖도록 맞춤 설계된 집적회로와 개발된 COP 기반 공정으로 제작된 평면형 전극을 사용하여 구현되었다. 먼저, 5극성 자극의 효과를 확인하고자 이 자극으로 전기장을 한 곳에 더 집중된 형태로 만들 수 있음이 단극성 자극과의 비교를 통하여 검증되었다. 그리고 유한 요소 분석과 생체 외 평가 둘 모두를 통하여, 5극성 자극으로 인한 가상 채널 형성을 뜻하는 전기장 분포가 인접한 두 전극에서 나오는 자극의 진폭비와 그 전극으로부터 떨어진 거리에 따라 변화됨이 추정되었다. 셋째로, 본 연구에서는 눈에 이식된 채로 실시간 이미지를 얻음으로써 완전 이식형 시각 보철 시스템을 구성하는 이식형 카메라를 새로운 이미지 획득 방식으로써 제안한다. 이 이식형 카메라는 실명 환자들이 자연스러운 눈의 움직임을 따라서 물체를 볼 수 있으며 잠이나 샤워, 달리기와 같은 일상적인 활동들을 방해 받지 않고 수행할 수 있도록 돕는다는 점에서 독특한 장점을 갖는다. 기존의 부분 이식형 시각 보철 시스템에서 쓰이는 안경 부착형 카메라와 같은 착용 장비로는 이러한 장점들을 얻을 수 없다. 게다가, 이식형 카메라는 망막 임플란트의 미세 포토다이오드 어레이와 달리 완전한 카메라 구조를 이용하여 다양한 이미지 정보를 획득할 수 있다는 장점을 갖는다. 이러한 이점들을 달성하기 위하여, 그 이식형 카메라는 수분 침투를 막고자 생체적합한 에폭시로 코팅되었고 생체적합성과 유연성을 얻기 위하여 의료용 실리콘 엘라스토머로 밀봉된 후에 눈에 충분히 삽입될 수 있는 형태 및 크기로 제작되었다. 이 장치의 동작은 흑백으로 처리된 이미지를 표시하는 무선 이미지 획득으로 시험되었다. 그리고 몸 안에서 이식형 카메라 갖는 안정적인 통신 거리를 측정하기 위하여, 장치가 생체 내 환경을 모사하기 위한 8 mm 두께의 생체 물질로 덮인 상태에서 그 장치의 신호 대 잡음비가 측정되었다. 마지막으로, 기존의 시각 보철 시스템에서 몸에 부착된 형태의 외부 하드웨어는 이식된 장치에 전력과 데이터를 안정적으로 전달하고 이미지 신호를 수집하기 위하여 일반적으로 사용되었다. 그럼에도 불구하고, 이러한 하드웨어는 외부로부터의 손상으로 인한 기능적인 결함과 수면 및 샤워, 달리기, 수영 활동 중 이용 불가능성, 외형적인 이슈 등을 포함하는 공통적인 문제들을 야기한다. 전력 및 데이터 전송을 위한 외부 코일은 시각 보철 시스템에서 컨트롤러와 프로세서에 유선으로 연결되고, 이러한 연결은 그 코일이 앞서 언급된 문제들에 특히 취약하게 만든다. 이러한 이슈를 해결하고자, 휴대용 무선 컨트롤러로 제어되는 완전 이식형 신경 자극 시스템이 제안된다. 이 휴대용 무선 컨트롤러는 저전력이지만 비교적 장거리 통신이 가능한 직비 (ZigBee) 무선 통신을 통하여 재충전 가능한 배터리로 동작하는 완전 이식형 자극기를 제어할 수 있다. 이 외에도, 이 휴대용 컨트롤러를 사용하면 폭넓은 응용을 위한 두 가지 기능을 추가로 수행할 수 있다. 하나는 유선 경피 자극이며, 다른 하나는 재충전 가능한 배터리의 유도 충전 기능이다. 또한, 이 휴대용 컨트롤러의 간단한 스위치를 사용하면 사용자는 게임패드와 같이 자극 파라미터를 쉽게 조절할 수 있다. 이러한 휴대 가능하고 사용자 친화적인 인터페이스를 통해 다양한 상황에서 그 컨트롤러를 쉽게 사용할 수 있다. 그 컨트롤러의 기능은 생체 외 평가뿐만 아니라 조류의 움직임 제어를 위한 유선 경피 자극 및 원격 제어를 통해 생체 내에서도 평가되었다. 또한, 그 컨트롤러를 사용한 원격 신경 자극 제어의 수행 가능성을 검증하기 위하여 두 생체 내 실험의 결과가 서로 비교되었다. 결론적으로, COP 기반의 간단한 제작 공정과 5극성 자극, 이식형 카메라, 휴대용 다기능 무선 컨트롤러를 포함하는 연구 결과에 대한 여러 논의가 이루어진다. 그리고 이러한 결과와 고찰에 기초하여, 본 학위논문의 연구가 완전 이식형 시각 보철 시스템의 구현에 어떻게 적용될 수 있는 지가 이 논문의 끝에서 상세히 설명된다.Abstract ------------------------------------------------------------------ i Contents ---------------------------------------------------------------- vi List of Figures ---------------------------------------------------------- xi List of Tables ----------------------------------------------------------- xx List of Abbreviations ------------------------------------------------ xxii Chapter 1. Introduction --------------------------------------------- 1 1.1. Visual Prosthetic System --------------------------------------- 2 1.1.1. Current Issues ------------------------------------------------- 2 1.1.1.1. Substrate Materials ---------------------------------------- 3 1.1.1.2. Electrode Configurations --------------------------------- 5 1.1.1.3. External Hardware ----------------------------------------- 6 1.1.1.4. Other Issues ------------------------------------------------- 7 1.2. Suggested Visual Prosthetic System ------------------------ 8 1.3. Four Motivations ---------------------------------------------- 10 1.4. Proposed Approaches ---------------------------------------- 11 1.4.1. Cyclic Olefin Polymer (COP) ------------------------------ 11 1.4.2. Penta-Polar Stimulation ----------------------------------- 13 1.4.3. Implantable Camera --------------------------------------- 16 1.4.4. Handheld Remote Controller ---------------------------- 18 1.5. Objectives of this Dissertation ------------------------------ 20 Chapter 2. Materials and Methods ----------------------------- 23 2.1. COP-Based Fabrication and Encapsulation -------------- 24 2.1.1. Overview ----------------------------------------------------- 24 2.1.2. Simple Fabrication Process ------------------------------- 24 2.1.3. Depth-Type Microprobe ---------------------------------- 26 2.1.3.1. Design ----------------------------------------------------- 26 2.1.3.2. Characterization ----------------------------------------- 27 2.1.3.3. In Vivo Neural Signal Recording ---------------------- 30 2.1.4. COP Encapsulation ---------------------------------------- 31 2.1.4.1. In Vitro Reliability Test ---------------------------------- 33 2.2. Penta-Polar Stimulation ------------------------------------- 34 2.2.1. Overview ---------------------------------------------------- 34 2.2.2. Design and Fabrication ----------------------------------- 35 2.2.2.1. Integrated Circuit (IC) Design ------------------------- 35 2.2.2.2. Surface-Type Electrode Fabrication ------------------ 38 2.2.3. Evaluations -------------------------------------------------- 39 2.2.3.1. Focused Electric Field Measurement ---------------- 42 2.2.3.2. Steered Electric Field Measurement ----------------- 42 2.3. Implantable Camera ----------------------------------------- 43 2.3.1. Overview ---------------------------------------------------- 43 2.3.2. Design and Fabrication ----------------------------------- 43 2.3.2.1. Circuit Design -------------------------------------------- 43 2.3.2.2. Wireless Communication Program ------------------ 46 2.3.2.3. Epoxy Coating and Elastomer Sealing -------------- 47 2.3.3. Evaluations ------------------------------------------------- 50 2.3.3.1. Wireless Image Acquisition --------------------------- 50 2.3.3.2. Signal-to-Noise Ratio (SNR) Measurement -------- 52 2.4. Multi-Functional Handheld Remote Controller --------- 53 2.4.1. Overview ---------------------------------------------------- 53 2.4.2. Design and Fabrication ----------------------------------- 53 2.4.2.1. Hardware Description ---------------------------------- 53 2.4.2.2. Software Description ----------------------------------- 57 2.4.3. Evaluations -------------------------------------------------- 57 2.4.3.1. In Vitro Evaluation -------------------------------------- 57 2.4.3.2. In Vivo Evaluation --------------------------------------- 59 Chapter 3. Results ------------------------------------------------- 61 3.1. COP-Based Fabrication and Encapsulation ------------- 62 3.1.1. Fabricated Depth-Type Microprobe ------------------- 62 3.1.1.1. Electrochemical Impedance -------------------------- 63 3.1.1.2. Mechanical Characteristics --------------------------- 64 3.1.1.3. In Vivo Neural Signal Recording --------------------- 66 3.1.2. COP Encapsulation --------------------------------------- 68 3.1.2.1. In Vitro Reliability Test --------------------------------- 68 3.2. Penta-Polar Stimulation ------------------------------------ 70 3.2.1. Fabricated IC and Surface-Type Electrodes ---------- 70 3.2.2. Evaluations ------------------------------------------------- 73 3.2.2.1. Focused Electric Field Measurement --------------- 73 3.2.2.2. Steered Electric Field Measurement ---------------- 75 3.3. Implantable Camera ---------------------------------------- 76 3.3.1. Fabricated Implantable Camera ----------------------- 76 3.3.2. Evaluations ------------------------------------------------ 