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

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

Traumatic brain injury neuroelectrochemical monitoring: behind-the-ear micro-instrument and cloud application

BACKGROUND: Traumatic Brain Injury (TBI) is a leading cause of fatality and disability worldwide, partly due to the occurrence of secondary injury and late interventions. Correct diagnosis and timely monitoring ensure effective medical intervention aimed at improving clinical outcome. However, due to the limitations in size and cost of current ambulatory bioinstruments, they cannot be used to monitor patients who may still be at risk of secondary injury outside the ICU. METHODS: We propose a complete system consisting of a wearable wireless bioinstrument and a cloud-based application for real-time TBI monitoring. The bioinstrument can simultaneously record up to ten channels including both ECoG biopotential and neurochemicals (e.g. potassium, glucose and lactate), and supports various electrochemical methods including potentiometry, amperometry and cyclic voltammetry. All channels support variable gain programming to automatically tune the input dynamic range and address biosensors' falling sensitivity. The instrument is flexible and can be folded to occupy a small space behind the ear. A Bluetooth Low-Energy (BLE) receiver is used to wirelessly connect the instrument to a cloud application where the recorded data is stored, processed and visualised in real-time. Bench testing has been used to validate device performance. RESULTS: The instrument successfully monitored spreading depolarisations (SDs) - reproduced using a signal generator - with an SNR of 29.07 dB and NF of 0.26 dB. The potentiostat generates a wide voltage range from -1.65V to +1.65V with a resolution of 0.8mV and the sensitivity of the amperometric AFE was verified by recording 5 pA currents. Different potassium, glucose and lactate concentrations prepared in lab were accurately measured and their respective working curves were constructed. Finally,the instrument achieved a maximum sampling rate of 1.25 ksps/channel with a throughput of 105 kbps. All measurements were successfully received at the cloud. CONCLUSION: The proposed instrument uniquely positions itself by presenting an aggressive optimisation of size and cost while maintaining high measurement accuracy. The system can effectively extend neuroelectrochemical monitoring to all TBI patients including those who are mobile and those who are outside the ICU. Finally, data recorded in the cloud application could be used to help diagnosis and guide rehabilitation

Recent Advances in Neural Recording Microsystems

The accelerating pace of research in neuroscience has created a considerable demand for neural interfacing microsystems capable of monitoring the activity of large groups of neurons. These emerging tools have revealed a tremendous potential for the advancement of knowledge in brain research and for the development of useful clinical applications. They can extract the relevant control signals directly from the brain enabling individuals with severe disabilities to communicate their intentions to other devices, like computers or various prostheses. Such microsystems are self-contained devices composed of a neural probe attached with an integrated circuit for extracting neural signals from multiple channels, and transferring the data outside the body. The greatest challenge facing development of such emerging devices into viable clinical systems involves addressing their small form factor and low-power consumption constraints, while providing superior resolution. In this paper, we survey the recent progress in the design and the implementation of multi-channel neural recording Microsystems, with particular emphasis on the design of recording and telemetry electronics. An overview of the numerous neural signal modalities is given and the existing microsystem topologies are covered. We present energy-efficient sensory circuits to retrieve weak signals from neural probes and we compare them. We cover data management and smart power scheduling approaches, and we review advances in low-power telemetry. Finally, we conclude by summarizing the remaining challenges and by highlighting the emerging trends in the field

High-Density Neurochemical Microelectrode Array to Monitor Neurotransmitter Secretion

Neuronal exocytosis facilitates the propagation of information through the nervous system pertaining to bodily function, memory, and emotions. Using amperometry, an electrochemical technique that directly detects electroactive molecules, the sub-millisecond dynamics of exocytosis are revealed and the modulation of neurotransmitter secretion due to neurodegenerative diseases or pharmacological treatments can be studied. The method of detection using amperometry is the exchange of electrons due to a redox reaction at an electrochemically sensitive electrode. As electroactive molecules, such as dopamine, undergo oxidation, electrons are released from the molecule to the electrode and an oxidation current is generated and recorded. Despite the significance of traditional single-cell amperometry, it is a costly, labor-intensive, and low-throughput, procedure. The focus of this dissertation is the development of a monolithic CMOS-based neurochemical sensing system that can provide a high-throughput of up to 1024 single-cell recordings in a single experiment, significantly reducing the number of experiments required for studying the effects of neurodegenerative diseases or new pharmacological treatments on the exocytosis process. The neurochemical detection system detailed in this dissertation is based on a CMOS amplifier array that contains 1024 independent electrode-amplifier units, each of which contains a transimpedance amplifier with comparable noise performance to a high-quality electrophysiology amplifier that is used for traditional single-cell amperometry. Using this novel technology, single exocytosis events are monitored simultaneously from numerous single-cells in experiments to reveal the secretion characteristics from groups of cells before and after pharmacological treatments which target the modulation of neurotransmitters in the brain, such as drugs for depression or Parkinson\u27s disease

