WO2012114056A1 - Capacitance detection in electrochemical assay with improved response - Google Patents
Capacitance detection in electrochemical assay with improved response Download PDFInfo
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- WO2012114056A1 WO2012114056A1 PCT/GB2011/001211 GB2011001211W WO2012114056A1 WO 2012114056 A1 WO2012114056 A1 WO 2012114056A1 GB 2011001211 W GB2011001211 W GB 2011001211W WO 2012114056 A1 WO2012114056 A1 WO 2012114056A1
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- test cell
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- ohms
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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
- G01N27/307—Disposable laminated or multilayered electrodes
-
- 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
-
- 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
- G01N27/3271—Amperometric enzyme electrodes for analytes in body fluids, e.g. glucose in blood
- G01N27/3274—Corrective measures, e.g. error detection, compensation for temperature or hematocrit, calibration
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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
- G01N27/416—Systems
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/483—Physical analysis of biological material
- G01N33/487—Physical analysis of biological material of liquid biological material
-
- 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
- G01N27/02—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating impedance
- G01N27/22—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating impedance by investigating capacitance
Definitions
- Analyte detection in physiological fluids is of ever increasing importance to today's society.
- Analyte detection assays find use in a variety of applications, including clinical laboratory testing, home testing, etc., where the results of such testing play a prominent role in diagnosis and management in a variety of disease conditions.
- Analytes of interest include glucose for diabetes management, cholesterol, and the like.
- analyte detection protocols and devices for both clinical and home use have been developed.
- One type of method that is employed for analyte detection is an electrochemical method.
- an aqueous liquid sample is placed into a sample-receiving test cell in an electrochemical cell that includes two electrodes, e.g., a counter and working electrode.
- the analyte is allowed to react with a redox reagent to form an oxidizable (or reducible) substance in an amount corresponding to the analyte concentration.
- the quantity of the oxidizable (or reducible) substance present is then PATENT
- Such systems are susceptible to various modes of inefficiency and/or error.
- variations in temperatures can affect the results of the method. This is especially relevant when the method is carried out in an uncontrolled environment, as is often the case in home applications or in third world countries.
- Errors can also occur when the sample size is insufficient to get an accurate result.
- Partially filled test strips can potentially give an inaccurate result because the measured test currents are proportional to the area of the working electrode that is wetted with sample.
- partially filled test strips can under certain conditions provide a glucose concentration that is negatively biased.
- biosensor electrochemical test cell of a test strip has two electrodes disposed in the electrochemical test cell and coupled to a microcontroller via respective strip connectors.
- the method can be achieved by: depositing a fluid PATENT
- predetermined frequency to the electrochemical test cell; determining a phase angle between an output signal and the oscillating signal from the electrochemical test cell; measuring an amplitude of the output signal from the electrochemical test cell;
- the ascertaining may also include establishing a resistance of the test cell with the total impedance and the resistance between the test cell and one of the connectors.
- the establishing may include extracting the complex impedance from the ascertaining and establishing and the extracting may include calculating a new phase angle without the resistance between the test cell and the connectors.
- the calculating may include transforming the new phase angle into a capacitive reactance, and the capacitance of the test cell is related to the capacitive reactance by a product of the ratio of any circle's circumference to its diameter and the predetermined frequency.
- the measuring may include ascertaining a first sampling-time interval for measurement of an output signal based on a predetermined sampling rate per cycle of the output signal at the
- the second sampling-time interval may be based on a predetermined offset time with respect to the first sampling-time interval.
- the first sampling-time interval may include a duration between each step change in magnitude of the output signal.
- the offset time may be a percentage of the first sampling-time interval, and the percentage may be a range PATENT
- the ascertaining may include determining a duration for one wave of the signal at the predetermined frequency; dividing the duration over a number of measurement samples for each wave to obtain a time duration; and setting the first sampling-time interval as being generally equal to the time duration.
- the ascertaining may include evaluating the output signal to determine a time duration between each step change of the output signal; and setting the first sampling-time interval as being generally equal to the time duration, and the offset time may include a percentage of the first sampling-time interval, and the percentage may include a range from about 5% to about 30% of the first sampling-time interval.
- a method to evaluate a condition of an electrochemical test strip has at least two electrodes disposed in a test cell and connected to corresponding connectors.
- the method may be achieved by: depositing a fluid sample in the electrochemical test cell; applying an oscillating signal of a predetermined frequency to the fluid sample in the electrochemical test cell; measuring an amplitude of the output signal from the electrochemical test cell;
- the resistance range may be from about zero ohms to about 100,000 ohms; the capacitance range may be from about 410 nanoFarads to about 450 nanoFarads. In a variation, the capacitance range may be from about 590 nanoFarads to about 630 nanoFarads. In this aspect, the
- predetermined resistance may be a value selected from a range of about zero ohms to about 200 ohms.
- the predetermined resistance may be selected PATENT
- the establishing may include ascertaining a total impedance of the test cell from the phase angle; arriving at a resistance of the test cell with the predetermined resistance.
- the quantifying may include extracting the complex impedance from the ascertaining and arriving.
- the extracting may include calculating a new phase angle without the predetermined resistance.
- the calculating may include transforming the new phase angle into a capacitive reactance.
- the capacitance of the test cell is related to the capacitive reactance by a product of the ratio of a circle's
- the predetermined resistance range may include a range from about zero ohms to about 120,000 ohms and the predetermined capacitance range comprises a range from about 500 nanoFarads to about 650 nanoFarads.
- a system to evaluate a condition of an electrochemical test strip includes a test strip and a microcontroller.
- the test strip includes at least two electrodes having respective electrode ends disposed in a test cell; and at least two connectors coupled to the respective at least two electrodes such that a strip electrical resistance is intrinsically established (i.e., determined by assumptions or by an average of multiple measurements of each of a plurality of sample strips) between at least one of the connectors and the electrodes.