77 3.3.2.1. Wireless Image Acquisition -------------------------- 77 3.3.2.2. SNR Measurement ------------------------------------ 78 3.4. Multi-Functional Handheld Remote Controller ------- 80 3.4.1. Fabricated Remote Controller ------------------------- 80 3.4.2. Evaluations ------------------------------------------------ 81 3.4.2.1. In Vitro Evaluation ------------------------------------ 81 3.4.2.2. In Vivo Evaluation ------------------------------------- 83 Chapter 4. Discussions ------------------------------------------ 86 4.1. COP-Based Fabrication and Encapsulation ------------ 87 4.1.1. Fabrication Process and Fabricated Devices -------- 87 4.1.2. Encapsulation and Optical Transparency ------------ 89 4.2. Penta-Polar Stimulation------------------------------------ 99 4.2.1. Designed IC and Electrode Configurations --------- 99 4.2.2. Virtual Channels in Two Dimensions ---------------- 101 4.3. Implantable Camera -------------------------------------- 102 4.3.1. Enhanced Reliability by Epoxy Coating ------------- 106 4.4. Multi-Functional Handheld Remote Controller ------ 107 4.4.1. Brief Discussions of the Two Extra Functions ------ 108 4.5. Totally Implantable Visual Prosthetic System --------- 113 Chapter 5. Conclusion ------------------------------------------ 117 References -------------------------------------------------------- 121 Supplements ------------------------------------------------------ 133 국문 초록 ----------------------------------------------------------- 143Docto

A Study on Low-Cost, Effective, and Reliable Liquid Crystal Polymer-Based Cochlear Implant System

학위논문 (박사)-- 서울대학교 대학원 : 전기·컴퓨터공학부, 2015. 2. 김성준.The pace of technological change in implantable devices such as cochlear implants, artificial retinas, and deep brain stimulators has been relatively slow compared to that in other areas, such as memory and mobile phones. Most implantable devices, including cochlear implants, still use bulky titanium electronic packages with complex fabrication processes and wire-based electrodes which are manually fabricated by skilled workers. As a result, the cost of these devices is very high and the widespread use of these devices is limited in low- and middle income countries. Innovative approaches are essential to make implantable devices as affordable as possible while not sacrificing their performance metrics. In this study, we adopt high-performance liquid crystal polymer (LCP) as a backbone for a novel polymer-based cochlear implant. As a material for cochlear implants, LCP enables new capabilities such as miniaturization, a simpler manufacturing process, better long-term reliability, and MRI compatibility, all of which are distinct from the properties of conventional cochlear implants. Moreover, LCP also enables an extremely low-cost device based on mass production with low materials and labor costs. In this study, we report a fabrication method for the creation of a LCP-based cochlear implant system. Specifically, LCP-based electronics and packaging techniques are addressed in detail. Previous studies of LCP-based packaging use a thermally deformed package cover to secure the electronics cavity and additional laser-cut LCP bonding layers with lower melting temperatures. This method, however, requires additional metal jigs to deform the package cover, and it requires a cavity-filling material such as PDMS. We applied a