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

Implantable CMOS Biomedical Devices

The results of recent research on our implantable CMOS biomedical devices are reviewed. Topics include retinal prosthesis devices and deep-brain implantation devices for small animals. Fundamental device structures and characteristics as well as in vivo experiments are presented

An update on retinal prostheses

Retinal prostheses are designed to restore a basic sense of sight to people with profound vision loss. They require a relatively intact posterior visual pathway (optic nerve, lateral geniculate nucleus and visual cortex). Retinal implants are options for people with severe stages of retinal degenerative disease such as retinitis pigmentosa and age-related macular degeneration. There have now been three regulatory-approved retinal prostheses. Over five hundred patients have been implanted globally over the past 15 years. Devices generally provide an improved ability to localize high-contrast objects, navigate, and perform basic orientation tasks. Adverse events have included conjunctival erosion, retinal detachment, loss of light perception, and the need for revision surgery, but are rare. There are also specific device risks, including overstimulation (which could cause damage to the retina) or delamination of implanted components, but these are very unlikely. Current challenges include how to improve visual acuity, enlarge the field-of-view, and reduce a complex visual scene to its most salient components through image processing. This review encompasses the work of over 40 individual research groups who have built devices, developed stimulation strategies, or investigated the basic physiology underpinning retinal prostheses. Current technologies are summarized, along with future challenges that face the field

FPGA design and implementation of a framework for optogenetic retinal prosthesis

PhD ThesisThere are 285 million people worldwide with a visual impairment, 39 million of whom are completely blind and 246 million partially blind, known as low vision patients. In the UK and other developed countries of the west, retinal dystrophy diseases represent the primary cause of blindness, especially Age Related Macular Degeneration (AMD), diabetic retinopathy and Retinitis Pigmentosa (RP). There are various treatments and aids that can help these visual disorders, such as low vision aids, gene therapy and retinal prosthesis. Retinal prostheses consist of four main stages: the input stage (Image Acquisition), the high level processing stage (Image preparation and retinal encoding), low level processing stage (Stimulation controller) and the output stage (Image displaying on the opto-electronic micro-LEDs array). Up to now, a limited number of full hardware implementations have been available for retinal prosthesis. In this work, a photonic stimulation controller was designed and implemented. The main rule of this controller is to enhance framework results in terms of power and time. It involves, first, an even power distributor, which was used to evenly distribute the power through image sub-frames, to avoid a large surge of power, especially with large arrays. Therefore, the overall framework power results are improved. Second, a pulse encoder was used to select different modes of operation for the opto-electronic micro-LEDs array, and as a result of this the overall time for the framework was improved. The implementation is completed using reconfigurable hardware devices, i.e. Field Programmable Gate Arrays (FPGAs), to achieve high performance at an economical price. Moreover, this FPGA-based framework for an optogenetic retinal prosthesis aims to control the opto-electronic micro-LED array in an efficient way, and to interface and link between the opto-electronic micro-LED array hardware architecture and the previously developed high level retinal prosthesis image processing algorithms.University of Jorda

An external control unit implemented for stimulator ASIC testing

This paper presents the design and development of an external control unit (ECU) for a stimulator ASIC testing purposes. The ECU consists of a graphical user interface (GUI) from the PC, a data transceiver and a power transmitter. The GUI was developed using MATLAB for stimulation data setup. The data transceiver was designed using hardware description language (HDL) Verilog code and was implemented in a Virtex-II Pro FPGA board. The overall stimulator ASIC design architecture and its operation for an epiretinal implant application are briefly explained to correlate with the ECU’s design requirements. The flexible multichannel stimulator ASIC was successfully fabricated in a 0.35μm AMS HVCMOS technology. Conducted simulation and measurement results on stimulation waveform generation, supply voltage compliance and external control of supply voltage adaptation validate the functionality of the designed ECU and the stimulator ASIC.Keywords: external control unit; data transceiver; stimulator ASIC; retinal prosthesis; epiretinal implant; stimulation waveform; Manchester data; voltage compliance

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

Current Stimulator IC for Retinal Prosthesis Using Nanowire FET Switch Array and in vitro Experiment with rd1 Mouse