A high performance ASIC for electrical and neurochemical traumatic brain injury monitoring

Traumatic Brain Injury (TBI) can be defined as a non-degenerative, non-congenital brain trauma due to an external mechanical force. TBI is a major cause of death and disability in all age groups and the leading cause of death and disability in working people and among young adults. This Thesis presents the first application specific integrated chip (ASIC) for monitoring patients suffering from TBI. The microelectronic chip was designed to meet the demands of processing physiological signals for an alternative method of TBI monitoring. It has been studied that by monitoring electrical (ECoG) and chemical (glucose, lactate and potassium) signals, the report of spreading depolarisation (SD) waves could be a good indicator for an upcoming secondary brain injury. The ultimate aim of this Thesis has been to support the idea of a “behind-the-ear” micro-platform, which could enable the monitoring of mobile (or mobilized) patients suffering a TBI who, currently, are not monitored. Switched-capacitor (SC) circuits have been adopted for the implementation of both current and voltage analogue front-ends (AFEs). Advanced techniques to minimise noise and improve the noise performance of the circuit were employed. Moreover, a digitally enabled automatic transimpedance gain control circuit, suitable for current analogue front-ends, was developed and tested in order to provide an automated way to adjust the gain and to counterbalance for the drop in sensitivity of the biosensors due to drift. Measured results confirming the operation of the TBI ASIC and its sub-circuits are reported. Finally, a novel circuit that mimics the Butler-Volmer dynamics is presented. The basic building blocks arise from the combination of Translinear (TL) Circuits and the Non- linear Bernoulli Cell Formalism (NBCF). The developed electrical equivalent circuit has been compared to an ideal model, which was developed in MATLAB. The robustness of the microelectronic system was evaluated by means of Monte Carlo simulations.Open Acces

Development Of Carbon Based Neural Interface For Neural Stimulation/recording And Neurotransmitter Detection

Electrical stimulation and recording of neural cells have been widely used in basic neuroscience studies, neural prostheses, and clinical therapies. Stable neural interfaces that effectively communicate with the nervous system via electrodes are of great significance. Recently, flexible neural interfaces that combine carbon nanotubes (CNTs) and soft polymer substrates have generated tremendous interests. CNT based microelectrode arrays (MEAs) have shown enhanced electrochemical properties compared to commonly used electrode materials such as tungsten, platinum or titanium nitride. On the other hand, the soft polymer substrate can overcome the mechanical mismatch between the traditional rigid electrodes (or silicon shank) and the soft tissues for chronic use. However, most fabrication techniques suffer from low CNT yield, bad adhesion, and limited controllability. In addition, the electrodes were covered by randomly distributed CNTs in most cases. In this study, a novel fabrication method combining XeF2 etching and parylene deposition was presented to integrate the high quality vertical CNTs grown at high temperature with the heat sensitive parylene substrate in a highly controllable manner. Lower stimulation threshold voltage and higher signal to noise ratio have been demonstrated using vertical CNTs bundles compared to a Pt electrode and other randomly distributed CNT films. Adhesion has also been greatly improved. The work has also been extended to develop cuff shaped electrode for peripheral nerve stimulation. Fast scan cyclic voltammetry is an electrochemical detection technique suitable for in-vivo neurotransmitter detection because of the miniaturization, fast time response, good sensitivity and selectivity. Traditional single carbon fiber microelectrode has been limited to single detection for in-vivo application. Alternatively, pyrolyzed photoresist film (PPF) is a good candidate for this application as they are readily compatible with the microfabrication process for precise fabrication of microelectrode arrays. By the oxygen plasma treatment of photoresist prior to pyrolysis, we obtained carbon fiber arrays. Good sensitivity in dopamine detection by this carbon fiber arrays and improved adhesion have been demonstrated

