Characterization and development towards electrochemical real-time LAMP detection in an integrated and portable device

Dissertação de mestrado integrado em Engenharia Biomédica (área de especialização em Eletrónica Médica)Nos últimos anos os biossensores eletroquímicos têm sido reportados como uma abordagem promis sora para a deteção de DNA. São atrativos para dispositivos point-of-care pela facilidade de miniaturização, compatibilidade com técnicas de microfabricação e facilidade de instrumentação. Contudo, a integração de uma fase de amplificação com a deteção de sinais continua a ser um desafio. A técnica LAMP (loop mediated isothermal amplification ) surgiu como solução, destacando-se pela sua robustez e sensibilidade. Uma plataforma portátil para deteção eletroquímica de DNA (Mobi-E) foi desenvolvida para incorporar as caraterísticas mencionadas. Neste trabalho foram caraterizados os principais componentes do disposi tivo: potencióstatos ASIC, controlo de temperatura e um chip fluídico que integra elétrodos e estruturas de aquecimento impressas. Seguidamente, efetuou-se uma pesquisa para funcionalização universal desses elétrodos utilizando MD LAMP (mediator displacement LAMP). O desempenho do potencióstato, especificamente a rotina de voltametria de onda quadrada e a leitura quase simultânea dos 6 elétrodos de trabalho de uma câmara, foi provado e comparado com um dispositivo comercial, obtendo-se resultados qualitativamente comparáveis. Foram ainda realizadas otimizações para estabilização do potencial de referência, através da conversão Ag/AgCl por FeCl3, e para precaver dificuldades de medição resultantes da limitada tensão de conformidade do potencióstato (1.8 V). Para tal, aumentou-se a área do elétrodo auxiliar, através da impressão de 8 camadas de Au (4 no elétrodo de trabalho), e efetuou-se, entre medições, o curto-circuito entre o elétrodo auxiliar e o de referência. O sistema de controlo de temperatura provou ser efetivo no aquecimento das câmaras até 65 ºC em 2.5 min e na monitorização assertiva das suas temperaturas. Não foi detetado cross-talk entre câmaras vizinhas, nem a formação severa de bolhas de ar. Como prova de conceito, foram testadas quatro abordagens para MD LAMP e foi identificada uma alternativa promissora (Stem-Loop ) ao standard, com a respetiva mudança relativa de sinal: 0.3 e 177.6. Esta dissertação culmina com a otimização da reação LAMP para uma libertação eficiente do medi ador. Duas promissoras combinações de concentrações de mediador, primer modificado e loop primer foram identificadas: 200 nM, 400 nM, 400 nM e 100 nM, 200 nM, 600 nM, respetivamente, obtendo-se uma relação sinal/ruído de 3.7 e 2.9. Os conhecimentos adquiridos viabilizam o avanço da investigação no sentido da obtenção de um dispositivo capaz de realizar LAMP eletroquímico em tempo real.Electrochemical biosensors have been reported in recent years as a promising approach for DNA detection. The ease of miniaturization, compatibility with microfabrication techniques and simple instru mentation make these sensors attractive for point-of-care (POC) devices. However, integrating an ampli fication stage with signal detection remains a challenge. Loop-mediated isothermal amplification (LAMP) has emerged as a robust and highly sensitive isothermal strategy. A novel portable platform for rapid electrochemical DNA detection (Mobi-E device) was developed to incorporate the aforementioned features. Within this work, an extensive characterization of the main components of the Mobi-E device, which comprises ASIC potentiostats, temperature control, and a fluidic chip with integrated inkjet-printed electrodes and heating structures, was performed, followed by a research towards target-independent electrode functionalization employing mediator displacement (MD) LAMP. The operation of the general functionalities of the ASIC potentiostat, specifically the square wave voltammetry (SWV) routine and the quasi-simultaneous read-out of all 6 working electrodes (WEs) of a chamber, was proven and its performance was benchmarked against a commercial device, achieving qualitatively comparable results. Inherent optimizations of the device were performed to stabilize the reference electrode (RE) potential, through Ag/AgCl conversion by FeCl3, and to address the criticality that the 1.8 V compliance voltage of the potentiostat brought to the measurements. For this issue, it is suggested to increase the counter electrode (CE) area by printing 8 Au layers (WE with 4 layers) and to short-circuit the CE and RE between measurements. The temperature control system proved to be effective in heating the chambers to 65 ºC in about 2.5 min and assertively monitoring their temperature. Furthermore, no cross-talk between neighbouring chambers and no severe bubble formation was detected. Four concepts for target-independent MD LAMP were tested as proof-of-concept and a promising alternative (”Stem-Loop universal reporter (UR)”) to the standard approach was identified. The following relative signal change was achieved: 0.3 and 177.6, respectively. This thesis culminates with the optimization of fluorescent LAMP reaction parameters towards an efficient mediator release. Two promising concentration combinations of mediator, modified primer (LB_Medc) and loop primer (LB) were identified: 200 nM, 400 nM, 400 nM and 100 nM, 200 nM, 600 nM, respectively. For these, the signal-to-noise ratio was 3.7 and 2.9. The knowledge acquired in this thesis allows moving forward towards a device able to perform electrochemical real-time LAMP readout