recessed cavity for the electronics with the stacking of laser-cut LCP multilayers. All packaging layers are composed of the same LCP films, which have a low melting temperature. Thus, the stacked multilayer structure itself acts as a bonding layer. This packaging technology enables the device packaging with a thin credit-card shape for miniaturized, simply fabricated and less invasive devices. Implantable electronics components were also fabricated using copper-clad LCP films with PCB technology. A patterned planar coil was integrated into an LCP electronics board to replace the thick platinum coil of the conventional implant, which is located outside of the metal package. Thus, we can reduce the device dimensions and realize a more efficient receiving coil with greater uniformity. Our group has developed an atraumatic 16-channel LCP-based cochlear electrode array using MEMS technology. This electrode array was used to develop the first functional prototype of an all-LCP-based cochlear implant system. We also evaluated the effectiveness of the developed LCP-based cochlear implant. The device was implanted into an animal model and the electrically evoked auditory brainstem response was successfully measured. We also verified the MRI compatibility of the LCP-based device compared to a metal-based implant, showing that the developed device has greatly superior MRI compatibility compared to a conventional metal-based device in a 3.0-T and an ultra-high 7.0-T MRI machine. In order to enhance the long-term reliability of the LCP-based device, we developed novel leak-barrier structures which have a nanoporous surface and microscale barriers with an anti-trapezoidal cross-sectional shape. This structure increases the water leakage path length and improves the mechanical interlocking force between the polymer and the metal layer. The reliability of the leak-barrier structure was determined by accelerated lifetime soak tests (110, 95, 75 °C). Preliminary results show that both the nanoporous surface and microscale barriers make significant contributions to improving the lifetime of the polymer-based electrode array. Lastly, we conducted a manufacturing cost analysis of the developed LCP-based cochlear implant system for a better understanding of the detailed cost structure and to determine if the cost could be reduced further. Our group also has experience in the development of cochlear implant systems, including titanium packages and wire-based electrode arrays similar to those in conventional devices, and the system developed by our group had been approved by the Korean FDA. The manufacturing costs of devices developed in the past were also analyzed for a comparison with the cost of an LCP-based device. The analysis revealed that the developed LCP-based cochlear implant has a significantly lower cost with regard to the materials. Also, the manufacturing cost per unit is approximately 10 % of the cost of a titanium-based cochlear implant. Also, the LCP-based device is a batch-processable product that therefore requires less labor. Thus, the manufacturing cost is greatly reduced in proportion to the overall production. This reduction in the manufacturing cost enables disruptive opportunities with regard to the use of cochlear implants in developing countries.Abstract Contents List of Figures List of Tables Chapter 1 Introduction 1.1 Overview of Cochlear Implants 1.2 Review