- the microcontroller is connected to a strip port connector having at least two terminals that connect to respective connectors of the test strip, the microcontroller configured to supply an oscillating signal to the chamber via the at least two electrodes, measure capacitive and resistive responses from the test cell based on a phase angle response of the test cell and the strip electrical resistance, and designate a test strip as defective whenever the capacitive and resistive responses are outside of a range of capacitance of the test cell with respect to a range of resistance of the PATENT
- the resistance range may be from about zero ohms to about 100,000 ohms; the capacitance range may be the capacitance range comprises from about 410 nanoFarads to about 450 nanoFarads. Alternatively, the capacitance range may be from about 590 nanoFarads to about 630 nanoFarads.
- the predetermined resistance is a value selected from a range of about zero ohms to about 200 ohms.
- the predetermined resistance is selected from any value of about zero ohms to about 200 ohms, in which the resistance range comprises from about zero ohms to about 100,000 ohms, and in which the capacitance range comprises from about 410 nanoFarads to about 630 nanoFarads.
- Figure 1 illustrates an exemplary analyte measurement system including an
- Figure 2 illustrates in simplified schematic view of an exemplary circuit board for the meter of Figure 1.
- Figure 3A illustrates an exploded perspective view of the test strip of Figure 1.
- Figure 3B illustrates a schematic electrical model of the test chamber 61 and a phasor diagram of the resistor-capacitive model.
- Figure 4 illustrates a simplified schematic of the components to determine
- Figure 5A illustrates the application of voltage over time applied to the test strip.
- Figure 5B illustrates the amplitude of the current output response from the test strip over time.
- Figure 6A illustrates a sampling of the current output indicated at area 602.
- Figure 6B illustrates the alternating current output once the direct-current
- Figures 6C and 6D illustrate the phase angle between the alternating voltage applied to the test strip and the alternating current output from the test strip.
- Figure 6E illustrates an interpolation of the sampled data to determine the crossover point of Figure 6D for comparison with the cross-over point of the applied current of Figure 6C.
- Figure 7A illustrates an overlay of an electrical model over an outline of a strip of
- Fig. 3A to show various resistor sources from respective components of the test strip and capacitance of the test cell.
- Figure 7B illustrates an electrical schematic representation of the model of the test cell 61 and resistance of the test strip connectors.
- Figure 7C illustrates a phasor diagram for the model of Fig. 7B.
- Figure 8A illustrates referential output responses in terms of test cell resistance and test cell capacitance in a referential model of the test strip of Figure 7B.
- Figure 8B illustrates actual output responses in terms of test cell resistance and test cell capacitance in an actual test strip.
- Figure 9A illustrates an output oscillating signal as sampled by the system showing that the signal is generated by 64 distinct current samples giving the output signal a piecewise or stepwise signal.
- Figure 9B shows an overlay of an actual sampled oscillating signal 904 as
- Figure 9C shows an overlay of an actual sampled oscillating signal 906 as
- Figures 9D and 9E illustrate in detail the error caused by the step change in the piecewise or stepwise output signal 906 as compared to a smooth output signal 902.
- Figure 9F illustrates graphically how the a first sampling time interval is modified by a time offset to provide for a second sampling-time interval which allows for more accurate capacitance measurements.
- Figure 10 illustrates the response curve of an embodiment which uses the
- Figure 11 illustrates an exemplary flow chart of a method of determining
- DDI5196WOPCT2 Attorney Docket No. DDI5196WOPCT2 used herein, the terms “patient,” “host,” “user,” and “subject” refer to any human or animal subject and are not intended to limit the systems or methods to human use, although use of the subject invention in a human patient represents a preferred embodiment.
- "oscillating signal” includes voltage signal(s) or current signal(s) that, respectively, change polarity or alternate direction of current or are multi-directional.
- the subject systems and methods are suitable for use in the determination of a wide variety of analytes in a wide variety of samples, and are particularly suited for use in the determination of analytes in whole blood, plasma, serum, interstitial fluid, or derivatives thereof.
- a glucose test system based on a thin-layer cell design with opposing electrodes and tri-pulse electrochemical detection that is fast (e.g., about 5 second analysis time), requires a small sample (e.g., about 0.4 ⁇ _( ⁇ )), and can provide improved reliability and accuracy of blood glucose measurements.
- glucose in the sample can be oxidized to gluconolactone using glucose dehydrogenase and an electrochemically active mediator can be used to shuttle electrons from the enzyme to a working electrode.
- a potentiostat can be utilized to apply a tri-pulse potential waveform to the working and counter electrodes, resulting in test current transients used to calculate the glucose concentration. Further, additional information gained from the test current transients may be used to discriminate between sample matrices and correct for variability in blood samples due to hematocrit, temperature variation, electrochemically active components, and identify possible system errors.
- an electrochemical cell can be in the form of a test strip.
- the test strip may include two opposing electrodes separated by a thin spacer for defining a sample-receiving test cell or zone in which a reagent layer is located.
- test strips including, for example, test strips with co-planar electrodes may also be used with the methods described herein.
- FIG. 1 illustrates a diabetes management system that includes a diabetes data management unit 10 and a biosensor in the form of a glucose test strip 80.
- the diabetes data management unit may be referred to as an analyte measurement and management unit, a glucose meter, a meter, and an analyte measurement device.
- the DMU may be combined with an insulin delivery device, an additional analyte testing device, and a drug delivery device.
- the DMU may be connected to the computer 26 or server 70 via a cable or a suitable wireless technology such as, for example, GSM, CDMA, BlueTooth, WiFi and the like.
- glucose meter 10 can include a housing 11, user
- User interface buttons (16, 18, and 20), a display 14, and a strip port opening 22 can be configured to allow the entry of data, navigation of menus, and execution of commands.
- User interface button 18 can be in the form of a two way toggle switch.
- Data can include values representative of analyte concentration, and/or information, which are related to the everyday lifestyle of an individual.
- Information, which is related to the everyday lifestyle, can include food intake, medication use, occurrence of health check-ups, and general health condition and exercise levels of an individual.
- the electronic components of meter 10 can be disposed on a circuit board 34 that is within housing 11.
- Figure 2 illustrates (in simplified schematic form) the electronic components disposed on a top surface of circuit board 34.
- the electronic components may include a strip port opening 308, a microcontroller 38, a non-volatile flash memory 306, a data port 13, a real time clock 42, and a plurality of operational amplifiers (46 - 49).