Electrochemical Plug-and-Power e-readers for Point-of-Care Applications

Point-of-Care diagnostic tests enable monitor health conditions and obtain fast results close to the patient, reducing medical costs, and allowing the control of infectious outbreaks. The interest in developing Point-of-Care devices is increasing due to they are suitable for a wide variety of applications. This doctoral thesis focuses on the development of Plug-and-Power electronic readers (e- readers) for electrochemical detections and the demonstration of their possibilities as Point-of-Care diagnostic testing. The solutions proposed in this study make it possible to improve Point-of-Care tests whose premises are laboratory decentralization, personalized medicine, rapid diagnosis, and improvement of patient care. Developed electronic readers can be powered from a conventional system, such as a USB port or a lithium battery, or can be defined as self-powered systems, capable of extracting energy from alternative energy sources, such as fuel cells, defining Plug-and-Power systems. The designed electrochemical detection devices in this thesis are based on low-power consumption electronic instrumentation circuits. These circuits are capable of controlling the sensing element, measuring its response, and representing the result quantitatively. The implemented devices can work with both electrochemical sensors and fuel cells. Furthermore, it is possible to adapt its measurement range, enabling its use in a wide variety of applications. Thanks to their reduced energy consumption, some of these developments can be defined as self-powered platforms able to operate only with the energy extracted from the biological sample, which in turn is monitored. These devices are easy-to-use and plug-and-play, enabling those unskilled individuals to carry out tests after prior training. Moreover, thanks to their user-friendly interface, results are clear and easy to understand. This doctoral dissertation is presented as an article compendium and composed of three publications detailed in chronological order of publication. The first contribution describes an innovative portable Point-of-Care device able to provide a quantitative result of the glucose concentration of a sample. The proposed system combines an e-reader and a disposable device based on two elements: a glucose paper-based power source, and a glucose fuel cell-based sensor. The battery-less e-reader extracts the energy from the disposable unit, acquires the signal, processes it, and shows the glucose concentration on a numerical display. Due to low-power consumption of the e-reader, the whole electronic system can operate only with the energy extracted from the disposable element. Furthermore, the proposed system minimizes the user interaction, which only must deposit the sample on the strip and wait a few seconds to see the test result. The second publication validates the e-reader in other scenarios following two approaches: using fuel cells as a power element, and as a dual powering and sensing element. The device was tested with glucose, urine, methanol, and ethanol fuel cells and electrochemical sensors in order to show the adaptability of this versatile concept to a wide variety of fields beyond clinical diagnostics, such as veterinary or environmental fields. The third study presents a low-cost, miniaturized, and customizable electronic reader for amperometric detections. The USB-powered portable device is composed of a full- custom electronic board for signal acquisition, and software, which controls the systems, represents and saves the results. In this study, the performance of the device was compared against three commercial potentiostats, showing comparable results to those obtained using three commercial systems, which were significantly more expensive. As proof of concept, the system was validated by detecting horseradish peroxidase samples. However, it could be easily extended its scope and measure other types of analytes or biological matrices since it can be easily adapted to detect currents a wide range of currents.Las pruebas de diagnostico Point-of-Care permiten monitorizar las condiciones de salud y obtener resultados rápidos cerca del paciente, reduciendo los costes médicos y permitiendo controlar brotes infecciosos. El interés por desarrollar dispositivos de Point- of-Care está aumentando debido a que son aplicables a una amplia variedad de aplicaciones. Esta tesis doctoral se centra en el desarrollo de lectores electrónicos (e-readers) Plug-and- Power para detecciones electroquímicas y la demostración de sus posibilidades como pruebas de diagnóstico de punto de atención (Point-of-Care). Las soluciones propuestas en este trabajo permiten mejorar las pruebas Point-of-Care, cuyas premisas son la descentralización de laboratorio, la medicina personalizada, el diagnóstico rápido y la mejora de la atención al paciente. Los lectores electrónicos desarrollados pueden ser alimentados desde un sistema convencional, como puede ser un puerto USB o una batería de litio, o definirse como sistemas autoalimentados, capaces de extraen energía de fuentes alternativas de energía, como celdas de combustible (fuel cells), definiendo así sistemas Plug-and-Power. Los dispositivos de detección electroquímica diseñados se basan en circuitos de instrumentación electrónica de bajo consumo. Estos circuitos son capaces controlar el elemento de sensado, medir su respuesta y representar el resultado de forma cuantitativa. Los dispositivos implementados pueden trabajar tanto con sensores electroquímicos como con fuel cells. Además, es posible adaptar su rango de medida, permitiendo su utilización en una amplia variedad de aplicaciones. Gracias a su reducido consumo de energía, algunos de estos desarrollos pueden definirse como plataformas autoalimentadas capaces de operar solo con la energía extraída de la muestra biológica, que a su vez es monitorizada. Estas plataformas electrónicas son fáciles de usar y Plug-and-Play, permitiendo que personas no cualificadas puedan utilizarlas después de un previo entrenamiento. Además, gracias a su interfaz fácil de usar, los resultados son claros y fáciles de interpretar

