Microelectronics-Based Biosensors Dedicated to the Detection of Neurotransmitters: A Review
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paper_title: Electrochemical biosensor based on protein–polysaccharide hybrid for selective detection of nanomolar dopamine metabolite of 3,4-dihydroxyphenylacetic acid (DOPAC)

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Abstract A strategy for the preparation of tyrosinase biosensor has been proposed to determine dopamine metabolite of 3,4-dihydroxyphenylacetic acid (DOPAC). An amino-polysaccharide chitosan was successfully used as matrix to entrap tyrosinase on glassy carbon electrode surface on basis of tyrosinase conjugated with chitosan. The sensor was operated at −0.15 V. The current linearly increased with the increasing concentration of DOPAC over the concentration of 6 nM to 0.2 mM. The sensor can be used to selectively determine nanomolar DOPAC in the presence of physiological level of ascorbic acid (AA), uric acid (UA), acetaminophen, neurotransmitters including dopamine, l -dopa, adrenaline and noradrenaline.
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paper_title: Mass Spectrometric Detection of Neuropeptides Using Affinity-Enhanced Microdialysis with Antibody-Coated Magnetic Nanoparticles

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Microdialysis (MD) is a useful sampling tool for many applications due to its ability to permit sampling from an animal concurrent with normal activity. MD is of particular importance in the field of neuroscience, in which it is used to sample neurotransmitters (NTs) while the animal is behaving in order to correlate dynamic changes in NTs with behavior. One important class of signaling molecules, the neuropeptides (NPs), however, presented significant challenges when studied with MD, due to the low relative recovery (RR) of NPs by this technique. Affinity-enhanced microdialysis (AE-MD) has previously been used to improve recovery of NPs and similar molecules. For AE-MD, an affinity agent (AA), such as an antibody-coated particle or free antibody, is added to the liquid perfusing the MD probe. This AA provides an additional mass transport driving force for analyte to pass through the dialysis membrane and thus increases the RR. In this work, a variety of AAs have been investigated for AE-MD of NPs in vitro and in vivo, including particles with C18 surface functionality and antibody-coated particles. Antibody-coated magnetic nanoparticles (AbMnP) provided the best RR enhancement in vitro, with statistically significant (p < 0.05) enhancements for 4 out of 6 NP standards tested, and RR increases up to 41-fold. These particles were then used for in vivo MD in the Jonah crab, Cancer borealis, during a feeding study, with mass spectrometric (MS) detection. 31 NPs were detected in a 30 min collection sample, compared to 17 when no AA was used. The use of AbMnP also increased the temporal resolution from 4 to 18 h in previous studies to just 30 min in this study. The levels of NPs detected were also sufficient for reliable quantitation with the MS system in use, permitting quantitative analysis of the concentration changes for 7 identified NPs on a 30 min time course during feeding.
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paper_title: Collection of nanoliter microdialysate fractions in plugs for off-line in vivo chemical monitoring with up to 2s temporal resolution

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Abstract An off-line in vivo neurochemical monitoring approach was developed based on collecting nanoliter microdialysate fractions as an array of “plugs” segmented by immiscible oil in a piece of Teflon tubing. The dialysis probe was integrated with the plug generator in a polydimethlysiloxane microfluidic device that could be mounted on the subject. The microfluidic device also allowed derivatization reagents to be added to the plugs for fluorescence detection of analytes. Using the device, 2 nL fractions corresponding to 1–20 ms sampling times depending upon dialysis flow rate, were collected. Because axial dispersion was prevented between them, each plug acted as a discrete sample collection vial and temporal resolution was not lost by mixing or diffusion during transport. In vitro tests of the system revealed that the temporal resolution of the system was as good as 2 s and was limited by mass transport effects within the dialysis probe. After collection of dialysate fractions, they were pumped into a glass microfluidic chip that automatically analyzed the plugs by capillary electrophoresis with laser-induced fluorescence at 50 s intervals. By using a relatively low flow rate during transfer to the chip, the temporal resolution of the samples could be preserved despite the relatively slow analysis time. The system was used to detect rapid dynamics in neuroactive amino acids evoked by microinjecting the glutamate uptake inhibitor l -trans-pyrrolidine-2,4-dicarboxylic acid (PDC) or K + into the striatum of anesthetized rats. The resulted showed increases in neurotransmitter efflux that reached a peak in 20 s for PDC and 13 s for K + .
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paper_title: Microfluidic Electrophoresis Chip Coupled to Microdialysis for in Vivo Monitoring of Amino Acid Neurotransmitters

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Microfluidic electrophoresis devices were coupled on-line to microdialysis for in vivo monitoring of primary amine neurotransmitters in rat brain. The devices contained a sample introduction channel for dialysate, a precolumn reactor for derivatization with o-phthaldialdehyde, a flow-gated injector, and a separation channel. Detection was performed using confocal laser-induced fluorescence. In vitro testing revealed that the initial device design had detection limits for amino acids of ∼200 nM, relative standard deviation of peak heights of 2%, and separations within 95 s with up to 30 200 theoretical plates when applying an electric field of 370 V/cm. A second device design that allowed electric fields of 1320 V/cm to be applied while preserving the reaction time allowed separations within 20 s with up to 156 000 theoretical plates. Flow splitting into the electrokinetic network from hydrodynamic flow in the sample introduction channel was made negligible for sampling flow rates from 0.3 to 1.2 μL/min by...
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paper_title: Immobilization method to preserve enzyme specificity in biosensors: consequences for brain glutamate detection.

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Microelectrode biosensors are a promising technique to probe the brain interstitial fluid and estimate the extracellular concentration of neurotransmitters like glutamate. Their selectivity is largely based on maintaining high substrate specificity for the enzymes immobilized on microelectrodes. However, the effect of enzyme immobilization on substrate specificity is poorly understood. Furthermore, the accuracy of biosensor measurements for brain biological extracts has not been reliably established in comparison with conventional analytical techniques. In this study, microelectrode biosensors were prepared using different enzyme immobilization methods, including glutaraldehyde, a conventional cross-linker, and poly(ethylene glycol) diglycidyl ether (PEGDE), a milder immobilization reagent. Glutaraldehyde, but not PEGDE, significantly decreased the apparent substrate specificity of glutamate and glucose oxidase. For glutaraldehyde prepared biosensors, detection of secondary substrates by glutamate oxidase increased, resulting in a significant overestimate of glutamate levels. This effect was not observed with PEGDE-based biosensors, and when brain microdialysates were analyzed, the levels of glutamate detected by biosensors were consistent with those detected by capillary electrophoresis. In addition, basal concentrations of glutamate detected in vivo were approximately 10-fold lower than the levels detected with glutaraldehyde-based biosensors (e.g., 1.2 μM vs 16 μM, respectively). Overall, enzyme immobilization can significantly impact substrate specificity, and PEGDE is well-suited for the preparation of stable and selective biosensors. This development questions some of the previous biosensor studies aimed at detecting glutamate in the brain and opens new possibilities for specific neurotransmitter detection.
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paper_title: Recent trends in microdialysis sampling integrated with conventional and microanalytical systems for monitoring biological events: a review.

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Microdialysis (MD) is a sampling technique that can be employed to monitor biological events both in vivo and in vitro. When it is coupled to an analytical system, microdialysis can provide near real-time information on the time-dependent concentration changes of analytes in the extracellular space or other aqueous environments. Online systems for the analysis of microdialysis samples enable fast, selective and sensitive analysis while preserving the temporal information. Analytical methods employed for online analysis include liquid chromatography (LC), capillary (CE) and microchip electrophoresis and flow-through biosensor devices. This review article provides an overview of microdialysis sampling and online analysis systems with emphasis on in vivo analysis. Factors that affect the frequency of analysis and, hence, the temporal resolution of these systems are also discussed.
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paper_title: Novel micromachined silicon sensor for continuous glucose monitoring

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Abstract The construction and the application properties of a micromachined silicon sensor for continuous glucose monitoring are presented. The sensor uses the conventional enzymatic conversion of glucose with amperometric detection of H 2 O 2 . The innovation is the precise diffusion control of the analyte through a porous silicon membrane into a silicon etched cavity containing the immobilised enzyme. A variation of the number and size of the membrane pores allows to adjust the linear range of the sensor to the respective requirement. The sensor was tested in vitro as well as in clinical studies, being supplied with interstitial fluid. The cavity sensor was designed for a linear range between 0.5 and 20 mM. A signal response time of below 30 s and a signal stability exceeding 1 week is shown. By using a double cavity sensor falsification of the glucose signal by interfering substances can be compensated. In clinical trials the sensor measured continuously in interstitial fluid for up to 18 h without any signal drift and with good correlation to blood glucose reference values.
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paper_title: High temporal resolution electrochemical biosensor using nitrogen-incorporated nanodiamond ultra-microelectrode array

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Biosensors for detecting/measuring/monitoring the concentration of neurotransmitters that vary at sub-second time-scale can be achieved by using an electrode with high temporal resolution and fast electron transfer kinetics. Neurotransmitters, such as dopamine, undergo rapid fluctuations in concentrations occurring at a sub-second time scale. Real-time monitoring and measurement of these concentrationn changes, in-vivo or in-vitro, requires the use of ultra-microelectrode array (UMEA). This work reports on the development of a reliable UMEA electrochemical biosensor which can be used to identify, quantify, and monitor essential bio-analytes such as dopamine (DA), ascorbic acid (AA) and uric acid (UA) by using CVD nitrogen-incorporated nanodiamond UMEA without the need of electrode surface functionalization or modifications, making real-time detection possible. The application of fast-scan voltammetry (FSCV) for detecting dopamine and interfering bio-chemicals, including ascorbic acid and uric acid in 0.1M PBS (pH 7.4) by the UMEA has been realized. The detailed experiential method for the sensor array fabrication, and the UMEA sensitivity, selectivity, and detection limit for the detection of bio-analytes will be discussed.
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paper_title: Multi-target electrochemical biosensing enabled by integrated CMOS electronics

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An integrated electrochemical measurement system, based on CMOS technology, is presented, which allows the detection of several analytes in parallel (multi-analyte) and enables simultaneous monitoring at different locations (multi-site). The system comprises a 576-electrode CMOS sensor chip, an FPGA module for chip control and data processing, and the measurement laptop. The advantages of the highly versatile system are demonstrated by two applications. First, a label-free, hybridization-based DNA sensor is enabled by the possibility of large-scale integration in CMOS technology. Second, the detection of the neurotransmitter choline is presented by assembling the chip with biosensor microprobe arrays. The low noise level enables a limit of detection of, e.g., 0.3 µM choline. The fully integrated system is self-contained: it features cleaning, functionalization and measurement functions without the need for additional electrical equipment. With the power supplied by the laptop, the system is very suitable for on-site measurements.
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paper_title: Microfluidic systems for studying neurotransmitters and neurotransmission.

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Neurotransmitters and neuromodulators are molecules within the nervous system that play key roles in cell-to-cell communication. Upon stimulation, neurons release these signaling molecules, which then act at local or distant locations to elicit a physiological response. Ranging from small molecules, such as diatomic gases and amino acids, to larger peptides, these chemical messengers are involved in many functional processes including growth, reproduction, memory and behavior. Understanding signaling molecules and the conditions that govern their release in healthy or damaged networks promises to deliver insights into neural network formation and function. Microfluidic devices can provide optimal cell culture conditions, reduced volume systems, and precise control over the chemical and physical nature of the extracellular environment, making them well-suited for studying neurotransmission and other forms of cell-to-cell signaling. Here we review selected microfluidic approaches that are suitable for monitoring cell-to-cell signaling molecules. We highlight devices that improve in vivo sample collection as well as compartmentalized devices designed to isolate individual neurons or co-cultures in vitro, including a focus on systems used for studying neural injury and regeneration, and devices that allow selective chemical stimulations and the characterization of released molecules.
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paper_title: Neurotransmitters excreted in the urine as biomarkers of nervous system activity: Validity and clinical applicability

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Strategies for managing the nervous system are numerous while methods of evaluating the nervous system are limited. Given the physiological importance of neurotransmitters as signaling molecules in the nervous system, the measurement of neurotransmitters has significant potential as a clinical tool. Of all the biological fluids that can be utilized, urinary neurotransmitter testing, due to its stability, sensitivity, and non-invasiveness, is the desired method to analyze nervous system function. Increasing use of this technology in a clinical setting demands a review of its feasibility, utility, and clinical value. We review the current body of literature pertaining to the mechanism of neurotransmitter transport across the blood-brain barrier as well as neurotransmitter filtration and excretion by the kidneys. In addition, this review summarizes the historical use of urinary neurotransmitter assessment to diagnose pheochromocytoma. Early research also correlated urinary assessment of neurotransmitters to various clinical symptoms and treatments of which we present research only for depression, ADHD, and inflammation because of the abundant amount of research in these areas. Finally, we review the limitations and challenges of urinary neurotransmitter testing. Taken together, evidence suggests that neurotransmitters excreted in the urine may have a place in clinical practice as a biomarker of nervous system function to effectively assess disturbances and monitor treatment efficacy.
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paper_title: Electrochemical Detection of Selected Organic Components in the Eluate from High-Performance Liquid-Chromatography

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High-performance liquid chromatography can be combined with hydrodynamic thin-layer electrochemistry for determination of trace amounts of organic constituents in complex samples. With small and inexpensive analyzers based on these two techniques, as little as 1 pg of an electrochemically active component can be detected in a few minutes. Because many of the important low-molecular-weight organic constituents of body fluids— both endogenous metabolites and drugs—undergo electrochemical reactions, it seems reasonable to presume that useful assays might be developed by using the above methodology. Beginning to explore this presumption, we illustrate how uric acid, ascorbic acid, catecholamines, and related tyrosine metabolites might be measured in urine and serum. In some cases, liquid chromatography with electrochemical detection provides better sensitivity, selectivity, and speed than traditional methods, while minimizing the need for analytical reagents. We describe the basic approach and progress to date and suggest future applications.
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paper_title: Review: Carbon nanotube based electrochemical sensors for biomolecules.

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Carbon nanotubes (CNTs) have been incorporated in electrochemical sensors to decrease overpotential and improve sensitivity. In this review, we focus on recent literature that describes how CNT-based electrochemical sensors are being developed to detect neurotransmitters, proteins, small molecules such as glucose, and DNA. Different types of electrochemical methods are used in these sensors including direct electrochemical detection with amperometry or voltammetry, indirect detection of an oxidation product using enzyme sensors, and detection of conductivity changes using CNT-field effect transistors (FETs). Future challenges for the field include miniaturizing sensors, developing methods to use only a specific nanotube allotrope, and simplifying manufacturing.
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paper_title: Highly sensitive trivalent copper chelate-luminol chemiluminescence system for capillary electrophoresis detection of epinephrine in the urine of smoker.

