소형동물의 뇌신경 자극을 위한 완전 이식형 신경자극기

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

Improving the mechanistic study of neuromuscular diseases through the development of a fully wireless and implantable recording device

Neuromuscular diseases manifest by a handful of known phenotypes affecting the peripheral nerves, skeletal muscle fibers, and neuromuscular junction. Common signs of these diseases include demyelination, myasthenia, atrophy, and aberrant muscle activity—all of which may be tracked over time using one or more electrophysiological markers. Mice, which are the predominant mammalian model for most human diseases, have been used to study congenital neuromuscular diseases for decades. However, our understanding of the mechanisms underlying these pathologies is still incomplete. This is in part due to the lack of instrumentation available to easily collect longitudinal, in vivo electrophysiological activity from mice. There remains a need for a fully wireless, batteryless, and implantable recording system that can be adapted for a variety of electrophysiological measurements and also enable long-term, continuous data collection in very small animals. To meet this need a miniature, chronically implantable device has been developed that is capable of wirelessly coupling energy from electromagnetic fields while implanted within a body. This device can both record and trigger bioelectric events and may be chronically implanted in rodents as small as mice. This grants investigators the ability to continuously observe electrophysiological changes corresponding to disease progression in a single, freely behaving, untethered animal. The fully wireless closed-loop system is an adaptable solution for a range of long-term mechanistic and diagnostic studies in rodent disease models. Its high level of functionality, adjustable parameters, accessible building blocks, reprogrammable firmware, and modular electrode interface offer flexibility that is distinctive among fully implantable recording or stimulating devices. The key significance of this work is that it has generated novel instrumentation in the form of a fully implantable bioelectric recording device having a much higher level of functionality than any other fully wireless system available for mouse work. This has incidentally led to contributions in the areas of wireless power transfer and neural interfaces for upper-limb prosthesis control. Herein the solution space for wireless power transfer is examined including a close inspection of far-field power transfer to implanted bioelectric sensors. Methods of design and characterization for the iterative development of the device are detailed. Furthermore, its performance and utility in remote bioelectric sensing applications is demonstrated with humans, rats, healthy mice, and mouse models for degenerative neuromuscular and motoneuron diseases

Coupled resonator based wireless power transfer for bioelectronics

Implantable and wearable bioelectronics provide the ability to monitor and modulate physiological processes. They represent a promising set of technologies that can provide new treatment for patients or new tools for scientific discovery, such as in long-term studies involving small animals. As these technologies advance, two trends are clear, miniaturization and increased sophistication i.e. multiple channels, wireless bi-directional communication, and responsiveness (closed-loop devices). One primary challenge in realizing miniaturized and sophisticated bioelectronics is powering. Integration and development of wireless power transfer (WPT) technology, however, can overcome this challenge. In this dissertation, I propose the use of coupled resonator WPT for bioelectronics and present a new generalized analysis and optimization methodology, derived from complex microwave bandpass filter synthesis, for maximizing and controlling coupled resonator based WPT performance. This newly developed set of analysis and optimization methods enables system miniaturization while simultaneously achieving the necessary performance to safely power sophisticated bioelectronics. As an application example, a novel coil to coil based coupled resonator arrangement to wirelessly operate eight surface electromyography sensing devices wrapped circumferentially around an able-bodied arm is developed and demonstrated. In addition to standard coil to coil based systems, this dissertation also presents a new form of coupled resonator WPT system built of a large hollow metallic cavity resonator. By leveraging the analysis and optimization methods developed here, I present a new cavity resonator WPT system for long-term experiments involving small rodents for the first time. The cavity resonator based WPT arena exhibits a volume of 60.96 x 60.96 x 30.0 cm3. In comparison to prior state of the art, this cavity resonator system enables nearly continuous wireless operation of a miniature sophisticated device implanted in a freely behaving rodent within the largest space. Finally, I present preliminary work, providing the foundation for future studies, to demonstrate the feasibility of treating segments of the human body as a dielectric waveguide resonator. This creates another form of a coupled resonator system. Preliminary experiments demonstrated optimized coupled resonator wireless energy transfer into human tissue. The WPT performance achieved to an ultra-miniature sized receive coil (2 mm diameter) is presented. Indeed, optimized coupled resonator systems, broadened to include cavity resonator structures and human formed dielectric resonators, can enable the effective use of coupled resonator based WPT technology to power miniaturized and sophisticated bioelectronics

Dissection of Affective Catecholamine Circuits Using Traditional and Wireless Optogenetics