A fully integrated CMOS microelectrode system for electrochemistry

Electroanalysis has proven to be one of the most widely used technologies for point-of-care devices. Owing to the direct recording of the intrinsic properties of biochemical functions, the field has been involved in the study of biology since electrochemistry’s conception in the 1800’s. With the advent of microelectronics, humanity has welcomed self-monitoring portable devices such as the glucose sensor in its everyday routine. The sensitivity of amperometry/ voltammetry has been enhanced by the use of microelectrodes. Their arrangement into microelectrode arrays (MEAs) took a step forward into sensing biomarkers, DNA and pathogens on a multitude of sites. Integrating these devices and their operating circuits on CMOS monolithically miniaturised these systems even more, improved the noise response and achieved parallel data collection. Including microfluidics on this type of devices has led to the birth of the Lab-on-a-Chip technology. Despite the technology’s inclusion in many bioanalytical instruments there is still room for enhancing its capabilities and application possibilities. Even though research has been conducted on the selective preparation of microelectrodes with different materials in a CMOS MEA to sense several biomarkers, limited effort has been demonstrated on improving the parallel electroanalytical capabilities of these devices. Living and chemical materials have a tendency to alter their composition over time. Therefore analysing a biochemical sample using as many electroanalytical methods as possible simultaneously could offer a more complete diagnostic snapshot. This thesis describes the development of a CMOS Lab-on-a-Chip device comprised of many electrochemical cells, capable of performing simultaneous amperometric/voltammetric measurements in the same fluidic chamber. The chip is named an electrochemical cell microarray (ECM) and it contains a MEA controlled by independent integrated potentiostats. The key stages in this work were: to investigate techniques for the electrochemical cell isolation through simulations; to design and implement a CMOS ECM ASIC; to prepare the CMOS chip for use in an electrochemical environment and encapsulate it to work with liquids; to test and characterise the CMOS chip housed in an experimental system; and to make parallel measurements by applying different simultaneous electroanalytical methods. It is envisaged that results from the system could be combined with multivariate analysis to describe a molecular profile rather than only concentration levels. Simulations to determine the microelectrode structure and the potentiostat design, capable of constructing isolated electrochemical cells, were made using the Cadence CAD software package. The electrochemical environment and the microelectrode structure were modelled using a netlist of resistors and capacitors. The netlist was introduced in Cadence and it was simulated with potentiostat designs to produce 3-D potential distribution and electric field intensity maps of the chemical volume. The combination of a coaxial microelectrode structure and a fully differential potentiostat was found to result in independent electrochemical cells isolated from each other. A 4 x 4 integrated ECM controlled by on-chip fully differential potentiostats and made up by a 16 × 16 working electrode MEA (laid out with the coaxial structure) was designed in an unmodified 0.35 μm CMOS process. The working electrodes were connected