- the electronic components may include a plurality of analog switches, a backlight driver, and an electrically erasable programmable read-only memory (EEPROM, not shown).
- EEPROM electrically erasable programmable read-only memory
- Microcontroller 38 can be electrically connected to strip port opening 308, non-volatile flash memory 306, data port 13, real time clock 42, the plurality of operational amplifiers (46 - 49), the plurality of analog switches, the backlight driver, and the EEPROM. 0 PATENT
- the plurality of operational amplifiers can include gain stage operational amplifiers (46 and 47), a trans-impedance operational amplifier 48, and a bias driver operational amplifier 49.
- the plurality of operational amplifiers can be configured to provide a portion of the potentiostat function and the current measurement function.
- the potentiostat function can refer to the application of a test voltage between at least two electrodes of a test strip.
- the current function can refer to the measurement of a test current resulting from the applied test voltage. The current measurement may be performed with a current-to-voltage converter.
- Microcontroller 38 can be in the form of a mixed signal microprocessor (MSP) such as, for example, the Texas Instrument MSP 430.
- MSP mixed signal microprocessor
- the MSP 430 can be configured to also perform a portion of the potentiostat function and the current measurement function.
- the MSP 430 can also include volatile and non-volatile memory.
- many of the electronic components can be integrated with the microcontroller in the form of an application specific integrated circuit (ASIC).
- ASIC application specific integrated circuit
- Strip port connector 308 can be located proximate the strip port opening 22 and configured to form an electrical connection to the test strip.
- Display 14 can be in the form of a liquid crystal display for reporting measured glucose levels, and for facilitating entry of lifestyle related information. Display 14 can optionally include a backlight.
- Data port 13 can accept a suitable connector attached to a connecting lead, thereby allowing glucose meter 10 to be linked to an external device such as a personal computer.
- Data port 13 can be any port that allows for transmission of data such as, for example, a serial, USB, or a parallel port.
- Real time clock 42 can be configured to keep current time related to the
- Real time clock 42 may include a clock circuit 45, a crystal 44, and a super capacitor 43.
- the DMU can be configured to be electrically connected to a power supply such as, for example, a battery.
- the super capacitor 43 can be configured to provide power for a prolonged period of time to power real time clock 42 in case there is an interruption in the power supply.
- FIG 3A illustrates an exemplary test strip 80, which includes an elongate body extending from a distal end 80 to a proximal end 82, and having lateral edges.
- the test strip 80 also includes a first electrode layer 66a, insulation layer 66b, a second electrode layer 64a, insulation layer 64b, and a spacer 60 sandwiched in between the two electrode layers 64a and 66a.
- the first electrode layer 66a can include a first electrode 67a, a first connection track 76, and a first contact pad 47, where the first connection track 76 electrically connects the first electrode layer 66a to the first contact pad 67, as shown in Figs. 3A and 4.
- the first electrode 67a is a portion of the first electrode layer 66a that is immediately underneath the reagent layer 72.
- the second electrode layer 64a can include a second electrode 67b, a second connection track 78, and a second contact pad 78, where the second connection track 78 electrically connects the second electrode 67b with the second contact pad 78, as shown in Figures 3 and 4.
- the second electrode includes a portion of the second electrode layer 64a that is above the reagent layer 72.
- the sample-receiving electrochemical test cell 61 is defined by the first electrode 67a, the second electrode 67b, and the spacer 60 near the distal end 80 of the test strip 80.
- the first electrode 67a and the second electrode 67b can define the bottom and the top of sample-receiving electrochemical test cell 61, respectively.
- a cutout area 68 of the spacer 60 can define the sidewalls of the sample-receiving electrochemical test cell 61.
- the sample-receiving electrochemical test cell 61 can include ports 70 that provide a sample inlet and/or a vent.
- one of the ports can allow a fluid sample to ingress and the other port can allow air to egress.
- the first electrode layer 66a and the second electrode layer 64a can be made from sputtered palladium and sputtered gold, respectively. Suitable materials that can be employed as spacer 60 2 PATENT
- Attorney Docket No. DDI5196WOPCT2 include a variety of insulating materials, such as, for example, plastics (e.g., PET, PETG, polyimide, polycarbonate, polystyrene), silicon, ceramic, glass, adhesives, and combinations thereof.
- the spacer 60 may be in the form of a double sided adhesive coated on opposing sides of a polyester sheet where the adhesive may be pressure sensitive or heat activated.
- the area of first electrode and second electrode can be defined by the two lateral edges and cutout area 68. Note that the area can be defined as the surface of the electrode layer that is wetted by liquid sample.
- the adhesive portion of spacer 60 can intermingle and/or partially dissolve the reagent layer so that the adhesive forms a bond to the first electrode layer 66A. Such an adhesive bond helps define the portion of the electrode layer that can be wetted by liquid sample and also electrooxidize or electroreduce mediator.
- Either the first electrode or the second electrode can perform the function of a working electrode depending on the magnitude and/or polarity of the applied test voltage.
- the working electrode may measure a limiting test current that is proportional to the reduced mediator concentration.
- the current limiting species is a reduced mediator (e.g., ferrocyanide)
- ferrocyanide e.g., ferrocyanide
- the first electrode performs the function of the working electrode and the second electrode performs the function of a counter/ reference electrode.
- a counter/reference electrode simply as a reference electrode or a counter electrode.
- a limiting oxidation occurs when all reduced mediator has been depleted at the working electrode surface such that the measured oxidation current is proportional to the flux of reduced mediator diffusing from the bulk solution towards the working electrode surface.
- the term bulk solution refers to a portion of the solution sufficiently far away from the working electrode where the reduced mediator is not located within a depletion zone.
- second electrode if the test voltage is sufficiently greater than the redox mediator potential, then the reduced mediator can be oxidized at the second electrode as a limiting current. In such a situation, the second electrode performs the function of the working electrode and the first electrode performs the function of the counter/reference electrode. Details regarding the exemplary test strip, operation of the strip and the test meter are found in U.S. Patent Application Publication No. 20090301899, which is incorporated by reference in its entirety herein.
- test strip 80 can include one or more working electrodes and a counter electrode.
