46 research outputs found

    Microelectronics-Based Biosensors Dedicated to the Detection of Neurotransmitters: A Review

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    Dysregulation of neurotransmitters (NTs) in the human body are related to diseases such as Parkinson's and Alzheimer's. The mechanisms of several neurological disorders, such as epilepsy, have been linked to NTs. Because the number of diagnosed cases is increasing, the diagnosis and treatment of such diseases are important. To detect biomolecules including NTs, microtechnology, micro and nanoelectronics have become popular in the form of the miniaturization of medical and clinical devices. They offer high-performance features in terms of sensitivity, as well as low-background noise. In this paper, we review various devices and circuit techniques used for monitoring NTs in vitro and in vivo and compare various methods described in recent publications

    A Low-Power, Highly Stabilized Three-Electrode Potentiostat Using Subthreshold Techniques

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    Implantable micro- and nano- sensors and implantable microdevices (IMDs) have demonstrated potential for monitoring various physiological parameters such as glucose, lactate, CO2 [carbon dioxide], pH, etc. Potentiostats are essential components of electrochemical sensors such as glucose monitoring devices for diabetic patients. Diabetes is a metabolic disorder associated with insufficient production or inefficient utilization of insulin. The most important role of this enzyme is to regulate the metabolic breakdown of glucose generating the necessary energy for human activities. Diabetic patients typically monitor their blood glucose levels by pricking a fingertip with a lancing device and applying the blood to a glucose meter. This painful process may need to be repeated once before each meal and once 1- 4 hour after meal. Patients may need to inject insulin manually to keep the blood glucose level at 3.9-6.7 mmol [mili mol] /liter. Frequent glucose measurement can help reduce the long term complication of this disease which includes kidney disease, nerve damage, heart and blood vessel diseases, gum disease, glaucoma and etc. Having an implanted close loop insulin delivery system can help increase the frequency of glucose measurement and the accuracy of insulin injection. The implanted close loop system consists of three main blocks: (1) an electrochemical sensor in conjunction with a potentiostat to measure the blood glucose level, (2) a control block that defines the level of insulin injection and (3) an implanted insulin pump. To provide a continuous health-care monitoring the implantable unit has to be powered up using wireless techniques. Minimizing the power consumption associated with the implantable system can improve the battery life times or minimize the power transfer through the human body. The focus of this work is on the design of low-power potentiostats for the implantable glucose monitoring system. This work addresses the conventional structures in potentiostat design and the problems associated with these designs. Based on this discussion a modification is made to improve the stability without increasing the complexity of the system. The proposed design adopts a subthreshold biasing scheme for the design of a highly-stabilized, low-power potentiostats

    A fully integrated CMOS microelectrode system for electrochemistry

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    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 ÎŒm 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 ÎŒm side length while the counter and reference electrodes had an 11 ÎŒm 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

    Advancing the interfacing performances of chronically implantable neural probes in the era of CMOS neuroelectronics

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    Tissue penetrating microelectrode neural probes can record electrophysiological brain signals at resolutions down to single neurons, making them invaluable tools for neuroscience research and Brain-Computer-Interfaces (BCIs). The known gradual decrease of their electrical interfacing performances in chronic settings, however, remains a major challenge. A key factor leading to such decay is Foreign Body Reaction (FBR), which is the cascade of biological responses that occurs in the brain in the presence of a tissue damaging artificial device. Interestingly, the recent adoption of Complementary Metal Oxide Semiconductor (CMOS) technology to realize implantable neural probes capable of monitoring hundreds to thousands of neurons simultaneously, may open new opportunities to face the FBR challenge. Indeed, this shift from passive Micro Electro-Mechanical Systems (MEMS) to active CMOS neural probe technologies creates important, yet unexplored, opportunities to tune probe features such as the mechanical properties of the probe, its layout, size, and surface physicochemical properties, to minimize tissue damage and consequently FBR. Here, we will first review relevant literature on FBR to provide a better understanding of the processes and sources underlying this tissue response. Methods to assess FBR will be described, including conventional approaches based on the imaging of biomarkers, and more recent transcriptomics technologies. Then, we will consider emerging opportunities offered by the features of CMOS probes. Finally, we will describe a prototypical neural probe that may meet the needs for advancing clinical BCIs, and we propose axial insertion force as a potential metric to assess the influence of probe features on acute tissue damage and to control the implantation procedure to minimize iatrogenic injury and subsequent FBR