to a circuit capable of multiplexing them along a voltammetric measurement, maintaining their diffusion layers during stand-by time. Two readout methods were integrated, a simple resistor for an analogue readout and a discrete time digital current-to-frequency charge-sensitive amplifier. Working electrodes were designed with a 20 μm side length while the counter and reference electrodes had an 11 μm width. The microelectrodes were designed using the aluminium top metal layer of the CMOS process. The chips were received from the foundry unmodified and passivated, thus they were post-process fabricated with photolithographic processes. The passivation layer had to be thinned over the MEA and completely removed on top of the microelectrodes. The openings were made 25 % smaller than the top metal layer electrode size to ensure a full coverage of the easily corroded Al metal. Two batches of chips were prepared, one with biocompatible Au on all the microelectrodes and one altered with Pd on the counter and Ag on the reference electrode. The chips were packaged on ceramic pin grid array packages and encapsulated using chemically resistant materials. Electroplating was verified to deposit Au with increased roughness on the microelectrodes and a cleaning step was performed prior to electrochemical experiments. An experimental setup containing a PCB, a PXIe system by National Instruments, and software programs coded for use with the ECM was prepared. The programs were prepared to conduct various voltammetric and amperometric methods as well as to analyse the results. The first batch of post-processed encapsulated chips was used for characterisation and experimental measurements. The on-chip potentiostat was verified to perform alike a commercial potentiostat, tested with microelectrode samples prepared to mimic the coaxial structure of the ECM. The on-chip potentiostat’s fully differential design achieved a high 5.2 V potential window range for a CMOS device. An experiment was also devised and a 12.3 % cell-to-cell electrochemical cross-talk was found. The system was characterised with a 150 kHz bandwidth enabling fast-scan cyclic voltammetry(CV) experiments to be performed. A relatively high 1.39 nA limit-of-detection was recorded compared to other CMOS MEAs, which is however adequate for possible applications of the ECM. Due to lack of a current polarity output the digital current readout was only eligible for amperometric measurements, thus the analogue readout was used for the rest of the measurements. The capability of the ECM system to perform independent parallel electroanalytical measurements was demonstrated with 3 different experimental techniques. The first one was a new voltammetric technique made possible by the ECM’s unique characteristics. The technique was named multiplexed cyclic voltammetry and it increased the acquisition speed of a voltammogram by a parallel potential scan on all the electrochemical cells. The second technique measured a chemical solution with 5 mM of ferrocene with constant potential amperometry, staircase cyclic voltammetry, normal pulse voltammetry, and differential pulse voltammetry simultaneously on different electrochemical cells. Lastly, a chemical solution with 2 analytes (ferrocene and decamethylferrocene) was prepared and they were sensed separately with constant potential amperometry and staircase cyclic voltammetry on different cells. The potential settings of each electrochemical cell were adjusted to detect its respective analyte