of Cochlear Implant Research 1.3 Challenges for Future Cochlear Implant Systems 1.4 Proposed Cochlear Implant System 1.5 Objectives of the Dissertation Chapter 2 Materials and Methods 2.1 System Description 2.1.1 External Speech Processor 2.1.1.1 Hardware Design and Implementation based on Traditional Approach 2.1.1.2 Speech Processing Strategy for Cochlear Stimulation 2.1.1.3 Novel Speech Processor using Smartphone 2.2 Liquid Crystal Polymer (LCP)-Based Implantable Cochlear Implant System 2.2.1 Implantable Electronic Module for the LCP-based Cochlear Implant 2.2.1.1 Electronics Design 2.2.1.2 Electronics Fabrication and Assembly 2.2.2 Electronics Packaging for the LCP-based Cochlear Implant 2.2.3 LCP-based Thin-Film Cochlear Electrode Array 2.3 System Evaluation 2.3.1 Bench-Top Tests of the Fabricated LCP-based Cochlear Implant System 2.3.2 Preliminary In Vivo Animal Study 2.3.2.1 Animal Preparation 2.3.2.2 Experimental Setup and Protocol 2.3.3 In Vivo Animal Study 2.3.3.1 Animal Preparation 2.3.3.2 Improved Experimental Setup and Protocol 2.3.4 Magnetic Resonance Imaging Compatibility Tests 2.4 Leak-Free LCP-based Neural Electrode using Multiple Barrier Structures 2.4.1 Test Devices and Sample Categorization 2.4.2 Fabrication Methods 2.4.3 Electrochemical Characterization of the Electrode 2.4.4 Long-Term Reliability Test of the Leak-Free LCP-Based Neural Electrode 2.5 Manufacturing Cost Analysis 2.5.1 Overview of the Cost Structure 2.5.2 Comparative Analysis of the Manufacturing Cost of the LCP- and Titanium-Based Cochlear Implants Chapter 3 Results 3.1 Fabricated System 3.1.1 External Speech Processor 3.1.2 LCP-based Cochlear Implant 3.1.2.1 Packaging Process 3.1.2.2 Fabricated LCP-based Cochlear Implant 3.1.2.3 Bench-Top Test of the LCP-based Cochlear Implant 3.2 In Vivo Animal Study 3.3 Magnetic Resonance Imaging Compatibility 3.4 Leak-Free LCP-based Neural Electrode using Multiple Barrier Structures 3.4.1 Fabricated Electrode 3.4.2 Characterization of the Electrode 3.4.3 Long-Term Reliability 3.5 Comparative Analysis of the Manufacturing Cost of the LCP- and Titanium-based Cochlear Implants Chapter 4 Discussion 4.1 LCP-based Electronics Packaging 4.2 Comparison of LCP-Based Cochlear Implant to Conventional Metal-Based Cochlear Implant 4.3 Effectiveness of the LCP-Based Cochlear Implant 4.4 Reliability of the Titanium- and LCP-Based Neural Prostheses 4.5 MRI Compatibility 4.6 Manufacturing Cost Analysis Chapter 5 Conclusion References Abstract in Korean 162 감사의 글 166Docto

광 다이오드 기반 인공 망막 시스템을 위한 저전력 설계 및 LCP 패키징에 대한 연구

학위논문 (박사)-- 서울대학교 대학원 : 전기·컴퓨터공학부, 2017. 2. 김성준.The retinal prosthesis is an implantable electronic device that delivers electrical stimuli containing visual information to the retina for the visual restoration of the blinds. The currently available retinal prostheses have several problems in the number of pixels. They are limited in the number of pixels, which restricts the amount of visual information they can deliver. Many research groups are trying to improve their device in this aspect. In order to achieve a significant number of pixels, retinal prosthesis needs large stimulus power dissipation. A typical device consumes more than 20 mW of power to drive 1000 channels. Some of this power can lead to temperature rise which is a safety issue. As the power dissipation scales up with the increase in the number of channels, it is desired