A 110 nA pacemaker sensing channel in CMOS on silicon-on-insulator

PostprintThe design of a sensing channel for implantable cardiac pacemakers in CMOS on silicon-on-insulator (SOI) technology is presented. The total current consumption is lowered to only 110nA thanks to the optimization at the architectural level, the application of a new class AB design approach at the operational transconductance amplifier (OTA) and the exploitation of the improved characteristics of thin-film fully depleted SOI CMOS technology. The core of the prototyped sense channel (OTA and comparator) occupies 0.06mm/sup 2/ in a 3/spl mu/m technology and is suitable for operation from implantable grade batteries with power supply voltages from 2.8V down to 2V. Experimental results of the building blocks and complete sensing channel performance are presented. The achieved results demonstrate the benefits of fully depleted SOI CMOS technology for micropower applications

A 100nA cardiac sensing channel

An ultra low power cardiac sensing channel for pacemaker applications, designed in 0.6um HV CMOS technology.Agencia Nacional de Investigación e Innovació

A 100nA cardiac sensing channel

An ultra low power cardiac sensing channel for pacemaker applications, designed in 0.6um HV CMOS technology.Agencia Nacional de Investigación e Innovació

An asymmetrical bulk-modified composite MOS transistor with enhanced linearity

In this work, an asymmetrical bulk-linearized composite MOSFET is presented, with an enhanced linear range and an equivalent saturation voltage of up to several hundred mV even in weak inversion, allowing to implement large MOS resistors. Some preliminary measurements are presented, as well as 150MΩ and 200MΩ equivalent resistors simulations, with a linear range up to 1.5V. A low frequency, 40dB gain, fully integrated cardiac sensing channel filter/amplifier is also shown. Taking advantage of the proposed technique, the circuit consumes only 25nA of supply current.Agencia Nacional de Investigación e Innovació

Chemical Bionics - a novel design approach using ion sensitive field effect transistors

In the late 1980s Carver Mead introduced Neuromorphic engineering in which various aspects of the neural systems of the body were modelled using VLSI1 circuits. As a result most bio-inspired systems to date concentrate on modelling the electrical behaviour of neural systems such as the eyes, ears and brain. The reality is however that biological systems rely on chemical as well as electrical principles in order to function. This thesis introduces chemical bionics in which the chemically-dependent physiology of specific cells in the body is implemented for the development of novel bio-inspired therapeutic devices. The glucose dependent pancreatic beta cell is shown to be one such cell, that is designed and fabricated to form the first silicon metabolic cell. By replicating the bursting behaviour of biological beta cells, which respond to changes in blood glucose, a bio-inspired prosthetic for glucose homeostasis of Type I diabetes is demonstrated. To compliment this, research to further develop the Ion Sensitive Field Effect Transistor (ISFET) on unmodified CMOS is also presented for use as a monolithic sensor for chemical bionic systems. Problems arising by using the native passivation of CMOS as a sensing surface are described and methods of compensation are presented. A model for the operation of the device in weak inversion is also proposed for exploitation of its physical primitives to make novel monolithic solutions. Functional implementations in various technologies is also detailed to allow future implementations chemical bionic circuits. Finally the ISFET integrate and fire neuron, which is the first of its kind, is presented to be used as a chemical based building block for many existing neuromorphic circuits. As an example of this a chemical imager is described for spatio-temporal monitoring of chemical species and an acid base discriminator for monitoring changes in concentration around a fixed threshold is also proposed

Advances in Microelectronics for Implantable Medical Devices

Implantable medical devices provide therapy to treat numerous health conditions as well as monitoring and diagnosis. Over the years, the development of these devices has seen remarkable progress thanks to tremendous advances in microelectronics, electrode technology, packaging and signal processing techniques. Many of today’s implantable devices use wireless technology to supply power and provide communication. There are many challenges when creating an implantable device. Issues such as reliable and fast bidirectional data communication, efficient power delivery to the implantable circuits, low noise and low power for the recording part of the system, and delivery of safe stimulation to avoid tissue and electrode damage are some of the challenges faced by the microelectronics circuit designer. This paper provides a review of advances in microelectronics over the last decade or so for implantable medical devices and systems. The focus is on neural recording and stimulation circuits suitable for fabrication in modern silicon process technologies and biotelemetry methods for power and data transfer, with particular emphasis on methods employing radio frequency inductive coupling. The paper concludes by highlighting some of the issues that will drive future research in the field