Biosensors for Biomolecular Computing: a Review and Future Perspectives

Biomolecular computing is the field of engineering where computation, storage, communication, and coding are obtained by exploiting interactions between biomolecules, especially DNA, RNA, and enzymes. They are a promising solution in a long-term vision, bringing huge parallelism and negligible power consumption. Despite significant efforts in taking advantage of the massive computational power of biomolecules, many issues are still open along the way for considering biomolecular circuits as an alternative or a complement to competing with complementary metal–oxide–semiconductor (CMOS) architectures. According to the Von Neumann architecture, computing systems are composed of a central processing unit, a storage unit, and input and output (I/O). I/O operations are crucial to drive and read the computing core and to interface it to other devices. In emerging technologies, the complexity overhead and the bottleneck of I/O systems are usually limiting factors. While computing units and memories based on biomolecular systems have been successfully presented in literature, the published I/O operations are still based on laboratory equipment without a real development of integrated I/O. Biosensors are suitable devices for transducing biomolecular interactions by converting them into electrical signals. In this work, we explore the latest advancements in biomolecular computing, as well as in biosensors, with focus on technology suitable to provide the required and still missing I/O devices. Therefore, our goal is to picture out the present and future perspectives about DNA, RNA, and enzymatic-based computing according to the progression in its I/O technologies, and to understand how the field of biosensors contributes to the research beyond CMOS

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

Design and Implementation of an Integrated Biosensor Platform for Lab-on-a-Chip Diabetic Care Systems

Recent advances in semiconductor processing and microfabrication techniques allow the implementation of complex microstructures in a single platform or lab on chip. These devices require fewer samples, allow lightweight implementation, and offer high sensitivities. However, the use of these microstructures place stringent performance constraints on sensor readout architecture. In glucose sensing for diabetic patients, portable handheld devices are common, and have demonstrated significant performance improvement over the last decade. Fluctuations in glucose levels with patient physiological conditions are highly unpredictable and glucose monitors often require complex control algorithms along with dynamic physiological data. Recent research has focused on long term implantation of the sensor system. Glucose sensors combined with sensor readout, insulin bolus control algorithm, and insulin infusion devices can function as an artificial pancreas. However, challenges remain in integrated glucose sensing which include degradation of electrode sensitivity at the microscale, integration of the electrodes with low power low noise readout electronics, and correlation of fluctuations in glucose levels with other physiological data. This work develops 1) a low power and compact glucose monitoring system and 2) a low power single chip solution for real time physiological feedback in an artificial pancreas system. First, glucose sensor sensitivity and robustness is improved using robust vertically aligned carbon nanofiber (VACNF) microelectrodes. Electrode architectures have been optimized, modeled and verified with physiologically relevant glucose levels. Second, novel potentiostat topologies based on a difference-differential common gate input pair transimpedance amplifier and low-power voltage controlled oscillators have been proposed, mathematically modeled and implemented in a 0.18μm [micrometer] complementary metal oxide semiconductor (CMOS) process. Potentiostat circuits are widely used as the readout electronics in enzymatic electrochemical sensors. The integrated potentiostat with VACNF microelectrodes achieves competitive performance at low power and requires reduced chip space. Third, a low power instrumentation solution consisting of a programmable charge amplifier, an analog feature extractor and a control algorithm has been proposed and implemented to enable continuous physiological data extraction of bowel sounds using a single chip. Abdominal sounds can aid correlation of meal events to glucose levels. The developed integrated sensing systems represent a significant advancement in artificial pancreas systems