Parsing the complexity of the mammalian brain has challenged neuroscientists for thousands of years. In the early 21st century, advances in materials science and neuroscience have enabled unprecedented control of neural circuitry. In particular, cell-type selective manipulations, such as those with optogenetics and chemogenetics, routinely provide answers to previously intractable neurobiological questions in the intact, behaving animal. In this two-part dissertation, I first introduce new minimally invasive, wireless technology to perturb neural activity in the ventral tegmental area dopaminergic system of freely moving animals. I report a series of novel devices for studying and perturbing intact neural systems through optogenetics, microfluidic pharmacology, and electrophysiology. Unlike optogenetic approaches that rely on rigid, glass fiber optics coupled to external light sources, these novel devices utilize flexible substrates to carry microscale, inorganic light emitting diodes (μ-ILEDs), multimodal sensors, and/or microfluidic channels into the brain. Each class of device can be wirelessly controlled, enabling studies in freely behaving mice and achieving previously untenable control of catecholamine neural circuitry. In the second part of this dissertation, I apply existing cell-type selective approaches to dissect the role of the locus coeruleus noradrenergic (LC-NE) system in anxiety-like and aversive behaviors. The LC-NE system is one of the first systems engaged following a stressful event. While LC-NE neurons are known to be activated by many different stressors, the underlying neural circuitry and the role of this activity in generating stress-induced anxiety has not been elucidated until now. I demonstrate that increased tonic activity of LC-NE neurons is both necessary and sufficient for stress-induced anxiety; a behavior which is driven by LC projections to the basolateral amygdala. Furthermore, this activity and behavior is elicited by corticotropin releasing hormone-containing afferent inputs into the LC from the central amygdala. These studies position the LC-NE system as a critical mediator of acute stress-induced anxiety and offer a potential intervention for preventing stress-related affective disorders. Together these two objectives provide a rich technological toolbox for neuroscientists and yield important knowledge of how small catecholamine structures with widespread forebrain innervation can selectively mediate higher order behaviors

High-performance wireless power and data transfer interface for implantable medical devices

