A Novel In Vitro Sensing Configuration for Retinal Physiology Analysis of a Sub-Retinal Prosthesis

This paper presents a novel sensing configuration for retinal physiology analysis, using two microelectrode arrays (MEAs). In order to investigate an optimized stimulation protocol for a sub-retinal prosthesis, retinal photoreceptor cells are stimulated, and the response of retinal ganglion cells is recorded in an in vitro environment. For photoreceptor cell stimulation, a polyimide-substrate MEA is developed, using the microelectromechanical systems (MEMS) technology. For ganglion cell response recording, a conventional glass-substrate MEA is utilized. This new sensing configuration is used to record the response of retinal ganglion cells with respect to three different stimulation methods (monopolar, bipolar, and dual-monopolar stimulation methods). Results show that the geometrical relation between the stimulation microelectrode locations and the response locations seems very low. The threshold charges of the bipolar stimulation and the monopolar stimulation are in the range of 10∼20 nC. The threshold charge of the dual-monopolar stimulation is not obvious. These results provide useful guidelines for developing a sub-retinal prosthesis

MICROELECTRODE ARRAY FOR CAPACITIVE TRANSDUCTION OF RETINAL RESPONSES

Neural degenerative diseases and traumatic injuries to the eye affect millions of people worldwide, motivating the development of neural prosthetic interfaces to restore sensory or motor function in affected individuals. Advances in neural sensing and stimulation interface technology will allow a more comprehensive understanding of neural function while leading to the development of hybrid biological-electronic sensor devices for robust, functioning neural prosthetic systems. Current techniques of neural activity sensing employ multi-electrode arrays (MEAs) that typically incorporate metal electrodes and measure currents via an electrochemical junction, leading to corrosion and charge transfer across the electrode-tissue interface. High-density neural interface technology will require active circuitry within the implant; the device must withstand corrosion and induce minimal damage at the electrode/tissue interface. The work shown here demonstrates a prototype neural interface device based on capacitive coupling through hafnium oxide encapsulation of a novel 3D device architecture, advancing neural sensing technology toward long-term implantable neural interfaces. The functionalization of biosensors interfaced with neural tissue is important to ensure that the active components of the sensor are fully protected from the surrounding biological environment. Self-assembled monolayers (SAMs) have been extensively studied as coatings for implantable devices due to their ability to tailor surface properties and relative ease of film formation. We report a series of studies aimed at investigating the stability of phosphonate self-assembled monolayers, octdecylphosphonic acid (ODPA) or perfluorophosphonic acid (PFPA) on various oxide surfaces (SiO2, TiO2, Al2O3 and HfO2) to serve as the biotic-abiotic interface of the prototype neural device developed here. The monolayers were deposited by a series of techniques including self-assembly from solution, tethering by aggregation and growth and Langmuir-Blodgett (LB). SAMs prepared by LB were primarily used in our stability investigations because they were found to be the most uniform and reproducible. All films deposited on oxide-coated substrates were characterized by means of water contact angle measurements, spectroscopic ellipsometry, X-ray photoelectron spectroscopy (XPS) and atomic force microscopy (AFM). XPS data conclusively showed covalent phosphonate formation on all substrates except SiO2, which had background spectra that interfered with the data analysis. AFM images of SAMs formed on SiO2 and TiO2 showed significant surface reorganization upon exposure to water within 30 minutes. SAMs formed on Al2O3 and HfO2 were much more stable upon exposure to water. PFPA SAMs on HfO2 were found to be the most stable SAMs studied here in either water or phosphate buffer at room temperature. This is the first report of a SAM-oxide system showing stability for an extended period of time, greater than 20 days. These data suggest that phosphonate SAMs should be considered for implantable neural devices that require longer-term stability under aqueous conditions. To examine the encoding and processing of information by networks of neurons, microelectrode arrays (MEAs) have been developed and applied, but evolving scientific questions and biomedical applications require higher density sampling and wider spatial coverage. The integration of 3D electrodes can provide closer contact with neurons to facilitate detection and resolution of single cell action potentials. The fabrication methods implemented here allows reliable fabrication of a novel MEA consisting of probes with dimensions of a few microns, unlike most other approaches to 3D electrode arrays, which produce structures on the scale of tens of microns or more. The device incorporates over 3,800 micro pillar electrodes, grouped into 60 independent sensors for compatibility with existing electronics, spread over an area of 750 μm2; each sensor site consists of an 8x8 array of micropillars, interconnected by a lead to an output pad of the device. Individual 3D pillars are 3 μm in diameter with a height of 8 μm. Our experience has suggested that such microstructured probes can achieve more intimate contact with the surface of neural tissue, and enhance the quality of neuronal recordings. Electrochemical impedance spectroscopy (EIS) at 1 kHz measured average magnitude and phase shift of 710 W and 17°, respectively, for a single sensor site. These values confirm the robustness of our fabrication process for developing highly conductive 3D microelectrodes. The results shown here demonstrate high-density, three-dimensional microfabrication technology that was applied to the development of an advanced capacitive sensor array for neural tissue. Applications in sensing technology now require electro-neural interface devices to withstand corrosion and induce minimal damage at the electrode/tissue interface. We have developed a platform suitable for hermetic sealing and have shown encapsulation through atomic layer deposition of hafnium oxide over the active components of the device to overcome the direct current limitations of existing MEA technology. EIS was used to study the oxide deposition on the 3D micro pillar sensor array to ensure a pinhole-free dielectric coating. The characteristic impedance magnitudes increase up to 3 orders of magnitude upon oxide deposition and the phase indicates fully capacitive sensor sites. The fabrication process and electrochemical impedance study shown here, demonstrates the usefulness of such techniques for building high-density 3D arrays that can be fully encapsulated with a protective dielectric coating. This work advances the technology towards capacitive sensing of retinal neurons with a robust, non-invasive sensing device. Sensing retinal neurons with the 3D micropillar array developed here was performed for direct current and capacitive configurations of the device. Electroretinograms (ERGs) were recorded and the overall performance of the device was analyzed. The devices showed good consistency across all 60 Pt electrode clusters during characterization and when interfaced with retinal tissue. ERGs were recorded by more than 80% of the direct current electrode sites and the performance was evenly distributed around the mean response. This performance surpasses previous reports of 3D electrode arrays interfaced with retinal tissue, where typically 1-6 electrode signals are recorded successfully. Encapsulation of the device platform was achieved and successful recordings of ERG signals were shown. This work is the first report of sensing the overall electrical behavior of retinal tissue with a coupled capacitive MEA