Smartphone-enabled Biotelemetric System For a Smart Contact Lens

Diabetes describes a disordered metabolic state with an overabundance of glucose in the bloodstream, due to insu cient production or utilization of insulin to allow tissue cells from consuming glucose. People with unmanaged diabetes could lead to many serious complications such as heart disease, stroke, coma, kidney failure, blindness, amputation, and premature death. Diabetes can be managed by monitoring the blood glucose level, and control the glucose level by taking insulin, and exercising a carefully planned lifestyle with appropriate diet and physical activities. An elegant solution for glucose monitoring is the integration of electrochemical-based glucose sensor and microelectronics within a contact lens, namely a smart contact lens, which can measure the tear glucose in the eye, and correlate it to blood glucose. Currently, there is no functional smart contact lens devices for glucose detection in the market. This thesis focuses on providing proof of concept prototypes for implementing energy harvesting and wireless data transmission on a smart contact lens. An all-in-one solution is proposed to harvest energy from a smartphone, and use the same smartphone to support glucose data extraction by backscattering. The appropriate prototype architectures are justi ed based on a system speci cation estimated from related works. The prototypes are designed in simulation, and then fabricated on PCBs using o -the-shelf components and equipment. Measurements are conducted on the prototypes to evaluate their performance against the initial assessment of requirements from related works

Design of a Programmable Passive SoC for Biomedical Applications Using RFID ISO 15693/NFC5 Interface

Low power, low cost inductively powered passive biotelemetry system involving fully customized RFID/NFC interface base SoC has gained popularity in the last decades. However, most of the SoCs developed are application specific and lacks either on-chip computational or sensor readout capability. In this paper, we present design details of a programmable passive SoC in compliance with ISO 15693/NFC5 standard for biomedical applications. The integrated system consists of a 32-bit microcontroller, a sensor readout circuit, a 12-bit SAR type ADC, 16 kB RAM, 16 kB ROM and other digital peripherals. The design is implemented in a 0.18 μ m CMOS technology and used a die area of 1.52 mm × 3.24 mm. The simulated maximum power consumption of the analog block is 592 μ W. The number of external components required by the SoC is limited to an external memory device, sensors, antenna and some passive components. The external memory device contains the application specific firmware. Based on the application, the firmware can be modified accordingly. The SoC design is suitable for medical implants to measure physiological parameters like temperature, pressure or ECG. As an application example, the authors have proposed a bioimplant to measure arterial blood pressure for patients suffering from Peripheral Artery Disease (PAD)

INTEGRATION OF CMOS TECHNOLOGY INTO LAB-ON-CHIP SYSTEMS APPLIED TO THE DEVELOPMENT OF A BIOELECTRONIC NOSE

This work addresses the development of a lab-on-a-chip (LOC) system for olfactory sensing. The method of sensing employed is cell-based, utilizing living cells to sense stimuli that are otherwise not easily sensed using conventional transduction techniques. Cells have evolved over millions of years to be exquisitely sensitive to their environment, with certain types of cells producing electrical signals in response to stimuli. The core device that is introduced here is comprised of living olfactory sensory neurons (OSNs) on top of a complementary metal-oxide-semiconductor (CMOS) integrated circuit (IC). This hybrid bioelectronic approach to sensing leverages the sensitivity of OSNs with the electronic signal processing capability of modern ICs. Intimately combining electronics with biology presents a number of unique challenges to integration that arise from the disparate requirements of the two separate domains. Fundamentally the obstacles arise from the facts that electronic devices are designed to work in dry environments while biology requires not only a wet environment, but also one that is precisely controlled and non-toxic. Design and modeling of such heterogeneously integrated systems is complicated by the lack of tools that can address the multiple domains and techniques required for integration, namely IC design, fluidics, packaging, and microfabrication, and cell culture. There also arises the issue of how to handle the vast amount of data that can be generated by such systems, and specifically how to efficiently identify signals of interest and communicate them off-chip. The primary contributions of this work are the development of a new packaging scheme for integration of CMOS ICs into fluidic LOC systems, a methodology for cross-coupled multi-domain iterative modeling of heterogeneously integrated systems, demonstration of a proof-of-concept bioelectronic olfactory sensor, and a novel event-based technique to minimize the bandwidth required to communicate the information contained in bio-potential signals produced by dense arrays of electrically active cells