    Biosensors

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    A biosensor is defined as a detecting device that combines a transducer with a biologically sensitive and selective component. When a specific target molecule interacts with the biological component, a signal is produced, at transducer level, proportional to the concentration of the substance. Therefore biosensors can measure compounds present in the environment, chemical processes, food and human body at low cost if compared with traditional analytical techniques. This book covers a wide range of aspects and issues related to biosensor technology, bringing together researchers from 11 different countries. The book consists of 16 chapters written by 53 authors. The first four chapters describe several aspects of nanotechnology applied to biosensors. The subsequent section, including three chapters, is devoted to biosensor applications in the fields of drug discovery, diagnostics and bacteria detection. The principles behind optical biosensors and some of their application are discussed in chapters from 8 to 11. The last five chapters treat of microelectronics, interfacing circuits, signal transmission, biotelemetry and algorithms applied to biosensing

    Conception et fabrication d'un biocapteur à haute sensibilité pour la détection des neurotransmetteurs

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    Dans ce mĂ©moire, nous prĂ©sentons de nouvelles architectures de diffĂ©rents biocapteurs Ă©lectrochimiques discrets et intĂ©grĂ©s appelĂ©s potentiostats. Tous les potentiostats dĂ©veloppĂ©s sont basĂ©s sur une structure entiĂšrement diffĂ©rentielle pour une meilleure sensibilitĂ© et une meilleure prĂ©cision. Deux conceptions discrĂštes Ă  un et quatre canaux ont Ă©tĂ© proposĂ©es. La conception discrĂšte Ă  un canal dĂ©tecte la molĂ©cule de dopamine avec un courant de l’ordre du nA et une consommation Ă©lectrique de 120 mW. Cette architecture a Ă©tĂ© dĂ©veloppĂ©e sur une carte de circuit imprimĂ© (PCB) de 20 mm x 35 mm. L’architecture discrĂšte Ă  quatre canaux est la version amĂ©liorĂ©e de la prĂ©cĂ©dente en termes de superficie, de sensibilitĂ© et de consommation Ă©lectrique. Une autre version du potentiostat, implĂ©mentĂ©e sur un PCB de 15 mm x 15 mm, peut mesurer les courants d’oxydorĂ©duction dans la plage du pA avec une consommation de puissance de 60 mW. L’avantage de la structure Ă  multicanaux est qu’elle offre des sensibilitĂ©s diffĂ©rentes allant du pA au mA pour chaque canal. Une chambre microfluidique de 7,5 mm x 5 mm avec deux entrĂ©es et une sortie a Ă©tĂ© dĂ©posĂ©e sur le PCB. Une solution saline tampon au phosphate (PBS) avec une solution de ferrocyanure a Ă©tĂ© utilisĂ©e pour tester la fonctionnalitĂ© du systĂšme rĂ©alisĂ©. La voltampĂ©romĂ©trie cyclique a Ă©tĂ© utilisĂ©e comme technique de dĂ©tection. Un comportement linĂ©aire a Ă©tĂ© observĂ© lorsque la concentration des neurotransmetteurs change. De plus, un potentiostat intĂ©grĂ© a Ă©tĂ© proposĂ© et fabriquĂ© en technologie CMOS 180 nm, basĂ© sur une structure entiĂšrement « diffĂ©rentiel de diffĂ©rence » (Fully Differential Diffrence Amplifier FDDA) pour une faible consommation de puissance et un systĂšme Ă  haute sensibilitĂ©. Cette nouvelle configuration a Ă©tĂ© conçue pour la dĂ©tection des neurotransmetteurs en trĂšs faible concentration avec un faible bruit et une plage dynamique Ă©levĂ©e. Cette architecture intĂ©grĂ©e peut dĂ©tecter les courants dans une plage infĂ©rieure au pA avec un bruit d’entrĂ©e faible de 6,9 ÎŒVrms tout en consommant seulement 53,9 ÎŒW. Le potentiostat proposĂ© est dĂ©diĂ© aux dispositifs implantables Ă  faible consommation de puissance et Ă  sensibilitĂ© et linĂ©aritĂ© Ă©levĂ©es.In this thesis, we present different discrete and integrated electrochemical biosensors. All these designed potentiostats are based on fully-differential architecture to enhance sensitivity and accuracy. Two complete single channel and four-channel discrete designs were fabricated. The single channel discrete design imaged the dopamine neurotransmitter with the sensed current of approximately low nano-ampere and power consumption of 120 mW implemented on a 20 x 35 mm PCB. The four-channel discrete design was the improved version of previous one in terms of area, sensitivity and power consumption. The 15 x 15 mm PCB was able to measure the reduction-oxydation currents in the range of high pico-ampere while consuming 60 mW. The advantage of the multichannel architecture is to provide a system with different sensitivity going from pA to mA for each channel. A microfluidic 7.5 x 5 mm chamber with two inlets and one outlet was bonded to the PCB. A phosphate buffered saline (PBS) with ferrocyanide solution was used to test the functionality of the implemented system. Cyclic voltammetry has been used as a detection technique. A linear behavior had been observed when the neurotransmitter concentration changed. An integrated CMOS potentiostat was designed and fabricated in 180 nm technology based on a fully-differential-difference architecture for a low power consumption and also high sensitivity system. This new architecture was designed in order to sense ultra-low concentration of neurotransmitters with low noise and high dynamic range. This integrated design was able to image currents in the range of sub-pA with low input-referred noise of 6.9 ”Vrms while consuming only 53.9 ”W. The proposed potentiostat is dedicated for implantable devices with low power consumption and high sensitivity and linearity