Development of a Novel Platform for in vitro Electrophysiological Recording

The accurate monitoring of cell electrical activity is of fundamental importance for pharmaceutical research and pre-clinical trials that impose to check the cardiotoxicity of all new drugs. Traditional methods for preclinical evaluation of drug cardiotoxicity exploit animal models, which tend to be expensive, low throughput, and exhibit species-specific differences in cardiac physiology (Mercola, Colas and Willems, 2013). Alternative approaches use heterologous expression of cardiac ion channels in non-cardiac cells transfected with genetic material. However, the use of these constructs and the inhibition of specific ionic currents alone is not predictive of cardiotoxicity. Drug toxicity evaluation based on the human ether-\ue0-go-go-related gene (hERG) channel, for example, leads to a high rate of false-positive cardiotoxic compounds, increasing drug attrition at the preclinical stage. Consequently, from 2013, the Comprehensive in Vitro Proarrhythmia Assay (CiPA) initiative focused on experimental methods that identify cardiotoxic drugs and to improve upon prior models that have largely used alterations in the hERG potassium ion channel. The most predictive models for drug cardiotoxicity must recapitulate the complex spatial distribution of the physiologically distinct myocytes of the intact adult human heart. However, intact human heart preparations are inherently too costly, difficult to maintain, and, hence, too low throughput to be implemented early in the drug development pipeline. For these reasons the optimization of methodologies to differentiate human induced Pluripotent Stem Cells (hiPSCs) into cardiomyocytes (CMs) enabled human CMs to be mass-produced in vitro for cardiovascular disease modeling and drug screening (Sharma, Wu and Wu, 2013). These hiPSC-CMs functionally express most of the ion channels and sarcomeric proteins found in adult human CMs and can spontaneously contract. Recent results from the CiPA initiative have confirmed that, if utilized appropriately, the hiPSC-CM platform can serve as a reliable alternative to existing hERG assays for evaluating arrhythmogenic compounds and can sensitively detect the action potential repolarization effects associated with ion channel\u2013blocking drugs (Millard et al., 2018). Data on drug-induced toxicity in hiPSC-CMs have already been successfully collected by using several functional readouts, such as field potential traces using multi-electrode array (MEA) technology (Clements, 2016), action potentials via voltage-sensitive dyes (VSD) (Blinova et al., 2017) and cellular impedance (Scott et al., 2014). Despite still under discussion, scientists reached a consensus on the value of using electrophysiological data from hiPSC-CM for predicting cardiotoxicity and how it\u2019s possible to further optimize hiPSC-CM-based in vitro assays for acute and chronic cardiotoxicity assessment. In line with CiPA, therefore, the use of hiPSC coupled with MEA technology has been selected as promising readout for these kind of experiments. These platforms are used as an experimental model for studying the cardiac Action Potentials (APs) dynamics and for understanding some fundamental principles about the APs propagation and synchronization in healthy heart tissue. MEA technology utilizes recordings from an array of electrodes embedded in the culture surface of a well. When cardiomyocytes are grown on these surfaces, spontaneous action potentials from a cluster of cardiomyocytes, the so called functional syncytium, can be detected as fluctuations in the extracellular field potential (FP). MEA measures the change in FP as the action potential propagates through the cell monolayer relative to the recording electrode, neverthless FP in the MEA do not allows to recapitualte properly the action potential features. It is clear, therefore, that a MEA technology itself is not enough to implement cardiotoxicity assays on hIPSCs-CMs. Under this issue, researchers spread in the world started to think about solutions to achieve a platform able to works both at the same time as a standard MEA and as a patch clamp, allowing the recording of extracellular signals as usual, with the opportunity to switch to intracellular-like signals from the cytosol. This strong interest stimulated the development of methods for intracellular recording of action potentials. Currently, the most promising results are represented by multi-electrode arrays (MEA) decorated with 3D nanostructures that were introduced in pioneering papers (Robinson et al., 2012; Xie et al., 2012), culminating with the recent work from the group of H. Park (Abbott et al., 2017) and of F. De Angelis (Dipalo et al., 2017). In these articles, they show intracellular recordings on electrodes refined with 3D nanopillars after electroporation and laser optoporation from different kind of cells. However, the requirement of 3D nanostructures set strong limitations to the practical spreading of these techniques. Thus, despite pioneering results have been obtained exploiting laser optoporation, these technologies neither been applied to practical cases nor reached the commercial phase. This PhD thesis introduces the concept of meta-electrodes coupled with laser optoporation for high quality intracellular signals from hiPSCs-CM. These signals can be recorded on high-density commercial CMOS-MEAs from 3Brain characterized by thousands of electrode covered by a thin film of porous Platinum without any rework of the devices, 3D nanostructures or circuitry for electroporation7. Subsequently, I attempted to translate these unique features of low invasiveness and reliability to other commercial MEA platforms, in order to develop a new tool for cardiac electrophysiological accurate recordings. The whole thesis is organized in three main sections: a first single chapters that will go deeper in the scientific and technological background, including an explanation of the cell biology of hiPSCs-CM followed by a full overview of MEA technology and devices. Then, I will move on state-of-the-art approaches of intracellular recording, discussing many works from the scientific literature. A second chapter will describe the main objectives of the whole work, and a last chapter with the main results of the activity. A final chapter will resume and recapitulate the conclusion of the work

