EP1226425A1 - Microscopic combination amperometric and potentiometric sensor - Google Patents
Microscopic combination amperometric and potentiometric sensorInfo
- Publication number
- EP1226425A1 EP1226425A1 EP00976858A EP00976858A EP1226425A1 EP 1226425 A1 EP1226425 A1 EP 1226425A1 EP 00976858 A EP00976858 A EP 00976858A EP 00976858 A EP00976858 A EP 00976858A EP 1226425 A1 EP1226425 A1 EP 1226425A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- sensor
- electrode
- amperometric
- electrodes
- sensors
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
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Classifications
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
- G01N27/28—Electrolytic cell components
- G01N27/30—Electrodes, e.g. test electrodes; Half-cells
- G01N27/327—Biochemical electrodes, e.g. electrical or mechanical details for in vitro measurements
- G01N27/3275—Sensing specific biomolecules, e.g. nucleic acid strands, based on an electrode surface reaction
- G01N27/3277—Sensing specific biomolecules, e.g. nucleic acid strands, based on an electrode surface reaction being a redox reaction, e.g. detection by cyclic voltammetry
Definitions
- the present invention relates to an amperomet ⁇ c and potentiomet ⁇ c sensor array More specifically, the present invention relates to a microscopic amperomet ⁇ c and potentiomet ⁇ c sensor array 2 DESCRIPTION OF RELATED ART
- a typical electrode site includes an electrode, a driving element coupled to the electrode for applying an electrical stimulus to the electrode, and a local memory coupled to the driving element for receiving and storing a signal indicative of a magnitude of the electrical stimulus to be applied to the electrode
- an electronic device for monitoring active biological operations including a support substrate, at least one amperomet ⁇ c sensor, and at least one potentiomet ⁇ c sensor
- Figures 1 A and B is a schematic diagram of a sensor array with rectangular electrode geometry
- Figure 1A is a three electrode conformation where the counter electrode serves the dual function as potentiometric electrode
- Figure 1 B is a four electrode conformation
- Figure 2 is a cross section image of the working and reference electrodes;
- Figure 3 is a legend showing distinctions between platinum, silver and the contact;
- Figure 4 is a schematic showing a 2 ⁇ m contact size
- Figure 5 is a schematic showing a 4 ⁇ m contact size
- Figure 6 is a schematic showing an 8 ⁇ m contact size
- Figure 7 is a schematic showing a 32 ⁇ m contact size
- Figure 8 is a schematic showing a 100 ⁇ m contact size
- Figure 9 is a picture showing an X ⁇ m contact size
- FIG. 10 is a block diagram for the present invention.
- Figures 11 is a photomicrograph of an X ⁇ m electrode size
- Figure 12 is a photomicrograph of a 32 ⁇ m electrode
- Figures 13 is a photomicrograph of a 100 ⁇ m electrode which is in complete scale with the above figures;
- Figure 14 is a schematic showing the amperometric circuitry of the present invention.