    Multifunctional Neural Interfaces for Closed-Loop Control of Neural Activity

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    Microfabrication and nanotechnology have significantly expanded the technological capabilities for monitoring and modulating neural activity with the goal of studying the nervous system and managing neurological disorders. This feature article initially provides a tutorial‐like review of the prominent technologies for enabling this two‐way communication with the nervous system via electrical, chemical, and optical means. Following this overview, the article discusses emerging high‐throughput methods for identifying device attributes that enhance the functionality of interfaces. The discussion then extends into opportunities and challenges in integrating different device functions within a small footprint with the goal of closed‐loop control of neural activity with high spatiotemporal resolution and reduced adverse tissue response. The article concludes with an outline of future directions in the development and applications of multifunctional neural interfaces

    Biocapteur ampérométrique intégré pour une unité de détection dédiée aux neurotransmetteurs

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    RÉSUMÉ La signalisation chimique intercellulaire façonnĂ©e par l’interaction des neurotransmetteurs joue un rĂŽle capital dans le fonctionnement des processus cĂ©rĂ©braux. L’analyse de l’activitĂ© neuronale chimique en temps rĂ©el dans toute sa complexitĂ© aiderait les neuroscientifiques Ă  comprendre les mĂ©canismes du cerveau humain et de ses pathologies neurodĂ©gĂ©nĂ©ratives. Les systĂšmes actuellement employĂ©s dans les laboratoires de neuroscience sont limitĂ©s dans leur capacitĂ© Ă  fournir des mesures prĂ©cises et adaptĂ©es aux Ă©vĂšnements hĂ©tĂ©rogĂšnes associĂ©es Ă  l’activitĂ© de plusieurs neurotransmetteurs. Pour ce faire, le laboratoire de neurotechnologies Polystim envisage la conception d’un laboratoire sur puce (LSP) implantable, dĂ©diĂ© au monitorage des substances neurochimiques circulant dans l’espace intercellulaire cĂ©rĂ©bral. Ce mĂ©moire propose une unitĂ© de dĂ©tection Ă©lectrochimique associĂ©e Ă  un tel systĂšme et conçue pour la quantification des neurotransmetteurs du liquide intercĂ©rĂ©bral. Nous proposons une architecture composĂ©e de biocapteurs utilisant un potentiostat intĂ©grĂ© avec la technologie CMOS comme transducteur et des Ă©lectrodes de mesure fonctionnalisĂ©es avec des nanotubes de carbone pour une dĂ©tection sensible et sĂ©lective. Le potentiostat intĂ©grĂ© proposĂ© gĂ©nĂšre des mesures de temps facilement traitables numĂ©riquement qui sont proportionnelles aux courants d’oxydo-rĂ©duction produits Ă  l’interface des Ă©lectrodes de mesure. Sa configuration quantifie sĂ©parĂ©ment les courants d’oxydation et de rĂ©duction Ă  l’aide de deux canaux de mesures, selon une technique d’ampĂ©rometrie Ă  tension constante. L’architecture est composĂ©e d’un amplificateur, d’un comparateur haute vitesse et d’un convertisseur numĂ©rique Ă  analogique (Digital to Analog Converter - DAC). Ce dernier est partagĂ© entre les deux canaux de sorte Ă  rĂ©duire le temps de mesure total en fonction de l’amplitude des courants dĂ©tectĂ©s. Cette topologie procure un compromis entre la plage dynamique d’entrĂ©e, la frĂ©quence d’échantillonnage et la rĂ©solution de mesures, trois paramĂštres importants pour accommoder la dĂ©tection et la quantification d’une grande variĂ©tĂ© de neurotransmetteurs en temps-rĂ©el. Afin de valider le prototype du potentiostat implĂ©mentĂ©, une plateforme multi-Ă©lectrodes de mesure est fabriquĂ©e et fonctionnalisĂ©e avec des films composites Ă  base de nanotubes de carbone (Carbon Nanotubes - CNT), pour une dĂ©tection sĂ©lective Ă  la dopamine et au glutamate, deux neurotransmetteurs communs. Le circuit intĂ©grĂ© du potentiostat est implĂ©mentĂ© avec la technologie 0,13 ”m CMOS d’IBM. Un circuit imprimĂ© (Printed Circuit Board - PCB) comprenant un FPGA pour la gestion des signaux de contrĂŽle et l’acquisition des donnĂ©es a Ă©tĂ© fabriquĂ© pour la caractĂ©risation expĂ©rimentale du circuit. MalgrĂ© une non-linĂ©aritĂ© du DAC intĂ©grĂ© fabriquĂ©, des courants d’oxydation et de rĂ©duction d’une plage de 600 nA Ă  20 pA Ă  une frĂ©quence d’échantillonnage minimale de 1,25 kHz ont pu ĂȘtre mesurĂ©s expĂ©rimentalement en utilisant un DAC commercial externe. Également, le biocapteur formĂ© du potentiostat fabriquĂ© et de la plateforme d’électrodes fonctionnalisĂ©es est validĂ© par des mesures biologiques en milieu in vitro concluantes pour diffĂ©rentes concentrations de dopamine et de glutamate en solution, en termes de sensibilitĂ© et de sĂ©lectivitĂ© des mesures ampĂ©romĂ©triques obtenues. Ces rĂ©sultats fondent la preuve de concept du biocapteur proposĂ© comme composant de base de l’unitĂ© de dĂ©tection.----------ABSTRACT Intercellular chemical signaling shaped by the interaction of neurotransmitters plays a crucial role in the functioning of brain processes. The analysis of chemical neural activity in real time in all its complexity would help neuroscientists understand the mechanisms of the human brain and its neurodegenerative diseases. Systems currently used in neuroscience laboratories are limited in their ability to provide accurate and appropriate measurements to the heterogeneous events associated with the activity of several neurotransmitters. Polystim Neurotechnologies Laboratory is therefore designing an implantable Lab on Chip (LOC) dedicated to the monitoring of neurochemicals circulating in the brain's intercellular space that provides the needed features. This thesis presents an electrochemical detection unit associated with such system, designed for the quantification of neurotransmitters in the intracerebral liquid. We propose an architecture composed of biosensors using a potentiostat integrated with CMOS technology as transducer, and measuring electrodes with functionalized carbon nanotubes for sensitive and selective measurements. The proposed integrated potentiostat generates time measurements easily treatable digitally, which are proportional to redox currents produced at the interface of the measuring electrodes. Its configuration separately quantizes oxidation and reduction currents by using two measuring channels, according to a constant voltage amperometry technique. The architecture consists of an amplifier, a high-speed comparator and a digital-to-analog converter (DAC). The latter is shared between the two channels in order to reduce the total measurement time as a function of the detected currents amplitude. This topology provides a compromise between the input dynamic range, sampling frequency and resolution measurements, three important parameters to accommodate the detection and quantification of a wide variety of neurotransmitters in real time. To validate the prototype of the implemented potentiostat, a multi-electrode measuring platform is fabricated and functionalized with composite films based on carbon nanotubes (CNTs), for dopamine and glutamate, two common neurotransmitters, selective detection. The potentiostat integrated circuit is implemented with IBM 0.13 ”m CMOS technology. A printed circuit board (PCB) containing an FPGA managing control signals and data acquisition, was made to experimentally characterize the fabricated circuit. Despite the non-linearity of the manufactured integrated DAC, oxidation and reduction currents ranging from 600 nA to 20 pA at a minimum sampling frequency of 1.25 kHz could be measured experimentally using an external commercial DAC. Also, the biosensor formed by the potentiostat and the functionalized electrodes platform is validated by conclusive in vitro biological measurements of dopamine and glutamate in solutions, in terms of sensitivity and selectivity. These results forms the proof of concept of the proposed biosensor as the base component of the detection unit

