WO2014192393A1 - 検体センサおよび検体センシング方法 - Google Patents
検体センサおよび検体センシング方法 Download PDFInfo
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- WO2014192393A1 WO2014192393A1 PCT/JP2014/058559 JP2014058559W WO2014192393A1 WO 2014192393 A1 WO2014192393 A1 WO 2014192393A1 JP 2014058559 W JP2014058559 W JP 2014058559W WO 2014192393 A1 WO2014192393 A1 WO 2014192393A1
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N29/00—Investigating or analysing materials by the use of ultrasonic, sonic or infrasonic waves; Visualisation of the interior of objects by transmitting ultrasonic or sonic waves through the object
- G01N29/02—Analysing fluids
- G01N29/022—Fluid sensors based on microsensors, e.g. quartz crystal-microbalance [QCM], surface acoustic wave [SAW] devices, tuning forks, cantilevers, flexural plate wave [FPW] devices
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N29/00—Investigating or analysing materials by the use of ultrasonic, sonic or infrasonic waves; Visualisation of the interior of objects by transmitting ultrasonic or sonic waves through the object
- G01N29/22—Details, e.g. general constructional or apparatus details
- G01N29/30—Arrangements for calibrating or comparing, e.g. with standard objects
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N29/00—Investigating or analysing materials by the use of ultrasonic, sonic or infrasonic waves; Visualisation of the interior of objects by transmitting ultrasonic or sonic waves through the object
- G01N29/44—Processing the detected response signal, e.g. electronic circuits specially adapted therefor
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N29/00—Investigating or analysing materials by the use of ultrasonic, sonic or infrasonic waves; Visualisation of the interior of objects by transmitting ultrasonic or sonic waves through the object
- G01N29/44—Processing the detected response signal, e.g. electronic circuits specially adapted therefor
- G01N29/4409—Processing the detected response signal, e.g. electronic circuits specially adapted therefor by comparison
- G01N29/4436—Processing the detected response signal, e.g. electronic circuits specially adapted therefor by comparison with a reference signal
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2291/00—Indexing codes associated with group G01N29/00
- G01N2291/01—Indexing codes associated with the measuring variable
- G01N2291/012—Phase angle
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2291/00—Indexing codes associated with group G01N29/00
- G01N2291/02—Indexing codes associated with the analysed material
- G01N2291/022—Liquids
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2291/00—Indexing codes associated with group G01N29/00
- G01N2291/02—Indexing codes associated with the analysed material
- G01N2291/025—Change of phase or condition
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2291/00—Indexing codes associated with group G01N29/00
- G01N2291/02—Indexing codes associated with the analysed material
- G01N2291/025—Change of phase or condition
- G01N2291/0255—(Bio)chemical reactions, e.g. on biosensors
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2291/00—Indexing codes associated with group G01N29/00
- G01N2291/02—Indexing codes associated with the analysed material
- G01N2291/025—Change of phase or condition
- G01N2291/0256—Adsorption, desorption, surface mass change, e.g. on biosensors
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2291/00—Indexing codes associated with group G01N29/00
- G01N2291/04—Wave modes and trajectories
- G01N2291/042—Wave modes
- G01N2291/0423—Surface waves, e.g. Rayleigh waves, Love waves
Definitions
- the present invention relates to a sample sensor and a sample sensing method capable of measuring a property of a sample or a target contained in the sample.
- a surface acoustic wave sensor that measures a property of a liquid or a component of a liquid using a surface acoustic wave element is known.
- a surface acoustic wave sensor has a detection unit that reacts with a component contained in a specimen sample on a piezoelectric substrate, and measures an electrical signal based on a change in a surface acoustic wave (SAW) propagated through the detection unit.
- SAW surface acoustic wave
- Patent Document 1 measures the analyte concentration by detecting the phase difference of SAW.
- a quadrature modulation method is generally employed because of the wide range of measurable phase ranges (for example, Non-Patent Document 1).
- the quadrature modulation method has a problem that it is difficult to reduce the size because of the large number of parts for realizing it. Furthermore, there is a problem in that current consumption increases due to an increase in digital processing.
- An analyte sensor includes a detection unit that changes in mass according to adsorption of a target contained in a sample or reaction with the target, and is an AC signal according to a change in mass of the detection unit.
- the phase difference from the first measurement signal is different from the first calculation unit for obtaining the first measurement signal by the method and the heterodyne method from the second signal and the fourth signal ( ⁇ 18).
- (Except °) a second calculation unit for obtaining a second measurement signal, and calculating two first phase change candidate values from the first measurement signal, and calculating two second phase change candidate values from the second measurement signal
- a measuring unit that sets a combination of the two first phase change candidate values and the two second phase change candidate values that are closest to each other as a first phase change value and a second phase change value
- a selection unit that selects, as the phase change value, a signal output value closer to a reference value among the first phase change value and the second phase change value;
- the detection unit of the detection element in which the mass of an analyte solution containing an analyte with a target changes according to the adsorption of the target or the reaction with the target, and the target
- a sample solution supply step for supplying to a reference portion of a reference element that does not adsorb or react with the target, a detection signal that is an AC signal according to a change in mass of the detection portion that is output from the sample detection element, and
- One of the reference signals which is an AC signal corresponding to the mass of the reference section output from the reference element, is branched into a first signal and a second signal, and the other signal is divided into a third signal and a fourth signal.