- FIGS 15 A-C are schematics of the ultra-low noise potentiomet ⁇ c
- Figure 16 is a schematic of the ultra-low noise amperometric current-to-
- Figure 17 is a schematic of an amperometric sensor function generator
- Figure 18 is a schematic of an amperometric controller functional block
- Figure 19 is an image of the carrier printed circuit board and the sensor controlling/monitoring circuitry constructed on bread boards,
- Figure 20 is an amperometric dose response curve for dopamine which oxidizes at approximately 300mV v Ag/AgCI reference, 650mV signal remains unaltered,
- Figure 21 is a cyclic voltammogram of dopamine in conditioned culture medium
- Figure 22 is superimposed traces of oxidatively derived current versus time transduced by all 16 amperometric sensors in the array simultaneously,
- Figure 23 is an image of the six foot Baker EdgeGARD horizontal laminar flow hood encased with stainless steel screen and plastic sheeting to provide a Faraday cage free of electronic noise with constant temperature environment,
- Figure 24 is a photomicrograph of nearly confluent hNT cells cultured on a 4 ⁇ m electrode size sensor array
- Figures 25 A and B are a photomicrographs wherein Figure 25A is a light field and Figure 25B is a dark field illumination of hNT cells on day 4 of
- the present invention provides an electronic device 10 for monitoring active biological operations and/or analyte chemical reactions having a support substrate 12, at least one amperometric sensor 14, and at least one potentiomet ⁇ c sensor 16
- the sensors of the present invention can detect neuronal action potentials and the resulting release of neurotransmitting and/or hormones
- the sensors can also detect the diffusion, dispersion, degradation, and re-uptake of neurotransmitters, hormones and/or other cellular metabolites
- support substrate it is meant a substrate on which a sensor array is placed or integrated This can be made of, but is not limited to, ceramic, glass and silicon
- Coulometry is the determination of charge passed or projected to pass during complete or nearly complete electrolysis of an analyte, either directly on the electrode or through one or more electron transfer agents
- the current, and therefore analyte concentration is determined by measurement of charge passed during partial or nearly complete electrolysis of the analyte or, more often, by multiple measurements during the electrolysis of a decaying current and elapsed time
- a "counter electrode” refers to an electrode paired with the working electrode, through which passes an electrochemical current equal in magnitude
- counter electrode is meant to include counter electrodes which can have the dual function as a potentiometric reference electrode (i e a counter/potentiomet ⁇ c electrode)
- An “amperometric electrochemical sensor” is a device configured to detect the presence and/or measure the concentration of an analyte via electrochemical oxidation and reduction reactions on the sensor These reactions are transduced to an electrical signal that can be correlated to an amount or concentration of analyte
- Electrolysis is the electrooxidation or electroreduction of a compound either directly at an electrode or via one or more electron transfer agents
- An example of this includes, but is not limited to, using Glucose Oxidase to catalyze Glucose oxidation creating oxidized Glucose and Peroxide, where the Peroxide is being measured
- facing electrodes refers to a configuration of the working and counter electrodes in which the working surface of the working electrode is disposed in approximate apposition to a surface of the counter electrode A compound is "immobilized” on a surface when it is physically entrapped on or chemically bound to the surface
- the "measurement zone” is defined herein as a region of the sample chamber sized to contain only that portion of the sample that is to be interrogated during the analyte assay
- a “non-leachable” or “non-releasable” compound is a compound which does not substantially diffuse away from the working surface of the working and/or counter electrodes for the duration of the analyte assay
- a “redox mediator” is an electron transfer agent for carrying electrons between the analyte and the working electrode, either directly, or via a second electron transfer agent
- a “reference electrode” is an electrode used to monitor and account for voltage drop due to medium resistance in amperometric sensors, and supplies a reference potential for comparison in potentiometric electrodes
- a “second electron transfer agent” is a molecule which carries electrons between the redox mediator and the analyte (See example above)