- Test strip 80 can also include a plurality of electrical contact pads, where each electrode can be in electrical communication with at least one electrical contact pad.
- Strip port connector 308 can be configured to electrically interface to the electrical contact pads and form electrical communication with the electrodes.
- Test strip 80 can include a reagent layer that is disposed over at least one electrode. The reagent layer can include an enzyme and a mediator.
- Exemplary enzymes suitable for use in the reagent layer include glucose oxidase, glucose dehydrogenase (with pyrroloquinoline quinone co-factor, "PQQ”), and glucose dehydrogenase (with flavin adenine dinucleotide co-factor, "FAD”).
- An exemplary mediator suitable for use in the reagent layer includes ferricyanide, which in this case is in the oxidized form.
- the reagent layer can be configured to physically transform glucose into an enzymatic by-product and in the process generate an amount of reduced mediator (e.g., ferrocyanide) that is proportional to the glucose
- the working electrode can then measure a concentration of the reduced mediator in the form of a current.
- glucose meter 10 can convert the current magnitude into a glucose concentration. Details of the preferred test strip are provided in U.S. Patent Nos. 6179979; 6193873; 6284125; 6413410; 6475372; 6716577; 6749887; 6863801; 6890421; 7045046; 7291256; 7498132, all of which are incorporated by reference in their entireties herein. 4 PATENT
- Figure 4 illustrates, in simplified schematic form, of various functional
- the components include a microcontroller 300.
- a preferred embodiment of the microcontroller 300 is available from Texas Instrument as ultra-low power microcontroller model MSP430.
- Microcontroller (“MC") 300 may be provided with DAC output and built-in A-D conversion.
- MC 300 is suitably connected to a LCD screen 304 to provide a display of the test results or other information related to the test results.
- Memory 306 is electrically connected to the MC 300 for storage of test results, sensed current and other necessary information or data.
- the test strip may be coupled for a test measurement via a strip port connector (“SPC") 308.
- SPC 308 allows the test strip to interface with MC 300 via a first contact pad 47a, 47b and a second contact pad 43.
- the second contact pad 43 can be used to establish an electrical connection to the test meter through a U-shaped notch 45, as illustrated in FIG. 4.
- SPC 308 may also be provided with electrode connectors 308a and 308c.
- the first contact pad 47 can include two prongs denoted as 47a and 47b. In one exemplary embodiment, the first electrode connectors 308a and 308c separately connect to prongs 47a and 47b, respectively.
- the second electrode connector 308b can connect to second contact pad 43.
- the test meter 10 can measure the resistance or electrical continuity between the prongs 47a and 47b to determine whether the test strip 80 is electrically connected to the test meter 10.
- SPC 308 is connected to switch 310.
- Switch 310 is
- Bias driver 312 is provided with the DAC signal 312a; current drive 312b and switch signal 312c.
- the MC 300 provides the DAC signal 312a, which includes analogue voltages in the range 0 to Vref (e.g., about 2.048V).
- the bias driver 312 can operate in two modes - constant voltage, or constant current.
- the current-driver line 312b controls the mode of the bias driver 312. Setting the line 312b low converts an op-amp in the bias driver 312 to a voltage follower amplifier.
- DAC signal 312a output is scaled to Vref/2 +/- 400mV full scale. The op-amp in the bias driver outputs this voltage directly to the MC 300 as line PATENT
- driver-line 312d The voltage of line 312d is generated with respect to the Vref/2 virtual ground. So to drive a suitable bias (e.g., about 20mV bias), the DAC must drive (through a suitable scaler) about 1.044V. To drive a bias of about +300mV, the DAC must generally provide about 1.324V, and for the -300mV bias, the DAC must generally provide about 0.724V.
- the bias driver circuit 312 also generates the 109Hz sine wave, which is used for fill detection via capacitance measurement.
- Bias driver 312 is also connected to a trans-impedance amplifier circuit (“TIA circuit") 314.
- TIA circuit 314 converts the current flowing though the strip's electrode layer 66a (e.g., palladium) to electrode layer 64a (e.g., gold) contacts into a voltage.
- the overall gain is controlled by a resistor in TIA circuit 314. Because the strip 80 is a highly capacitive load, normal low-offset amplifiers tend to oscillate. For this reason a low-cost op-amp is provided in the TIA circuit 314 as a unity gain buffer and incorporated within the overall feedback loop.
- circuit 314 acts as dual op-amp system with both high drive capability and low voltage offset.
- the TIA circuit 314 also utilizes a virtual ground (or virtual earth) to generate the 1.024V bias on the electrode layer 64a (e.g., gold) contact of the SPC 308.
- Circuit 314 is also connected to a Vref amplifier circuit 316.
- This circuit when in current measuring mode, uses a virtual ground rail set at Vref/2 (approximately 1.024V), allowing both positive and negative currents to be measured. This voltage feeds all of the gain amplifier stage 318. To prevent any circuit loads from 'pulling' this voltage, a unity gain buffer amplifier may be utilized within the Vref amplifier circuit 316. 6 PATENT
- the strip current signal 314a from the TIA circuit 314 and the virtual ground rail 316a ( ⁇ Vref/2) from the voltage reference amplifier 316 are scaled up as needed for various stages of the test measurement cycle.
- MC 300 is provided with four channels of amplified signal sensed from the test strip with varying amplifications of the sensed current as need for different stages of the measurement cycle of the test strip during an analyte assay.
- the test meter 10 can apply a test voltage and/or a current between the first contact pad 47 and the second contact pad 43 of the test strip 80. Once the test meter 10 recognizes that the strip 80 has been inserted, the test meter 10 turns on and initiates a fluid detection mode. In one embodiment, the meter attempts to drive a small current (e.g. 0.2 to 1 ⁇ ) through the strip 80. When there is no sample present the resistance is greater than several Mega Ohms, the driving voltage on the op- amp trying to apply the current goes to the rail. When a sample is introduced the resistance drops precipitously and the driving voltage follows. When the driving voltage drops below a pre-determined threshold the test sequence is initiated.
- a small current e.g. 0.2 to 1 ⁇
- Figure 5A shows the voltage to be applied between the electrodes. Time zero is taken to be when the sample detection method has detected that a sample first begins to fill the strip. Note that the sine wave component shown at approximately 1.3 seconds in Figure 5A is not drawn on the correct timescale for illustration purposes.