- a change candidate value is calculated, two second phase change candidate values are calculated from the second measurement signal, and the largest value of the two first phase change candidate values and the two second phase change candidate values is calculated.
- the specimen sensor and the specimen sensing method according to the embodiment of the present invention it is possible to combine measurement in a wide phase range with small size and low current consumption.
- FIG. 1 is a principle configuration diagram of an analyte sensor according to a first embodiment of the present invention. It is a schematic diagram explaining the signal processing of a heterodyne system.
- FIG. 3A is a diagram showing a schematic trajectory of the first measurement signal and the second measurement signal
- FIG. 3B is a diagram showing a trajectory of the selected measurement signal.
- FIG. 5 is a perspective view of a state in which a part of the specimen sensor shown in FIG. 4 is broken.
- 6A is a cross-sectional view taken along line VIa-VIa in FIG. 4, and FIG. 6B is a cross-sectional view taken along line VIb-VIb in FIG.
- FIG. 5 is a top view excluding a part of the specimen sensor shown in FIG. 4. It is a fundamental block diagram of the sample sensor which concerns on 2nd Embodiment of this invention. It is a fundamental lineblock diagram of the sample sensor concerning other embodiments of the present invention.
- FIG. 9A is a diagram showing a sample sensor according to another embodiment of the present invention, and FIG. 9A is a diagram showing trajectories of the first measurement signal, the second measurement signal, and the third measurement signal, and FIG. ) Is a diagram showing a trajectory of a selected measurement signal. It is a fundamental lineblock diagram of the sample sensor concerning other embodiments of the present invention.
- the analyte sensor may be set in any direction upward or downward, but in the following, for convenience, the orthogonal coordinate system xyz is defined and the positive side in the z direction is defined as the upper side and the lower side. The following terms shall be used.
- FIG. 1 is a schematic diagram for explaining the principle of the analyte sensor 100.
- the analyte sensor 100 includes a detection element 110, a reference element 120, a branching unit 130, a calculation unit 140, a measurement unit 150, a selection unit 160, and a detection amount calculation unit 170.
- a detection element 110 a reference element 120
- a branching unit 130 a calculation unit 140
- a measurement unit 150 a selection unit 160
- a detection amount calculation unit 170 a detection amount calculation unit 170.
- the detection element 110 has a detection unit 111 that adsorbs a target present in the specimen or changes its mass in accordance with the reaction with the target.
- the detection unit 111 immobilizes a reactive group having a reactivity that specifically adsorbs a target on a gold (Au) film that is not affected by electrical properties such as the conductivity of the specimen. Can be realized.
- the target itself may not be adsorbed.
- a reactive group having a property that reacts with a target and does not react with a substance other than the target present in the specimen may be immobilized on the Au film.
- the Au film is desirably electrically grounded. With such a configuration, the mass of the detection unit 111 changes according to the amount of the target.
- the reference element 120 includes a reference unit 121 that does not adsorb a target or does not react with the target.
- the reference unit 121 does not have such a reactivity as to be specifically adsorbed to a target present in the specimen or cause a substitution reaction with a substance in the specimen by causing a structural change. is there.
- the Au film not having the above reactive group immobilized thereon, or the DNA, RNA, etc. having the same amount of substance as the above reactive group and having a random base sequence are immobilized on the Au film. Can be used. With such a configuration, it is possible to suppress the reference unit 121 from causing a mass change depending on the amount of the target.
- An input signal is given to the detection element 110 and the reference element 120 from the outside.
- An input signal given to the detection element 110 passes through the detection unit 111 and is output as a detection signal through a change corresponding to a mass change of the detection unit 111.
- an input signal given to the reference element 120 passes through the reference unit 121 and is output as a reference signal through a change corresponding to the mass of the reference unit 121.
- the detection signal and the reference signal are AC signals, and the reference signal serves as a reference signal for the detection signal.
- the branching unit 130 includes a first branching unit 131 and a second branching unit 132.
- the first branch unit 131 is connected to the detection element 110 and branches a detection signal corresponding to a mass change of the detection unit 111 of the detection element 110 into a first signal and a second signal.
- the first signal and the second signal are signals having the same phase. That is, the detection signal is branched into two identical signals A.
- the second branching unit 132 branches the reference signal from the reference element 120 into a third signal and a fourth signal.
- the third signal has the same phase as the first signal.
- the fourth signal is shifted in phase from the first signal by a value excluding 180 °. In this example, the phase is shifted by 90 °.
- the third signal is represented by B and the fourth signal is represented by B ′.