Dopamiinin hapettumisen lukija-anturirajapinta 65 nm CMOS teknologialla

Sensing and monitoring of neural activities within the central nervous system has become a fast-growing area of research due to the need to understand more about how neurons communicate. Several neurological disorders such as Parkinson’s disease, Schizophrenia, Alzeihmers and Epilepsy have been reported to be associated with imbalance in the concentration of neurotransmitters such as glutamate and dopamine [1] - [5]. Hence, this thesis proposes a solution for the measurement of dopamine concentration in the brain during neural communication. The proposed design of the dopamine oxidation readout sensor interface is based on a mixed-signal front-end architecture for minimizing noise and high resolution of detected current signals. The analog front-end is designed for acquisition and amplification of current signals resulting from oxidation and reduction at the biosensor electrodes in the brain. The digital signal processing (DSP) block is used for discretization of detected dopamine oxidation and reduction current signals that can be further processed by an external system. The results from the simulation of the proposed design show that the readout circuit has a current resolution of 100 pA and can detect minimum dopamine concentration of 10 μMol based on measured data from novel diamond-like carbon electrodes [6]. Higher dopamine concentration can be detected from the sensor interface due to its support for a wide current range of 1.2 μA(±600 nA). The digital code representation of the detected dopamine has a resolution of 14.3-bits with RMS conversion error of 0.18 LSB which results in an SNR of 88 dB at full current range input. However, the attained ENOB is 8-bits due to the effect of nonlinearity in the oscillator based ADC. Nonetheless, the achieved resolution of the readout circuit provides good sensitivity of released dopamine in the brain which is useful for further understanding of neurotransmitters and fostering research into improved treatments of related neurodegenerative diseases.Keskushermoston aktiivisuuden havainnointi ja tarkkailu on muodostunut tärkeäksi tutkimusalaksi, sillä tarve ymmärtää neuronien viestintää on kasvanut. Monien hermostollisten sairauksien kuten Parkinsonin taudin, skitsofrenian, Alzheimerin taudin ja epilepsian on huomattu aiheuttavan muutoksia välittäjäaineiden, kuten glutamaatin ja dopamiinin, pitoisuuksissa [1] - [5]. Aiheeseen liittyen tässä työssä esitetään ratkaisu dopamiinipitoisuuden mittaamiseksi aivoista. Esitetty dopamiinipitoisuuden lukijapiiri perustuu sekamuotoiseen etupäärakenteeseen, jolla saavutetaan matala kohinataso ja hyvä tarkkuus signaalien ilmaisemisessa. Suunniteltu analoginen etupää kykenee lukemaan ja vahvistamaan dopamiinipitoisuuden muutosten aiheuttamia virran muutoksia aivoihin asennetuista elektrodeista. Digitaalisen signaalinkäsittelyn avulla voidaan havaita dopamiinin hapettumis-ja pelkistymisvirtasignaalit, ja välittää ne edelleen ulkoisen järjestelmän muokattavaksi. Simulaatiotulokset osoittavat, että suunniteltu piiri saavuttaa 100 pA virran erottelukyvyn. Simuloinnin perustuessa hiilipohjaisiin dopamiinielektrodeihin piiri voi havaita 10 μMol dopamiinipitoisuuden [6]. Myös suurempia dopamiinipitoisuuksia voidaan havaita, sillä etupäärajapinta tukee 1.2 μA(±600 nA) virta-aluetta. Digitaalinen esitysmuoto tukee 14.3 bitin esitystarkkuutta 0.18 bitin RMS virheellä saavuttaen 88 dB dynaamisen virta-alueen. Saavutettu ENOB (tehollinen bittimäärä) on kuitenkin 8 bittiä oskillaattoripohjaisen ADC:n (analogia-digitaalimuuntimen) epälineaarisuuden takia. Saavutettu tarkkuus tuottaa hyvän herkkyyden dopamiinin havaitsemiseksi ja hyödyttää siten välittäjäainetutkimusta ja uusien hoitomuotojen kehittämistä hermostollisiin sairauksiin

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

Development of a Dual-Mode CMOS Microelectrode Array for the Simultaneous Study of Electrochemical and Electrophysiological Activities of the Brain

Medical diagnostic devices are in high demand due to increasing cases of neurodegenerative diseases in the aging population and pandemic outbreaks in our increasingly connected global community. Devices capable of detecting the presence of a disease in its early stages can have dramatic impacts on how it can be treated or eliminated. High cost and limited accessibility to diagnostic tools are the main barriers preventing potential patients from receiving a timely disease diagnosis. This dissertation presents several devices that are aimed at providing higher quality medical diagnostics at a low cost. Brain function is commonly studied with systems detecting the action potentials that are formed when neurons fire. CMOS technology enables extremely high-density electrode arrays to be produced with integrated amplifiers for high-throughput action potential measurement systems while greatly reducing the cost per measurement compared to traditional tools. Recently, CMOS technology has also been used to develop high-throughput electrochemical measurement systems. While action potentials are important, communication between neurons occurs by the flow of neurotransmitters at the synapses, so measurement of action potentials alone is incapable of fully studying neurotransmission. In many neurodegenerative diseases the breakdown in neurotransmission begins well before the disease manifests itself. The development of a dual-mode CMOS device that is capable of simultaneous high-throughput measurement of both action potentials and neurotransmitter flow via an on-chip electrode array is presented in this dissertation. This dual-mode technology is useful to those studying the dynamic decay of the neurotransmission process seen in many neurodegenerative diseases using a low-cost CMOS chip. This dissertation also discusses the development of more traditional diagnostic devices relying on PCR, a method commonly used only in centralized laboratories and not readily available at the point-of-care. These technologies will enable faster, cheaper, more accurate, and more accessible diagnostics to be performed closer to the patient