- the voltage between the strip electrodes is stepped to a suitable voltage in millivolts of magnitude and maintained for a set amount of time, e.g., about 1 second, then stepped to a higher voltage and held for a fixed amount of time, then a sine wave voltage is applied on top of the DC voltage for a set amount of time, then the DC voltage is applied for a further amount of time, then reversed to a negative voltage and held for a set amount of time.
- the voltage is then disconnected from the strip.
- the current signal from about 0 to about 1 second may be used for error checking and to distinguish a control solution sample from a blood sample.
- the signal from about 1 to about 5 seconds is analyzed to obtain a glucose result.
- the signal during this period is also analyzed for various errors.
- the signal from about 1.3 to 1.4 seconds is used to detect whether or not the sensor is completely filled with sample.
- the current from 1.3 to 1.32 seconds, denoted here as trace 500, is sampled at approximately 150 microsecond intervals to determine whether sufficient volume of physiological fluid has filled chamber 61 of the test strip.
- a magnitude of the capacitance can be proportional to the area of an electrode that has been coated with sample fluid. Once the magnitude of the capacitance is measured, if the value is greater than a threshold and thus the test strip has a sufficient volume of liquid for an accurate measurement, a glucose concentration can be outputted. But if the value is not greater than a threshold, indicating that the test strip has insufficient volume of liquid for an accurate measurement, and then an error message can be outputted.
- the voltage between the strip electrodes is stepped to a suitable voltage in millivolts of magnitude and maintained for a set amount of time, e.g., about 1 second, then stepped to a higher voltage and held for a fixed amount of time, then a sine wave voltage is applied on top of the DC voltage for a set amount of time, then the DC voltage is applied for a further amount of time, then reversed to a negative voltage and held for a set amount of time. The voltage is then disconnected from the strip. 8 PATENT
- test current can be mathematically processed, as described in further detail below, to determine a capacitance value.
- biosensor test chamber 61 with the electrode layers can be modeled in the form of a circuit having a parallel resistor and capacitor as shown in Fig. 3B.
- R represents the resistance encountered by the current and C represents a capacitance resulting from the combination of the physiological fluid and reagent electrically coupled to the electrodes.
- an alternating bias voltage may be applied across the respective electrodes disposed in the chamber, and a current from the chamber is measured.
- the filling of the chamber 61 is believed to be generally a measure of capacitance only and thus any parasitic resistance, such as, for example, R, must not be included in any determination or calculation of capacitance.
- any parasitic resistance is believed to affect the measured output signal.
- Applicant has discovered a technique to derive capacitance without requiring utilization or knowledge of the resistance through the chamber as modeled above. In order to further explain this technique, a short discussion of the mathematical foundation underlying the technique is warranted.
- total current ( i T ) through the circuit of Fig. 3B is approximately the sum of the current flowing through the resistor ( i R ) and through the capacitor ( i c ).
- V alternating voltage
- the resistor current ( i K ) may be expressed as: 9 PATENT
- Capacitor current ( c ) can be expressed as:
- j is an imaginary number operator indicating that current leads voltage by about 90 degrees in a capacitor
- ⁇ is the angular frequency Irtf where f is frequency in Hertz.
- ⁇ represents the phase angle of the input as compared to the output.
- i T represents the total current
- ⁇ represents the phase angle
- / represents the frequency of the applied signal
- V represents the magnitude of the applied signal
- an AC test voltage ( ⁇ 50 mV peak-to-peak) of approximately 109 Hz can be applied for 2 cycles during approximately 1-1.3 seconds or at least one cycle.
- the first cycle can be used as a conditioning pulse and the second cycle can be used to determine the capacitance.
- the alternating test voltage can be of a suitable waveform, such as, for example, a sine wave of approximately 109 Hertz with approximately 50 millivolts peak (Fig. 6C).
- the sampling can be of any suitable sampling size per cycle, such as, for example approximately 64-65 samples per cycle, shown here in Figure 6A. Hence, each sample represents approximately 5.6 degrees of the exemplary sine wave. 1 PATENT
- the RMS value of the positive values could also be taken, but applicants believe that the positive values are disjointed due to being split across the first and fourth quadrants of the overall cycle, and therefore the negative values are preferred.
- the system or processor 300 can compare the oscillating input voltage, shown here in Figure 6C to the oscillating output current to determine the phase angle.
- the sampled data 604 is analyzed to determine a cross-over point from positive to negative current. Because the sampling is based on a discrete number of samples, interpolation can be used to determine substantially when the output current crosses over the zero current line. In the embodiment described here, the phase angle ⁇ is less than 90 degrees and approximately 87 degrees. For increased accuracy, interpolation can be performed at another cross-over point with approximately 180 degrees subtracted from this second interpolated point. The two interpolated values should be within a few degrees and may be averaged out to increase accuracy.
- a two-point calibration can be performed to normalize the capacitance value to a value that is independent of any tolerances of the analog components (e.g., resistors, capacitors, op-amps, switches and the like).
- the two-point calibration is performed by: placing a 550nF capacitor with 30k parallel resistance across the measurement input; command the meter to measure the capacitance, and note the value produced; place a 800nF capacitor with 30k parallel resistance across the measurement input; command the meter to measure the capacitance, and note the value produced.
- an evaluation is made to determine whether the test chamber 61 has been sufficiently filled with test fluid.
- the evaluation can be based on a capacitance magnitude of at least 65% to 85% of an average capacitance value derived from a large sample of good filled test strips.
- the biosensor test strip 80 and test cell 61 with the electrode layers in Fig. 3A can be represented as a series of resistors f ontact/ RpdFiim, RAuContact; and R AU Fiim in Fig. 7A
- the test cell 61 can be represented as a parallel resistor-capacitor circuit having Rceii Conductance and C DO ubieUayer »n Fig. 7A.