- Sorbent material is material which wicks, retains, or is wetted by a fluid sample in its void volume and which does not substantially prevent diffusion of the analyte to the electrode
- a "counter electrode” is an electrode at which analyte is electrooxidized or electroreduced with or without the agency of a redox mediator
- the "working electrode” supplies the potential source to affect oxidation/reduction
- a “working surface” is that portion of the working electrode which is coated with redox mediator and configured for exposure to sample
- Electrochemical detection specifically amperometry, has been used in
- the proposed system employs two particular forms of amperometry, cyclic and constant voltage voltammetry Second, utilizing a micro-screen printing device, such as a New Long LS-15TV, several different selectivity membranes can be applied over the individual sensors to eliminate background measurement of unwanted compounds (such as ascorbic acid) and impart specificity onto the microscopic electrodes comprising the sensor (Goldberg et al, 1994) Finally, by encapsulating the multi-site sensor array leads with silicon nitride, a substrate upon which neurons can be made to readily attach, the sensor array is in very close apposition to the secreting neurons allowing measurement of the relatively high neurotransmitter concentrations in the immediate vicinity of the axon, prior to degradation, dilution, dispersion, and re-uptake
- An amperometric process is a technique whereby a cyclically repeated triangular waveform of potential is applied between the working and counter electrodes
- Individual analytes such as neurotransmitters, have characteristic oxidation and reduction potentials based on their chemical moieties (Adams, 1969, Dryhurst et al, 1982) When the voltage between the
- Cyclic voltammetry is capable of providing further confirmation of the identity of an analyte by measuring its reduction potential as well as its oxidation potential (Oldham et al , 1989, Heineman et al , 1989) As the electrode potential is scanned toward a negative potential, a cathodic peak is obtained due to reduction of the analyte, Ox, to form a reduced metabolite, Red, according to the following equation
- ne is the number of electrons transferred in the reaction (Hush et al, 1971 )
- the voltage sweep then reverses direction and scans towards a positive potential If the scan rate is sufficiently rapid, some of the Red produced by the
- cathodic sweep can still be in the vicinity of the electrodes and are reoxidized to Ox, producing the anodic peak (Adams, 1969)
- the anodic and cathodic peak potentials are separated by the
- ne is the number of electrons involved in the oxidation and reduction (Oldham et al , 1989) If the electrode reaction is not completely reversible, i e stable intermediate reaction products are produced, then the peak potentials are separated by a characteristic, but more than expected value (Oldham et al, 1989, Hush et al, 1971 ) This is the case for ascorbate the oxidation of ascorbate produces dehydroascorbate, a fairly stable product (Adams, 1969, Oldham et al, 1989, Rose, 1989) For totally irreversible reactions, one of the peaks disappears completely Independent of the extent of reversibility, the anodic/cathodic peak voltage difference is constant for any particular voltage scan rate, and in addition to oxidation voltage, it can be used to determine analyte identity (Rose et al, 1989, Wang et al, 1997)
- Amperometric techniques are very sensitive to the voltage scan rate When slow scan rates ( ⁇ 200 mV/sec) are used, all of the analyte in the immediate vicinity of the electrodes is oxidized Sensor measurements are then limited by the diffusion of unoxidized analyte to the electrode surface This
- Cyclic voltammetry provides the ability to measure the concentrations of several molecules sequentially in a single scan, as long as their oxidation potentials differ For example, the concentrations of dopamine, norepineph ⁇ ne, serotonin, and ascorbate can all be monitored sequentially from a mixture of these compounds, the value of oxidatively-de ⁇ ved current flow is captured at the characteristic potentials for each analyte Once the identity of the analyte is confirmed using cyclic voltammetry, high speed measurements (> 20 kHz) can be achieved by utilizing constant voltage voltammetry
- Constant voltage voltammetry employs a single operating potential to effect oxidation This technique is used most commonly by investigators since it is the simplest to implement, both in terms of the controlling circuitry, and especially in the data acquisition phase