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Epinephrine (EP) is one of the most important neurotransmitters and hormones. Some previous literatures show that there is a close relation between its release and smoking. To compare the levels of EP in urines of smokers and nonsmokers, a sensitive chemiluminescence (CL) system, luminol-diperiodatocuprate (III) (K(5)[Cu(HIO(6))(2)], DPC), has been developed and validated for the determination of EP after CE separation. The DPC-luminol-EP CL reaction showed very intensive emission and fast kinetic characteristics, thus led to a high sensitivity in the flow-through detection mode for capillary electrophoresis. With the peak height as a quantitative parameter, the relative CL intensity was linear with the EP concentration in the range of 2.0-400ng/mL, with a limit of detection of 0.82ng/mL (S/N=3). The reproducibility was assessed by intra- and inter-day relative standard deviations (RSDs) for 11 replicate determinations of EP standard samples at low, medium and high concentrations. The intra- and inter-day RSDs for CL signals were 5.5%-6.6% and 6.1%-7.5%, respectively, and those for migration times were 3.4%-5.8% and 4.3%-6.3%, respectively. The presented method was successfully applied to the determination of EP in EP injection and urine samples of smokers and nonsmokers. The recovery test results for urine samples ranged from 86.5 to 112.0%, which demonstrated the reliability of this method. The results for urine sample detection indicate that the average level of EP in the urines of the smoker group is obviously higher than that in the urines of the nonsmoker group, which may demonstrate that smoking can stimulate the release of EP in human body.
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paper_title: Specific needs of dopamine neurons for stimulation in order to survive: implication for Parkinson disease

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Parkinson disease (PD) is a degenerative brain disorder characterized by motor symptoms that are unequivocally associated with the loss of dopaminergic (DA) neurons in the substantia nigra (SN). Although our knowledge of the mechanisms that contribute to DA cell death in both hereditary and sporadic forms of the disease has advanced significantly, the nature of the pathogenic process remains poorly understood. In this review, we present evidence that neurodegeneration occurs when the electrical activity and excitability of these neurons is reduced. In particular, we will focus on the specific need these neurons may have for stimulation in order to survive and on the molecular and cellular mechanisms that may be compromised when this need is no longer met in PD.
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paper_title: Biosensor Based on Electrocodeposition of Carbon Nanotubes/Polypyrrole/Laccase for Neurotransmitter Detection

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A new biosensor has been developed by a simple electrocodeposition of multiwalled carbon nanotubes (MWCNT), polypyrrole (PPy) and laccase (Lac) on the platinum (Pt) electrode surface. The neurotransmitter biosensor was applied to the detection of dopamine in urine samples using differential pulse voltammetry (DPV). The Pt/MWCNT/PPy/Lac biosensor exhibited a detection limit of 0.14 µM, which is an adequate level for monitoring dopamine in urine. Reproducibility and repeatability values of 2.9 % and 1.7 %, respectively, were obtained compared to the conventional procedure. The proposed biosensor was successfully applied in the determination of dopamine in urine, and the obtained results were in full agreement with those from the HPLC procedure.
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paper_title: Amperometric and voltammetric detection for capillary electrophoresis

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The focus of this article is amperometric and voltammetric detection coupled with capillary electrophoresis. Fundamental concepts and progress in the field of capillary electrophoresis with electrochemical detection (CEEC) that have occurred within the past three years, including new methodologies and unique applications, are highlighted. This review contains 95 references.
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paper_title: Integrated biosensors in CMOS

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This paper reviews several integrated biosensing technologies compatible with standard CMOS process. With a particular focus on detecting biomolecules and molecular interactions, the selected sensing modalities include electrochemical biosensor, fluorescent biosensor, magnetic biosensor, and gravimetric biosensor. For each modality, the sensing mechanism is first presented, and is then followed by a typical design example. Advantages as well as limitations of the sensing technology are also discussed.
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paper_title: Development of a PDMS-based microchip electrophoresis device for continuous online in vivo monitoring of microdialysis samples.

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A PDMS-based microfluidic system for online coupling of microdialysis sampling to microchip electrophoresis with fluorescence detection for in vivo analysis of amino acid neurotransmitters using naphthalene-2,3-dicarboxaldehyde and sodium cyanide as the derivatization reagents is described. Fabricating chips from PDMS rather than glass was found to be simpler and more reproducible, especially for chips with complex designs. The microchip incorporated a 20-cm serpentine channel in which sample plugs were introduced using a "simple" injection scheme; this made fluid handling and injection on-chip easier for the online system compared with gated or valve-based injection. The microchip was evaluated offline for the analysis of amino acid standards and rat brain microdialysis samples. Next, precolumn derivatization was incorporated into the chip and in vivo online microdialysis-microchip electrophoresis studies were performed. The system was employed for the continuous monitoring of amino acid neurotransmitters in the extracellular fluid of the brain of an anesthetized rat. Fluorescein was dosed intravenously and monitored simultaneously online as a marker of in vivo blood-brain barrier permeability. The microdialysis-microchip electrophoresis system described here will be employed in the future for simultaneous monitoring of changes in blood-brain barrier permeability and levels of amino acid neurotransmitters in the rat stroke model.
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paper_title: The Growing Burden of Alzheimer's Disease

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Most dementias in people at least 65 years of age are attributable to Alzheimer's disease (AD). While approximately 5.4 million Americans are now believed to have AD, the AD population is expected to nearly triple over the next 40 years, reaching approximately 14.5 million. Presently, there is no cure for AD, but a 2-year delay in AD onset would reduce the expected prevalence by 1.94 million within 50 years. The most important risk factor for AD is age, followed by presence of the apolipoprotein E-4 allele. Other risk factors for AD include sex (female), history of head trauma, family history of Down syndrome or dementia, and cerebrovascular risk factors. The initial neurodegenerative process that causes AD is unknown. However, it is accepted that the presence of amyloid plaques, neurofibrillary tangles, neuronal loss (and synapses), and cerebral amyloid angiopathy are the central pathogenic events. There is selective vulnerability of the limbic system and heteromodal association areas in AD pathology. The most affected neurotransmitter in AD is acetylcholine, as enzymes that are part of its metabolic pathway are depleted. The clinical presentation of AD is heterogeneous and insidious, and the psychological and financial effects of AD on caregivers and family members are significant.
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paper_title: Microdialysis Microneedles for Continuous Medical Monitoring

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nzyme based biosensors suffer from loss of activity and sensitivity through a variety of processes. One major reason for the loss is through large molecular weight proteins settling onto the sensor and affecting sensor signal stability and disrupting enzyme function. One way to minimize loss of sensor activity is to filter out large molecular weight compounds before sensing small biochemicals such as glucose. A novel microdialysis microneedle is introduced that is capable of excluding large MW compounds based on size. Preliminary experimental evidence of membrane permeability is shown, as well as diffusion and permeability modeling. Microdialysis microneedles present an attractive first step towards decreasing size, patient discomfort and energy consumption of portable medical monitors over existing technologies.
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paper_title: RNA aptamer-based electrochemical biosensor for selective and label-free analysis of dopamine.

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The inherent redox activity of dopamine enables its direct electrochemical in vivo analysis ( Venton , B. J.; Wightman, M. R. Anal. Chem. 2003, 75, 414A). However, dopamine analysis is complicated by the interference from other electrochemically active endogenous compounds present in the brain, including dopamine precursors and metabolites and other neurotransmitters (NT). Here we report an electrochemical RNA aptamer-based biosensor for analysis of dopamine in the presence of other NT. The biosensor exploits a specific binding of dopamine by the RNA aptamer, immobilized at a cysteamine-modified Au electrode, and further electrochemical oxidation of dopamine. Specific recognition of dopamine by the aptamer allowed a selective amperometric detection of dopamine within the physiologically relevant 100 nM to 5 μM range in the presence of competitive concentrations of catechol, epinephrine, norepinephrine, 3,4-dihydroxy-phenylalanine (L-DOPA), 3,4-dihydroxyphenylacetic acid (DOPAC), methyldopamine, and tyramine, which gave negligible signals under conditions of experiments (electroanalysis at 0.185 V vs Ag/AgCl). The interference from ascorbic and uric acids was eliminated by application of a Nafion-coated membrane. The aptasensor response time was <1 s, and the sensitivity of analysis was 62 nA μM(-1) cm(-2). The proposed design of the aptasensor, based on electrostatic interactions between the positively charged cysteamine-modified electrode and the negatively charged aptamer, may be used as a general strategy not to restrict the conformational freedom and binding properties of surface-bound aptamers and, thus, be applicable for the development of other aptasensors.
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paper_title: Microfabricated FSCV-compatible microelectrode array for real-time monitoring of heterogeneous dopamine release

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Fast scan cyclic voltammetry (FSCV) has been used previously to detect neurotransmitter release and reuptake in vivo. An advantage that FSCV has over other electrochemical techniques is its ability to distinguish neurotransmitters of interest (i.e. monoamines) from their metabolites using their respective characteristic cyclic voltammograms. While much has been learned with this technique, it has generally only been used in a single working electrode arrangement. Additionally, traditional electrode fabrication techniques tend to be difficult and somewhat irreproducible. Described in this report is a fabrication method for a FSCV compatible microelectrode array (FSCV-MEA) that is capable of functioning in vivo. The microfabrication techniques employed here allow for better reproducibility than traditional fabrication methods of carbon fiber microelectrodes, and enable batch fabrication of electrode arrays. The reproducibility and electrochemical qualities of the probes were assessed along with crosstalk in vitro. Heterogeneous release of electrically evoked dopamine was observed in real-time in the striatum of an anesthetized rat using the FSCV-MEA. The heterogeneous effects of pharmacology on the striatum were also observed and shown to be consistent across multiple animals.
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paper_title: Influence of different biological environments on the stability of serotonin detection on carbon-based electrodes

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Abstract Serotonin (5-HT) is a key neurotransmitter that is found in the brain, blood and gastrointestinal tract. Due to the interest in measuring this important biogenic amine in these various environments, measurements have been conducted using carbon-based sensors without understanding the influence of the matrix on the stability of recordings. Electrochemical recordings were carried out in PBS buffer, 0.5% w/v mucin and 5% w/v albumin on the glassy carbon (GC) and boron-doped diamond (BDD) electrodes. During recordings of 5-HT on the GC electrode, the 5% w/v albumin matrix was protective against electrode fouling compared to 0.5% w/v mucin, which enhanced the rate of electrode fouling. On the BDD electrode, 0.5% w/v mucin once again enhanced the rate of electrode fouling, however 5% w/v albumin did not alter the rate of fouling compared to PBS buffer. This data suggests that all proteins cannot be considered to behave in a similar fashion for electroanalytical measurements and thus careful consideration on the matrix effect needs to be considered before biological monitoring.
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paper_title: Comparison of Nafion- and overoxidized polypyrrole-carbon nanotube electrodes for neurotransmitter detection

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Permselective polymer coatings improve selectivity and sensitivity of microelectrodes for cationic neurotransmitters. Immobilizing carbon nanotubes (CNTs) into these polymers should further improve sensitivity by increasing the electroactive surface area. The goal of this study was to compare the electrochemical properties of overoxidized polypyrrole (oPPY)-CNT and Nafion-CNT coated microelectrodes. Fast-scan cyclic voltammetry was used to test their response to neurochemicals. For dopamine, the average increase in oxidation current compared to bare electrodes was 3.7 ± 0.5 for oPPY-CNT electrodes (limit of detection (LOD) = 3.3 ± 0.6 nM) and 3.3 ± 0.8 for Nafion-CNT electrodes (LOD = 4 ± 1 nM). The selectivity for dopamine over ascorbic acid was better with oPPY-CNT electrodes. oPPY-CNT electrodes also displayed increased electron transfer kinetics for anions while Nafion-CNT electrodes did not, which proves that polymer deposition can affect the electrocatalytic properties of the CNTs. Both oPPY-CNT and Nafion-CNT electrodes were used to detect stimulated dopamine release in the caudate-putamen of anesthetized rats after 2, 4 and 12 pulse stimulation trains. oPPY-CNT electrodes could also detect small amounts of dopamine after 4 and 12 pulse stimulations in the basolateral amygdala (BLA). Although Nafion-CNT electrodes were easier to make, oPPY-CNT electrodes were more advantageous for dopamine detection because they were reproducibly fabricated, measured higher currents in vivo, and maintained selectivity over anions. The addition of CNTs to polymer coatings facilitates measurements of small concentrations of neurotransmittersin vivo.
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paper_title: Head-to-head comparisons of carbon fiber microelectrode coatings for sensitive and selective neurotransmitter detection by voltammetry.

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Voltammetry is widely used to investigate neurotransmission and other biological processes but is limited by poor chemical selectivity and fouling of commonly used carbon fiber microelectrodes (CFMs). We performed direct comparisons of three key coating materials purported to impart selectivity and fouling resistance to electrodes: Nafion, base-hydrolyzed cellulose acetate (BCA), and fibronectin. We systematically evaluated the impact on a range of electrode parameters. Fouling due to exposure to brain tissue was investigated using an approach that minimizes the use of animals while enabling evaluation of statistically significant populations of electrodes. We find that BCA is relatively fouling-resistant. Moreover, detection at BCA-coated CFMs can be tuned by altering hydrolysis times to minimize the impact on sensitivity losses while maintaining fouling resistance. Fibronectin coating is associated with moderate losses in sensitivity after coating and fouling. Nafion imparts increased sensitivity for dopamine and norepinephrine but not serotonin, as well as the anticipated selectivity for cationic neurotransmitters over anionic metabolites. Although Nafion has been suggested to resist fouling, both dip-coating and electrodeposition of Nafion are associated with substantial fouling, similar to levels observed at bare electrodes after exposure to brain tissue. Direct comparisons of these coatings identified unique electroanalytical properties of each that can be used to guide selection tailored to the goals and environment of specific studies.
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paper_title: Trace voltammetric detection of serotonin at carbon electrodes: comparison of glassy carbon, boron doped diamond and carbon nanotube network electrodes.

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The characteristics of three different carbon electrodes, glassy carbon (GC), oxygen-terminated polycrystalline boron-doped diamond (pBDD) and "pristine" carbon nanotube networks (CNTN) as voltammetric sensors for detection of the neurotransmitter serotonin have been investigated. For each electrode, detection sensitivity was determined using cyclic voltammetry (CV), a technique often used to provide information on chemical identity in electrochemical assays. The CNTN electrodes were found to exhibit background current densities ca. two orders of magnitude smaller than the GC electrode and ca. twenty times smaller than pBDD, as a consequence of their "pristine" low capacitance and low surface coverage. This was a major factor in determining serotonin detection limits from CV, of 10 nM for the CNTN electrode, 500 nM for pBDD and 2 microM for GC. The two most sensitive electrodes (CNTN and pBDD) were further investigated in terms of resistance to electrode fouling. CV analysis showed that fouling was less on the pBDD electrode compared to the CNTN and, furthermore, for the case of pBDD could be significantly minimised by careful selection of the CV potential limits, in particular by scanning the electrode potential to suitably cathodic values after oxidation of the serotonin.
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paper_title: SELECTIVE DPV METHOD OF DOPAMINE DETERMINATION IN BIOLOGICAL SAMPLES CONTAINING ASCORBIC ACID

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A modified carbon paste electrode that incorporates the anionic surfactant sodium dodecyl sulfate (SDS) in the paste (SDS-CP) is reported. It is shown that the SDS-CP electrode discriminates effectively between the cationic form of dopamine and the anionic electroactive species existing in biological fluids at the physiological pH. Therefore, a differential pulse voltammetry method has been developed. It has the detection limit comprised in the submicromolar range and the capability to remove the interference of the ascorbic acid and to diminish the interference of the uric acid. The method has been tested with good results on real samples of deproteinized serum.
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paper_title: Implantable Microprobe with Arrayed Microsensors for Combined Amperometric Monitoring of the Neurotransmitters, Glutamate and Dopamine

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Abstract An implantable, micromachined microprobe with a microsensor array for combined monitoring of the neurotransmitters, glutamate (Glut) and dopamine (DA), by constant potential amperometry has been created and characterized. Microprobe studies in vitro revealed Glut and DA microsensor sensitivities of 126 ± 5 nA μM −1 cm −2 and 3250 ± 50 nA μM −1 cm −2 , respectively, with corresponding detection limits of 2.1 ± 0.2 μM and 62 ± 8 nM, both at comparable ∼1 s response times. No diffusional interaction of H 2 O 2 among arrayed microelectrodes was observed. Also, no responses from the electroactive interferents, ascorbic acid (AA), uric acid (UA), DOPA (a DA catabolite) or DOPAC (a DA precursor), over their respective physiological concentration ranges, were detected. The dual sensing microbe attributes of size, detection limit, sensitivity, response time and selectivity make it attractive for combined sensing of Glut and DA in vivo .
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paper_title: High temporal resolution electrochemical biosensor using nitrogen-incorporated nanodiamond ultra-microelectrode array

paper_content:

Biosensors for detecting/measuring/monitoring the concentration of neurotransmitters that vary at sub-second time-scale can be achieved by using an electrode with high temporal resolution and fast electron transfer kinetics. Neurotransmitters, such as dopamine, undergo rapid fluctuations in concentrations occurring at a sub-second time scale. Real-time monitoring and measurement of these concentrationn changes, in-vivo or in-vitro, requires the use of ultra-microelectrode array (UMEA). This work reports on the development of a reliable UMEA electrochemical biosensor which can be used to identify, quantify, and monitor essential bio-analytes such as dopamine (DA), ascorbic acid (AA) and uric acid (UA) by using CVD nitrogen-incorporated nanodiamond UMEA without the need of electrode surface functionalization or modifications, making real-time detection possible. The application of fast-scan voltammetry (FSCV) for detecting dopamine and interfering bio-chemicals, including ascorbic acid and uric acid in 0.1M PBS (pH 7.4) by the UMEA has been realized. The detailed experiential method for the sensor array fabrication, and the UMEA sensitivity, selectivity, and detection limit for the detection of bio-analytes will be discussed.
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paper_title: Analysis of biogenic amines in a single Drosophila larva brain by capillary electrophoresis with fast-scan cyclic voltammetry detection.

paper_content:

Drosophila, the fruit fly, is a common model organism in biology; however, quantifying neurotransmitters in Drosophila is challenging because of the small size of the central nervous system (CNS). Here, we develop neurotransmitter quantification by capillary electrophoresis with fast-scan cyclic voltammetry (CE-FSCV) detection, which allows peak identification by both migration time and the cyclic voltammogram, in contrast to traditional amperometric detection which provides no chemical identification. Tissue content of biogenic amine neurotransmitters was determined in a single CNS dissected from a Drosophila larva. Low detection limits, 1 nM for dopamine and serotonin, 2.5 nM for tyramine, and 4 nM for octopamine, were achieved using field-amplified sample stacking by diluting the homogenized tissue with percholoric acid and acetonitrile. Two different strains of wild-type flies, Oregon R and Canton S, have similar dopamine and serotonin levels but different octopamine content. When flies are fed NSD-1015, which inhibits dopamine decarboxylase (Ddc) a synthesis enzyme in the dopamine and serotonin pathways, dopamine significantly decreases by 52%. A genetically altered driver line, Ddc-GAL4, had lower serotonin and dopamine content as did w(118) flies. When the Ddc-GAL4 line was used to produce flies overexpressing the serotonin synthesis enzyme tryptophan hydroxylase (Ddc-GAL4;UAS-Trh), the serotonin tissue content was greater than for Ddc-GAL4 but not significantly different than the wild-type. These results show that CE-FSCV is useful for monitoring the impact of genetic and pharmacological manipulations on the content of multiple neurotransmitters in a CNS from a Drosophila larva.
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paper_title: Microfabricated Microelectrode Sensor for Measuring Background and Slowly Changing Dopamine Concentrations

paper_content:

The electrochemical detection of neurotransmitters in vivo has centered on fast scan cyclic voltammetry (FSCV) due to its temporal resolution, sensitivity and chemical selectivity. FSCV is a differential technique that records phasic (second-to-second) changes in the concentration of electroactive neurotransmitters such as dopamine (DA). To isolate the currents due to fluctuations in analyte concentration, in other words to make these phasic measurements, requires the subtraction of a large background current. The subtraction of this background and its volatility renders FSCV unable to determine background or slowly varying concentrations of electroactive analytes. However, there is still a need to readily determine the background and slowly changing concentrations of electroactive analytes in tissue. For example, the background concentrations of DA vary throughout the brain and can affect the dynamics of dopaminergic systems. So, this report presents a microfabricated electrochemical sensor for measuring background and slowly changing concentrations of DA in vitro with the selectivity and sensitivity of FSCV. The sensor is comprised of two microfabricated microelectrodes which are spaced 8 μm apart. Varying the applied potential of the outer electrode manipulates the local concentration of electroactive species including concentration at the inner electrode. These changes are measured at the inner electrode using FSCV. The resulting signal with calibration can determine the background and slowly changing concentration of DA with the selectivity and sensitivity of FSCV. In this study the background of DA is determined in vitro using this sensor. The DA signal is shown to be the result of adsorption/desorption at the outer electrode. Interference from ascorbate on the DA signal is shown to be minimal for this approach.
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paper_title: Electrochemically synthesized polymers in molecular imprinting for chemical sensing

paper_content:

This critical review describes a class of polymers prepared by electrochemical polymerization that employs the concept of molecular imprinting for chemical sensing. The principal focus is on both conducting and nonconducting polymers prepared by electropolymerization of electroactive functional monomers, such as pristine and derivatized pyrrole, aminophenylboronic acid, thiophene, porphyrin, aniline, phenylenediamine, phenol, and thiophenol. A critical evaluation of the literature on electrosynthesized molecularly imprinted polymers (MIPs) applied as recognition elements of chemical sensors is presented. The aim of this review is to highlight recent achievements in analytical applications of these MIPs, including present strategies of determination of different analytes as well as identification and solutions for problems encountered.
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paper_title: Highly selective determination of ascorbic acid, dopamine, and uric acid by differential pulse voltammetry using poly(sulfonazo III) modified glassy carbon electrode

paper_content:

Abstract A highly selective electrochemical method was developed for the simultaneous determination of ascorbic acid (AA), dopamine (DA), and uric acid (UA) using sulfonazo III film-modified on glassy carbon electrode. The modified electrode showed excellent electrocatalytic activity toward the oxidation of AA, DA, and UA. The calibration curves were obtained with 0.5–1300.0 μmol L −1 AA, 0.05–470.0 μmol L −1 DA, and 0.2–100.0 μmol L −1 UA. Detection limits of 0.17 μmol L −1 AA, 0.03 μmol L −1 DA, and 0.11 μmol L −1 UA were obtained. The influence of various substances on the selectivity of the sensor was studied. The results confirm the high selectivity, good sensitivity, and stability of the modified electrode. Satisfactory results were achieved for the determination of DA, AA, and UA with dopamine injection solution, vitamin C tablets, and human urine samples.
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paper_title: Chemical and biochemical sensors based on advances in materials chemistry

paper_content:

The advance of materials chemistry has influenced the design of analytical sensors, especially those using spectroscopic or electrochemical methods for generating the signal. New methods of immobilizing enzymes, chromophores, and electron-transfer catalysts have resulted from initiatives in materials science. Systems based on sol-gel chemistry are especially noteworthy in this regard, but other important materials for chemical and biochemical sensors include zeolites, organic polymers, and various conducting composites. Applications cited include determinations of inorganic ions, gases, neurotransmitters, alcohols, carbohydrates, amino acids, proteins, and DNA.
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paper_title: Amperometric and voltammetric detection for capillary electrophoresis

paper_content:

The focus of this article is amperometric and voltammetric detection coupled with capillary electrophoresis. Fundamental concepts and progress in the field of capillary electrophoresis with electrochemical detection (CEEC) that have occurred within the past three years, including new methodologies and unique applications, are highlighted. This review contains 95 references.
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paper_title: Preparation of thiolated polymeric nanocomposite for sensitive electroanalysis of dopamine

paper_content:

Abstract We report on the thiol-ene chemistry guided preparation of novel thiolated polymeric nanocomposite films of abundant anionic carboxylic groups for electrostatic enrichment and sensitive electroanalysis of cationic dopamine (DA) in neutral solution. Briefly, the thiol-ene nucleophilic reaction of a carboxylated thiol with oxidized polypyrrole (PPy), which was electrosynthesized on an Au electrode in the presence of solution-dispersed acidified multiwalled carbon nanotubes (MWCNTs), produced an a PPy–thiol–MWCNTs/Au electrode, and the PPy can be electrochemically overoxidized (OPPy) to form an OPPy–thiol–MWCNTs/Au electrode. The carboxylic groups of the polymeric nanocomposite film originate from the acidified MWCNTs, PPy-tethered carboxylated thiol, and OPPy. The carboxylated thiols examined are mercaptosuccinic acid (MSA) and thioglycolic acid, with β-mercaptoethanol as a control. Electrochemical quartz crystal microbalance, scanning electron microscopy, Fourier transform infrared spectroscopy and ultraviolet–visible spectroscopy were used for film characterization and process monitoring. Under the optimized condition, the differential pulse voltammetry peak current of DA oxidation at OPPy–MSA–MWCNTs/Au electrode is linear with DA concentration from 1.00×10 –9 to 2.87×10 –6 mol L −1 , with a limit of detection of 0.4 nmol L −1 , good anti-interferent ability and stability.
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paper_title: An Integrated Flexible Implantable Micro-Probe for Sensing Neurotransmitters

paper_content:

In this work, we have developed an integrated flexible implantable probe on a polyimide-film substrate for sensing neurotransmitters. The flexibility of the probe helps to prevent scar forming in tissues aiming for long-term in vivo monitoring. A micro Ag/AgCl reference electrode was integrated in the same probe with the Au/Cr or Pt/Cr working electrodes providing measurements without the need of a separate reference probe. Several electrode configurations have been considered and designed for implantation at various locations in the central nervous system. The prototype device for proof of principle was an enzyme-based electrochemical L-glutamate sensor using L-glutamate oxidase. A comparison between Au and Pt thin films was conducted by cyclic voltammetry to evaluate their performance as working electrodes. The L-glutamate oxidase was deposited on the working electrodes followed by a meta-Phenylenediamine electropolymerization process to improve the selectivity. The self-referencing technique was also utilized to enhance both the limit of detection and selectivity. The assembled sensors were calibrated and tested at various concentrations of L-glutamate with and without the presence of interfering molecules. The results showed good sensitivity and selectivity. In vivo animal tests were conducted to show the capability of detecting changes of electrochemical signals responding to graded peripheral somatosensory stimuli.
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paper_title: Comonitoring of adenosine and dopamine using the Wireless Instantaneous Neurotransmitter Concentration System: proof of principle

paper_content:

Object The authors of previous studies have demonstrated that local adenosine efflux may contribute to the therapeutic mechanism of action of thalamic deep brain stimulation (DBS) for essential tremor. Real-time monitoring of the neurochemical output of DBS-targeted regions may thus advance functional neurosurgical procedures by identifying candidate neurotransmitters and neuromodulators involved in the physiological effects of DBS. This would in turn permit the development of a method of chemically guided placement of DBS electrodes in vivo. Designed in compliance with FDA-recognized standards for medical electrical device safety, the authors report on the utility of the Wireless Instantaneous Neurotransmitter Concentration System (WINCS) for real-time comonitoring of electrical stimulation–evoked adenosine and dopamine efflux in vivo, utilizing fast-scan cyclic voltammetry (FSCV) at a polyacrylonitrile-based (T-650) carbon fiber microelectrode (CFM). Methods The WINCS was used for FSCV, which consisted ...
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paper_title: Chronic microsensors for longitudinal, subsecond dopamine detection in behaving animals

paper_content:

A chronically implanted biocompatible electrochemical microsensor allows long-term recording of subsecond dopamine dynamics in vivo. The microsensor can reliably detect behaviorally evoked dopamine release from dopamine neurons in the brain over a period of months in rats.
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paper_title: High temporal resolution electrochemical biosensor using nitrogen-incorporated nanodiamond ultra-microelectrode array

paper_content:

Biosensors for detecting/measuring/monitoring the concentration of neurotransmitters that vary at sub-second time-scale can be achieved by using an electrode with high temporal resolution and fast electron transfer kinetics. Neurotransmitters, such as dopamine, undergo rapid fluctuations in concentrations occurring at a sub-second time scale. Real-time monitoring and measurement of these concentrationn changes, in-vivo or in-vitro, requires the use of ultra-microelectrode array (UMEA). This work reports on the development of a reliable UMEA electrochemical biosensor which can be used to identify, quantify, and monitor essential bio-analytes such as dopamine (DA), ascorbic acid (AA) and uric acid (UA) by using CVD nitrogen-incorporated nanodiamond UMEA without the need of electrode surface functionalization or modifications, making real-time detection possible. The application of fast-scan voltammetry (FSCV) for detecting dopamine and interfering bio-chemicals, including ascorbic acid and uric acid in 0.1M PBS (pH 7.4) by the UMEA has been realized. The detailed experiential method for the sensor array fabrication, and the UMEA sensitivity, selectivity, and detection limit for the detection of bio-analytes will be discussed.
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paper_title: Microfabricated Microelectrode Sensor for Measuring Background and Slowly Changing Dopamine Concentrations

paper_content:

The electrochemical detection of neurotransmitters in vivo has centered on fast scan cyclic voltammetry (FSCV) due to its temporal resolution, sensitivity and chemical selectivity. FSCV is a differential technique that records phasic (second-to-second) changes in the concentration of electroactive neurotransmitters such as dopamine (DA). To isolate the currents due to fluctuations in analyte concentration, in other words to make these phasic measurements, requires the subtraction of a large background current. The subtraction of this background and its volatility renders FSCV unable to determine background or slowly varying concentrations of electroactive analytes. However, there is still a need to readily determine the background and slowly changing concentrations of electroactive analytes in tissue. For example, the background concentrations of DA vary throughout the brain and can affect the dynamics of dopaminergic systems. So, this report presents a microfabricated electrochemical sensor for measuring background and slowly changing concentrations of DA in vitro with the selectivity and sensitivity of FSCV. The sensor is comprised of two microfabricated microelectrodes which are spaced 8 μm apart. Varying the applied potential of the outer electrode manipulates the local concentration of electroactive species including concentration at the inner electrode. These changes are measured at the inner electrode using FSCV. The resulting signal with calibration can determine the background and slowly changing concentration of DA with the selectivity and sensitivity of FSCV. In this study the background of DA is determined in vitro using this sensor. The DA signal is shown to be the result of adsorption/desorption at the outer electrode. Interference from ascorbate on the DA signal is shown to be minimal for this approach.
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paper_title: Carbon Paste Gold Nanoparticles Sensor for the Selective Determination of Dopamine in Buffered Solutions

paper_content:

�1 universal buffer solution pH 7.4 is introduced. The sensor is based on a carbon paste CP electrode modified with gold nanoparticles. In a mixture of DA, AA, and UA, the sensor shows high selective response toward DA and no response for AA or UA. The effect of various experimental parameters including time of deposition of gold nanoparticles on the CP electrode, pH, and scan rate on the voltammetric response of DA was investigated. At the optimum conditions, the concentration of DA was determined using differential pulse voltammetry in a linear range of 1.0 10 �7 to 5.0 10 �6 mol L �1 and 5.0 10 �6 to 1.3 10 �4 mol L �1 with correlation coefficients of 0.9995 and 0.9988 and a detection limit of 5.9 10 �9 and 8.2 10 �8 mol L �1 , respectively. The modified electrode can be used for the determination of DA spiked into human serum samples, and excellent recovery results were obtained over a wide concentration range of DA. Moreover, validation parameters, such as reproducibility, sensitivity, and recovery were evaluated successfully in the determination of DA in diluted human urine.
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paper_title: Head-to-head comparisons of carbon fiber microelectrode coatings for sensitive and selective neurotransmitter detection by voltammetry.

paper_content:

Voltammetry is widely used to investigate neurotransmission and other biological processes but is limited by poor chemical selectivity and fouling of commonly used carbon fiber microelectrodes (CFMs). We performed direct comparisons of three key coating materials purported to impart selectivity and fouling resistance to electrodes: Nafion, base-hydrolyzed cellulose acetate (BCA), and fibronectin. We systematically evaluated the impact on a range of electrode parameters. Fouling due to exposure to brain tissue was investigated using an approach that minimizes the use of animals while enabling evaluation of statistically significant populations of electrodes. We find that BCA is relatively fouling-resistant. Moreover, detection at BCA-coated CFMs can be tuned by altering hydrolysis times to minimize the impact on sensitivity losses while maintaining fouling resistance. Fibronectin coating is associated with moderate losses in sensitivity after coating and fouling. Nafion imparts increased sensitivity for dopamine and norepinephrine but not serotonin, as well as the anticipated selectivity for cationic neurotransmitters over anionic metabolites. Although Nafion has been suggested to resist fouling, both dip-coating and electrodeposition of Nafion are associated with substantial fouling, similar to levels observed at bare electrodes after exposure to brain tissue. Direct comparisons of these coatings identified unique electroanalytical properties of each that can be used to guide selection tailored to the goals and environment of specific studies.
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paper_title: Amplified voltammetric detection of dopamine using ferrocene-capped gold nanoparticle/streptavidin conjugates.

paper_content:

Dopamine (DA) is one of the most important neurotransmitters present in brain tissues and body fluids of mammals. The change in the concentration levels has been associated with various diseases and disorders. Thus, sensitive and selective determination of DA is much preferred. In this work, sandwich-type electrochemical biosensor was developed, in which phenylboronic acid immobilized onto gold electrodes was used to capture DA. The anchored DA was then derivatized with biotin for the attachment of ferrocene-capped gold nanoparticle/streptavidin conjugates. The voltammetric responses were found to be proportional to the concentrations of DA ranging from 0.5 to 50 nM. A detection limit of 0.2 nM was achieved, which is 1~2 orders of magnitude lower than those achievable at various chemically modified electrodes. Analytical merits (e.g., dynamic range, reproducibility, detection level, selectivity and interference) were evaluated. The feasibility of the method for analysis of DA in artificial cerebrospinal fluid and dopamine hydrochloride injection has been demonstrated.
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paper_title: Highly selective determination of ascorbic acid, dopamine, and uric acid by differential pulse voltammetry using poly(sulfonazo III) modified glassy carbon electrode

paper_content:

Abstract A highly selective electrochemical method was developed for the simultaneous determination of ascorbic acid (AA), dopamine (DA), and uric acid (UA) using sulfonazo III film-modified on glassy carbon electrode. The modified electrode showed excellent electrocatalytic activity toward the oxidation of AA, DA, and UA. The calibration curves were obtained with 0.5–1300.0 μmol L −1 AA, 0.05–470.0 μmol L −1 DA, and 0.2–100.0 μmol L −1 UA. Detection limits of 0.17 μmol L −1 AA, 0.03 μmol L −1 DA, and 0.11 μmol L −1 UA were obtained. The influence of various substances on the selectivity of the sensor was studied. The results confirm the high selectivity, good sensitivity, and stability of the modified electrode. Satisfactory results were achieved for the determination of DA, AA, and UA with dopamine injection solution, vitamin C tablets, and human urine samples.
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paper_title: Chemical and biochemical sensors based on advances in materials chemistry

paper_content:

The advance of materials chemistry has influenced the design of analytical sensors, especially those using spectroscopic or electrochemical methods for generating the signal. New methods of immobilizing enzymes, chromophores, and electron-transfer catalysts have resulted from initiatives in materials science. Systems based on sol-gel chemistry are especially noteworthy in this regard, but other important materials for chemical and biochemical sensors include zeolites, organic polymers, and various conducting composites. Applications cited include determinations of inorganic ions, gases, neurotransmitters, alcohols, carbohydrates, amino acids, proteins, and DNA.
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paper_title: Modification of platinum microelectrode with molecularly imprinted over-oxidized polypyrrole for dopamine measurement in rat striatum

paper_content:

Abstract A highly sensitive and selective electrochemical microelectrode using the molecularly imprinted (MIP) electropolymer of over-oxidized polypyrrole (OPPy) was proposed for in vivo detection of dopamine (DA) which process is different from current approaches for in vitro DA detection using MIP-based macroelectrode. The proposed MIP electrosynthesized by our present method under a DA/pyrrole-monomer concentration ratio of 1 mM/10 mM yielded the best results for DA adsorption, reaching 2.6-fold that of similar microelectrodes without imprinting. Differential normal pulse voltammetry techniques was used to evaluate the DA-imprinted OPPy microelectrodes for demonstrating high selectivity for in vitro DA detection under conditions with various competitive electroactive molecules. The validity of the modified OPPy-MIP thin-film microelectrodes was further verified with amperometric i – t measurements, which showed a lower DA levels of detection (10–100 nM) and the low detection limit of 4.5 nM with signal to noise ratio of 3. Good reproducibility with relative standard deviation of 5.45% and long-term stability within two weeks were also observed. The developed OPPy-MIP microelectrode has been successfully applied for acute in vivo DA detection in the striatum of anesthetized rats with 3,4-dihydroxy -l -phenylalanine ( l -DOPA) administration, which can be used for future evaluation of novel therapeutic treatments in Parkinsonian rats.
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paper_title: Application of multiway-variate calibration to simultaneous voltammetric determination of three catecholamines

paper_content:

Three structurally similar catecholamines, adrenaline (AA), dopamine (DA) and noradrenaline (NA), which are neurotransmitters well known for their treatment of neural disorders and many other diseases, were investigated at a glassy carbon electrode (GCE) with the use of differential pulse stripping voltammetry (DPSV). The aim was to develop a simple, rapid and cost effective method of simultaneous analysis of these three substances in typical samples such as human urine. Each analyte showed typical reversible redox behaviour with the use of cyclic voltammetry in aqueous medium in the pH range of 4.0–7.9, and composite voltammograms of the three analytes were found to consist of three significantly overlapping peaks corresponding to the three individual substances. Thus, two- and three-way multi-variate data analysis methods were investigated. These included unfolding methods such as—partial least squares (UPLS), principal component regression (UPCR) and radial basis function-artificial neural networks (URBF-ANN), as well as trilinear models, such as parallel factor analysis (PARAFAC) and N-way PLS (NPLS). The results were compared with those obtained from two-way voltammetric data matrix with the use of conventional models, PLS, PCR and RBF-ANN. It was found that most of the three-way models, such as PARAFAC and UPLS, performed somewhat better than others on the basis of the %RPET (5.6∼5.9) and mean %Recovery (94∼102). The proposed methods were then applied for the determination of human urine samples spiked with the three catecholamines, and the results were satisfactory.
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paper_title: Functional groups modulate the sensitivity and electron transfer kinetics of neurochemicals at carbon nanotube modified microelectrodes.

paper_content:

The surface properties of carbon-based electrodes are critically important for the detection of biomolecules and can modulate electrostatic interactions, adsorption and electrocatalysis. Carbon nanotube (CNT) modified electrodes have previously been shown to have increased oxidative sensitivity and reduced overpotential for catecholamine neurotransmitters, but the effect of surface functionalities on these properties has not been characterized. In this study, we modified carbon-fiber microelectrodes (CFMEs) with three differently functionalized single-wall carbon nanotubes and measured their response to serotonin, dopamine, and ascorbic acid using fast-scan cyclic voltammetry. Both carboxylic acid functionalized and amide functionalized CNTs increased the oxidative current of CFMEs by approximately 2-6 fold for the cationic neurotransmitters serotonin and dopamine, but octadecylamine functionalized CNTs resulted in no significant signal change. Similarly, electron transfer was faster for both amide and carboxylic acid functionalized CNT modified electrodes but slower for octadecylamine CNT modified electrodes. Oxidation of ascorbic acid was only increased with carboxylic acid functionalized CNTs although all CNT-modified electrodes showed a trend towards increased reversibility for ascorbic acid. Carboxylic acid-CNT modified disk electrodes were then tested for detection of serotonin in the ventral nerve cord of a Drosophila melanogaster larva, and the increase in sensitivity was maintained in biological tissue. The functional groups of CNTs therefore modulate the electrochemical properties, and the increase in sensitivity from CNT modification facilitates measurements in biological samples.
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paper_title: Comparison of Nafion- and overoxidized polypyrrole-carbon nanotube electrodes for neurotransmitter detection

paper_content:

Permselective polymer coatings improve selectivity and sensitivity of microelectrodes for cationic neurotransmitters. Immobilizing carbon nanotubes (CNTs) into these polymers should further improve sensitivity by increasing the electroactive surface area. The goal of this study was to compare the electrochemical properties of overoxidized polypyrrole (oPPY)-CNT and Nafion-CNT coated microelectrodes. Fast-scan cyclic voltammetry was used to test their response to neurochemicals. For dopamine, the average increase in oxidation current compared to bare electrodes was 3.7 ± 0.5 for oPPY-CNT electrodes (limit of detection (LOD) = 3.3 ± 0.6 nM) and 3.3 ± 0.8 for Nafion-CNT electrodes (LOD = 4 ± 1 nM). The selectivity for dopamine over ascorbic acid was better with oPPY-CNT electrodes. oPPY-CNT electrodes also displayed increased electron transfer kinetics for anions while Nafion-CNT electrodes did not, which proves that polymer deposition can affect the electrocatalytic properties of the CNTs. Both oPPY-CNT and Nafion-CNT electrodes were used to detect stimulated dopamine release in the caudate-putamen of anesthetized rats after 2, 4 and 12 pulse stimulation trains. oPPY-CNT electrodes could also detect small amounts of dopamine after 4 and 12 pulse stimulations in the basolateral amygdala (BLA). Although Nafion-CNT electrodes were easier to make, oPPY-CNT electrodes were more advantageous for dopamine detection because they were reproducibly fabricated, measured higher currents in vivo, and maintained selectivity over anions. The addition of CNTs to polymer coatings facilitates measurements of small concentrations of neurotransmittersin vivo.
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paper_title: Review: Carbon nanotube based electrochemical sensors for biomolecules.

paper_content:

Carbon nanotubes (CNTs) have been incorporated in electrochemical sensors to decrease overpotential and improve sensitivity. In this review, we focus on recent literature that describes how CNT-based electrochemical sensors are being developed to detect neurotransmitters, proteins, small molecules such as glucose, and DNA. Different types of electrochemical methods are used in these sensors including direct electrochemical detection with amperometry or voltammetry, indirect detection of an oxidation product using enzyme sensors, and detection of conductivity changes using CNT-field effect transistors (FETs). Future challenges for the field include miniaturizing sensors, developing methods to use only a specific nanotube allotrope, and simplifying manufacturing.
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paper_title: Neurotransmitter detection by enzyme-immobilized CNT-FET

paper_content:

Abstract Glutamate is the principal excitatory neurotransmitter in the brain, and its excessive release plays a key role in neuronal death associated with a wide range of neural disorders. Real time monitoring of extracellular glutamate levels would be very helpful in understanding the excitotoxic process of neurotransmitters, as well as brain injury during or after surgery. In order to detect l -glutamate, we immobilized l -glutamate oxidase (GLOD) on carbon nanotube (CNT) network junctions by a non-covalent functionalized method to preserve their electronic characteristics. After immobilizing GLOD on the CNT network, the excess reactive groups of linker molecule remaining on its surface were deactivated and blocked by ethanolamine. The electrical property of the GLOD-immobilized CNT network transistor was characterized as source–drain current that depended on liquid gate voltage. From the changes in the I sd vs. V g plot about the CNT network transistor before and after the immobilization of GLOD, we confirmed that GLOD immobilization decreased the conductance of CNT network junctions, regardless of the sign on the net charge in the protein. The real time electronic response of the GLOD-coated CNT network transistor was conducted with a glutamate standard solution in vitro and the 11 vessel occlusion (11VO) rat model in vivo . The ultrahigh sensitivity, selectivity, and fast response time of GLOD-immobilized CNT-FET could provide great potential for the real time electronic detection of extracellular glutamate levels in the brain.
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paper_title: Biosensor Based on Electrocodeposition of Carbon Nanotubes/Polypyrrole/Laccase for Neurotransmitter Detection

paper_content:

A new biosensor has been developed by a simple electrocodeposition of multiwalled carbon nanotubes (MWCNT), polypyrrole (PPy) and laccase (Lac) on the platinum (Pt) electrode surface. The neurotransmitter biosensor was applied to the detection of dopamine in urine samples using differential pulse voltammetry (DPV). The Pt/MWCNT/PPy/Lac biosensor exhibited a detection limit of 0.14 µM, which is an adequate level for monitoring dopamine in urine. Reproducibility and repeatability values of 2.9 % and 1.7 %, respectively, were obtained compared to the conventional procedure. The proposed biosensor was successfully applied in the determination of dopamine in urine, and the obtained results were in full agreement with those from the HPLC procedure.
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paper_title: Rapid, Sensitive Detection of Neurotransmitters at Microelectrodes Modified with Self-assembled SWCNT Forests

paper_content:

Carbon nanotube (CNT) modification of microelectrodes can result in increased sensitivity without compromising time response. However, dip coating CNTs is not very reproducible and the CNTs tend to lay flat on the electrode surface which limits access to the electroactive sites on the ends. In this study, aligned CNT forests were formed using a chemical self-assembly method, which resulted in more exposed CNT ends to the analyte. Shortened, carboxylic acid functionalized single-walled CNTs were assembled from a dimethylformamide (DMF) suspension onto a carbon-fiber disk microelectrode modified with a thin iron hydroxide-decorated Nafion film. The modified electrodes were highly sensitive, with 36-fold higher oxidation currents for dopamine using fast-scan cyclic voltammetry than bare electrodes and 34-fold more current than electrodes dipped in CNTs. The limit of detection (LOD) for dopamine was 17 ± 3 nM at a 10 Hz repetition rate and 65 ± 7 nM at 90 Hz. The LOD at 90 Hz was the same as a bare electrode at 10 Hz, allowing a 9-fold increase in temporal resolution without a decrease in sensitivity. Similar increases were observed for other cationic catecholamine neurotransmitters, and the increases in current were greater than for anionic interferents such as ascorbic acid and 3,4-dihydroxyphenylacetic acid (DOPAC). The CNT forest electrodes had high sensitivity at 90 Hz repetition rate when stimulated dopamine release was measured in Drosophila . The sensitivity, temporal resolution, and spatial resolution of these CNT forest modified disk electrodes facilitate enhanced electrochemical measurements of neurotransmitter release in vivo.
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paper_title: Carbon nanotubes in biology and medicine: An overview

paper_content:

Rapid development in the field of nanomedicine is bringing novel opportunities for improved disease diagnosis and drug delivery. Among various nanomaterials involved in nanomedicine, carbon nanotubes (CNTs) possessing a unique one-dimensional structure with interesting intrinsic mechanical, physical, and chemical properties have been extensively explored for a wide range of applications in biology and medicine. This review article provides an overview of how CNTs are used in different aspects of biomedicine including drug delivery and cancer treatment, bio-sensing, biomedical imaging, as well as tissue engineering. The recent developments, future perspective, and major challenges in this field are discussed.
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paper_title: Mediator-less highly sensitive voltammetric detection of glutamate using glutamate dehydrogenase/vertically aligned CNTs grown on silicon substrate.

paper_content:

A sensitive glutamate biosensor is prepared based on glutamate dehydrogenase/vertically aligned carbon nanotubes (GLDH, VACNTs). Vertically aligned carbon nanotubes were grown on a silicon substrate by direct current plasma enhanced chemical vapor deposition (DC-PECVD) method. The electrochemical behavior of the synthesized VACNTs was investigated by cyclic voltammetry and electrochemical impedance spectroscopic methods. Glutamate dehydrogenase covalently attached on tip of VACNTs. The electrochemical performance of the electrode for detection of glutamate was investigated by cyclic and differential pulse voltammetry. Differential pulse voltammetric determinations of glutamate are performed in mediator-less condition and also, in the presence of 1 and 5 μM thionine as electron mediator. The linear calibration curve of the concentration of glutamate versus peak current is investigated in a wide range of 0.1-500 μM. The mediator-less biosensor has a low detection limit of 57 nM and two linear ranges of 0.1-20 μM with a sensitivity of 0.976 mA mM(-1) cm(-2) and 20-300 μM with a sensitivity of 0.182 mA mM(-1) cm(-2). In the presence of 1 μM thionine as an electron mediator, the prepared biosensor shows a low detection limit of 68 nM and two linear ranges of 0.1-20 with a calibration sensitivity of 1.17 mA mM(-1) cm(-2) and 20-500 μM with a sensitivity of 0.153 mA mM(-1) cm(-2). The effects of the other biological compounds on the voltammetric behavior of the prepared biosensor and its response stability are investigated. The results are demonstrated that the GLDH/VACNTs electrode even without electron mediator is a suitable basic electrode for detection of glutamate.
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paper_title: Electroless deposition of bis(4'-(4-Pyridyl)-2,2':6',2''-terpyridine)iron(II) thiocyanate complex onto carbon nanotubes modified glassy carbon electrode: application to simultaneous determination of ascorbic acid, dopamine and uric acid

paper_content:

A glassy carbon (GC) electrode modified by multi-walled carbon nanotubes (MWNTs) and bis(pyterpy)iron(II) thiocyanate complex (pyterpy = 4'-(4-pyridyl)-2,2':6',2''-terpyridine) was investigated by voltammetric methods in acetate buffer solution (pH 5). Performances of the iron(II)-complex/MWNTs modified electrode were evaluated with differential pulse voltammetry and scanning electron microscopy (SEM). The modified glassy carbon electrode shows an excellent electrochemical response for ascorbic acid (AA), dopamine (DA) and uric acid (UA). The differential pulse voltammetry oxidation peaks for AA and DA, DA and UA, AA and UA are separated by 210, 136 and 346 mV, respectively. This separation permits the simultaneous determination of AA, DA and UA. The anodic peak currents of AA, DA and UA increase linearly with concentration in the range of 1.10×10-5-1.50×10-3 mol L-1, 9.0×10-7-1.20×10-3 mol L-1 and 2.00×10-6-1.50×10-3 mol L-1, respectively, with a correlation coefficient (r) always higher than 0.998. In addition, the modified electrode also shows good sensitivity and stability. Satisfactory results were achieved for the determination of AA in vitamin C tablets, DA in dopamine injection solution and UA in human blood serum samples
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paper_title: SELECTIVE DPV METHOD OF DOPAMINE DETERMINATION IN BIOLOGICAL SAMPLES CONTAINING ASCORBIC ACID

paper_content:

A modified carbon paste electrode that incorporates the anionic surfactant sodium dodecyl sulfate (SDS) in the paste (SDS-CP) is reported. It is shown that the SDS-CP electrode discriminates effectively between the cationic form of dopamine and the anionic electroactive species existing in biological fluids at the physiological pH. Therefore, a differential pulse voltammetry method has been developed. It has the detection limit comprised in the submicromolar range and the capability to remove the interference of the ascorbic acid and to diminish the interference of the uric acid. The method has been tested with good results on real samples of deproteinized serum.
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paper_title: A Sensitive Simultaneous Determination of Adrenalin and Paracetamol on a Glassy Carbon Electrode Coated with a Film of Chitosan/Room Temperature Ionic Liquid/Single‐Walled Carbon Nanotubes Nanocomposite

paper_content:

The present work demonstrates that simultaneous determination of adrenalin (AD) and paracetamol (PAR) can be performed on single-walled carbon nanotube/chitosan/ionic liquid modified glassy carbon electrode (SWCNT-CHIT-IL/GCE). The electro-oxidations of AD and PAR were investigated with cyclic voltammetry (CV), differential pulse voltammetry (DPV) and also chronoamperometry (CA) methods. DPV experiments showed that the oxidation peak currents of AD and PAR are proportional to the corresponding concentrations over the 1–580 μmol/L and 0.5–400 μmol/L ranges, respectively. The RSD at a concentration level of 15 μmol/L AD and 15 μmol/L PAR were 1.69% and 1.82%, respectively. Finally the modified electrode was used for simultaneous determination of AD and PAR in real samples with satisfactory results.
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paper_title: A novel multi-walled carbon nanotube modified sensor for the selective determination of epinephrine in smokers

paper_content:

Abstract Epinephrine (EP), an important neurotransmitter, energizes and speeds up the various body systems and plays an important role during the time of stress and low blood sugar level. There is a close relation between the release of epinephrine and smoking. Edge plane pyrolytic graphite electrode modified with multi-walled carbon nanotubes (MWNTs/EPPGE) has been used as a sensor for the efficient quantitative determination of epinephrine in body fluids of smokers and nonsmokers in resting stage at physiological pH 7.2 by using cyclic voltammetry (CV) and square wave voltammetry (SWV). The oxidation of epinephrine occurred in a well-defined peak having peak potential ( E p ) ∼150 mV at pH 7.2. The limit of detection (3 σ /slope) and limit of quantification were found to be 0.15 × 10 −9 and 0.48 × 10 −9 M using proposed sensor, respectively. The modified electrode was also utilized for the analysis of commercial sample of epinephrine in order to examine the accuracy of the proposed method. The analytical performance of the modified electrode has been evaluated for quantification of EP in real samples even in the presence of common coexisting biomolecules such as uric acid, ascorbic acid, dopamine and norepinephrine. The voltammetric response of the developed nanosensor towards epinephrine determination in body fluids is fast, sensitive and selective having desirable reproducibility and stability. A comparison of results with high performance liquid chromatography (HPLC) shows a good agreement.
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paper_title: Electrochemical quantification of serotonin in the live embryonic zebrafish intestine.

paper_content:

We monitored real-time in vivo levels of serotonin release in the digestive system of intact zebrafish embryos during early development (5 days postfertilization, dpf) using differential pulse voltammetry with implanted carbon fiber microelectrodes modified with carbon nanotubes dispersed in nafion. A detection limit of 1 nM, a linear range between 5 and 200 nM, and a sensitivity of 83.65 nA x microM(-1) were recorded. The microelectrodes were implanted at various locations in the intestine of zebrafish embryos. Serotonin levels of up to 29.9 (+/-1.13) nM were measured in vivo in normal physiological conditions. Measurements were performed in intact live embryos without additional perturbation beyond electrode insertion. The sensor was able to quantify pharmacological alterations in serotonin release and provide the longitudinal distribution of this neurotransmitter along the intestine with high spatial resolution. In the presence of fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), concentrations of 54.1 (+/-1.05) nM were recorded while in the presence of p-chloro-phenylalanine (PCPA), a tryptophan hydroxylase inhibitor, the serotonin levels decreased to 7.2 (+/-0.45) nM. The variation of serotonin levels was correlated with immunohistochemical analysis. We have demonstrated the first use of electrochemical microsensors for in vivo monitoring of intestinal serotonin levels in intact zebrafish embryos.
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paper_title: Simultaneous determination of epinephrine and norepinephrine in human blood plasma and urine samples using nanotubes modified edge plane pyrolytic graphite electrode.

paper_content:

Abstract The simultaneous determination of catecholamines – epinephrine and norepinephrine by square wave voltammetry (SWV) at physiological pH 7.2 is reported using multi-walled carbon nanotubes modified edge plane pyrolytic graphite electrode (MWNT/EPPGE). A broad bump at ∼250 mV is appeared for the oxidation of epinephrine (EP) and norepinephrine (NE) at bare EPPGE whereas at MWNT/EPPGE two well-separated peaks at ∼150 and ∼215 mV are appeared for the oxidation of EP and NE, respectively. The oxidation peak current of both the neurotransmitters also increased significantly along with the negative shift of peak potentials using MWNT/EPPGE. The oxidation of both compounds occurred in a pH dependent, 2e and 2H+ process and the electrode reaction followed diffusion controlled pathway. Linear calibration curves were obtained for epinephrine and norepinephrine in the range 0.5–100 nM with limits of detection 0.15 × 10−9 and 0.90 × 10−10 M, respectively. The developed protocol is implemented for the simultaneous determination of epinephrine and norepinephrine in blood plasma and urine samples of smokers as well as in athletes.
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paper_title: A Sensitive Simultaneous Determination of Adrenalin and Paracetamol on a Glassy Carbon Electrode Coated with a Film of Chitosan/Room Temperature Ionic Liquid/Single‐Walled Carbon Nanotubes Nanocomposite

paper_content:

The present work demonstrates that simultaneous determination of adrenalin (AD) and paracetamol (PAR) can be performed on single-walled carbon nanotube/chitosan/ionic liquid modified glassy carbon electrode (SWCNT-CHIT-IL/GCE). The electro-oxidations of AD and PAR were investigated with cyclic voltammetry (CV), differential pulse voltammetry (DPV) and also chronoamperometry (CA) methods. DPV experiments showed that the oxidation peak currents of AD and PAR are proportional to the corresponding concentrations over the 1–580 μmol/L and 0.5–400 μmol/L ranges, respectively. The RSD at a concentration level of 15 μmol/L AD and 15 μmol/L PAR were 1.69% and 1.82%, respectively. Finally the modified electrode was used for simultaneous determination of AD and PAR in real samples with satisfactory results.
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paper_title: Carbon nanotubes in biology and medicine: In vitro and in vivo detection, imaging and drug delivery

paper_content:

Carbon nanotubes exhibit many unique intrinsic physical and chemical properties and have been intensively explored for biological and biomedical applications in the past few years. In this comprehensive review, we summarize the main results from our and other groups in this field and clarify that surface functionalization is critical to the behavior of carbon nanotubes in biological systems. Ultrasensitive detection of biological species with carbon nanotubes can be realized after surface passivation to inhibit the non-specific binding of biomolecules on the hydrophobic nanotube surface. Electrical nanosensors based on nanotubes provide a label-free approach to biological detection. Surface-enhanced Raman spectroscopy of carbon nanotubes opens up a method of protein microarray with detection sensitivity down to 1 fmol/L. In vitro and in vivo toxicity studies reveal that highly water soluble and serum stable nanotubes are biocompatible, nontoxic, and potentially useful for biomedical applications. In vivo biodistributions vary with the functionalization and possibly also size of nanotubes, with a tendency to accumulate in the reticuloendothelial system (RES), including the liver and spleen, after intravenous administration. If well functionalized, nanotubes may be excreted mainly through the biliary pathway in feces. Carbon nanotube-based drug delivery has shown promise in various In vitro and in vivo experiments including delivery of small interfering RNA (siRNA), paclitaxel and doxorubicin. Moreover, single-walled carbon nanotubes with various interesting intrinsic optical properties have been used as novel photoluminescence, Raman, and photoacoustic contrast agents for imaging of cells and animals. Further multidisciplinary explorations in this field may bring new opportunities in the realm of biomedicine.
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paper_title: Biosensor Based on Electrocodeposition of Carbon Nanotubes/Polypyrrole/Laccase for Neurotransmitter Detection

paper_content:

A new biosensor has been developed by a simple electrocodeposition of multiwalled carbon nanotubes (MWCNT), polypyrrole (PPy) and laccase (Lac) on the platinum (Pt) electrode surface. The neurotransmitter biosensor was applied to the detection of dopamine in urine samples using differential pulse voltammetry (DPV). The Pt/MWCNT/PPy/Lac biosensor exhibited a detection limit of 0.14 µM, which is an adequate level for monitoring dopamine in urine. Reproducibility and repeatability values of 2.9 % and 1.7 %, respectively, were obtained compared to the conventional procedure. The proposed biosensor was successfully applied in the determination of dopamine in urine, and the obtained results were in full agreement with those from the HPLC procedure.
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paper_title: Carbon nanotubes in medicine & biology - therapy and diagnostics.

paper_content:

This Special Issue of Advanced Drug Delivery Reviews is intended to highlight the wide range and multidisciplinary nature of interests that application of carbon nanotubes for therapeutic and diagnostic purposes have captured during the last decade.
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paper_title: Carbon nanofiber electrode array for electrochemical detection of dopamine using fast scan cyclic voltammetry.

paper_content:

A carbon nanofiber (CNF) electrode array was integrated with the Wireless Instantaneous Neurotransmitter Concentration Sensor System (WINCS) for the detection of dopamine using fast scan cyclic voltammetry (FSCV). Dopamine detection performance by CNF arrays was comparable to that of traditional carbon fiber microelectrodes (CFMs), demonstrating that CNF arrays can be utilized as an alternative carbon electrode for neurochemical monitoring.
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paper_title: Development of the Wireless Instantaneous Neurotransmitter Concentration System for intraoperative neurochemical monitoring using fast-scan cyclic voltammetry: Technical note

paper_content:

Object Emerging evidence supports the hypothesis that modulation of specific central neuronal systems contributes to the clinical efficacy of deep brain stimulation (DBS) and motor cortex stimulation (MCS). Real-time monitoring of the neurochemical output of targeted regions may therefore advance functional neurosurgery by, among other goals, providing a strategy for investigation of mechanisms, identification of new candidate neurotransmitters, and chemically guided placement of the stimulating electrode. The authors report the development of a device called the Wireless Instantaneous Neurotransmitter Concentration System (WINCS) for intraoperative neurochemical monitoring during functional neurosurgery. This device supports fast-scan cyclic voltammetry (FSCV) at a carbon-fiber microelectrode (CFM) for real-time, spatially and chemically resolved neurotransmitter measurements in the brain. Methods The FSCV study consisted of a triangle wave scanned between −0.4 and 1 V at a rate of 300 V/second and appli...
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paper_title: Mediator-less highly sensitive voltammetric detection of glutamate using glutamate dehydrogenase/vertically aligned CNTs grown on silicon substrate.

paper_content:

A sensitive glutamate biosensor is prepared based on glutamate dehydrogenase/vertically aligned carbon nanotubes (GLDH, VACNTs). Vertically aligned carbon nanotubes were grown on a silicon substrate by direct current plasma enhanced chemical vapor deposition (DC-PECVD) method. The electrochemical behavior of the synthesized VACNTs was investigated by cyclic voltammetry and electrochemical impedance spectroscopic methods. Glutamate dehydrogenase covalently attached on tip of VACNTs. The electrochemical performance of the electrode for detection of glutamate was investigated by cyclic and differential pulse voltammetry. Differential pulse voltammetric determinations of glutamate are performed in mediator-less condition and also, in the presence of 1 and 5 μM thionine as electron mediator. The linear calibration curve of the concentration of glutamate versus peak current is investigated in a wide range of 0.1-500 μM. The mediator-less biosensor has a low detection limit of 57 nM and two linear ranges of 0.1-20 μM with a sensitivity of 0.976 mA mM(-1) cm(-2) and 20-300 μM with a sensitivity of 0.182 mA mM(-1) cm(-2). In the presence of 1 μM thionine as an electron mediator, the prepared biosensor shows a low detection limit of 68 nM and two linear ranges of 0.1-20 with a calibration sensitivity of 1.17 mA mM(-1) cm(-2) and 20-500 μM with a sensitivity of 0.153 mA mM(-1) cm(-2). The effects of the other biological compounds on the voltammetric behavior of the prepared biosensor and its response stability are investigated. The results are demonstrated that the GLDH/VACNTs electrode even without electron mediator is a suitable basic electrode for detection of glutamate.
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paper_title: Are Carbon Nanotubes a Natural Solution? Applications in Biology and Medicine

paper_content:

Carbon nanotubes and materials based on carbon nanotubes have many perceived applications in the field of biomedicine. Several highly promising examples have been highlighted in the literature, ranging from their use as growth substrates or tissue scaffolds to acting as intracellular transporters for various therapeutic and diagnostic agents. In addition, carbon nanotubes have a strong optical absorption in the near-infrared region (in which tissue is transparent), which enables their use for biological imaging applications and photothermal ablation of tumors. Although these advances are potentially game-changing, excitement must be tempered somewhat as several bottlenecks exist. Carbon nanotube-based technologies ultimately have to compete with and out-perform existing technologies in terms of performance and price. Moreover, issues have been highlighted relating to toxicity, which presents an obstacle for the transition from preclinical to clinical use. Although many studies have suggested that well-fun...
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paper_title: Simultaneous determination of epinephrine and norepinephrine in human blood plasma and urine samples using nanotubes modified edge plane pyrolytic graphite electrode.

paper_content:

Abstract The simultaneous determination of catecholamines – epinephrine and norepinephrine by square wave voltammetry (SWV) at physiological pH 7.2 is reported using multi-walled carbon nanotubes modified edge plane pyrolytic graphite electrode (MWNT/EPPGE). A broad bump at ∼250 mV is appeared for the oxidation of epinephrine (EP) and norepinephrine (NE) at bare EPPGE whereas at MWNT/EPPGE two well-separated peaks at ∼150 and ∼215 mV are appeared for the oxidation of EP and NE, respectively. The oxidation peak current of both the neurotransmitters also increased significantly along with the negative shift of peak potentials using MWNT/EPPGE. The oxidation of both compounds occurred in a pH dependent, 2e and 2H+ process and the electrode reaction followed diffusion controlled pathway. Linear calibration curves were obtained for epinephrine and norepinephrine in the range 0.5–100 nM with limits of detection 0.15 × 10−9 and 0.90 × 10−10 M, respectively. The developed protocol is implemented for the simultaneous determination of epinephrine and norepinephrine in blood plasma and urine samples of smokers as well as in athletes.
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paper_title: Electroless deposition of bis(4'-(4-Pyridyl)-2,2':6',2''-terpyridine)iron(II) thiocyanate complex onto carbon nanotubes modified glassy carbon electrode: application to simultaneous determination of ascorbic acid, dopamine and uric acid

paper_content:

A glassy carbon (GC) electrode modified by multi-walled carbon nanotubes (MWNTs) and bis(pyterpy)iron(II) thiocyanate complex (pyterpy = 4'-(4-pyridyl)-2,2':6',2''-terpyridine) was investigated by voltammetric methods in acetate buffer solution (pH 5). Performances of the iron(II)-complex/MWNTs modified electrode were evaluated with differential pulse voltammetry and scanning electron microscopy (SEM). The modified glassy carbon electrode shows an excellent electrochemical response for ascorbic acid (AA), dopamine (DA) and uric acid (UA). The differential pulse voltammetry oxidation peaks for AA and DA, DA and UA, AA and UA are separated by 210, 136 and 346 mV, respectively. This separation permits the simultaneous determination of AA, DA and UA. The anodic peak currents of AA, DA and UA increase linearly with concentration in the range of 1.10×10-5-1.50×10-3 mol L-1, 9.0×10-7-1.20×10-3 mol L-1 and 2.00×10-6-1.50×10-3 mol L-1, respectively, with a correlation coefficient (r) always higher than 0.998. In addition, the modified electrode also shows good sensitivity and stability. Satisfactory results were achieved for the determination of AA in vitamin C tablets, DA in dopamine injection solution and UA in human blood serum samples
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paper_title: Nafion-CNT coated carbon-fiber microelectrodes for enhanced detection of adenosine.

paper_content:

Adenosine is a neuromodulator that regulates neurotransmission. Adenosine can be monitored using fast-scan cyclic voltammetry at carbon-fiber microelectrodes and ATP is a possible interferent in vivo because the electroactive moiety, adenine, is the same for both molecules. In this study, we investigated carbon-fiber microelectrodes coated with Nafion and carbon nanotubes (CNTs) to enhance the sensitivity of adenosine and decrease interference by ATP. Electrodes coated in 0.05 mg mL(-1) CNTs in Nafion had a 4.2 ± 0.2 fold increase in current for adenosine, twice as large as for Nafion alone. Nafion-CNT electrodes were 6 times more sensitive to adenosine than ATP. The Nafion-CNT coating did not slow the temporal response of the electrode. Comparing different purine bases shows that the presence of an amine group enhances sensitivity and that purines with carbonyl groups, such as guanine and hypoxanthine, do not have as great an enhancement after Nafion-CNT coating. The ribose group provides additional sensitivity enhancement for adenosine over adenine. The Nafion-CNT modified electrodes exhibited significantly more current for adenosine than ATP in brain slices. Therefore, Nafion-CNT modified electrodes are useful for sensitive, selective detection of adenosine in biological samples.
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paper_title: Rapid, Sensitive Detection of Neurotransmitters at Microelectrodes Modified with Self-assembled SWCNT Forests

paper_content:

Carbon nanotube (CNT) modification of microelectrodes can result in increased sensitivity without compromising time response. However, dip coating CNTs is not very reproducible and the CNTs tend to lay flat on the electrode surface which limits access to the electroactive sites on the ends. In this study, aligned CNT forests were formed using a chemical self-assembly method, which resulted in more exposed CNT ends to the analyte. Shortened, carboxylic acid functionalized single-walled CNTs were assembled from a dimethylformamide (DMF) suspension onto a carbon-fiber disk microelectrode modified with a thin iron hydroxide-decorated Nafion film. The modified electrodes were highly sensitive, with 36-fold higher oxidation currents for dopamine using fast-scan cyclic voltammetry than bare electrodes and 34-fold more current than electrodes dipped in CNTs. The limit of detection (LOD) for dopamine was 17 ± 3 nM at a 10 Hz repetition rate and 65 ± 7 nM at 90 Hz. The LOD at 90 Hz was the same as a bare electrode at 10 Hz, allowing a 9-fold increase in temporal resolution without a decrease in sensitivity. Similar increases were observed for other cationic catecholamine neurotransmitters, and the increases in current were greater than for anionic interferents such as ascorbic acid and 3,4-dihydroxyphenylacetic acid (DOPAC). The CNT forest electrodes had high sensitivity at 90 Hz repetition rate when stimulated dopamine release was measured in Drosophila . The sensitivity, temporal resolution, and spatial resolution of these CNT forest modified disk electrodes facilitate enhanced electrochemical measurements of neurotransmitter release in vivo.
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paper_title: Preparation of thiolated polymeric nanocomposite for sensitive electroanalysis of dopamine

paper_content:

Abstract We report on the thiol-ene chemistry guided preparation of novel thiolated polymeric nanocomposite films of abundant anionic carboxylic groups for electrostatic enrichment and sensitive electroanalysis of cationic dopamine (DA) in neutral solution. Briefly, the thiol-ene nucleophilic reaction of a carboxylated thiol with oxidized polypyrrole (PPy), which was electrosynthesized on an Au electrode in the presence of solution-dispersed acidified multiwalled carbon nanotubes (MWCNTs), produced an a PPy–thiol–MWCNTs/Au electrode, and the PPy can be electrochemically overoxidized (OPPy) to form an OPPy–thiol–MWCNTs/Au electrode. The carboxylic groups of the polymeric nanocomposite film originate from the acidified MWCNTs, PPy-tethered carboxylated thiol, and OPPy. The carboxylated thiols examined are mercaptosuccinic acid (MSA) and thioglycolic acid, with β-mercaptoethanol as a control. Electrochemical quartz crystal microbalance, scanning electron microscopy, Fourier transform infrared spectroscopy and ultraviolet–visible spectroscopy were used for film characterization and process monitoring. Under the optimized condition, the differential pulse voltammetry peak current of DA oxidation at OPPy–MSA–MWCNTs/Au electrode is linear with DA concentration from 1.00×10 –9 to 2.87×10 –6 mol L −1 , with a limit of detection of 0.4 nmol L −1 , good anti-interferent ability and stability.
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paper_title: Comparison of Nafion- and overoxidized polypyrrole-carbon nanotube electrodes for neurotransmitter detection

paper_content:

Permselective polymer coatings improve selectivity and sensitivity of microelectrodes for cationic neurotransmitters. Immobilizing carbon nanotubes (CNTs) into these polymers should further improve sensitivity by increasing the electroactive surface area. The goal of this study was to compare the electrochemical properties of overoxidized polypyrrole (oPPY)-CNT and Nafion-CNT coated microelectrodes. Fast-scan cyclic voltammetry was used to test their response to neurochemicals. For dopamine, the average increase in oxidation current compared to bare electrodes was 3.7 ± 0.5 for oPPY-CNT electrodes (limit of detection (LOD) = 3.3 ± 0.6 nM) and 3.3 ± 0.8 for Nafion-CNT electrodes (LOD = 4 ± 1 nM). The selectivity for dopamine over ascorbic acid was better with oPPY-CNT electrodes. oPPY-CNT electrodes also displayed increased electron transfer kinetics for anions while Nafion-CNT electrodes did not, which proves that polymer deposition can affect the electrocatalytic properties of the CNTs. Both oPPY-CNT and Nafion-CNT electrodes were used to detect stimulated dopamine release in the caudate-putamen of anesthetized rats after 2, 4 and 12 pulse stimulation trains. oPPY-CNT electrodes could also detect small amounts of dopamine after 4 and 12 pulse stimulations in the basolateral amygdala (BLA). Although Nafion-CNT electrodes were easier to make, oPPY-CNT electrodes were more advantageous for dopamine detection because they were reproducibly fabricated, measured higher currents in vivo, and maintained selectivity over anions. The addition of CNTs to polymer coatings facilitates measurements of small concentrations of neurotransmittersin vivo.
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paper_title: An Ultrasensitive Nanowire-Transistor Biosensor for Detecting Dopamine Release from Living PC12 Cells under Hypoxic Stimulation

paper_content:

Dopamine (DA) is an important neurotransmitter that is involved in neuronal signal transduction and several critical illnesses. However, the concentration of DA is extremely low in patients and is difficult to detect using existing electrochemical biosensors with detection limits typically around nanomolar levels (∼10–9 M). Here, we developed a nanoelectronic device as a biosensor for ultrasensitive and selective DA detection by modifying DNA-aptamers on a multiple-parallel-connected (MPC) silicon nanowire field-effect transistor (referred to as MPC aptamer/SiNW-FET). Compared with conventional electrochemical methods, the MPC aptamer/SiNW-FET has been demonstrated to improve the limit of DA detection to <10–11 M and to possess a detection specificity that is able to distinguish DA from other chemical analogues, such as ascorbic acid, catechol, phenethylamine, tyrosine, epinephrine, and norepinephrine. This MPC aptamer/SiNW-FET was also applied to monitor DA release under hypoxic stimulation from living P...
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paper_title: 192-channel CMOS neurochemical microarray

paper_content:

A 16×12-channel neurochemical microarray is presented. Each channel acquires bidirectional currents down to pico-amperes proportional to the concentration of a neurochemical. By combining the current-to-frequency and the single-slope analog-to-digital converter (ADC) 110dB of dynamic range is achieved. The ADC in each channel generates a 16-bit output in less than a millisecond. The microarray with flat and 3D gold electrodes and an on-chip microfluidic network is experimentally validated in in-situ recording of neurotransmitter dopamine.
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paper_title: Multi-target electrochemical biosensing enabled by integrated CMOS electronics

paper_content:

An integrated electrochemical measurement system, based on CMOS technology, is presented, which allows the detection of several analytes in parallel (multi-analyte) and enables simultaneous monitoring at different locations (multi-site). The system comprises a 576-electrode CMOS sensor chip, an FPGA module for chip control and data processing, and the measurement laptop. The advantages of the highly versatile system are demonstrated by two applications. First, a label-free, hybridization-based DNA sensor is enabled by the possibility of large-scale integration in CMOS technology. Second, the detection of the neurotransmitter choline is presented by assembling the chip with biosensor microprobe arrays. The low noise level enables a limit of detection of, e.g., 0.3 µM choline. The fully integrated system is self-contained: it features cleaning, functionalization and measurement functions without the need for additional electrical equipment. With the power supplied by the laptop, the system is very suitable for on-site measurements.
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paper_title: Low power noise immune circuit for implantable CMOS neurochemical sensor applied in neural prosthetics

paper_content:

In this manuscript, we present the features and describe the operation of a low power, noise immune circuit for a CMOS based neurochemical sensor for implantable neural prosthetics. This microsystem consists of a single ended low noise low power amplifier and an integrator, in addition to a 10-bit first order sigma delta Analog to Digital Converter (ADC). Using electrochemical techniques, it senses picoscale to microscale current which corresponds to micro molar neurotransmitter concentration and converts the measurement to a 10-bit digital code. Combining amperometry and fast-scan cyclic voltammetry electrochemical technique results in a sensor with a high selectivity while having elevated temporal resolution. The microsystem consumes 120.85 μW which is the lowest reported brain implant and biosensor power consumption. This circuit is designed in CMOS 0.18 μm technology. Integration is an averaging operation and provides significant noise immunity. The low noise characteristics of our design make this device suitable for the noisy environment often encountered in-vivo.
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paper_title: 5×5 CMOS capacitive sensor array for detection of the neurotransmitter dopamine.

paper_content:

This work presents miniaturized CMOS (complementary metal oxide semiconductor) capacitive sensors for detection of the neurotransmitter dopamine (DA) down to the sub-fM range. Sensing resolution is significantly enhanced by monolithic sensor integration to reduce the parasitic effect and the use of sub-μm interdigitated microelectrodes as the sensing interface. The 5 × 5 sensor array contains five designs of different electrode sizes and each design has five sensors. The positive charges produced from protonation of boronate and amino group after immobilization of 4-carboxyphenylboronic acid (CPBA) result in an increase of the electrode-analyte capacitance. Then the negative charges produced after binding of CPBA and DA molecules decrease the electrode-analyte capacitance. Signal transduction is achieved through a CMOS readout circuit whose output frequency is inversely proportional to the capacitance. Experimental results showed the ratios of average percentage capacitance changes of the experiment groups over those of the control groups were all larger than one for the five designs at DA concentration of 0.1 fM. Selectivity against the non-analyte species, such as tyramine, has also been demonstrated.
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paper_title: Determination of Epinephrine in Carp Brain Cells by Square-Wave Anodic Stripping Voltammetry with Carbon Nanotubes

paper_content:

Real-time assay of the neurotransmitter epinephrine (EP) was investigated using square-wave anodic stripping voltammetry (SWASV) with modified carbon nanotubes (CNE) electrode. The developed results indicated a sensitive oxidation peak current for EP. A linear working range was obtained within of 5–40 and 40–240 ug/L, with a 45-sec accumulation time in an acetic acid electrolyte. Under optimum conditions, the relative standard deviation of 30.0 ug/l EP was 0.1016% (n = 12) via SW. Here analytical detection limit (S/N) was 0.30 ug/L (1.63 × 10−9 M). The results can be applied to the brain cells and core of a carp. These findings can have applications in biological neurodiagnostics and in other fields of EP analysis.
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paper_title: Parallel recording of neurotransmitters release from chromaffin cells using a 10×10 CMOS IC potentiostat array with on-chip working electrodes.

paper_content:

Neurotransmitter release is modulated by many drugs and molecular manipulations. We present an active CMOS-based electrochemical biosensor array with high throughput capability (100 electrodes) for on-chip amperometric measurement of neurotransmitter release. The high-throughput of the biosensor array will accelerate the data collection needed to determine statistical significance of changes produced under varying conditions, from several weeks to a few hours. The biosensor is designed and fabricated using a combination of CMOS integrated circuit (IC) technology and a photolithography process to incorporate platinum working electrodes on-chip. We demonstrate the operation of an electrode array with integrated high-gain potentiostats and output time-division multiplexing with minimum dead time for readout. The on-chip working electrodes are patterned by conformal deposition of Pt and lift-off photolithography. The conformal deposition method protects the underlying electronic circuits from contact with the electrolyte that covers the electrode array during measurement. The biosensor was validated by simultaneous measurement of amperometric currents from 100 electrodes in response to dopamine injection, which revealed the time course of dopamine diffusion along the surface of the biosensor array. The biosensor simultaneously recorded neurotransmitter release successfully from multiple individual living chromaffin cells. The biosensor was capable of resolving small and fast amperometric spikes reporting release from individual vesicle secretions. We anticipate that this device will accelerate the characterization of the modulation of neurotransmitter secretion from neuronal and endocrine cells by pharmacological and molecular manipulations of the cells.
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paper_title: Post-CMOS Fabrication of Working Electrodes for On-Chip Recordings of Transmitter Release

paper_content:

The release of neurotransmitters and hormones from secretory vesicles plays a fundamental role in the function of the nervous system including neuronal communication. High-throughput testing of drugs modulating transmitter release is becoming an increasingly important area in the fields of cell biology, neurobiology, and neurology. Carbon-fiber amperometry provides high-resolution measurements of amount and time course of the transmitter release from single vesicles, and their modulation by drugs and molecular manipulations. However, these methods do not enable the rapid collection of data from a large number of cells. To allow this testing, we have developed a complementary metal-oxide semiconductor (CMOS) potentiostat circuit that can be scaled to a large array. In this paper, we present two post-CMOS fabrication methods to incorporate the electrochemical electrode material. We demonstrate by proof of principle the feasibility of on-chip electrochemical measurements of dopamine, and catecholamine release from adrenal chromaffin cells. The measurement noise is consistent with the typical electrode noise in recordings with external amplifiers. The electronic noise of the potentiostat in recordings with 400-?s integration time is ~ 0.11 pA and is negligible compared to the inherent electrode noise.
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paper_title: A novel multi-walled carbon nanotube modified sensor for the selective determination of epinephrine in smokers

paper_content:

Abstract Epinephrine (EP), an important neurotransmitter, energizes and speeds up the various body systems and plays an important role during the time of stress and low blood sugar level. There is a close relation between the release of epinephrine and smoking. Edge plane pyrolytic graphite electrode modified with multi-walled carbon nanotubes (MWNTs/EPPGE) has been used as a sensor for the efficient quantitative determination of epinephrine in body fluids of smokers and nonsmokers in resting stage at physiological pH 7.2 by using cyclic voltammetry (CV) and square wave voltammetry (SWV). The oxidation of epinephrine occurred in a well-defined peak having peak potential ( E p ) ∼150 mV at pH 7.2. The limit of detection (3 σ /slope) and limit of quantification were found to be 0.15 × 10 −9 and 0.48 × 10 −9 M using proposed sensor, respectively. The modified electrode was also utilized for the analysis of commercial sample of epinephrine in order to examine the accuracy of the proposed method. The analytical performance of the modified electrode has been evaluated for quantification of EP in real samples even in the presence of common coexisting biomolecules such as uric acid, ascorbic acid, dopamine and norepinephrine. The voltammetric response of the developed nanosensor towards epinephrine determination in body fluids is fast, sensitive and selective having desirable reproducibility and stability. A comparison of results with high performance liquid chromatography (HPLC) shows a good agreement.
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paper_title: Commercialisation of CMOS Integrated Circuit Technology in Multi-Electrode Arrays for Neuroscience and Cell-Based Biosensors

paper_content:

The adaptation of standard integrated circuit (IC) technology as a transducer in cell-based biosensors in drug discovery pharmacology, neural interface systems and electrophysiology requires electrodes that are electrochemically stable, biocompatible and affordable. Unfortunately, the ubiquitous Complementary Metal Oxide Semiconductor (CMOS) IC technology does not meet the first of these requirements. For devices intended only for research, modification of CMOS by post-processing using cleanroom facilities has been achieved. However, to enable adoption of CMOS as a basis for commercial biosensors, the economies of scale of CMOS fabrication must be maintained by using only low-cost post-processing techniques. This review highlights the methodologies employed in cell-based biosensor design where CMOS-based integrated circuits (ICs) form an integral part of the transducer system. Particular emphasis will be placed on the application of multi-electrode arrays for in vitro neuroscience applications. Identifying suitable IC packaging methods presents further significant challenges when considering specific applications. The various challenges and difficulties are reviewed and some potential solutions are presented.
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paper_title: Integrated biosensors in CMOS

paper_content:

This paper reviews several integrated biosensing technologies compatible with standard CMOS process. With a particular focus on detecting biomolecules and molecular interactions, the selected sensing modalities include electrochemical biosensor, fluorescent biosensor, magnetic biosensor, and gravimetric biosensor. For each modality, the sensing mechanism is first presented, and is then followed by a typical design example. Advantages as well as limitations of the sensing technology are also discussed.
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paper_title: Adaptive CMOS analog circuits for 4G mobile terminals - Review and state-of-the-art survey

paper_content:

The fourth-generation (4G) of cellular terminals will integrate the services provided by previous generations second-generation/third-generation (2G/3G) with other applications like global positioning system (GPS), digital video broadcasting (DVB) and wireless networks, covering metropolitan (IEEE 802.16), local (IEEE 802.11) and personal (IEEE 802.15) areas. This new generation of hand-held wireless devices, also named always-best-connected systems, will require low-power and low-cost multi-standard chips, capable of operating over different co-existing communication protocols, signal conditions, battery status, etc. Moreover, the efficient implementation of these chipsets will demand for reconfigurable radio frequency (RF) and mixed-signal circuits that can adapt to the large number of specifications with minimum power dissipation at the lowest cost. Nanometer CMOS processes are expected to be the base technologies to develop 4G systems, assuring mass production at low cost through increased integration levels and extensive use of digital signal processing. However, the integration in standard CMOS of increasingly complex analog/RF parts imposes a number of challenges and trade-offs that make their design critical. These challenges are addressed in this paper through a comprehensive revision of the state-of-the-art on transceiver architectures, building blocks and design trade-offs of reconfigurable and adaptive CMOS RF and mixed-signal circuits for emerging 4G systems.
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paper_title: Biosensor systems in standard CMOS processes: Fact or fiction?

paper_content:

In this paper, we discuss the advantages and limitations of using standard CMOS fabrication processes for the design of integrated affinity-based biosensor systems. In particular, we examine the compatibility of CMOS with various assaying techniques and the possibility of fabricating their transducer structures.
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paper_title: Impedance characterization and modeling of electrodes for biomedical applications

paper_content:

A low electrode-electrolyte impedance interface is critical in the design of electrodes for biomedical applications. To design low-impedance interfaces a complete understanding of the physical processes contributing to the impedance is required. In this work a model describing these physical processes is validated and extended to quantify the effect of organic coatings and incubation time. Electrochemical impedance spectroscopy has been used to electrically characterize the interface for various electrode materials: platinum, platinum black, and titanium nitride; and varying electrode sizes: 1 cm/sup 2/, and 900 /spl mu/m/sup 2/. An equivalent circuit model comprising an interface capacitance, shunted by a charge transfer resistance, in series with the solution resistance has been fitted to the experimental results. Theoretical equations have been used to calculate the interface capacitance impedance and the solution resistance, yielding results that correspond well with the fitted parameter values, thereby confirming the validity of the equations. The effect of incubation time, and two organic cell-adhesion promoting coatings, poly-L-lysine and laminin, on the interface impedance has been quantified using the model. This demonstrates the benefits of using this model in developing a better understanding of the physical processes occurring at the interface in more complex, biomedically relevant situations.
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paper_title: CMOS chips for bio molecule sensing purposes

paper_content:

A topical review is given concerning CMOS-based DNA microarrays. Considering the entire application chain, functionalization techniques, required CMOS process extensions and consequences, and a number of readout techniques are discussed. Related circuit design issues and CMOS implementations are highlighted as well.
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paper_title: CMOS Capacitive Sensors With Sub- $\mu$m Microelectrodes for Biosensing Applications

paper_content:

Miniaturized complementary metal-oxide semiconductor (CMOS) capacitive sensors presented in this work are capable of providing sensitive detection in the sub-nM range for biosensing applications. A convenient post-CMOS fabrication process is proposed to make sub-μm interdigitated microelectrodes covered by inter-metal dielectric layer as the sensing interface. Capacitance change due to the electrode-analyte impedance is detected by the integrated continuous-time sensing circuit. For immunodetection of mouse IgG and anti-mouse IgG enhanced by 25% gold nanoparticles, the produced interface capacitance changes after specific bindings were -4, -7.4, and -17 fF for the 13-, 95-, and 925-fF microelectrode designs, respectively. Detection of the 200-nM neurotransmitter dopamine (DA) showed interface capacitance changes of 0.22,1.46, and 22 fF for the three designs. Based on the measured circuit noise of 14.2 μV/Hz1/2, the minimum detectable capacitance changes were 0.3, 2.9, and 22.5 aF, equivalent to detectable DA concentrations of 309, 394, and 203 pM, respectively.
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paper_title: CMOS Cell Sensors for Point-of-Care Diagnostics

paper_content:

The burden of health-care related services in a global era with continuously increasing population and inefficient dissipation of the resources requires effective solutions. From this perspective, point-of-care diagnostics is a demanded field in clinics. It is also necessary both for prompt diagnosis and for providing health services evenly throughout the population, including the rural districts. The requirements can only be fulfilled by technologies whose productivity has already been proven, such as complementary metal-oxide-semiconductors (CMOS). CMOS-based products can enable clinical tests in a fast, simple, safe, and reliable manner, with improved sensitivities. Portability due to diminished sensor dimensions and compactness of the test set-ups, along with low sample and power consumption, is another vital feature. CMOS-based sensors for cell studies have the potential to become essential counterparts of point-of-care diagnostics technologies. Hence, this review attempts to inform on the sensors fabricated with CMOS technology for point-of-care diagnostic studies, with a focus on CMOS image sensors and capacitance sensors for cell studies.
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paper_title: Dielectrophoresis-Based Integrated Lab-on-Chip for Nano and Micro-Particles Manipulation and Capacitive Detection

paper_content:

In the above paper (ibid., vol. 6, no. 2, pp. 120-132, Apr. 2012), the list of authors is incomplete. The complete list of authors is as follows: Mohamed Amine Miled, Genevieve Massicotte, and Mohamad Sawan.
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paper_title: Electrode robustness in artificial cerebrospinal fluid for dielectrophoresis-based LoC

paper_content:

In this paper, we present hybrid microelectronics / microfluidic Lab-on-Chip (LoC) platform intended for implantable medical microsystems for neurotransmitter detection. In vitro experiments were achieved using artificial cerebrospinal fluid (ACSF) from Tocris Bioscience where microspheres were immersed to test the behaviour of the designed LoC. One of main features of the proposed LoC platform is its thin thickness, including micro-channels and silicon CMOS chip. The latter is integrated into the glass top-layer of the LoC measuring 0.5 mm. The size of the device is 9 mm × 5 mm. the electrode architecture is composed of 8×2×2 L-shaped electrodes in a 650 µm channel width and 4 sites for interdigitited electrodes. 32 L-shaped electrodes were connected to a electronics circuit for cells manipulation using dielectrophoresis (DEP). The described LoC achieved an efficient separation within a concentration of 50 µl of a solution of microspheres, distilled water (DW) and 500 µl of ACSF. Beyond this concentration, electrode destruction was observed.
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paper_title: An efficient time-based CMOS potentiostat for neurotransmitters sensing

paper_content:

A time-based potentiostat measuring electrochemical redox currents is described for the detection and quantification of neurotransmitters. The CMOS potentiostat is controlled by an adaptive sampling algorithm to increase power efficiency, input dynamic range and sampling frequency. The integrated circuit is characterized through post-layout simulation, using 0.13 μm CMOS technology. Results show a 94 dB dynamic range, a minimum sampling frequency of 1.25 kHz and a minimum analog power consumption of 13 μW per channel. The proposed electrochemical sensor is suitable for neurochemical in-vivo monitoring specifications.
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paper_title: Epinephrine Kinetics in Humans: Radiotracer Methodology*

paper_content:

The use of the plasma epinephrine (EPI) level as an index of adrenomedullary activity in humans is complicated by the rapid removal of EPI from plasma by many tissues. To determine whether the kinetics of distribution and metabolism of EPI could be best quantified using the isotope dilution method or a mathematical modeling technique, eight human subjects received a [3H]EPI infusion for 50–60 min. Analysis of the steady state arterialized plasma levels of EPI and [3H]EPI using the isotope dilution technique showed that the basal plasma EPI appearance rate is 0.87 ± 0.11 nmol/m2-min, and the basal plasma EPI clearance rate is 1.63 ± 0.14 L/min-m2. Mathematical modeling of the [3H]EPI levels revealed that a biexponential curve fit was superior to monoexponential and triexponential curve fits. A two-compartment model was the minimal compartment model that accurately described EPI kinetics. The basal plasma EPI appearance (0.82 ± 0.16 nmol/m2-min) and EPI clearance (1.67 ± 0.15 L/min-m2) rates that were estim...
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paper_title: Interfacial Janus gold nanoclusters as excellent phase- and orientation-specific dopamine sensors

paper_content:

This investigation, following our recent report on the one-pot hemi-micellar interfacial synthesis of Janus gold nanoclusters and the inter-cluster electron coupling establishing insulator–metal transition in the oriented Janus monolayers [Langmuir, 2010, 26(17), 14047], was to fabricate modified electrodes for sensing dopamine, the neurotransmitter. With a detection limit in the sub-nanomolar range, the apparent electron transfer rate constants for dopamine detection signified an intricate Janus cluster 2D phase dependency. Surface pressure as a thermodynamic variable controlled the electronic communication between the clusters as a result of varied inter-cluster distance and size, ultimately reflecting on the sensitivity and detection limit for dopamine sensing. The non-covalent nature of the ligands on the core metal clusters facilitated the overall electro-catalytic oxidation of dopamine. The notable feature of this precise work was that it established a more effective phase- and orientation-specific Janus cluster sensing than those reported through patterned gold nanowire based sensors.
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paper_title: Functional groups modulate the sensitivity and electron transfer kinetics of neurochemicals at carbon nanotube modified microelectrodes.

paper_content:

The surface properties of carbon-based electrodes are critically important for the detection of biomolecules and can modulate electrostatic interactions, adsorption and electrocatalysis. Carbon nanotube (CNT) modified electrodes have previously been shown to have increased oxidative sensitivity and reduced overpotential for catecholamine neurotransmitters, but the effect of surface functionalities on these properties has not been characterized. In this study, we modified carbon-fiber microelectrodes (CFMEs) with three differently functionalized single-wall carbon nanotubes and measured their response to serotonin, dopamine, and ascorbic acid using fast-scan cyclic voltammetry. Both carboxylic acid functionalized and amide functionalized CNTs increased the oxidative current of CFMEs by approximately 2-6 fold for the cationic neurotransmitters serotonin and dopamine, but octadecylamine functionalized CNTs resulted in no significant signal change. Similarly, electron transfer was faster for both amide and carboxylic acid functionalized CNT modified electrodes but slower for octadecylamine CNT modified electrodes. Oxidation of ascorbic acid was only increased with carboxylic acid functionalized CNTs although all CNT-modified electrodes showed a trend towards increased reversibility for ascorbic acid. Carboxylic acid-CNT modified disk electrodes were then tested for detection of serotonin in the ventral nerve cord of a Drosophila melanogaster larva, and the increase in sensitivity was maintained in biological tissue. The functional groups of CNTs therefore modulate the electrochemical properties, and the increase in sensitivity from CNT modification facilitates measurements in biological samples.
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paper_title: Carbon Nanofiber Electrode for Neurochemical Monitoring

paper_content:

The ability to rapidly detect neurotransmitter release has broad implications in the study of a variety of neurodegenerative diseases. Electrochemical detection methods using carbon nanofiber nanoelectrodes integrated into the Wireless Instantaneous Neurotransmitter Concentration Sensing System (WINCS) offer many important advantages including biocompatibility, selectivity, sensitivity, and rapid adsorption kinetics. Carbon nanofiber nanoelectrodes exhibit greater selectivity and sensitivity in the electrochemical detection of neurotransmitters compared to macroelectrodes and are able to resolve a ternary mixture of dopamine (DA), serotonin (5-HT), and ascorbic acid as well as to detect individual neurotransmitters in concentrations as low as 50 nM for DA and 100 nM for 5-HT using differential pulse voltammetry. Adsorption kinetics studies and isopropyl alcohol treatments modeled on previous studies on carbon fiber microelectrodes were conducted to investigate the analogous properties on carbon nanofiber electrodes using fast-scan cyclic voltammetry with WINCS and showed analogous results in carbon nanofiber electrodes compared with carbon fiber microelectrodes.
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paper_title: Comparison of Nafion- and overoxidized polypyrrole-carbon nanotube electrodes for neurotransmitter detection

paper_content:

Permselective polymer coatings improve selectivity and sensitivity of microelectrodes for cationic neurotransmitters. Immobilizing carbon nanotubes (CNTs) into these polymers should further improve sensitivity by increasing the electroactive surface area. The goal of this study was to compare the electrochemical properties of overoxidized polypyrrole (oPPY)-CNT and Nafion-CNT coated microelectrodes. Fast-scan cyclic voltammetry was used to test their response to neurochemicals. For dopamine, the average increase in oxidation current compared to bare electrodes was 3.7 ± 0.5 for oPPY-CNT electrodes (limit of detection (LOD) = 3.3 ± 0.6 nM) and 3.3 ± 0.8 for Nafion-CNT electrodes (LOD = 4 ± 1 nM). The selectivity for dopamine over ascorbic acid was better with oPPY-CNT electrodes. oPPY-CNT electrodes also displayed increased electron transfer kinetics for anions while Nafion-CNT electrodes did not, which proves that polymer deposition can affect the electrocatalytic properties of the CNTs. Both oPPY-CNT and Nafion-CNT electrodes were used to detect stimulated dopamine release in the caudate-putamen of anesthetized rats after 2, 4 and 12 pulse stimulation trains. oPPY-CNT electrodes could also detect small amounts of dopamine after 4 and 12 pulse stimulations in the basolateral amygdala (BLA). Although Nafion-CNT electrodes were easier to make, oPPY-CNT electrodes were more advantageous for dopamine detection because they were reproducibly fabricated, measured higher currents in vivo, and maintained selectivity over anions. The addition of CNTs to polymer coatings facilitates measurements of small concentrations of neurotransmittersin vivo.
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paper_title: A molecule-imprinted polyaniline membrane modified on carbon fiber for detection of glycine

paper_content:

A layer of L-glycine-molecule-imprinted polyaniline (LMIP-PANI) polymer film has been modified on a carbon fiber electrode for the determination of L-glycine standard samples and L-glycine in cerebrospinal fluid of wistar mice. It has been found that a linear relationship exists between current and concentration for the glycine standard samples in the range of 0-12 μM by using the LMIP-PANI-modified carbon fiber electrode as a sensor. However, there is no any relationship between current and concentration for the carbon fiber electrode modified with no-glycine-molecule-imprinted polyaniline (NIP-PANI). The MIP-PANI- and NIP-PANI-modified carbon fiber films have been characterized by scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS) and electrochemistry methods. The investigation shows that the MIP-PANI-imprinted carbon fiber electrode will have a potential application in in-situ monitoring neurotransmitter due to its easy fabrication, low cost, bio-compatibility and flexibility.
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paper_title: New integrated in vivo microdialysis-electrochemical device for determination of the neurotransmitter dopamine in rat striatum of freely moving rats

paper_content:

A new kind of device was developed based on integrating in-vivo microdialysis with electrochemical microsensing. It can be applied to in-vivo determination of dopamine in rat striatum of freely moving rats. The microsensor was fabricated by electrochemically depositing a film containing overoxidized polypyrrole and multi-wall carbon nanotubes onto a carbon fiber microelectrode. It causes efficient and selective electrocatalytic oxidation of dopamine and displays relatively good stability and lifetime. The oxidation currents for dopamine are linear in the concentration range from 5.0 nM to 10 μM, and the detection limit (at S/N = 3) is 0.5 nM. The integrated device was successfully applied to assessing the impact of an endogenous donor of nitric oxide (sodium nitroprusside) on the concentration of dopamine in striatum of moving rats. This is of significance to understand the physiological basis of Parkinson’s disease.
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paper_title: 5×5 CMOS capacitive sensor array for detection of the neurotransmitter dopamine.

paper_content:

This work presents miniaturized CMOS (complementary metal oxide semiconductor) capacitive sensors for detection of the neurotransmitter dopamine (DA) down to the sub-fM range. Sensing resolution is significantly enhanced by monolithic sensor integration to reduce the parasitic effect and the use of sub-μm interdigitated microelectrodes as the sensing interface. The 5 × 5 sensor array contains five designs of different electrode sizes and each design has five sensors. The positive charges produced from protonation of boronate and amino group after immobilization of 4-carboxyphenylboronic acid (CPBA) result in an increase of the electrode-analyte capacitance. Then the negative charges produced after binding of CPBA and DA molecules decrease the electrode-analyte capacitance. Signal transduction is achieved through a CMOS readout circuit whose output frequency is inversely proportional to the capacitance. Experimental results showed the ratios of average percentage capacitance changes of the experiment groups over those of the control groups were all larger than one for the five designs at DA concentration of 0.1 fM. Selectivity against the non-analyte species, such as tyramine, has also been demonstrated.
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paper_title: Analysis of biogenic amines in a single Drosophila larva brain by capillary electrophoresis with fast-scan cyclic voltammetry detection.

paper_content:

Drosophila, the fruit fly, is a common model organism in biology; however, quantifying neurotransmitters in Drosophila is challenging because of the small size of the central nervous system (CNS). Here, we develop neurotransmitter quantification by capillary electrophoresis with fast-scan cyclic voltammetry (CE-FSCV) detection, which allows peak identification by both migration time and the cyclic voltammogram, in contrast to traditional amperometric detection which provides no chemical identification. Tissue content of biogenic amine neurotransmitters was determined in a single CNS dissected from a Drosophila larva. Low detection limits, 1 nM for dopamine and serotonin, 2.5 nM for tyramine, and 4 nM for octopamine, were achieved using field-amplified sample stacking by diluting the homogenized tissue with percholoric acid and acetonitrile. Two different strains of wild-type flies, Oregon R and Canton S, have similar dopamine and serotonin levels but different octopamine content. When flies are fed NSD-1015, which inhibits dopamine decarboxylase (Ddc) a synthesis enzyme in the dopamine and serotonin pathways, dopamine significantly decreases by 52%. A genetically altered driver line, Ddc-GAL4, had lower serotonin and dopamine content as did w(118) flies. When the Ddc-GAL4 line was used to produce flies overexpressing the serotonin synthesis enzyme tryptophan hydroxylase (Ddc-GAL4;UAS-Trh), the serotonin tissue content was greater than for Ddc-GAL4 but not significantly different than the wild-type. These results show that CE-FSCV is useful for monitoring the impact of genetic and pharmacological manipulations on the content of multiple neurotransmitters in a CNS from a Drosophila larva.
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paper_title: First Evidence of Increased Plasma Serotonin Levels in Tako-Tsubo Cardiomyopathy

paper_content:

Background. There is no data about the serotonergic activity during the acute phase of Tako-Tsubo Cardiomyopathy (TTC). The objective of our study was to investigate evidence of serotonin release from patients with TTC in comparison with patients with ST elevation myocardial infarction (STEMI) and healthy control subjects (HCS). Methods and Results. Plasma serotonin levels in 14 consecutive patients with TTC were compared with those in 14 patients with STEMI and 14 HCS. Plasma serotonin levels at admission were markedly higher in patients with TTC and STEMI as compared to HCS (, versus control; , versus control; and ng/mL, resp.). There was no difference in serotonin levels between patients with TTC and those with STEMI (). Conclusion. This finding suggests that serotonin could participate to the pathophysiology of TTC.
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paper_title: Sources and Significance of Plasma Levels of Catechols and Their Metabolites in Humans

paper_content:

Human plasma contains several catechols, including the catecholamines norepinephrine, epinephrine, and dopamine, their precursor, l-3,4-dihydroxyphenylalanine (l-DOPA), and their deaminated metabolites, dihydroxyphenylglycol, the main neuronal metabolite of norepinephrine, and dihydroxyphenylacetic acid, a deaminated metabolite of dopamine. Products of metabolism of catechols include 3-methoxytyrosine (from l-DOPA), homovanillic acid and dopamine sulfate (from dopamine), normetanephrine, vanillylmandelic acid, and methoxyhydroxyphenylglycol (from norepinephrine), and metanephrine (from epinephrine). Plasma levels of catechols and their metabolites have related but distinct sources and therefore reflect different functions of catecholamine systems. This article provides an update about plasma levels of catechols and their metabolites and the relevance of those levels to some issues in human health and disease.
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paper_title: An Ultrasensitive Nanowire-Transistor Biosensor for Detecting Dopamine Release from Living PC12 Cells under Hypoxic Stimulation

paper_content:

Dopamine (DA) is an important neurotransmitter that is involved in neuronal signal transduction and several critical illnesses. However, the concentration of DA is extremely low in patients and is difficult to detect using existing electrochemical biosensors with detection limits typically around nanomolar levels (∼10–9 M). Here, we developed a nanoelectronic device as a biosensor for ultrasensitive and selective DA detection by modifying DNA-aptamers on a multiple-parallel-connected (MPC) silicon nanowire field-effect transistor (referred to as MPC aptamer/SiNW-FET). Compared with conventional electrochemical methods, the MPC aptamer/SiNW-FET has been demonstrated to improve the limit of DA detection to <10–11 M and to possess a detection specificity that is able to distinguish DA from other chemical analogues, such as ascorbic acid, catechol, phenethylamine, tyrosine, epinephrine, and norepinephrine. This MPC aptamer/SiNW-FET was also applied to monitor DA release under hypoxic stimulation from living P...
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paper_title: CMOS Capacitive Sensors With Sub- $\mu$m Microelectrodes for Biosensing Applications

paper_content:

Miniaturized complementary metal-oxide semiconductor (CMOS) capacitive sensors presented in this work are capable of providing sensitive detection in the sub-nM range for biosensing applications. A convenient post-CMOS fabrication process is proposed to make sub-μm interdigitated microelectrodes covered by inter-metal dielectric layer as the sensing interface. Capacitance change due to the electrode-analyte impedance is detected by the integrated continuous-time sensing circuit. For immunodetection of mouse IgG and anti-mouse IgG enhanced by 25% gold nanoparticles, the produced interface capacitance changes after specific bindings were -4, -7.4, and -17 fF for the 13-, 95-, and 925-fF microelectrode designs, respectively. Detection of the 200-nM neurotransmitter dopamine (DA) showed interface capacitance changes of 0.22,1.46, and 22 fF for the three designs. Based on the measured circuit noise of 14.2 μV/Hz1/2, the minimum detectable capacitance changes were 0.3, 2.9, and 22.5 aF, equivalent to detectable DA concentrations of 309, 394, and 203 pM, respectively.
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paper_title: Mediator-less highly sensitive voltammetric detection of glutamate using glutamate dehydrogenase/vertically aligned CNTs grown on silicon substrate.

paper_content:

A sensitive glutamate biosensor is prepared based on glutamate dehydrogenase/vertically aligned carbon nanotubes (GLDH, VACNTs). Vertically aligned carbon nanotubes were grown on a silicon substrate by direct current plasma enhanced chemical vapor deposition (DC-PECVD) method. The electrochemical behavior of the synthesized VACNTs was investigated by cyclic voltammetry and electrochemical impedance spectroscopic methods. Glutamate dehydrogenase covalently attached on tip of VACNTs. The electrochemical performance of the electrode for detection of glutamate was investigated by cyclic and differential pulse voltammetry. Differential pulse voltammetric determinations of glutamate are performed in mediator-less condition and also, in the presence of 1 and 5 μM thionine as electron mediator. The linear calibration curve of the concentration of glutamate versus peak current is investigated in a wide range of 0.1-500 μM. The mediator-less biosensor has a low detection limit of 57 nM and two linear ranges of 0.1-20 μM with a sensitivity of 0.976 mA mM(-1) cm(-2) and 20-300 μM with a sensitivity of 0.182 mA mM(-1) cm(-2). In the presence of 1 μM thionine as an electron mediator, the prepared biosensor shows a low detection limit of 68 nM and two linear ranges of 0.1-20 with a calibration sensitivity of 1.17 mA mM(-1) cm(-2) and 20-500 μM with a sensitivity of 0.153 mA mM(-1) cm(-2). The effects of the other biological compounds on the voltammetric behavior of the prepared biosensor and its response stability are investigated. The results are demonstrated that the GLDH/VACNTs electrode even without electron mediator is a suitable basic electrode for detection of glutamate.
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Title: Microelectronics-Based Biosensors Dedicated to the Detection of Neurotransmitters: A Review

Section 1: Introduction
Description 1: Provide an overview of neurotransmitters, their importance in the diagnosis and treatment of neurological diseases, and traditional detection methods and their limitations.

Section 2: Voltammetry, Amperometry and Potentiostat
Description 2: Discuss the principles of voltammetry, amperometry, and potentiostat techniques, their use in neurotransmitter detection, types of voltammetric methods, and electrode modifications to enhance sensitivity and selectivity.

Section 3: Voltammetry in Wireless and Implantable Devices
Description 3: Explore how voltammetry can be integrated into wireless and implantable devices for real-time neurotransmitter monitoring, and review existing research and advancements in this field.

Section 4: Voltammetry for Simultaneous Measurement of NTs
Description 4: Explain the challenges and techniques for the simultaneous measurement of multiple neurotransmitters, focusing on electrode modifications and innovative approaches to achieve selective detection.

Section 5: Carbon Nanotubes Electrodes
Description 5: Describe the use of carbon nanotubes (CNTs) in electrode fabrication for neurotransmitter detection, highlighting the advantages of CNTs, different methods of incorporating CNTs into electrodes, and recent research findings.

Section 6: CNTs in Simultaneous Detection of Neurotransmitters
Description 6: Discuss the application of CNTs for the simultaneous detection of multiple neurotransmitters, examining research on CNT-modified electrodes and their performance in real-world samples.

Section 7: CNTs in Implantable Devices
Description 7: Review the integration of CNTs in implantable devices for in vivo neurotransmitter monitoring, considering the benefits and challenges, including long-term biocompatibility and sensitivity.

Section 8: CMOS Technology
Description 8: Investigate the role of complementary metal-oxide semiconductor (CMOS) technology in developing biosensors for neurotransmitter detection, focusing on the scalability, low-cost production, and integration of CMOS with electrochemical sensing techniques.

Section 9: Further Direction
Description 9: Suggest future research directions and potential innovations in microelectronics-based biosensor technology for neurotransmitter detection, including hybrid microelectronics/microfluidic platforms and other advanced techniques.

Section 10: Applicability
Description 10: Evaluate the practical applicability of the discussed technologies, emphasizing devices' capability to detect neurotransmitters in clinically relevant concentrations and their potential for in vivo and in vitro applications.

Section 11: Conclusions
Description 11: Summarize the key points discussed in the review, the potential of microelectronic biosensors in neurotransmitter detection, and the future outlook for these technologies in diagnostic and neuroprosthetic applications.