- the resistors of the strip 80 and the parallel resistor-capacitor of test cell 61 can be modeled in the form of a circuit having a series resistor RST IP for the biosensor's gold and palladium layers and a parallel 3 PATENT
- R S TRIP resistance of R S TRIP was determined to be in the range of about 120 Ohms to about 150 Ohms (with about 135 Ohms being common and utilized in the preferred embodiments) depending on the variation of the resistance of the Au and Pd contacts. It was believed that the resistance for RSTRIP in the range of about 150 Ohms was negligible in comparison to the much larger impedance of RCELL and QEII- Hence, with the assumption that nominal value for R ce n is about 33 kilo-Ohms and C ce ii of about 600 nanoFarads at 109 Hertz, the phase angle was approximately 85.6 degrees.
- the compensation phase angle ⁇ ? ⁇ ranges from about 3 to about 25 degrees and preferably about 11 degrees.
- the modeled circuit of Figure 7B predicted a response of the electrochemical test cell 61 that varies as a function of the capacitance of the electrochemical test cell (CCELL), resistance of the electrochemical test cell (RCELL), and the strip resistance
- the predicted or referential capacitive response 702 of the electrochemical test cell 61 is generally linear over the resistance of the electrochemical test cell 61 from about 120 kilo- ohms to about 20 kilo-ohms at which point the predicted or referential capacitive response increases non-linearly but not to the extent of the capacitive response 700 with about zero strip resistance.
- the predicted or referential capacitive response 704 of the electrochemical test cell 61 is generally linear over the resistance of the test cell 61 from about 120 kilo-ohms to about 20 kilo-ohms at which point the predicted or referential capacitive response decreases somewhat non-linearly.
- the predicted or referential capacitive response 704 of the test cell 61 is generally linear over the resistance of the test cell 61 from about 120 kilo- ohms to about 20 kilo-ohms at which point the predicted or referential capacitive response decreases exponentially.
- the actual capacitive and resistive responses in Fig. 8B from representative test strips of Fig. 3A are quite different from the referential capacitive/resistive responses of Fig. 8A.
- the capacitive responses do not converge toward a common capacitive value at the higher value of R C ELL-
- the capacitive responses of the actual strip exhibited, at the low end of the resistance of RCELL / a contrary behavior to the referential or predicted model of Fig. 8A by converging toward a generally common value of about 590 nanoFarads at the R C ELL of about zero Ohms in Fig. 8B.
- the referential model utilizes a pure sine wave whereas the actual wave 900 is generated piecewise with 64 distinct current samples per wave, which is shown here in Fig. 9A. Because the wave 900 of Fig. 9A includes steps rather than a smooth line, this is believed to produce a different response of the measurement circuit that turns out to be highly dependent on RSTRIP-
- the piecewise output signal should be sampled at the right time after a step change of the piecewise wave 906.
- the piecewise wave 906 tends to lag or lead a pure wave 902 during a change in direction of the wave 906 as compared to a pure wave 902.
- Fig. 9E Taking an enlarged portion of Fig. 9D, shown here in Fig. 9E, it can be seen that there is a time differential At between a peak 908 of the piecewise wave 906 and where the piecewise wave 906 crosses over the pure wave 902 at cross-over point 910.
- the driving frequency of about 109 Hz and 64 samples per cycle of the wave 20% of a duration of a step change of 143 microseconds is about 28 microseconds. It is noted, however, other values from 5% to 40% (or about 17 microseconds to about 38 microseconds) will also work, depending on the driving frequency, sampling rate, duration of a step change, and the meter and strip system in use.
- the method includes applying an oscillating signal of a predetermined frequency to the chamber; ascertaining a first sampling-time interval for measurement of an output signal based on a predetermined sampling rate per cycle of the output signal at the predetermined frequency; sampling the output signal from the chamber at a second sampling-time interval different than the first sampling-time interval such that a magnitude of each sampled output signal is measured at each succession of the second sampling-time interval instead of at the first time interval; determining a phase angle between an output signal and the oscillating input signal PATENT
- the oscillating signal may be an alternating current ("AC") signal (in the form of voltage or current) or a multi-directional signal and the predetermined frequency may be about 109 Hertz.
- AC alternating current
- the predetermined frequency of the input signal is about 109 cycles per second, which means that one cycle of the output signal takes about 0.009 second.
- the desired sampling rate is N, for example, 64 samples per second, then each sample (e.g., SI, S2, S3 ...
- Sn is taken by dividing the time taken by one wave (0.009 seconds) over N (or 64) samples resulting in a sampling time of about 143 microseconds.
- the magnitude of the output response 602 is sampled every 143 microseconds and the measurement stored.
- the magnitude of the output signal is measured at a second sampling time interval different from the first sampling-time interval in order to ensure that the magnitude of the sampled output response does not deviate from a theoretical continuous output signal (e.g., pure sine wave output).
- the second sampling time interval can be a predetermined time offset from the first time interval or a percentage of the first sampling-time interval. The percentage can be from about 5% to about 30%.
- a time duration from peak -to-peak of the piecewise output signal can be used to set the first sampling-time interval STl.
- a time duration from peak 908 and peak 912 can be used to set the first sampling- time duration STl or an average of the peak-to-peak duration of all the peaks in one wave of the signal 906 can be used to set the first sampling-time duration.
- the second sampling time interval ST2 can be a percentage increase (or decrease depending the direction of the wave) of the first sampling-time interval STl. In one embodiment, the percentage can be any value from about 5% to about 30% and preferably about 20%.
- the method may be achieved by depositing a fluid sample in the electrochemical test cell in step 1100; applying an oscillating signal of a predetermined frequency to the electrochemical test cell 1102; determining a phase angle between a output signal and the oscillating signal from the electrochemical test cell in step 1104; measuring an amplitude of the output signal from the electrochemical test cell in step 1114; converting the measured amplitude into a complex impedance of the electrochemical test cell based on the oscillating signal, phase angle and electrical resistance between the test cell and the connectors in step 1116; and deriving a capacitance of the electrochemical test cell based on the complex impedance and predetermined frequency of the electrochemical test cell in step 11168.
- steps 1108, 1114 and 1116 can be used to allow for the derivation of the capacitance in step 1118
- steps 1106, 1108, 1110, and 1112 can be used to allow for a modified sampling time of the output response by the test cell, which would allow reduce or obviate the anomaly discovered herein.