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

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

Developing a new generation of neuro-prosthetic interfaces: structure-function correlates of viable retina-CNT biohybrids

PhD ThesisOne of the many challenges in the development of neural prosthetic devices is the choice of electrode material. Electrodes must be biocompatible, and at the same time, they must be able to sustain repetitive current injections in a highly corrosive physiological environment. We investigated the suitability of carbon nanotube (CNT) electrodes for retinal prosthetics by studying prolonged exposure to retinal tissue and repetitive electrical stimulation of retinal ganglion cells (RGCs). Experiments were performed on retinal wholemounts isolated from the Cone rod homeobox (CRX) knockout mouse, a model of Leber congenital amaurosis. Retinas were interfaced at the vitreo-retinal juncture with CNT assemblies and maintained in physiological conditions for up to three days to investigate any anatomical (immunohistochemistry and electron microscopy) and electrophysiological changes (multielectrode array stimulation and recordings; electrodes were made of CNTs or commercial titanium nitride). Anatomical characterisation of the inner retina, including RGCs, astrocytes and Müller cells as well as cellular matrix and inner retinal vasculature, provide strong evidence of a gradual remodelling of the retina to incorporate CNT assemblies, with very little indication of an immune response. Prolonged electrophysiological recordings, performed over the course of three days, demonstrate a gradual increase in signal amplitudes, lowering of stimulation thresholds and an increase in cellular recruitment for RGCs interfaced with CNT electrodes, but not with titanium nitride electrodes. These results provide for the first time electrophysiological, ultrastructural and cellular evidence of the time-dependent formation of strong and viable bio-hybrids between the RGC layer and CNT arrays in intact retinas. We conclude that CNTs are a promising material for inclusion in retinal prosthetic devices

Analysis of Factors Affecting the Performance of Retinal Prostheses Using Finite Element Modelling of Electric Field Distribution in the Retina