Very large time constant Gm-C Filters

In this study a set of tools for the design of fully integrated transconductor-capacitor (Gm-C) filters, with very large time constants and current consumption under one micro-Ampere are presented. The selected application is a 2nd order bandpass-filter-amplifier, with a gain of 400 from 0.5 to 7Hz, carrying out the signal conditioning of a piezoelectric accelerometer which is part of an implantable cardiac pacemaker. The main challenge is to achieve very large time constants, without using any discrete external component. The chosen circuit technique to fulfill the requirement is series-parallel current division applied to standard symmetrical transconductors (OTAs). These circuits have demonstrated to be an excellent solution regarding their occupied area, power consumption, noise, linearity, and particularly offset. OTAs as low as 33pS -equivalent to a 30G resistor-, with up to 1V linear range, and input referred offset of a few mV, were designed, fabricated in a standard 0.8 micron CMOS technology, and tested. The application requires the series-parallel association of a large number of transistors, and the use of bias currents as low as a few pico-Amperes, which is not very common in analog integrated circuits. In this case the designer should employ maximum care in the selection of the transistor models to be used. A central aspect of this thesis was also to evaluate and develop noise and offset estimation models which was not obvious in the very beginning of the research. In the first two chapters an introduction to the target application is presented, and several MOS transistor characteristics in terms of the inversion coefficient -using the ACM transistor model- are evaluated. In chapter 3 it is discussed whether the usual flicker and thermal noise models are consistent regarding series-parallel association, and adequately represent the expected noise behavior under different bias conditions. A consistent, physics-based, one-equation-all-regions model for flicker noise in the MOS transistor is then presented. Several noise measurements are included demonstrating that the new model accurately fits widely different bias situations. A new model for mismatch offset in MOS transistors is presented, as a corollary of the flicker noise analysis. Finally, the correlation between flicker noise and mismatch offset, that can be seen as a DC noise, is shown. In chapter 4, the design of OTAs with an extended linear range, and very low transconductance, using series-parallel current division is presented. Precise tools are introduced for the estimation of noise and mismatch offset in series-parallel current mirrors, that are shown to help in the reduction of inaccuracies in the copy of currents with a large copy factor. The design and measurement of several OTA examples are presented. In chapter 5, the developed tools, and the OTAs shown, are employed in the design of the above mentioned filter for the piezoelectric accelerometer. A general methodology for the design of Gm-C filters with similar characteristics is established. The filter was fabricated and tested, successfully operating with a total power consumption of 233nA, up to a 2V power supply, with an input noise and mismatch offset of 2-4 Vrms, and 18 V respectively. To summarize the main results obtained were: The development of a new flicker noise model, the study of the effect of mismatch regarding series-parallel association, a new design methodology for OTAs and Gm-C filters. It is our hope that this constitutes a helpful set of tools for the circuit designer.En esta tesis se presenta un conjunto de herramientas para el diseño de circuitos integrados que implementan filtros transconductor-capacitor (Gm-C), de muy altas constantes de tiempo, con bajo ruido, y consumo de corriente por debajo del micro-Ampere. Como ejemplo de aplicación se toma un amplificador-pasabanda 2º orden, de ganancia 400 