- One major advantage to constant voltage voltammetry is that the sensor can be sampled at a very high rate allowing elucidation of the dynamics of neurotransmitter secretion, degradation, and re-uptake
- the drawback to this technique is that it lacks specificity since all molecules within the vicinity of the electrodes whose oxidation potential is less than that applied to the electrodes oxidize and contribute to the value of the measurement
- membranes can be provided by depositing membranes on them Several different classes of membranes are available for use Several ion exchange materials, such as Nafion, poly(v ⁇ nylpy ⁇ d ⁇ ne), and poly(ester sulfonic acid) act as ion exclusion membranes (Wang et al , 1997, Su et al , 1990, Runnels et al , 1999, Brazell et
- Neurotransmitters produced by certain neurons are not electroactive, however, they are stored in vesicles and packaged with granms and chromogranins, protective anti-oxidant molecules that sac ⁇ ficially prevent neurotransmitter degradation (Winkler et al , 1992, Bassetti et al , 1990, Huttner et al , 1991 , Konecki et al , 1987) If the neuronal product is not oxidizable (such as magnocellular neurons in the hypothalamus) the co-secreted molecules can be measured Fortunately, these neuronal product is not oxidizable (such as magnocellular neurons in the hypothalamus) the co-secreted molecules can be measured Fortunately, these neuronal product is not oxidizable (such as magnocellular neurons in the hypothalamus) the co-secreted molecules can be measured Fortunately, these neuronal product is not oxidizable (such as magnocellular neurons in the hypothalamus) the co-secreted molecules can
- the small volume of the in vitro analyte sensors of the present invention are designed to measure the concentration of an analyte in a portion of a sample having a volume less than about 1 ⁇ L, preferably less than about 0 1 ⁇ L, more preferably less than about 0 01 ⁇ L, and most preferably less than about 0 001 ⁇ L
- the analyte of interest is typically provided in a solution or biological fluid, such as blood or serum
- a small volume, in vitro electrochemical sensor 20 of the invention generally includes a working electrode 22, a counter electrode 25, a reference electrode, and a sample chamber 26
- the sample chamber 26 is configured so that when a sample is provided in the chamber the sample is in electrolytic contact with both the working electrode 22, the counter electrode 25, and the reference electrode 24 This allows electrical current to flow between the electrodes to effect the electrolysis (electrooxidation or electroreduction) of the
- the counter and/or working electrode can be formed from a molded
- carbon fiber composite or can consist of an inert non-conducting base material, such as polyester, upon which a suitable conducting layer is deposited
- the conducting layer should have relatively low electrical resistance and should be
- Suitable conductors include gold, carbon, platinum, ir ⁇ dium, and palladium, as well as other non-corroding materials known to those skilled in the art
- the electrode and/or conducting layers are deposited on the surface of the inert material by methods such as vapor deposition or printing
- a tab 22 is provided on the end of each electrode 23 for easy connection of the electrode to external electronics such as a voltage source or current measuring equipment Other known methods or structures may be used to connect the electrodes 22 to the external electronics
- amperometric and potentiometric sensors were designed and constructed in a 4 x 4 array on silicon utilizing CMOS technology
- the amperometric and potentiometric sensors are general purpose devices which can be modified to detect and quantify a wide range of analytes (cellular products) depending upon the electronic method of operation at the amperometric sensors and upon the selection of membrane lonophores, enzymes, antibodies and for the potentiometric sensors
- membranes can also be utilized on the amperometric sensors to confer added specificity
- Table 1 contains a process for forming the sensor array
- the resulting sixteen sensor sites are arranged into a 4 x 4 array
- the surface of the counter and working electrodes are platinum to provide a
- each sensor site and the global reference electrode are coated with silver (Ag) and electrolytically chlo ⁇ dized to provide reversible Ag/AgCI electrodes
- a fabrication process was also used to chlo ⁇ dize the Ag reference electrodes in a batch-wise manner This fabrication process entails using a reactive ion etch (RIE) plasma as a chloride source
- RIE reactive ion etch