    Electrochemical Biosensors for On-line Monitoring of Cell Culture Metabolism

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    Current research in the biotechnological field is hampered by the lack of available technologies dedicated to cell monitoring. While on the one hand physicochemical parameters, such as pH, temperature, cell density and adhesion, can be monitored quite easily with automated systems, on the other the variation of cell metabolism is still challenging. Indeed, the real-time detection of metabolites can noticeably extend the knowledge of the molecular biology for therapeutic purposes, as well as for the investigation of several types of diseases. Electrochem- ical biosensors are the ideal candidates for cell monitoring, since they can be integrated with the electronic portion of the system, leading to high-density arrays of biosensors with better performance in terms of signal-to-noise ratio, sensor response, and sample volumes. The present research covers the design, the fabrication, the characterization, and the valida- tion of a minimally-invasive system for the real-time monitoring of different metabolites in a cell culture. The electrochemical biosensor consists of an array of gold working electrodes accomplished by standard microfabrication processes. The deposition of carbon nanotubes and the selective modification with enzymes onto metallic electrodes is performed by adapt- ing an ultra-low volume dispensing system for DNA and protein drop cast. The biological sensing element ensures high selectivity for the target molecule to detect, while nanomate- rials confer superior performance (e.g. sensitivity) with respect to standard immobilization strategies. The on-line detection of glucose, lactate, and glutamate is achieved with an ad hoc fluidic system. The use of a microdialysis probe in direct contact with the cell culture avoids contamination problems and dilution steps for metabolite measurements. Carbon nanotube-based biosensors and the system for real-time measurements are validated on two cell lines under different experimental conditions. The electronic system for electrochemical measurements is also designed and realized with discrete components to be interfaced with the platform. The adopted architecture is able to optimally record the current ranges involved in the electrochemical cell, while the wireless communication between the electronic system and the remote station ensures minimally invasiveness and high portability of the device. Existing technologies and materials are used in an original manner to achieve the on-line monitoring of metabolites in stem cell-like cultures, paving the way for the development of miniaturized, high-sensitive, and inexpensive devices for continuous cell monitoring
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