to minimize the power per channel as much as possible. Another problem is the absence of a suitable packaging material for the long-term reliable optical window. Due to the curved and narrow implant space available for this kind of device, as well as the transparency required for the incoming wavelengths of lights, it is quite difficult to choose a material that satisfies all requirements of long-term hermetic packaging with optically transparent window. Sapphire glass with titanium metal package are too bulky and rigid, and flexible transparent polymers such as polyimide and parylene-C have high moisture absorption for the implant. This dissertation proposes strategies and methods to solve the problems mentioned above. Two stimulation strategies are proposed. One strategy is to confine the stimulus level with a threshold that cell is activated. Thus we coin it as thresholding strategy.' The other strategy is to reduce the number of stimulation channels by using only outlines of images (outline extraction strategy). Prototype ICs were designed and fabricated for the verification of the effects of these strategies. The simulation and the measurement agree to show that retinal implant with the thresholding and outline extraction strategies consumes below one-third of the stimulus power of the conventional photodiode-based devices. Area-efficient designs of the voltage-controlled current source are also adopted to increase the number of channels. The unit pixel area of the fabricated prototype IC was 0.0072 mm2, expanding up to 1200-channels in the macular area. Liquid crystal polymer (LCP) is proposed as the long-term implantable packaging material with an optical window. It is an inert, biocompatible, and flexible polymer material that has a moisture absorption rate similar to Pyrex glass. We showed that an LCP film with a thickness less than 10 μm allows transmission of the lights in the visible wavelengths by more than 10 %, as the rate increases with thinner films. Thus a thinning process was developed. O2 DRIE was shown effective in reducing the roughness of the film, and the corresponding light scattering. The spatial resolution of LCP with 8.28 μm thickness showed a minimum distinguishable pitch of 90 μm, allowing a 1200 channel integration within a macular area.Chapter 1: Introduction 1 1.1. Retinal Prosthesis – State of the Arts 2 1.1.1. Retinal Prosthesis with External Camera 3 1.1.2. Retinal Prosthesis with Internal Photodiode Array 5 1.2. Photodiode-based Retinal Prosthesis 8 1.2.1. Problems 8 1.2.2. Possible Solutions 12 Chapter 2: Methods 17 2.1. Thresholding 17 2.1.1. Concept 17 2.1.2. Circuit Descriptions 19 2.2. Outline Extraction 28 2.2.1. Concept 28 2.2.2. Circuit Descriptions 30 2.3. Average Stimulus Power Estimation 40 2.3.1. Stimulus Patterns Generation of Conventional and Proposed Strategies 40 2.3.2. Minimum Distinguishable Channels to Recognize 41 2.4. Virtual Channel 43 2.4.1. Concept 43 2.4.2. Circuit Descriptions 44 2.5. Polymer Packaging 51 2.5.1. LCP as a Long-term Reliable Packaging Material 51 2.5.2. Test Methods 53 Chapter 3: Results 58 3.1. Thresholding 58 3.1.1. Fabricated IC 58 3.1.2. Test Setup 60 3.1.3. Test Results 61 3.2. Outline Extraction 65 3.2.1. Simulation Results 65 3.2.2. Fabricated IC 67 3.2.3. Test Setup 68 3.2.4. Test Results 72 3.3. Average Stimulus Power Estimation 76 3.4. Virtual Channels 79 3.4.1. Fabricated