- electrode orientation was altered from site to site This provides the capability to combine electrodes from adjacent sites to act as a single larger electrode providing more flexibility for studying the effect of electrode size on the electrochemical response curves
- a single platinum electrode can be used as a working electrode for the
- each of the former working electrodes is available to function as a potentiometric electrode
- This provides the capability to monitor 16 amperometric sensors (both with chrono-amperometry and cyclic voltammetry) and 16 potentiometric sensors simultaneously
- the only limitation this produces is that each amperometric sensor has to cycle in concert for the cyclic voltammograms This is not an issue since concerted cycling is generally employed
- the physical distance between the amperometric and potentiometric electrodes is very small (4-20 ⁇ m depending upon the electrode size) providing for example the ability to monitor neuronal action potentials and neurotransmitter release from a single cell
- Alternate configurations include producing arrays of four electrode units, three of which are used for amperometry while the fourth is used for potentiometric action potential determinations
- the sensor arrays are fabricated in a three-mask process with two (and/or three or four - see below) metal electrode layers, silver (Ag) and platinum (Pt) Since Ag and Pt are difficult to etch using wet chemistry, a resist lift-off process is used to pattern them, however wet chemistry can be employed to etch the Pt, Ag, or any other metals used
- the lift-off process provides an additional advantage in allowing the use of layered materials in the metal structure to modify electrode properties and still allows for patterning to occur in one step (see cross section presented in Figure 2)
- the metal lift-off step has been improved by utilizing a short undercut etch to promote easier release of excess material
- a short etch is performed on the underlying dielectric
- This etch is a wet HF acid etch of the silicon dioxide in the case of the platinum metallization and a reactive ion etch (RIE) of the silicon nitride for the silver (Ag) sites
- RIE reactive ion etch
- This etch performs two functions First, since the resist tends to be undercut in a wet etch, a small gap is formed under the resist edge After metal deposition, the gap forms a natural breakline during lift-off that prevents metal, coating the sidewalls of the resist, from remaining behind on the device forming vertical spikes or walls These spikes are very difficult to cover completely in later dielectric depositions and can form short circuits to solution Second, if the etch is timed properly, it also plana ⁇ zes the sensor topography by submerging the metal layer into the dielectric 38
- the Ag layer is deposited on top of a PECVD silicon nit ⁇ de layer Since wet etches for silicon nitride are difficult to control and react with metallization used in circuit processes, an RIE machine is used for the etching of this dielectric Due to the vertical directional nature of an RIE, it does not provide the undercut and gap described above in a wet etch However, the steep sidewalls created in the dielectric enhance the lift-off effect and with the addition of the recessed metal layer the result is that the surface is more planer than if no etch is performed If CMOS circuitry is not intended to be present on the chip, an undercut etch can be performed after the RIE which aids in the liftoff process
- LTO low temperature oxide
- nitride Parahne
- spin-on-glass Polyimide
- TEFLONTM TEFLONTM
- Evaporators presently used to deposit platinum for these devices have a maximum allowable thickness of 1000A Combined with the fine line-width for metallization on the smaller devices, this factor causes a large resistance in series with the electrodes To reduce this resistance an alternate metallization technology was devised After depositing the titanium adhesion layer, gold is evaporated onto the surface A second adhesion layer of titanium is applied
- PCB printed circuit boards
- Figure 19 Two printed circuit boards (PCB) ( Figure 19) 30 were designed and constructed to provide a simple and easy to use interface between the sensor bearing ceramic carrier and the potentiometric and amperometric circuitry
- the PCBs contain a zero insertion force (ZIF) 32 socket that allows rapid swapping of the ceramic carriers, and a series of connector rails 34 that provide access to each individual electrode within the sensor array
- ZIF zero insertion force
- the PCB 30 is a three-layer board with the inner layer constituting a ground plane to help reduce environmental noise
