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

Simulating and optimizing electrical current flow and neuronal activation in retinal implants

© 2018 Dr Timothy Bede Esler[Abstract Withheld

Egocentric Computer Vision and Machine Learning for Simulated Prosthetic Vision

Las prótesis visuales actuales son capaces de proporcionar percepción visual a personas con cierta ceguera. Sin pasar por la parte dañada del camino visual, la estimulación eléctrica en la retina o en el sistema nervioso provoca percepciones puntuales conocidas como “fosfenos”. Debido a limitaciones fisiológicas y tecnológicas, la información que reciben los pacientes tiene una resolución muy baja y un campo de visión y rango dinámico reducido afectando seriamente la capacidad de la persona para reconocer y navegar en entornos desconocidos. En este contexto, la inclusión de nuevas técnicas de visión por computador es un tema clave activo y abierto. En esta tesis nos centramos especialmente en el problema de desarrollar técnicas para potenciar la información visual que recibe el paciente implantado y proponemos diferentes sistemas de visión protésica simulada para la experimentación.Primero, hemos combinado la salida de dos redes neuronales convolucionales para detectar bordes informativos estructurales y siluetas de objetos. Demostramos cómo se pueden reconocer rápidamente diferentes escenas y objetos incluso en las condiciones restringidas de la visión protésica. Nuestro método es muy adecuado para la comprensión de escenas de interiores comparado con los métodos tradicionales de procesamiento de imágenes utilizados en prótesis visuales.Segundo, presentamos un nuevo sistema de realidad virtual para entornos de visión protésica simulada más realistas usando escenas panorámicas, lo que nos permite estudiar sistemáticamente el rendimiento de la búsqueda y reconocimiento de objetos. Las escenas panorámicas permiten que los sujetos se sientan inmersos en la escena al percibir la escena completa (360 grados).En la tercera contribución demostramos cómo un sistema de navegación de realidad aumentada para visión protésica ayuda al rendimiento de la navegación al reducir el tiempo y la distancia para alcanzar los objetivos, incluso reduciendo significativamente el número de colisiones de obstáculos. Mediante el uso de un algoritmo de planificación de ruta, el sistema encamina al sujeto a través de una ruta más corta y sin obstáculos. Este trabajo está actualmente bajo revisión.En la cuarta contribución, evaluamos la agudeza visual midiendo la influencia del campo de visión con respecto a la resolución espacial en prótesis visuales a través de una pantalla montada en la cabeza. Para ello, usamos la visión protésica simulada en un entorno de realidad virtual para simular la experiencia de la vida real al usar una prótesis de retina. Este trabajo está actualmente bajo revisión.Finalmente, proponemos un modelo de Spiking Neural Network (SNN) que se basa en mecanismos biológicamente plausibles y utiliza un esquema de aprendizaje no supervisado para obtener mejores algoritmos computacionales y mejorar el rendimiento de las prótesis visuales actuales. El modelo SNN propuesto puede hacer uso de la señal de muestreo descendente de la unidad de procesamiento de información de las prótesis retinianas sin pasar por el análisis de imágenes retinianas, proporcionando información útil a los ciegos. Esté trabajo está actualmente en preparación.<br /

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

Neuroengineering Tools/Applications for Bidirectional Interfaces, Brain–Computer Interfaces, and Neuroprosthetic Implants – A Review of Recent Progress

The main focus of this review is to provide a holistic amalgamated overview of the most recent human in vivo techniques for implementing brain–computer interfaces (BCIs), bidirectional interfaces, and neuroprosthetics. Neuroengineering is providing new methods for tackling current difficulties; however neuroprosthetics have been studied for decades. Recent progresses are permitting the design of better systems with higher accuracies, repeatability, and system robustness. Bidirectional interfaces integrate recording and the relaying of information from and to the brain for the development of BCIs. The concepts of non-invasive and invasive recording of brain activity are introduced. This includes classical and innovative techniques like electroencephalography and near-infrared spectroscopy. Then the problem of gliosis and solutions for (semi-) permanent implant biocompatibility such as innovative implant coatings, materials, and shapes are discussed. Implant power and the transmission of their data through implanted pulse generators and wireless telemetry are taken into account. How sensation can be relayed back to the brain to increase integration of the neuroengineered systems with the body by methods such as micro-stimulation and transcranial magnetic stimulation are then addressed. The neuroprosthetic section discusses some of the various types and how they operate. Visual prosthetics are discussed and the three types, dependant on implant location, are examined. Auditory prosthetics, being cochlear or cortical, are then addressed. Replacement hand and limb prosthetics are then considered. These are followed by sections concentrating on the control of wheelchairs, computers and robotics directly from brain activity as recorded by non-invasive and invasive techniques

Zapping the Retina - Understanding electrical responsiveness and electrical desensitization in mouse retinal ganglion cells