D’importants progès ont été réalisés dans le développement des systèmes biomédicaux implantables grâce aux dernières avancées de la microélectronique et des technologies sans fil. Néanmoins, ces appareils restent difficiles à commercialier. Cette situation est due particulièrement à un manque de stratégies de design capable supporter les fonctionnalités exigées, aux limites de miniaturisation, ainsi qu’au manque d’interface sans fil à haut débit fiable et faible puissance capable de connecter les implants et les périphériques externes. Le nombre de sites de stimulation et/ou d’électrodes d’enregistrement retrouvés dans les dernières interfaces cerveau-ordinateur (IMC) ne cesse de croître afin d’augmenter la précision de contrôle, et d’améliorer notre compréhension des fonctions cérébrales. Ce nombre est appelé à atteindre un millier de site à court terme, ce qui exige des débits de données atteingnant facilement les 500 Mbps. Ceci étant dit, ces travaux visent à élaborer de nouvelles stratégies innovantes de conception de dispositifs biomédicaux implantables afin de repousser les limites mentionnées ci-dessus. On présente de nouvelles techniques faible puissance beaucoup plus performantes pour le transfert d’énergie et de données sans fil à haut débit ainsi que l’analyse et la réalisation de ces dernières grâce à des prototypes microélectroniques CMOS. Dans un premier temps, ces travaux exposent notre nouvelle structure multibobine inductive à résonance présentant une puissance sans fil distribuée uniformément pour alimenter des systèmes miniatures d’étude du cerveaux avec des models animaux en ilberté ainsi que des dispositifs médicaux implantbles sans fil qui se caractérisent par une capacité de positionnement libre. La structure propose un lien de résonance multibobines inductive, dont le résonateur principal est constitué d’une multitude de résonateurs identiques disposés dans une matrice de bobines carrées. Ces dernières sont connectées en parallèle afin de réaliser des surfaces de puissance (2D) ainsi qu’une chambre d’alimentation (3D). La chambre proposée utilise deux matrices de résonateurs de base, mises face à face et connectés en parallèle afin d’obtenir une distribution d’énergie uniforme en 3D. Chaque surface comprend neuf bobines superposées, connectées en parallèle et réailsées sur une carte de circuit imprimé deux couches FR4. La chambre dispose d’un mécanisme naturel de localisation de puissance qui facilite sa mise en oeuvre et son fonctionnement. En procédant ainsi, nous évitons la nécessité d’une détection active de l’emplacement de la charge et le contrôle d’alimentation. Notre approche permet à cette surface d’alimentation unique de fournir une efficacité de transfert de puissance (PTE) de 69% et une puissance délivrée à la charge (PDL) de 120 mW, pour une distance de séparation de 4 cm, tandis que le prototype de chambre complet fournit un PTE uniforme de 59% et un PDL de 100 mW en 3D, partout à l’intérieur de la chambre avec un volume de chambre de 27 × 27 × 16 cm3. Une étape critique avant d’utiliser un dispositif implantable chez les humains consiste à vérifier ses fonctionnalités sur des sujets animaux. Par conséquent, la chambre d’énergie sans fil conçue sera utilisée afin de caractériser les performances d’ une interface sans fil de transmisison de données dans un environnement réaliste in vivo avec positionement libre. Un émetteur-récepteur full-duplex (FDT) entièrement intégré qui se caractérise par sa faible puissance est conçu pour réaliser une interfaces bi-directionnelles (stimulation et enregistrement) avec des débits asymétriques: des taux de tramnsmission plus élevés sont nécessaires pour l’enregistrement électrophysiologique multicanal (signaux de liaison montante) alors que les taux moins élevés sont utilisés pour la stimulation (les signaux de liaison descendante). L’émetteur (TX) et le récepteur (RX) se partagent une seule antenne afin de réduire la taille de l’implant. L’émetteur utilise la radio ultra-large bande par impulsions (IR-UWB) basée sur l’approche edge combining et le RX utilise la bande ISM (Industrielle, Scientifique et Médicale) de fréquence central 2.4 GHz et la modulation on-off-keying (OOK). Une bonne isolation (> 20 dB) est obtenue entre le TX et le RX grâce à 1) la mise en forme les impulsions émises dans le spectre UWB non réglementée (3.1-7 GHz), et 2) le filtrage espace-efficace (évitant l’utilisation d’un circulateur ou d’un diplexeur) du spectre du lien de communication descendant directement au niveau de l’ amplificateur à faible bruit (LNA). L’émetteur UWB 3.1-7 GHz utilise un e modultion OOK ainsi qu’une modulation par déplacement de phase (BPSK) à seulement 10.8 pJ / bits. Le FDT proposé permet d’atteindre 500 Mbps de débit de données en lien montant et 100 Mbps de débit de données de lien descendant. Il est entièrement intégré dans un procédé TSMC CMOS 0.18 um standard et possède une taille totale de 0.8 mm2. La consommation totale d’énergie mesurée est de 10.4 mW (5 mW pour RX et 5.4 mW pour TX au taux de 500 Mbps).In recent years, there has been major progress on implantable biomedical systems that support most of the functionalities of wireless implantable devices. Nevertheless, these devices remain mostly restricted to be commercialized, in part due to weakness of a straightforward design to support the required functionalities, limitation on miniaturization, and lack of a reliable low-power high data rate interface between implants and external devices. This research provides novel strategies on the design of implantable biomedical devices that addresses these limitations by presenting analysis and techniques for wireless power transfer and efficient data transfer. The first part of this research includes our proposed novel resonance-based multicoil inductive power link structure with uniform power distribution to wirelessly power up smart animal research systems and implanted medical devices with high power efficiency and free positioning capability. The proposed structure consists of a multicoil resonance inductive link, which primary resonator array is made of several identical resonators enclosed in a scalable array of overlapping square coils that are connected in parallel and arranged in power surface (2D) and power chamber (3D) configurations. The proposed chamber uses two arrays of primary resonators, facing each other, and connected in parallel to achieve uniform power distribution in 3D. Each surface includes 9 overlapped coils connected in parallel and implemented into two layers of FR4 printed circuit board. The chamber features a natural power localization mechanism, which simplifies its implementation and eases its operation by avoiding the need for active detection of the load location and power control mechanisms. A single power surface based on the proposed approach can provide a power transfer efficiency (PTE) of 69% and a power delivered to the load (PDL) of 120 mW, for a separation distance of 4 cm, whereas the complete chamber prototype provides a uniform PTE of 59% and a PDL of 100 mW in 3D, everywhere inside the chamber with a chamber size of 27×27×16 cm3. The second part of this research includes our proposed novel, fully-integrated, low-power fullduplex transceiver (FDT) to support bi-directional neural interfacing applications (stimulating and recording) with asymmetric data rates: higher rates are required for recording (uplink signals) than stimulation (downlink signals). The transmitter (TX) and receiver (RX) share a single antenna to reduce implant size. The TX uses impulse radio ultra-wide band (IR-UWB) based on an edge combining approach, and the RX uses a novel 2.4-GHz on-off keying (OOK) receiver. Proper isolation (> 20 dB) between the TX and RX path is implemented 1) by shaping the transmitted pulses to fall within the unregulated UWB spectrum (3.1-7 GHz), and 2) by space-efficient filtering (avoiding a circulator or diplexer) of the downlink OOK spectrum in the RX low-noise amplifier (LNA). The UWB 3.1-7 GHz transmitter using OOK and binary phase shift keying (BPSK) modulations at only 10.8 pJ/bit. The proposed FDT provides dual band 500 Mbps TX uplink data rate and 100 Mbps RX downlink data rate. It is fully integrated on standard TSMC 0.18 nm CMOS within a total size of 0.8 mm2. The total power consumption measured 10.4 mW (5 mW for RX and 5.4 mW for TX at the rate of 500 Mbps)

An Implantable Bio-Micro-system for Drug Monitoring

Multi-target and continuous monitoring by wireless implantable devices is of increasing interest for personalized therapy. In this work an implantable system is presented which is capable of measuring different drugs with Cyclic Voltammetry (CV) method. The wireless microsystem consists of four modules, namely (i) The inductive coil; (ii) Power management IC; (iii) Readout and control IC; (iv) Biosensor array. The power management IC provides 1.8 V with as high as 2 mW power for the readout IC. The configurable readout IC is able to control the biosensor array and measure the sensor current in CV method. CV experiments performed with this microsystem well agree with a commercial equipment for two well known anti-cancer drugs, Etoposide and Mitoxantrone, detection