- potentiometric electrodes In this manner, it was possible to monitor 16 amperometric sensors (both with constant voltage and cyclic voltammetry) and 16 potentiometric sensors simultaneously Further, the physical distance between the amperometric and potentiometric electrodes was very small (4 to
- amperometric sensors can be cycled independently, in which case the proximity of the electrodes must be carefully monitored to prevent interference between the electrodes
- the amperometric and potentiometric circuitry was constructed on breadboards allowing manipulation of the components responsible for gam, filtering, etc ( Figure 19) Using this technique, a variety of circuitry parameters were easily altered and optimized to provide relatively noise free data from the individual electrodes within each of the sensor arrays
- the 16 channels of output from the potentiometric sensor circuitry were connected to 16 channels of input on a high speed, 16-b ⁇ t, National Instruments a/d board (PCI-MIO16XH) housed in a PowerPC Macintosh computer
- PCI-MIO16XH National Instruments a/d board
- the 16 channels of output from the amperometric sensor circuitry were connected to 16 channels of input on another high speed, 16-b ⁇ t, National Instruments a/d board (NB-MIO16XH) housed in a separate Macintosh computer
- NB-MIO16XH National Instruments a/d board housed in a second computer
- the maximum sampling rate of the NB was less than that of the PCI
- the PCI board was used to monitor the potentiometnc sensors that transduced the neural action potentials (the highest speed component) while the NB board was used to monitor the amperometric sensors that transduced the secreted neurotransmitters (the slower speed component)
- the sample rates were maintained at the maximum that each board would allow while maintaining whole number multiples of each other, simplifying direct comparison of data from each computer system
- a/d sampling rates were 6kHz for the potentiometnc sensors and 2kHz for the amperometric sensors
- cellular activity was detected on a potentiomet ⁇ c/amperomet ⁇ c set of sensors, that subset of sensors was monitored at higher sampling rates
- 16 sensor 8 potentiometnc and 8 amperometric were monitored at 12kHz for the potentiometnc and 4kHz for the amperometric
- the potentiometnc rate was 60kHz and
- the sensor array was first coated with poly-D-lysme to promote bonding of the Mat ⁇ gel matrix Sterile poly-D-lysine, at a concentration of 10 ⁇ g/ml in distilled water, was applied to each of the 2mm x 2mm exposed sensor arrays and allowed to incubate at room temperature for 2 hours The poly-D-lysine solution was then aspirated with a sterile pipette The sensor arrays were placed at an incline with lids off in a sterile laminar flow hood and allowed to dry
- Mat ⁇ gel matrix was thawed overnight in a refrigerator, and then diluted to
- Mat ⁇ gel matrix was applied to each sensor array and spread evenly using a Pasture pipette The solution was allowed to completely dry at room temperature in a sterile laminar flow hood The Mat ⁇ gel application was then
- the sensor arrays could be stored for at least 2 months with one coat of poly-D-lysine and one coat of Mat ⁇ gel matrix The final coat of Mat ⁇ gel matrix
- the sensor arrays were tested for their ability to monitor neurotransmitters simultaneously and independently These measurements were conducted using hNT conditioned DMEM/F12 culture medium (Stratagene,
- the medium was equilibrated for temperature and CO 2 in a mammalian cell incubator for 30 minutes prior to testing
- Dose response curves for dopamine were generated by performing cyclic voltammetry utilizing the microscopic sensor arrays Oxidatively derived currents generated at the unique oxidation potential for dopamine, approximately 500mV versus silver/silver chloride reference, were stored and plotted as a dose response curve in Figure 20
- a six-foot EdgeGARD horizontal laminar flow hood (The Baker Company, Sanford, Maine) was modified for use in data acquisition
- the hood was lined with stainless steel small mesh screen
- the screening when grounded, provided a nearly electronic noise-free environment within the hood, essentially mimicking an