- the use of a modified or compensated sampling time interval would allow for the system to sample the signal at or close to the time when the output signal would follow a theoretically pure output wave signal.
- Z is the impedance
- V is the applied voltage
- X is the reactance
- ⁇ is the phase angle between the input and output
- Z is the impedance of the circuit.
- Equation 12 the resistance of the strip, denoted as total resistance or Rjotai is given by Equation 12.
- RTOTAL is the total resistance of the test strip
- ⁇ is the phase angle between the input and output
- Z is the impedance of the circuit
- the total resistance RTOTAL of the strip is the sum of the strip resistance R strip and the test cell resistance R ELL or as shown in Equation 13, the resistance of the cell R ce ii is the difference between the RTOTAL and RSTRIP- 2 PATENT
- ZNEW is the impedance reflective of subtraction of RSTRIP
- RCELL is the resistance of only the electrochemical test cell.
- ⁇ J>NEW is the new phase angle
- ZNEW is the impedance reflective of subtraction of RSTRIP.
- RCEU is the resistance of only the electrochemical test cell.
- Equation 16.1 From knowing the new phase angle and new impedance reflective of the resistance of the test cell, a reactance can be calculated in Eq. 16, which through further substitutions result in Equation 16.1:
- Equation (16) 3 PATENT
- XCELL is the reactance of the electrochemical test cell without the strip resistance R S TRIP-
- Equation (17) From knowing the reactance of the test cell and the frequency of the applied oscillating voltage, the capacitance of the test cell can be derived from the known relationship between capacitance and reactance in Equation (17) to give Equation (18) and via substitution of Equation 16.1, Equation (19) can be used to determine the capacitance of the test cell.
- the plots of the response e.g., actual capacitance and cell resistance
- the response curve 704" with the predetermined strip resistance being about 100 ohms
- the curve 704" is generally constant about 620 nanoFarads for cell resistance from about 100 kOhms to about 20 kOhms and increasing to about 625 nanoFarads for cell resistance from about 20 kOhms to about PATENT
- the response of the test cell is (curve 706") generally constant around 615 nanoFarads from about 100 kOhms to about 20 kOhms and decreasing from about 615 nanoFarads to about 610 nanoFarads over the range of cell resistance from about 20 kOhms to about zero ohm.
- the response (curve 705) of the test cell is generally constant around 610 nanoFarads from about 100 kOhms to about 20 kOhms and decreasing from about 610 nanoFarads to about 600 nanoFarads over the range of cell resistance from about 20 kOhms to about zero ohm. As such, it is believed that the results validated applicants' discovery of the response of the test cell.
- a method to evaluate a condition of an electrochemical test cell can be achieved by: depositing a fluid sample in the electrochemical test cell; applying an oscillating signal of a predetermined frequency to the fluid sample in the electrochemical test cell; determining a phase angle between a output signal and the oscillating signal from the electrochemical test cell; measuring an amplitude of the output signal from the electrochemical test cell; measuring a resistance for the electrochemical test cell; quantifying a capacitance for the electrochemical test cell; annunciating an error whenever at least one or both of (a) the measured resistance is outside a resistance range or (b) the quantified resistance is outside a capacitance range.
- the resistance range may be from about 100 kilo-ohms to about zero ohm, shown here in Figure 8A, and the capacitance range may be from about 415 nanoFarads to about 450 nanoFarads.
- the resistance range may be from about 100 kilo-Ohms to about zero ohm and the capacitance range of the cell may be from about 590 nanoFarads to about 630 nanoFarads so that whenever the measured test cell resistance and measured cell capacitance (with a preset strip resistance of any value from about 50 Ohms to about 200 Ohms for the strip being measured) is higher than these resistance range and capacitance range, the test strip is stored in the system or annunciated to the user as a strip error.
- a system to evaluate a condition of an electrochemical test strip includes a test strip and a microcontroller.
- the test strip includes at least two electrodes having respective electrode ends disposed in a test cell of the test strip and at least two connectors coupled to the respective at least two electrodes.
- the microcontroller is connected to an annuciator and a strip port connector having at least two terminals that connect to respective connectors of the test strip.
- the microcontroller is configured to supply an oscillating signal to the chamber via the at least two electrodes and measure capacitive and resistive responses from the test cell such that a test strip is annunciated by the microcontroller as defective whenever the responses are outside of a range of capacitance of the test cell with respect to a range of resistance of the test cell.
- the principles described herein are also applicable to any analyte measurement strips that utilize a physiological fluid on a reagent disposed between at least two electrodes.
- the microcontroller can be programmed to generally carry out the steps of various processes described herein.
- the microcontroller can be part of a particular device, such as, for example, a glucose meter, an insulin pen, an insulin pump, a server, a mobile phone, personal computer, or mobile hand held device.
- the various methods described herein can be used to generate software codes using off-the-shelf software development tools such as, for example, C or variants of C such as, for example, C+, C++, or C-Sharp.
- the methods may be transformed into other software languages depending on the requirements and the availability of new software languages for coding the methods.