학위논문 (석사)-- 서울대학교 대학원 : 전기·컴퓨터공학부, 2015. 2. 조동일.망막 색소 변성 (Retinitis pigmentosa) 및 노인성 황반 변성 (Age-related macular degeneration) 은 난치성 망막 변성 질환으로서 발병 후 수 년 내에 시력을 완전히 상실하게 한다. 이러한 망막 변성 질환을 치료하기 위해 전기 자극으로 시각 신경 신호를 발생시키는 인공망막 장치가 개발되어 왔다. 최근에는 세계 각지의 연구 그룹에서 자극 해상도를 1,000 픽셀 이상으로 높여 보다 뚜렷한 시각 정보를 전달하려는 시도를 하고 있다. 그러나 기존의 one-to-one interconnection 방식으로 전극과 자극기 회로를 연결할 경우, 배선이 복잡해져 유연한 인공망막 장치를 개발하기 어렵다. 이에 따라 본 연구진에서는 32 × 32 픽셀의 나노와이어 field-effect transistor (FET) 스위치 array 를 이용하여 배선의 복잡성을 줄인 고해상도 인공망막 장치를 개발하고 있다. 본 논문에서는 나노와이어 FET 스위치 기반의 인공망막 자극기 구동을 위한 자극기 회로에 대해 다루고 있다. 본 자극기 회로는 12 V 의 자극 전압을 사용하여, 0 ~ 100 μA 의 자극 전류를 주입할 수 있도록 설계하였다. 또한 나노와이어 FET 스위치 기반의 인공망막 자극 시스템 구동을 위한 디지털 인터페이스 회로를 포함하고 있다. 본 자극기 회로는 12 V 의 고전압 자극을 인가하기 위해 0.35 μm bipolar-CMOS (Complementary Metal-Oxide-Semiconductor)-DMOS (Double Diffused Metal-Oxide-Semiconductor) 공정을 이용하여 제작하였다. 자극기 회로의 기능 검증을 위해 전류 주입 실험 및 in vitro 실험을 진행하였다. 전류 주입 실험 결과 입력 신호에 따라 자극 전류의 세기가 적절히 변화하였으며, 시뮬레이션과 5% 내외의 오차를 보였다. 또한 in vitro 실험을 통해 전류 자극 세기에 따라 신경 반응이 조절되는 유효한 신경 자극을 인가할 수 있음을 확인하였다.Retina pigmentosa (RP) and Age-related macular degeneration (ARMD) are incurable retinal degenerative diseases that cause vision loss in several years after disease onset. Retinal prosthetic devices using electrical stimulations have been developed to restore vision of people blinded from the RP and ARMD. Recently, many research efforts have been tried to achieve a high-spatial resolution with more than 1,000 pixels. However, it is difficult to achieve the high-spatial resolution with the conventional one-to-one interconnection method that requires excessive wiring complexities. In our research group, a high-resolution retinal prosthetic system using a nanowire field-effect transistor (FET) switch integrated 32 × 32 microelectrode array (MEA) has been developed to resolve the wiring problem. In this paper, a current stimulator integrated circuit (IC) to operate the nanowire FET switch integrated MEA is presented. The stimulator circuit generates a biphasic stimulation current in a range of 0 to 100 μA using a high stimulation voltage of 12 V. The digital interface circuits are also integrated in the stimulator IC to operate the MEA. For the high voltage stimulation of 12 V, the stimulator IC is fabricated using a 0.35 μm bipolar-CMOS (Complementary Metal-Oxid-Semiconductor)-DMOS (Double Diffused Metal-Oxide-Semiconductor) process. Experimental results show that the amplitude of the stimulation current is properly modulated according to the level of the input signal. Errors between the measured current amplitudes and the simulated levels are approximately 5%. An in vitro experiment is also conducted to evaluate the neural stimulating function of the fabricated stimulator IC. In the in vitro experiment, the neural responses are successfully evoked by the current stimulation from the stimulator IC.제 1 장 서 론 1 제 1 절 연구의 배경 1 제 1 항 망막 변성 질환 1 제 2 항 시각 보철의 종류 5 제 3 항 인공망막 장치의 분류 7 제 4 항 인공망막 장치 연구 동향 12 제 5 항 고해상도 인공망막 자극기 개발의 필요성 15 제 6 항 고해상도 자극을 위한 나노와이어 FET 스위치 array 기반 인공망막 자극 시스템 17 제 2 장 본 론 19 제 1 절 설계 개념 19 제 1 항 나노와이어 FET 스위치 array 기반 인공망막 자극 시스템의 동작 개념 19 제 2 항 나노와이어 FET 스위치 array 기반 인공망막 자극기 회로의 동작 조건 21 제 2 절 설계 및 시뮬레이션 25 제 1 항 자극기 회로 전체 구성 25 제 2 항 Analog block 설계 27 제 3 항 Digital block 설계 36 제 4 항 Layout 43 제 3 절 시스템 구현 45 제 1 항 자극 시스템 구현을 위한 PCB 제작 45 제 4 절 실험 및 검증 48 제 1 항 전기적 특성 평가 48 제 2 항 in vitro 동물 실험 56 제 3 장 결 론 65 제 1 절 자극기 회로의 기능성 평가 65 제 2 절 향후 계획 67 참고문헌 68 ABSTRACT 74Maste

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

Photogenetic Retinal Prosthesis

The last few decades have witnessed an immense effort to develop working retinal implants for patients suffering from retinal degeneration diseases such as retinitis pigmentosa. However, it is becoming apparent that this approach is unable to restore levels of vision that will be sufficient to offer significant improvement in the quality of life of patients. Herein, a new type of retinal prosthesis that is based on genetic expression of microbial light sensitive ion channel, Chanelrhodopsin-2 (ChR2), and a remote light stimulation is examined. First, the dynamics of the ChR2 stimulation is characterized and it is shown that (1) the temporal resolution of ChR2-evoked spiking is limited by a continuous drop in its depolarization efficiency that is due to (a) frequency-independent desensitization process and (b) slow photocurrent shutting, which leads to a frequency-dependent post-spike depolarization and (2) the ChR2 response to light can be accurately reproduced by a four-state model consisting of two interconnected branches of open and close states. Then, a stimulation prototype is developed and its functionality is demonstrated in-vitro. The prototype uses a new micro-emissive matrix which enables generating of two-dimensional stimulation patterns with enhanced resolution compared to the conventional retinal implants. Finally, based on the micro-emitters matrix, a new technique for sub-cellular and network-level neuroscience experimentations is shown. The capacity to excite sub-cellular compartments is demonstrated and an example utility to fast map variability in dendrites conductance is shown. The outcomes of this thesis present an outline and a first proof-of-concept for a future photogenetic retinal prosthesis. In addition, they provide the emerging optogenetic technology with a detailed analysis of its temporal resolution and a tool to expand its spatial resolution, which can have immediate high impact applications in modulating the activity of sub-cellular compartments, mapping neuronal networks and studying synchrony and plasticity effects