While over half a century has passed since the introduction of enzyme glucose biosensors by Clark and Lyons, this important field has continued to be the focus of immense research activity. Extensive efforts during the past decade have led to major scientific and technological innovations towards tight monitoring of diabetes. Such continued progress toward advanced continuous glucose monitoring platforms, either minimal- or non-invasive, holds considerable promise for addressing the limitations of finger-prick blood testing toward tracking glucose trends over time, optimal therapeutic interventions, and improving the life of diabetes patients. However, despite these major developments, the field of glucose biosensors is still facing major challenges. The scope of this review is to present the key scientific and technological advances in electrochemical glucose biosensing over the past decade (2010-present), along with current obstacles and prospects towards the ultimate goal of highly stable and reliable real-time minimally-invasive or non-invasive glucose monitoring. After an introduction to electrochemical glucose biosensors, we highlight recent progress based on using advanced nanomaterials at the electrode-enzyme interface of three generations of glucose sensors. Subsequently, we cover recent activity and challenges towards next-generation wearable non-invasive glucose monitoring devices based on innovative sensing principles, alternative body fluids, advanced flexible materials, and novel platforms. This is followed by highlighting the latest progress in the field of minimally-invasive continuous glucose monitoring (CGM) which offers real-time information about interstitial glucose levels, by focusing on the challenges toward developing biocompatible membrane coatings to protect electrochemical glucose sensors against surface biofouling. Subsequent sections cover new analytical concepts of self-powered glucose sensors, paper-based glucose sensing and multiplexed detection of diabetes-related biomarkers. Finally, we will cover the latest advances in commercially available devices along with the upcoming future technologies.

Electrochemical glucose sensors in diabetes management: an updated review (2010-2020).

Energy autonomy is key to the next generation portable and wearable systems for several applications. Among these, the electronic-skin or e-skin is currently a matter of intensive investigations due to its wider applicability in areas, ranging from robotics to digital health, fashion and internet of things (IoT). The high density of multiple types of electronic components (e.g. sensors, actuators, electronics, etc.) required in e-skin, and the need to power them without adding heavy batteries, have fuelled the development of compact flexible energy systems to realize self-powered or energy-autonomous e-skin. The compact and wearable energy systems consisting of energy harvesters, energy storage devices, low-power electronics and efficient/wireless power transfer-based technologies, are expected to revolutionize the market for wearable systems and in particular for e-skin. This paper reviews the development in the field of self-powered e-skin, particularly focussing on the available energy-harvesting technologies, high capacity energy storage devices, and high efficiency power transmission systems. The paper highlights the key challenges, critical design strategies, and most promising materials for the development of an energy-autonomous e-skin for robotics, prosthetics and wearable systems. This paper will complement other reviews on e-skin, which have focussed on the type of sensors and electronics components.

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Energy autonomous electronic skin

The amalgamation of flexible electronics in biological systems has shaped the way health and medicine are administered. The growing field of flexible electrochemical bioelectronics enables the in situ quantification of a variety of chemical constituents present in the human body and holds great promise for personalized health monitoring owing to its unique advantages such as inherent wearability, high sensitivity, high selectivity, and low cost. It represents a promising alternative to probe biomarkers in the human body in a simpler method compared to conventional instrumental analytical techniques. Various bioanalytical technologies are employed in flexible electrochemical bioelectronics, including ion-selective potentiometry, enzymatic amperometry, potential sweep voltammetry, field-effect transistors, affinity-based biosensing, as well as biofuel cells. Recent key innovations in flexible electrochemical bioelectronics from electrochemical sensing modalities, materials, systems, fabrication, to applications are summarized and highlighted. The challenges and opportunities in this field moving forward toward future preventive and personalized medicine devices are also discussed.

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Flexible Electrochemical Bioelectronics: The Rise of In Situ Bioanalysis

Wearable electrochemical biosensors in North America.

This paper presents a novel approach to design a digitally programmable low pass filter (LPF) and variable gain amplifier (VGA) intended for a software-defined radio (SDR) front-end. These flexible analog circuits are driven by a network-on-chip (NoC) that is able to set performance parameters like cut-off frequency, selectivity, noise, and gain guaranteeing at any time a near-optimal power/perfomance trade-off. A design approach is proposed to tackle the challenges imposed by flexibility in analog design. A silicon prototype is realized in 0.13-μm CMOS technology with 1.2-V supply voltage to prove the validity of the proposed solution. The LPF provides a frequency tuning range between 0.35 MHz and 23.5 MHz with an adaptive integrated noise level between 85 μVrms and 163 μVrms whereby the power consumption conveniently varies from 0.72 mW to 21.6 mW according to the required performance. The VGA is made up of two cascaded gain stages and provides a gain range from about 0 dB to 39 dB with a reconfigurable power/bandwidth.

