Communication and control system for a 15-channel hermetic retinal prosthesis

A small, hermetic, wirelessly-controlled retinal prosthesis has been developed for pre-clinical studies in Yucatan minipigs. The device was attached conformally to the outside of the eye in the socket and received both power and data wirelessly from external sources. Based on the received image data, the prosthesis drove a subretinal thin-film polyimide array of sputtered iridium oxide stimulating electrodes. The implanted device included a hermetic titanium case containing a 15-channel stimulator and receiver chip and discrete circuit components. Feedthroughs in the hermetic case connected the chip to secondary power- and data-receiving coils, which coupled to corresponding external power and data coils driven by power amplifiers. Power was delivered by a 125 kHz carrier, and data were delivered by amplitude shift keying of a 15.5 MHz carrier at 100 kbps. Stimulation pulse strength, duration and frequency were programmed wirelessly from an external computer system. The final assembly was tested in vitro in physiological saline and in vivo in two minipigs for up to five and a half months by measuring stimulus artifacts generated by the implant's current drivers.United States. Dept. of Veteran AffairsUnited states. Dept. of Veterans Affairs. Boston Healthcare SystemNational Institutes of Health (U.S.)United States. Dept. of DefenseMassachusetts Lions Foundatio

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

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

Optimal electrical activation of retinal ganglion cells

Retinal prostheses are emerging as a viable therapy option for those blinded by degenerative eye conditions that destroy the photoreceptors of the retina but spare the retinal ganglion cells (RGCs). My research sought to address the issue of how a retinal prosthesis might best activate these cells by way of electrical stimulation. Whole-cell patch clamp recordings were made in explanted retinal wholemount preparations from normally-sighted rats. Stimulating electrodes were fabricated from nitrogen-doped ultra-nanocrystalline diamond (N-UNCD) and placed on the epiretinal surface, adjacent to the cell soma. Electrical stimuli were delivered against a distant monopolar return electrode. Using rectangular, biphasic constant current waveforms as employed by modern retinal prostheses, I examined which waveform parameters had the greatest effect on RGC activation thresholds. In a second set of experiments intracellular current injection was employed to assess the effectiveness of sinusoidal current waveforms in selectively activating different RGC subsets. These recordings were also used to validate a biophysical model of RGC activation. Where possible, recorded cells were identified and classified based on 3D confocal reconstruction of their morphology. Electrodes fabricated from N-UNCD were able to electrically activate RGCs while remaining well within the electrochemical limits of the material. They were found to exhibit high electrochemical stability and were resistant to morphological and electrochemical changes over one week of continuous pulsing at charge injection limits. Retinal ganglion cells invariably favoured cathodic-first biphasic current pulses of short first-phase duration, with a small interphase interval. The majority of cells (63\%) were most sensitive to a highly asymmetric waveform: a short-cathodic phase followed by a longer duration, lower amplitude anodic phase. Using the optimal interphase interval led to median charge savings of 14\% compared to the charge required in the absence of any inter-phase interval. Optimising phase duration resulted in median charge savings of 22\%. All RGCs became desensitised to repetitive electrical stimulation. The efficacy of a given stimulus delivered repeatedly decreased after the first stimulus, stabilising at a lower efficacy by the thirtieth pulse. This asymptotic efficacy decreased with increasing stimulus frequency. Cells with smaller somas and dendritic fields were better able to sustain repetitive activation at high frequency. Intracellular sinusoidal stimulation was used to demonstrate that certain RGC subsets, defined on the basis of morphological type, stratification, and size, were more responsive to high frequency stimulation. Simulated RGC responses were validated by experimental data, which confirmed that ON cell responses were heavily suppressed by stimulus frequencies of 20 Hz and higher. OFF cells, on the other hand, were able to sustain repetitive activation over all tested frequencies. Additional simulations suggest this difference may be plausibly attributed to the presence of low-voltage-activated calcium channels in OFF but not ON RGCs. The results of my work demonstrate that (a) N-UNCD is a suitable material for retinal prosthesis applications; (b) a careful choice of electrical waveform parameters can significantly improve prosthesis efficacy; and (c) it may be possible to bias neural activation for certain RGC populations by varying the frequency of stimulation