The field of science and technology has come a long way since the famous 70’s science fiction series “The Six Million Dollar Man,” where a disabled pilot was transformed into a bionic superhero after receiving artificial implants. What was indeed once a science fiction has now turned into a science fact with the development of various electronic devices interfacing the human neurons in the brain, retina, and limbs. One such advancement was the development of retinal implants. Over the past two decades, the field of retinal prosthetics has made significant advancement in restoring functional vision in patients blinded by diseases such as Retinitis pigmentosa (RP) and Age-related macular degeneration (AMD). RP and AMD are the two leading cause of degenerative blindness. While there is still no definitive cure for either of these diseases, various treatment strategies are currently being explored. Of the various options, the most successful one has been the retinal implants. Retinal implants are small microelectrode or photodiode arrays, which are implanted in the eye of a patient, to stimulate the degenerating retina electrically. They are broadly classified into three types depending on the placement ̶ epiretinal (close proximity to retinal ganglion cells, RGCs) , subretinal (close proximity to bipolar cells, BP) and suprachoroidal (close proximity to choroid). While the ongoing human trials have shown promising results, there remains a considerable variability among patients concerning the quality of visual percepts which limits the working potential of these implants. One such limitation often reported by the implanted patients is “ fading” of visual percepts. Fading refers to the limited ability to elicit temporally stable visual percepts. While, this is not a primary concern for epiretinal implants , it is often observed in subretinal and suprachoroidal implants which use the remaining retinal network to control the temporal spiking pattern of the ganglion cells. The neural correlate of fading is often referred to as “electrical desensitization”, which is the reduction of ganglion cell responses to repetitive electrical stimulation . While much is known about the temporal component of desensitization ( time constant, τ), the spatial aspects (space constant, λ) has not been well characterized. Further, how both these aspects interact to generate spiking responses, remains poorly understood. These crucial questions formed the critical components of my thesis. To address these questions, we stimulated the retinal network electrically, with voltage and current pulses and recorded the corresponding spiking activity using the microelectrode arrays (MEAs). While addressing the primary question of my thesis, we were able to address few idiosyncrasies which has currently stymied the field of retinal prosthetics. At a conceptual level, we have developed an experimental and analysis framework by which one can identify the single stimulus that will activate the most ganglion cells (Chapter 2, Part 1). This stimulus is optimal for ‘blind’ experiments where the specific response properties of each cell are unknown. Furthermore, we attempted to understand the correspondence between the electrical response patterns and visual response types (Chapter 2, Part2). In Chapter 3, we sought to understand better how the visual responses parameters change during ongoing electrical stimulation. We demonstrated that apart from the adaptation occurring due to visual stimulation and invitro experimental conditions, the electrical stimulation alters the RGC visual responses, suggesting the requirement for stimulation-induced changes to be incorporated in the designing of stimulation paradigms for the implant. Finally addressing the primary question (Chapter 4) of my thesis with which we started, we were able to demonstrate, that the electrical desensitization requires the interaction of both time and distance and is not a global phenomenon of the retina. In the final chapter (Chapter 5) we summarize the results of the thesis, discuss the key outcomes and its relevance to the prosthetic field and other vision restoration strategies and the potential future directions of this research. Therefore, in future, to improve the efficacy of retinal prostheses and patient outcomes, it is crucial to have an in-depth understanding of the responsiveness of the retinal circuitry to electrical stimulation

A 16 x 16 CMOS amperometric microelectrode array for simultaneous electrochemical measurements

There is a requirement for an electrochemical sensor technology capable of making multivariate measurements in environmental, healthcare, and manufacturing applications. Here, we present a new device that is highly parallelized with an excellent bandwidth. For the first time, electrochemical cross-talk for a chip-based sensor is defined and characterized. The new CMOS electrochemical sensor chip is capable of simultaneously taking multiple, independent electroanalytical measurements. The chip is structured as an electrochemical cell microarray, comprised of a microelectrode array connected to embedded self-contained potentiostats. Speed and sensitivity are essential in dynamic variable electrochemical systems. Owing to the parallel function of the system, rapid data collection is possible while maintaining an appropriately low-scan rate. By performing multiple, simultaneous cyclic voltammetry scans in each of the electrochemical cells on the chip surface, we are able to show (with a cell-to-cell pitch of 456 μm) that the signal cross-talk is only 12% between nearest neighbors in a ferrocene rich solution. The system opens up the possibility to use multiple independently controlled electrochemical sensors on a single chip for applications in DNA sensing, medical diagnostics, environmental sensing, the food industry, neuronal sensing, and drug discovery

Towards clinical trials of a novel Bionic Eye: Building evidence of safety and efficacy

In the quest for therapeutic solutions for the visually impaired, electrical stimulation of the retina is, and has been, the focus of intense research. Some of these efforts have led to the development of the Phoenix99 Bionic Eye, a device which combines promising technological features with novel stimulation strategies. For medical devices, considerable challenges must be overcome before they’re allowed to be trialled in their target population. The requirements for a study to be performed include the demonstration of a positive risk-benefit ratio of the research. The present dissertation is an attempt to address how pre-clinical trials in animals can be used to understand and minimise risks. A positive risk-benefit ratio means that the potential benefits of the research outweigh the risks of the intervention. In the case of retinal prostheses, the risks include the surgical intervention, the immune response to the device, the safety of the electrical stimuli, and the effects of device ageing. In this work, successful demonstration of the surgical safety and biocompatibility of passive Phoenix99 devices during long-term implantation in sheep called for the evaluation of the chronic effects of the novel stimulation paradigms it can deliver. As preparation for this study, the techniques used to evaluate the safety and efficacy of the stimuli in animals were refined. A systematic approach to minimise the impact of anaesthesia on the experimental results is presented, as well as a novel in vivo retinal recording technique. To maximise the clinical relevance of all animal trials, a computer model for the prediction of thresholds was developed. Finally, in vitro device ageing was performed to deepen our understanding of the design’s potential for long-term implantation. Protocols for a long-term device safety study in sheep and for an acute human trial are also presented, thus taking concrete and sensible steps towards the first clinical use of the Phoenix99 Bionic Eye

Microscopic imaging and photo-stimulation using micro-structured light emitting diodes

Imperial Users onl