Flexible baseband analog circuits for software-defined radio front-ends

This paper presents a self-powered wireless physiochemical sensing system for monitoring of glucose or lactate in bodily fluids. The biosensor chip consists of a duty-cycled biofuel cell (BFC) maximum power point tracker analog front end, a passive $\Delta \!\Sigma $ analog-to-digital converter (ADC), an RF power oscillator transmitter using a 1-cm external loop antenna, digital data storage, and timing and clock generation circuitries, all designed to operate from the dynamic 0.3-V BFC output voltage. The biosensor chip, implemented in 65-nm CMOS and exclusively powered via an enzymatic BFC, can successfully detect changes in glucose/lactate concentration between 2.5 and 15 mM, for the first demonstration of an integrated self-powered chemical biosensing system with digital wireless readout. The biosensor consumes an average power of 1.15 $\mu \text{W}$ .

A 0.3-V CMOS Biofuel-Cell-Powered Wireless Glucose/Lactate Biosensing System

A comparative design study of ultra-low-power discrete-time ΔΣ modulators (DT ΔΣMs) suited for medical implant devices is presented. Aiming to reduce the analog power consumption, the objective is to investigate the effectiveness of the switched-capacitor passive filter. Two design variants of 2nd-order ΔΣMs are analyzed and compared to a power-optimized standard active modulator (ΔΣMAA). The first variant (ΔΣMAP) employs an active filter in the 1st stage and a passive filter in the less critical 2nd stage. The second variant (OTA-less ΔΣMPP) makes use of passive filters in both stages. For practical verification, all three modulators are implemented on a single chip in 65 nm CMOS technology. Designed for 500-Hz signal bandwidth, the ΔΣMAA, ΔΣMAP, and ΔΣMPP achieve 76 dB, 70 dB and 67 dB peak SNDR, while consuming 2.1 μW, 1.27 μW, and 0.92 μW, respectively, from a 0.9 V supply. Furthermore, the ΔΣMPP can operate at a supply voltage reduced to 0.7 V, achieving a 65 dB SNDR at 430 nW power and 0.296 pJ/step.

Low-Power DT $\Delta \Sigma$ Modulators Using SC Passive Filters in 65 nm CMOS

Low-Power DT ΔΣ Modulators Using SC Passive Filters in 65 nm CMOS.

High-resolution sigma-delta ADCs are gaining significant interest in ultra-low-power medical applications, where accurate measurement of low-frequency and weak electrophysiological signals is required. Operational transconductance amplifiers (OTA) are the key analog component and the most power-hungry part of the sigma-delta (LA) modulators. This paper presents a study of OTAs for ultra-low-power operation, including design and a comparative analysis of four OTA architectures implemented in 65nm CMOS Technology. The requirements for OTA gain and GBW are driven in terms of SA ADC specifications. The OTAs' impact on modulator SNR has been investigated by simulation. The results show that a two-stage OTA with load compensation yields highest SNR and lowest power dissipation amongst the four OTAs in this study.

Design of OTAs for ultra-low-power sigma-delta ADCs in medical applications

This paper presents a simple and robust low-power ΔΣ modulator for accurate ADCs in implantable cardiac rhythm management devices such as pacemakers. Taking advantage of the very low signal bandwidth of 500 Hz which enables high oversampling ratio, the objective is to obtain high SNDR and low power consumption, while limiting the complexity of the modulator to a second-order architecture. Significant power reduction is achieved by utilizing a two-stage load-compensated OTA as well as the low-VT devices in analog circuits and switches, allowing the modulator to operate at 0.9 V supply. Fabricated in a 65 nm CMOS technology, the modulator achieves 80 dB peak SNR and 76 dB peak SNDR over a 500 Hz signal bandwidth. With a power consumption of 2.1 μW, the modulator obtains 0.4 pJ/step FOM. To the authors' knowledge, this is the lowest reported FOM, compared to the previously reported second-order modulators for such low-speed applications. The achieved FOM is also comparable to the best reported results from the higher-order ΔΣ modulators.

Ali Fazli Yeknami

Papers

A 0.3-V CMOS Biofuel-Cell-Powered Wireless Glucose/Lactate Biosensing System

Low-Power DT $\Delta \Sigma$ Modulators Using SC Passive Filters in 65 nm CMOS

Low-Power DT ΔΣ Modulators Using SC Passive Filters in 65 nm CMOS.

Design of OTAs for ultra-low-power sigma-delta ADCs in medical applications

A 2.1 μW 80 dB SNR DT ΔΣ modulator for medical implant devices in 65 nm CMOS