- the laminar flow hood was also modified to provide a heated, constant temperature environment (37C) to maintain normal physiological activity within the cultured cells Towards this goal, the hood was lined with an additional layer of plastic sheeting to make the inner chamber nearly air tight A standard hair dryer, controlled by an inexpensive digital temperature regulator (Fisher Scientific, Chicago, IL), was used as the heat source The hair dryer was located outside of the Faraday cage to minimize electronic noise at the sensor arrays The heated air was transported to the interior through a 4- ⁇ nch diameter metal dryer duct The thermocouple probe for the temperature controller was placed in close proximity to the cells This inexpensive setup provided a constant temperature environment with approximately 0 5C temperature fluctuations
- the experimental setup allowed rapid transfer and electrical connection of the culture chambers with integrated sensor arrays to the electronic circuitry Using this setup, one could easily monitor dozens of culture chambers with integrated sensor arrays daily hNT cells were procured from Stratagene (Catalog #204104, Lot
- membranes depositing membranes on them Several different classes of membranes are available for use Nafion acts as a cation exchange membrane (Brazell et al , 1987), allowing only uncharged molecules to gam access to the electrodes Additionally, various mixtures of cellulose acetate can be prepared which act as size exclusion membranes, allowing only specific molecular weight species to gam access to the electrodes This is critical when monitoring large bioagent molecules Often, large bioagent molecules degrade into a variety of breakdown products It is possible that only the parent bioagent exerts a biological effect and the break down products do not, however, several of the break down products may oxidize at potentials very close to the parent molecule when monitored amperomet ⁇ cally Using a variety of decreasing size exclusion membranes on the sensors in the array, the concentration of the parent bioagent molecule can be determined as well as each of its break-down products uniquely
- One goal of the present invention is to augment semiconductor sensor technologies with new formulations of membranes containing lonophores, antibodies and enzymes, to enable the array to monitor a wide range of biological analytes, environmental toxins, as well as standard blood chemistries (i e electrolytes, antibodies, steroid and protein hormones, anesthetics, a variety of herbicides, medicinal drugs, drugs of abuse, etc )
- Other complex molecules, such as neurotoxins and molecules of biological warfare can be detected by immobilizing antibodies and/or enzymes on the surface of an lon-
- One example of monitoring complex molecules with a membrane is a
- membranes include, but are not limited to, Cellulose Acetate, Poly-Urethane/Poly-Vmyl Chloride, and Si cone Rubber Each of these membrane compositions possess differing properties as related to enzyme and antibody immobilization and adherence to the silicon nitride surface of microscopic solid-state chemical sensors Several methods are available for immobilizing enzymes and antibodies on the surface of the membranes Additional techniques amenable to monitoring organophosphorous containing compounds, including Paraoxon, can also be used Enzymes have been incorporated into a hydrophihc polyurethane membrane and deposited on
- hydrophobic polyurethane membranes Cho et al , 1999
- enzymes can be immobilized on the membrane surface that cause local changes in pH in the presence of toxins
- the first method to be employed for the detection of organophosphorus compounds such as Paraoxon is to monitor the inhibition of the reaction catalyzed by butyrylchohnesterase, which breaks down butyrylchohne into chohne and butyric acid Paraoxon has been shown to inhibit this reaction linearly in proportion to its concentration (Campanella et al , 1996)
- Membrane adhesion has typically been a significant problem effecting useful lifetime of solid-state chemical sensors Many of the membranes utilized for traditional chemical sensors do not adhere well to the silicon-nitride surface, reducing the yield and lifetime Membrane adhesion is tested using a Q-Test II adhesion analyzer
- Membrane adhesion is a critical factor and must be optimized to provide stable electrochemical properties in a flow system The fluid flow system, necessary for sample delivery, calibration, washing, and regeneration of the sensors, tends to cause pealing of the membrane
- Membranes can be deposited using a set of micropipettes accurate to
- a New Long LS- 15TV screen printing system for patterning membranes and epoxies onto sensor surfaces can print with +/-5 micron alignment and 25 to 50 micron minimum feature size
- the lower level oxide layer specifications are:
- N1A, N1 B Ti/Pt 222/na A
- PECVD nitride is very uneven gas flows PECVD
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Abstract