- the various methods described, once transformed into suitable software codes may be embodied in any computer-readable storage medium that, when executed by a 6 PATENT
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Abstract
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Priority Applications (10)
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JP2013554933A JP5695219B2 (en) | 2011-02-24 | 2011-08-11 | Capacitance detection in electrochemical analysis with improved response |
CA2828100A CA2828100A1 (en) | 2011-02-24 | 2011-08-11 | Capacitance detection in electrochemical assay with improved response |
AU2011360141A AU2011360141B2 (en) | 2011-02-24 | 2011-08-11 | Capacitance detection in electrochemical assay with improved response |
BR112013021590A BR112013021590A2 (en) | 2011-02-24 | 2011-08-11 | capacitance detection in optimized response electrochemical testing |
CN201180068402.XA CN103392129B (en) | 2011-02-24 | 2011-08-11 | There is the capacitance detecting in the electrochemical analysis of the response of improvement |
RU2013143163/15A RU2596793C2 (en) | 2011-02-24 | 2011-08-11 | Capacitance detection in electrochemical assay with improved response |
EP11755417.0A EP2678678B1 (en) | 2011-02-24 | 2011-08-11 | Capacitance detection in electrochemical assay with improved response |
ES11755417.0T ES2538089T3 (en) | 2011-02-24 | 2011-08-11 | Capacity detection in electrochemical assay with improved response |
KR1020137024881A KR20140015386A (en) | 2011-02-24 | 2011-08-11 | Capacitance detection in electrochemical assay with improved response |
HK14106373.8A HK1193464A1 (en) | 2011-02-24 | 2014-06-25 | Capacitance detection in electrochemical assay with improved response |
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US13/034,281 US20110208435A1 (en) | 2010-02-25 | 2011-02-24 | Capacitance detection in electrochemical assays |
US13/034,281 | 2011-02-24 | ||
GBPCT/GB2011/000267 | 2011-02-25 | ||
PCT/GB2011/000267 WO2011104517A2 (en) | 2010-02-25 | 2011-02-25 | Capacitance detection in electrochemical assay |
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PCT/GB2011/001210 WO2012114055A1 (en) | 2011-02-24 | 2011-08-10 | Capacitance detection in electrochemical assay with improved sampling time offset |
PCT/GB2011/001211 WO2012114056A1 (en) | 2011-02-24 | 2011-08-11 | Capacitance detection in electrochemical assay with improved response |
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US (2) | US20110208435A1 (en) |
EP (3) | EP2678670B1 (en) |
JP (2) | JP5695218B2 (en) |
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CN (2) | CN103415767B (en) |
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US20140134655A1 (en) | 2012-11-09 | 2014-05-15 | Cilag Gmbh International | System and method for detection of sample volume during initial sample fill of a biosensor to determine glucose concentration in fluid samples or sample fill error |
US9575051B2 (en) | 2013-12-23 | 2017-02-21 | Cilag Gmbh International | Test strip connector contact protection |
KR101666978B1 (en) | 2014-09-17 | 2016-10-24 | 주식회사 아이센스 | Apparatus and Method for measuring concentration of Whole Blood Samples Using the same |
US9739774B2 (en) * | 2015-09-03 | 2017-08-22 | Nxp B.V. | Substance detection device |
US9632059B2 (en) * | 2015-09-03 | 2017-04-25 | Ashwin-Ushas Corporation, Inc. | Potentiostat/galvanostat with digital interface |
CN106290530B (en) * | 2016-08-31 | 2018-10-30 | 微泰医疗器械(杭州)有限公司 | It is a kind of can self-correction interference signal electrochemical analyte sensor-based system and method |
CN106596688A (en) * | 2016-12-21 | 2017-04-26 | 三诺生物传感股份有限公司 | Method, recognition device controller and recognition system for distinguishing quality control liquid from practical sample in electrochemical testing system |
CN111108398A (en) * | 2017-09-29 | 2020-05-05 | 勃林格殷格翰维特梅迪卡有限公司 | Testing and calibration of circuit arrangements |
CN109254251B (en) * | 2018-09-20 | 2021-03-09 | 大唐恩智浦半导体有限公司 | Battery impedance measuring device, method and chip |
CN109959685B (en) * | 2019-03-26 | 2021-07-20 | 深圳绿食宝科技有限公司 | Method and system for measuring nitrate ion content in biological product |
CN112710963B (en) * | 2020-12-28 | 2023-10-13 | 哈尔滨工业大学(深圳) | Switching power supply fault detection method based on impulse response |
CN115835486B (en) * | 2023-02-23 | 2023-04-14 | 南京柠檬科技发展有限公司 | Chemical analysis instrument signal processing device |
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2011
- 2011-02-24 US US13/034,281 patent/US20110208435A1/en not_active Abandoned
- 2011-08-10 EP EP11758533.1A patent/EP2678670B1/en not_active Not-in-force
- 2011-08-10 CN CN201180068457.0A patent/CN103415767B/en not_active Expired - Fee Related
- 2011-08-10 AU AU2011360140A patent/AU2011360140B2/en not_active Ceased
- 2011-08-10 CA CA2828097A patent/CA2828097A1/en not_active Abandoned
- 2011-08-10 KR KR1020137024882A patent/KR20140015387A/en not_active Application Discontinuation
- 2011-08-10 RU RU2013143142/15A patent/RU2571285C2/en not_active IP Right Cessation
- 2011-08-10 WO PCT/GB2011/001210 patent/WO2012114055A1/en active Application Filing
- 2011-08-10 JP JP2013554932A patent/JP5695218B2/en not_active Expired - Fee Related
- 2011-08-10 BR BR112013021666A patent/BR112013021666A2/en not_active Application Discontinuation
- 2011-08-10 ES ES11758533.1T patent/ES2543911T3/en active Active
- 2011-08-11 AU AU2011360141A patent/AU2011360141B2/en not_active Ceased
- 2011-08-11 ES ES11755417.0T patent/ES2538089T3/en active Active
- 2011-08-11 EP EP14157379.0A patent/EP2757365B1/en not_active Not-in-force
- 2011-08-11 RU RU2013143163/15A patent/RU2596793C2/en not_active IP Right Cessation
- 2011-08-11 EP EP11755417.0A patent/EP2678678B1/en not_active Not-in-force
- 2011-08-11 WO PCT/GB2011/001211 patent/WO2012114056A1/en active Application Filing
- 2011-08-11 JP JP2013554933A patent/JP5695219B2/en not_active Expired - Fee Related
- 2011-08-11 BR BR112013021590A patent/BR112013021590A2/en not_active Application Discontinuation
- 2011-08-11 CN CN201180068402.XA patent/CN103392129B/en not_active Expired - Fee Related
- 2011-08-11 CA CA2828100A patent/CA2828100A1/en not_active Abandoned
- 2011-08-11 ES ES14157379.0T patent/ES2559663T3/en active Active
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2014
- 2014-04-07 US US14/246,592 patent/US9645104B2/en not_active Expired - Fee Related
- 2014-06-25 HK HK14106373.8A patent/HK1193464A1/en not_active IP Right Cessation
- 2014-06-25 HK HK14106384.5A patent/HK1192945A1/en not_active IP Right Cessation
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2015
- 2015-01-22 HK HK15100697.9A patent/HK1200529A1/en not_active IP Right Cessation
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