This dissertation proposes a computational framework targeted at improving the design of currently employed retinal prostheses. The framework was used for analysing factors impacting the performance of prostheses in terms of electrical stimulation for retinal neurons, which might lead to a perception of pixelated vision. Despite their demonstrated effectiveness, the chronic and safe usage of these retinal prostheses in human and animal trials is jeopardised due to high stimulation thresholds. This is related to the distance between the stimulating electrodes and the retinal neurons resulting from the implantation procedure. The major goal of this dissertation was to evaluate the stimulation efficacy in current implantable planar microelectrode-based retinal prostheses and consequently demonstrate their weakness, thereby providing scope for the development of future implants. The effect of geometrical factors i.e., electrode-retina distance and electrode size on stimulation applied to the retina by retinal prostheses was studied. To this end, a finite element method based simulation framework to compute electric field distribution in the retina was constructed. An electrical model of the retina was an integral part of the framework, essentially represented by a resistivity profile of the multi-layered retina. The elements of a retinal prosthesis were modelled by incorporating realistic electrode sizes, an anatomical and electrical model of the retina, a precise positioning of stimulation and return electrodes and the location of the implant with respect to the retina representing the epiretinal and subretinal stimulation schemes. The simulations were carried out both in quasi-static and direct current (DC) modes. It was observed that electrode-electrolyte interface and tissue capacitance could be safely neglected in our model based on the magnitude of the applied voltage stimulus and frequencies under consideration. Therefore, all simulations were conducted in DC mode. Thresholds and lateral extents of the stimulation were computed for electrode sizes corresponding to existing and self-fabricated implants. The values and trends obtained were in agreement with experiments from literature and our collaborators at the les Hôpitaux Universitaires de Genève (HUG). In the subretinal stimulation scheme, the computed variation of impedance with electrode-retina distance correlated well with time varying in vivo impedance measurements in rats conducted in collaboration with the Institut de la Vision, INSERM, Paris. Finally, it was also reiterated that the currently employed retinal prostheses are not very efficient due to a significant distance between the stimulation electrode and the retinal cells. In addition, I present a new experimental technique for measuring the absolute and local resistivity profile in high-resolution along the retinal depth, based on impedance spectroscopy using a bipolar microprobe. This experiment was devised to extract the resistivity profile of an embryonic chick retina to construct an electrical model for the simulation framework to simulate in vitro retinal stimulation experiments conducted by HUG collaborators. We validated the capability of the technique in rat and embryonic chick retinas. In conclusion, the computational framework presented in this dissertation is more realistic than those found in literature, but represents only a preliminary step towards an accurate model of a real implantation scenario in vivo. The simulation results are in agreement with results from clinical trials in humans for epiretinal configuration (literature) and with in vitro results for epiretinal and subretinal stimulation applied to chick retinas (HUG). The developed simulation framework computes quantities that can form a reference for quality control during surgery while inserting implants in the eye and functionality checks by electrophysiologists. Furthermore, this framework is useful in deciding the specifications of stimulation electrodes such as optimal size, shape, material, array density, and the position of the reference electrode to name a few. The work presented here offers to aid in optimising retinal prostheses and implantation procedures for patients and eventually contributes towards improving their quality of life

Biomedical Engineering

Biomedical engineering is currently relatively wide scientific area which has been constantly bringing innovations with an objective to support and improve all areas of medicine such as therapy, diagnostics and rehabilitation. It holds a strong position also in natural and biological sciences. In the terms of application, biomedical engineering is present at almost all technical universities where some of them are targeted for the research and development in this area. The presented book brings chosen outputs and results of research and development tasks, often supported by important world or European framework programs or grant agencies. The knowledge and findings from the area of biomaterials, bioelectronics, bioinformatics, biomedical devices and tools or computer support in the processes of diagnostics and therapy are defined in a way that they bring both basic information to a reader and also specific outputs with a possible further use in research and development

Neuromorphic hardware for somatosensory neuroprostheses

In individuals with sensory-motor impairments, missing limb functions can be restored using neuroprosthetic devices that directly interface with the nervous system. However, restoring the natural tactile experience through electrical neural stimulation requires complex encoding strategies. Indeed, they are presently limited in effectively conveying or restoring tactile sensations by bandwidth constraints. Neuromorphic technology, which mimics the natural behavior of neurons and synapses, holds promise for replicating the encoding of natural touch, potentially informing neurostimulation design. In this perspective, we propose that incorporating neuromorphic technologies into neuroprostheses could be an effective approach for developing more natural human-machine interfaces, potentially leading to advancements in device performance, acceptability, and embeddability. We also highlight ongoing challenges and the required actions to facilitate the future integration of these advanced technologies

An Optoelectronic Stimulator for Retinal Prosthesis

Retinal prostheses require the presence of viable population of cells in the inner retina. Evaluations of retina with Age-Related Macular Degeneration (AMD) and Retinitis Pigmentosa (RP) have shown a large number of cells remain in the inner retina compared with the outer retina. Therefore, vision loss caused by AMD and RP is potentially treatable with retinal prostheses. Photostimulation based retinal prostheses have shown many advantages compared with retinal implants. In contrary to electrode based stimulation, light does not require mechanical contact. Therefore, the system can be completely external and not does have the power and degradation problems of implanted devices. In addition, the stimulating point is flexible and does not require a prior decision on the stimulation location. Furthermore, a beam of light can be projected on tissue with both temporal and spatial precision. This thesis aims at fi nding a feasible solution to such a system. Firstly, a prototype of an optoelectronic stimulator was proposed and implemented by using the Xilinx Virtex-4 FPGA evaluation board. The platform was used to demonstrate the possibility of photostimulation of the photosensitized neurons. Meanwhile, with the aim of developing a portable retinal prosthesis, a system on chip (SoC) architecture was proposed and a wide tuning range sinusoidal voltage-controlled oscillator (VCO) which is the pivotal component of the system was designed. The VCO is based on a new designed Complementary Metal Oxide Semiconductor (CMOS) Operational Transconductance Ampli er (OTA) which achieves a good linearity over a wide tuning range. Both the OTA and the VCO were fabricated in the AMS 0.35 µm CMOS process. Finally a 9X9 CMOS image sensor with spiking pixels was designed. Each pixel acts as an independent oscillator whose frequency is controlled by the incident light intensity. The sensor was fabricated in the AMS 0.35 µm CMOS Opto Process. Experimental validation and measured results are provided