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Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US16347199P | 1999-11-02 | 1999-11-02 | |
US163471P | 1999-11-02 | ||
PCT/US2000/030265 WO2001033206A1 (en) | 1999-11-02 | 2000-11-02 | Microscopic combination amperometric and potentiometric sensor |
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EP1226425A1 true EP1226425A1 (en) | 2002-07-31 |
EP1226425A4 EP1226425A4 (en) | 2003-06-04 |
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EP00976858A Withdrawn EP1226425A4 (en) | 1999-11-02 | 2000-11-02 | Microscopic combination amperometric and potentiometric sensor |
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EP (1) | EP1226425A4 (en) |
JP (1) | JP2003513274A (en) |
AU (1) | AU1457401A (en) |
WO (1) | WO2001033206A1 (en) |
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WO2005078118A1 (en) | 2004-02-06 | 2005-08-25 | Bayer Healthcare Llc | Oxidizable species as an internal reference for biosensors and method of use |
RU2386960C2 (en) | 2004-05-14 | 2010-04-20 | БАЙЕР ХЕЛТКЭР ЭлЭлСи | Voltammetric system for analysing biological substances |
AU2006272909B2 (en) | 2005-07-20 | 2013-02-07 | Bayer Healthcare Llc | Gated amperometry |
AU2006297572B2 (en) | 2005-09-30 | 2012-11-15 | Ascensia Diabetes Care Holdings Ag | Gated Voltammetry |
EP2679150B1 (en) | 2006-10-24 | 2020-07-22 | Ascensia Diabetes Care Holdings AG | Transient decay amperometry |
WO2009076302A1 (en) | 2007-12-10 | 2009-06-18 | Bayer Healthcare Llc | Control markers for auto-detection of control solution and methods of use |
DE102008027038A1 (en) * | 2008-06-06 | 2009-12-17 | Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. | Method for detecting chemical or biological species and electrode arrangement therefor |
DE102011010767A1 (en) * | 2011-02-09 | 2012-08-09 | Forschungszentrum Jülich GmbH | Method for producing a device for detecting an analyte, and device and their use |
JP2013220066A (en) * | 2012-04-17 | 2013-10-28 | Hitachi Ltd | Sensor chip and measuring method using the same |
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AT402452B (en) * | 1994-09-14 | 1997-05-26 | Avl Verbrennungskraft Messtech | PLANAR SENSOR FOR DETECTING A CHEMICAL PARAMETER OF A SAMPLE |
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US5718816A (en) * | 1996-05-16 | 1998-02-17 | Sendx Medical, Inc. | Locking sensor cartridge with integral fluid ports electrical connections, and pump tube |
US6159353A (en) * | 1997-04-30 | 2000-12-12 | Orion Research, Inc. | Capillary electrophoretic separation system |
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2000
- 2000-11-02 WO PCT/US2000/030265 patent/WO2001033206A1/en not_active Application Discontinuation
- 2000-11-02 EP EP00976858A patent/EP1226425A4/en not_active Withdrawn
- 2000-11-02 AU AU14574/01A patent/AU1457401A/en not_active Abandoned
- 2000-11-02 JP JP2001535041A patent/JP2003513274A/en not_active Withdrawn
Patent Citations (2)
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EP0600215A2 (en) * | 1992-11-28 | 1994-06-08 | PROMINENT DOSIERTECHNIK GmbH | Electrochemical sensor |
US5670031A (en) * | 1993-06-03 | 1997-09-23 | Fraunhofer-Gesellschaft Zur Angewandten Forschung E.V. | Electrochemical sensor |
Non-Patent Citations (5)
Title |
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CHEN Z-L ET AL: "Simultaneous amperometric and potentiometric detection of sugars, polyols and carboxylic acids in flow systems using copper wire electrodes" JOURNAL OF CHROMATOGRAPHY A, ELSEVIER SCIENCE, NL, vol. 766, no. 1-2, 4 April 1997 (1997-04-04), pages 27-33, XP004116779 ISSN: 0021-9673 * |
HAMPP N ET AL: "DESIGN AND APPLICATION OF THICK-FILM MULTISENSORS" SENSORS AND ACTUATORS A, ELSEVIER SEQUOIA S.A., LAUSANNE, CH, vol. A31, no. 1 / 3, 1 March 1992 (1992-03-01), pages 144-148, XP000276418 ISSN: 0924-4247 * |
KAKEROW R ET AL: "A MONOLITHIC SENSOR ARRAY OF INDIVIDUALLY ADDRESSABLE MICROELECTRODES" SENSORS AND ACTUATORS A, ELSEVIER SEQUOIA S.A., LAUSANNE, CH, vol. A43, no. 1/3, 1 May 1994 (1994-05-01), pages 296-301, XP000454125 ISSN: 0924-4247 * |
See also references of WO0133206A1 * |
SILBER A ET AL: "THICK-FILM MULTICHANNEL BIOSENSORS FOR SIMULTANEOUS AMPEROMETRIC AND POTENTIOMETRIC MEASUREMENTS" SENSORS AND ACTUATORS B, ELSEVIER SEQUOIA S.A., LAUSANNE, CH, vol. 30, no. 2, 15 January 1996 (1996-01-15), pages 127-132, XP000584838 ISSN: 0925-4005 * |
Also Published As
Publication number | Publication date |
---|---|
WO2001033206A1 (en) | 2001-05-10 |
JP2003513274A (en) | 2003-04-08 |
AU1457401A (en) | 2001-05-14 |
EP1226425A4 (en) | 2003-06-04 |
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