IC 79 3.4.2. Test Setup 80 3.4.3. Test Results 81 3.4.4. Two-dimensional Virtual Channel Generator– Test setup and Its Result 84 3.5. Polymer Packaging 87 3.5.1. Light Transmittance according to LCP Thickness 87 3.5.2. Thickness Control of LCP 89 3.5.3. Spatial Resolution of LCP 89 Chapter 4: Discussion 92 4.1. Average Stimulus Power 92 4.2. Visual Acuity 95 4.3. Hermeticity of the Thinned LCP Film 97 Chapter 5: Conclusion and Future Directions 99 References 103 Appendix – Generated Stimulus Patterns of Various the Number of Channels 112 국 문 초 록 139Docto

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

신경병증성 통증 조절을 위한 뇌 국소전위 기반의 폐회로 심부 뇌 자극 시스템 개발에 대한 연구

학위논문 (박사)-- 서울대학교 대학원 : 전기·컴퓨터공학부, 2015. 2. 김성준.심부 뇌 자극술은 뇌의 특정 부위를 전기적으로 자극함으로써 관련 신경질환들을 치료하는 신경외과적 기법이다. 이는 미국 식약처(FDA)의 승인을 받아 파킨슨씨 병, 경직장애, 우울증, 강박장애 등과 같은 다양한 질환 치료에 적용되고 있다. 그러나, 현 시스템은 개회로(開回路, open-loop)구조로, 환자의 증상 경중 여부와 무관한 동일 자극조건 전기신호를 인가함으로써, 조직에 무리를 주거나 시간에 따른 질환치료효과가 경감되는 등의 한계를 가지고 있다. 또한, 지속적인 전기자극파형을 발생시킴으로써 자극기 내의 배터리수명이 단축되어, 자극기 교체수술의 주기가 단축되어 환자의 불편을 야기하기도 한다. 이에, 본 연구는 신경병증성 통증의 증상 경중에 따라 자극조건을 조정하는 폐회로 (閉回路, closed-loop) 심부 뇌 자극시스템과 그 기반 기술을 개발하고자 하였다. 본 연구에서는 이를 위해 다채널 전극과 뇌 국소 전위 (Local field potential, LFP) 기반의 폐회로 심부 뇌 자극장치를 개발하였으며, 이와 관련된 기반 기술들을 개발하였다. 먼저, 다채널 전극을 집적하기 위하여 기존의 액정폴리머 공정을 개선하였다. 다음으로, 제작된 액정폴리머 기반의 다채널 심부 뇌 전극을 이용하여 다양한 자극 조건에 따른 통증모델 동물의 행동반응 실험과 신경신호의 변화들을 측정 및 분석함으로써 신경병증성 통증에의 효과적인 자극조건을 획득하였다. 그리고 두 실험방법론에 따라 얻어진 결과들간 연관성 분석 (Pearsons correlation analsys)을 수행함으로써 뇌 국소 전위의 특정 주파수에서의 변화가 신경병증성 통증의 신경신호 지표로 사용될 수 있음을 객관적으로 검증하였다. 이러한 결과들을 바탕으로 뇌 국소 전위 기반의 폐회로 제어 알고리즘을 개발하고, 이를 적용한 프로토타입 장치를 개발하였다. 개발된 폐회로 시스템의 효과와 성능을 검증하기 위하여, 시스템 동작성 시험과 함께 신경병증성 동물 모델에 적용하는 실험을 수행하였으며, 개발된 시스템이 통증 관련 뇌 국소 전위 신호의 발생과 그 정도에 따라 자동적으로 조정된 심부 뇌 자극을 인가하여 신경병증성 통증을 조절함을 확인하였다.Deep brain stimulation (DBS) is an effective therapy that can be used to alleviate symptoms of neuropathic disorders such as Parkinsons disease, essential tremor, dystonia, and neuropathic pain. Even though the method has matured for widespread implantation of the device worldwide, the therapeutic mechanisms of DBS are still unclear. Moreover, current DBS system is an open-loop system so a flexible and effective neuromodulation that depends on severity of patients symptoms is yet to be made available. The open-loop configuration also wastes power due to its continuous generation of stimulation current pulses, requiring frequent exchange of implanted battery. In this dissertation, we studied a local field potential-based closed-loop deep brain stimulation (CDBS) system and its use for controlling neuropathic pain. A multichannel DBS electrode was developed based on a novel LCP material using improved fabrication process. Stimulation parameters of the CDBS system were determined from preliminary experiments including behavioral tests and neural recordings. A correlation analysis was performed between changes in recorded local field potential (LFP) and changes in scored results of behavioral tests related to neuropathic pain proved to yield important information for the closed-loop strategy. Finally, a prototype CDBS system for neuropathic pain was developed and validated in vivo.Chapter 1. Introduction 1.1 Biological background 1.1.1 Neuropathic pain 1.1.2 Neural pathway of neuropathic pain and current treating methods 1.1.3 Anatomical characteristics of ventral posterior lateral nucleus 1.2 Overview of brain