en la banda de 0.5 a 7Hz, que realiza el acondicionamiento de señal de un acelerómetro piezoeléctrico a ser empleado en un marcapasos implantable. El principal desafío es realizar en dicho filtro de tiempo continuo, muy altas constantes de tiempo sin usar componentes externos. La técnica elegida para alcanzar tal objetivo es la división serie-paralelo de corriente en transconductores (OTAs) simétricos estándar. Estos circuitos demostraron ser una excelente solución en cuanto al área ocupada, su consumo, ruido, linealidad, y en particular offset. Se diseñaron, fabricaron, y midieron, OTAs hasta 33pS -equivalente a una resistencia de 30G -, con hasta 1V de rango de lineal, y offset a la entrada de algunos mV, utilizando una tecnología CMOS de 0.8 micras de largo mínimo de canal. La aplicación requiere la asociación serie-paralelo de un gran número de transistores, y polarización con corrientes de hasta pico-Amperes, lo que constituye una situación poco frecuente en circuitos integrados analógicos. En este marco el diseñador debe elegir los modelos de transistor con sumo cuidado. Un aspecto central de esta tesis es también, el estudio y presentación de modelos adecuados de ruido y offset, que no resultan obvios al principio. En los primeros dos capítulos se realiza una introducción y se revisa, utilizando el modelo ACM, diferentes características del transistor MOS en función del nivel de inversión. En el capítulo 3 revisa la pertinencia y consistencia frente a la asociación serie-paralelo, de los modelos usuales de ruido de flicker o 1/f, y térmico. Luego se presenta, incluyendo medidas, un nuevo modelo físico, consistente, simple, y válido en todas las regiones de operación del transistor MOS, para el ruido de flicker. Como corolario a este estudio se presenta un nuevo modelo para estimar el desapareo entre transistores, en función no solo de la geometría, pero también de la polarización. Se demuestra la correlación, debido a su origen físico análogo, entre el ruido de flicker y el offset por desapareo que puede ser visto como un ruido en DC. En el capítulo 4 se presenta el diseño de OTAs con rango de linealidad extendido, y muy baja transconductancia, utilizando división serie-paralelo de corriente. Se presentan herramientas precisas para la estimación de offset y ruido y se demuestra la utilidad de la técnica para reducir el offset en espejos de corriente. Se presenta el diseño y medida de diversos OTAs. En el capítulo 5, las herramientas desarrolladas, y los OTAs presentados, son empleados en el diseño del filtro descripto para un acelerómetro piezoeléctrico. Se establece una metodología general para el diseño de filtros Gm-C con características similares. El filtro se fabricó y midió, operando en forma satisfactoria, con un consumo total de 230nA y hasta los 2V de tensión de alimentación, con ruido y offset a la entrada de tan solo 2-4 Vrms, y 18 V respectivamente. El desarrollo de un nuevo modelo de ruido 1/f para el transistor MOS, el estudio de la influencia del offset frente a la asociación serie-paralelo y su aplicación en OTAs, la metodología de diseño empleada, la demostración del uso de técnicas novedosas en una aplicación como la elegida que tiene relevancia tecnológica e interés académico; esperamos que todo ello constituya una contribución valiosa para la comunidad científica en microelectrónica y un conjunto de herramientas de utilidad para el diseño de circuitos

Analogue micropower FET techniques review

A detailed introduction to published analogue circuit design techniques using Si and Si/SiGe FET devices for very low-power applications is presented in this review. The topics discussed include sub-threshold operation in FET devices, micro-current mirrors and cascode techniques, voltage level-shifting and class-AB operation, the bulk-drive approach, the floating-gate method, micropower transconductance-capacitance and log-domain filters and strained-channel FET technologies