An efficient telemetry system for restoring sight

PhD ThesisThe human nervous system can be damaged as a result of disease or trauma, causing conditions such as Parkinson’s disease. Most people try pharmaceuticals as a primary method of treatment. However, drugs cannot restore some cases, such as visual disorder. Alternatively, this impairment can be treated with electronic neural prostheses. A retinal prosthesis is an example of that for restoring sight, but it is not efficient and only people with retinal pigmentosa benefit from it. In such treatments, stimulation of the nervous system can be achieved by electrical or optical means. In the latter case, the nerves need to be rendered light sensitive via genetic means (optogenetics). High radiance photonic devices are then required to deliver light to the target tissue. Such optical approaches hold the potential to be more effective while causing less harm to the brain tissue. As these devices are implanted in tissue, wireless means need to be used to communicate with them. For this, IEEE 802.15.6 or Bluetooth protocols at 2.4GHz are potentially compatible with most advanced electronic devices, and are also safe and secure. Also, wireless power delivery can operate the implanted device. In this thesis, a fully wireless and efficient visual cortical stimulator was designed to restore the sight of the blind. This system is likely to address 40% of the causes of blindness. In general, the system can be divided into two parts, hardware and software. Hardware parts include a wireless power transfer design, the communication device, power management, a processor and the control unit, and the 3D design for assembly. The software part contains the image simplification, image compression, data encoding, pulse modulation, and the control system. Real-time video streaming is processed and sent over Bluetooth, and data are received by the LPC4330 six layer implanted board. After retrieving the compressed data, the processed data are again sent to the implanted electrode/optrode to stimulate the brain’s nerve cells

Data analysis of retinal recordings from multi-electrode arrays under in situ electrical stimulation

The development of retinal implants has become an important field of study in recent years, with increasing numbers of people falling victim to legal or physical blindness as a result of retinal damage. Important weaknesses in current retinal implants include a lack of the resolution necessary to give a patient a viable level of visual acuity, question marks over the amount of power and energy required to deliver adequate stimulation, and the removal of eye movements from the analysis of the visual scene. This thesis documents investigations by the author into a new CMOS stimulation and imaging chip with the potential to overcome these difficulties. An overview is given of the testing and characterisation of the componments incorporated in the device to mimic the normal functioning of the human retina. Its application to in situ experimental studies of frog retina is also described, as well as how the data gathered from these experiments enables the optimisation of the geometry of the electrode array through which the device will interface with the retina. Such optimisation is important as the deposit of excess electrical charge and energy can lead to detrimental medical side effects. Avoidance of such side effects is crucial to the realisation of the next generation of retinal implants

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

Large scale retinal modeling for the design of new generation retinal prostheses

With the help of modern technology, blindness caused by retinal diseases such as age-related macular degeneration or retinitis pigmentosa is now considered reversible. Scientists from various fields such as Neuroscience, Electrical Engineering, Computer Science, and Bioscience have been collaborating to design and develop retinal prostheses, with the aim of replacing malfunctioning parts of the retina and restoring vision in the blind. Human trials conducted to test retinal prostheses have yielded encouraging results, showing the potential of this approach in vision recovery. However, a retinal prosthesis has several limitations with regard to its hardware and biological functions, and several attempts have been made to overcome these limitations. This thesis focuses on the biological aspects of retinal prostheses: the biological processes occurring inside the retina and the limitations of retinal prostheses corresponding to those processes have been analysed. Based on these analyses, three major findings regarding information processing inside the retina have been presented and these findings have been used to conceptualise retinal prostheses that have the characteristics of asymmetrical and separate pathway stimulations. In the future, when nanotechnology gains more popularity and is completely integrated inside the prosthesis, this concept can be utilized to restore useful visual information such as colour, depth, and contrast to achieve high-quality vision in the blind

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

Large scale retinal modeling for the design of new generation retinal prostheses

With the help of modern technology, blindness caused by retinal diseases such as age-related macular degeneration or retinitis pigmentosa is now considered reversible. Scientists from various fields such as Neuroscience, Electrical Engineering, Computer Science, and Bioscience have been collaborating to design and develop retinal prostheses, with the aim of replacing malfunctioning parts of the retina and restoring vision in the blind. Human trials conducted to test retinal prostheses have yielded encouraging results, showing the potential of this approach in vision recovery. However, a retinal prosthesis has several limitations with regard to its hardware and biological functions, and several attempts have been made to overcome these limitations. This thesis focuses on the biological aspects of retinal prostheses: the biological processes occurring inside the retina and the limitations of retinal prostheses corresponding to those processes have been analysed. Based on these analyses, three major findings regarding information processing inside the retina have been presented and these findings have been used to conceptualise retinal prostheses that have the characteristics of asymmetrical and separate pathway stimulations. In the future, when nanotechnology gains more popularity and is completely integrated inside the prosthesis, this concept can be utilized to restore useful visual information such as colour, depth, and contrast to achieve high-quality vision in the blind