stimulation 1.2.1 Brain stimulation 1.2.2 Mechanisms and stimulation condition of DBS 1.2.3 Deep brain stimulation for neuropathic pain 1.3 Closed-loop deep brain stimulation system 1.3.1 Current deep brain stimulation system: Open-loop system 1.3.2 Closed-loop concept for neural prosthetic devices 1.3.3 Requirements for closed-loop deep brain stimulation system 1.4 Objectives of this dissertation 2. Materials and methods 2.1 Multichannel deep brain stimulation electrode 2.1.1 Liquid crystal polymer (LCP) 2.1.2 Electrode design 2.1.3 Volume of tissue activated (VTA) simulation 2.1.4 Surgical process design: Electrode implantation 2.1.5 Fabrication process 2.1.6 Characteristics measurements 2.2 Preliminary experiments 2.2.1 TST neuropathic modeling 2.2.2 Electrode implantation 2.2.3 Deep brain stimulation (DBS) 2.2.4 Behavioral tests (von Frey test and duration test) 2.2.5 Neural recording 2.2.6 Signal processing 2.2.7 Correlation analysis 2.3 Closed-loop stimulator 2.3.1 Overview of closed-loop DBS system for neuropathic pain 2.3.2 Closed-loop deep brain stimulation strategy for neuropathic pain 2.3.3 Prototype implementation 2.3.4 Prototype measurements: performance test 2.3.5 Animal experiments: in vivo application 3. Results 3.1 Multichannel deep brain stimulation electrode 3.1.1 Results of VTA simulation 3.1.2 Fabrication process 3.1.3 Developed electrode 3.1.4 Results of characteristics measurements 3.2 Results of preliminary experiments 3.2.1 Results of behavioral tests (von Frey tests and duration tests) 3.2.2 Results of neural recording (Local field potential, LFP) 3.2.3 Results of correlation analysis 3.2.4 Results of histological study 3.3 Closed-loop stimulator 3.3.1 Developed closed-loop deep brain stimulation strategy 3.3.2 Developed prototype closed-loop stimulator 3.3.3 Results of performance measurements 3.3.4 Results of in vivo experiments 4. Discussion 4.1 Improved LCP process for multiple LCP layers 4.2 Volume of tissue activated (VTA) issues 4.3 Correlation analysis 4.4 Closed-loop stimulator 4.4.1 Correction method based on neural spikes 4.4.2 Power consumption 4.4.3 Size of the system 4.4.4 Response time of closed-loop control 4.5 Gliosis 5. Conclusion References Acknowledgement Abstract in KoreanDocto

Microscopic Magnetic Stimulation of Neural Tissue

Electrical stimulation is currently used to treat a wide range of cardiovascular, sensory and neurological diseases. Despite its success, there are significant limitations to its application, including incompatibility with magnetic resonance imaging, limited control of electric fields and decreased performance associated with tissue inflammation. Magnetic stimulation overcomes these limitations but existing devices (that is, transcranial magnetic stimulation) are large, reducing their translation to chronic applications. In addition, existing devices are not effective for deeper, sub-cortical targets. Here we demonstrate that sub-millimeter coils can activate neuronal tissue. Interestingly, the results of both modelling and physiological experiments suggest that different spatial orientations of the coils relative to the neuronal tissue can be used to generate specific neural responses. These results raise the possibility that micro-magnetic stimulation coils, small enough to be implanted within the brain parenchyma, may prove to be an effective alternative to existing stimulation devices