- the first branch part 131 and the second branch part 132 are configured by, for example, a splitter.
- the second branching unit 132 may be realized by branching a signal into two by a normal method and then making one line length different from the other line length.
- the calculation unit 140 includes a first calculation unit 141 and a second calculation unit 142.
- the first calculation unit 141 obtains the first measurement signal from the first signal A and the third signal B by the heterodyne method.
- the first calculator 141 obtains a first measurement signal that is a value obtained by subtracting the third signal B from the first signal A by the heterodyne method.
- the second calculator 142 obtains the second measurement signal from the second signal A and the fourth signal B ′ by the heterodyne method.
- the second calculation unit 142 obtains a second measurement signal that is a value obtained by subtracting the fourth signal B ′ from the second signal A by the heterodyne method.
- Such first calculation unit 141 and second calculation unit 142 include, for example, a mixer and a low-pass filter.
- the measurement unit 150 calculates two first phase change candidate values from the first measurement signal, and determines one of them as the first phase change value. Similarly, two second phase change candidate values are calculated from the second measurement signal, and one of them is determined as the second phase change value.
- the first measurement signal and the second measurement signal are processed by the heterodyne method, as shown in FIG. 2, the first measurement signal and the second measurement signal are sinusoidal, and the voltage intensity (output value).
- the phase change value candidate There are two values x1 and x2 in the phase change value candidate corresponding to y1. This candidate value for phase change indicates the phase difference between the detection signal and the reference signal.
- first phase change candidate values x11 and x21 for the first measurement signal.
- second phase change candidate values x12 and x22 for the second measurement signal.
- the combination of x11 and x12, the combination of x11 and x22, the combination of x21 and x12, and the combination of x21 and x22 has the closest value (phase difference value).
- the phase change candidate values that are combined with each other are set as the first phase change value of the first measurement signal and the second phase change value of the second measurement signal, respectively.
- a difference is obtained for four combinations, and a combination having the smallest value is selected.
- the phase change candidate values forming the selected combination are set as the first phase change value of the first measurement signal and the second phase change value of the second measurement signal, respectively. This is due to the following mechanism.
- one of the two first phase change candidate values of the first measurement signal is the same as one of the two second phase change candidate values of the second measurement signal.
- This same value is the correct phase change value (first phase change value, second phase change value).
- the combination that minimizes the difference is discriminated as the first phase change value and the second phase change value.
- the phase change value can be determined from the phase change candidate value by using the two detection signals (first and second detection signals) as described above.
- the selection unit 160 selects one of the first measurement signal and the second measurement signal as a measurement signal used in the subsequent detection amount calculation unit 170. Similarly, if the measurement signal selected is the first measurement signal, the first phase change value is selected as the phase change value. If the second measurement signal is selected, the second phase change value is selected as the phase change value.
- the following steps are performed. First, the trajectory between the first measurement signal and the second measurement signal is obtained in advance, and two positive and negative intensities at the intersection of the first measurement signal and the second measurement signal are obtained. Then, the first measurement signal and the second measurement signal that are located between two positive and negative intensities at the intersection are selected as measurement signals.
- FIG. 3 (a) is a diagram showing the locus of theoretical values of the first measurement signal and the second measurement signal.
- the intensity of the first measurement signal is set to V1
- the intensity of the second measurement signal is set to V2
- the intensity of the intersection of the locus of the first measurement signal and the locus of the second measurement signal is set to Vmax and Vmin in descending order.
- the locus of the first measurement signal is indicated by a broken line
- the locus of the second measurement signal is indicated by a solid line.
- the intersection strengths Vmax and Vmin are 0.5 times and -0.5 times the maximum strength of V1 and V2.
- the section of the phase value is divided for each phase value at which the first measurement signal and the second measurement signal take the intensity of either intersection.
- sections 1 to 5 are shown.
- the sections 1 to 4 are repeated, and the sections 1 and 5 are the same.
- the second measurement signal is used as the measurement signal in section 1, the first measurement signal in section 2, the second measurement signal in section 3, the first measurement signal in section 4, and the second measurement signal in section 5. select.
- the first phase change value is the phase change value
- the second phase change value is the phase change value
- the trajectory of the measurement signal selected in this way is shown in FIG.
- the phase change value can also be selected according to the measurement signal selected according to the above conditions.
- the detection amount calculation unit 170 calculates the detection amount of the specimen using the phase change value selected through the above-described process.
- the detection amount calculation unit 170 is connected to the selection unit 160.
- the sample sensor according to the present embodiment processes signals by the heterodyne method, the sample detection amount can be calculated only by adding a mixer that takes the difference between the detection signal and the reference signal. For this reason, complicated signal processing is not required as compared with the orthogonal modulation method used conventionally, the number of necessary components is small, miniaturization is possible, and current consumption can be suppressed.
- the measurable phase range was only from 0 ° to 180 °.
- the first measurement signal and the second measurement signal are compared with the first and second phase change candidate values, so that the sign of the phase from the phase change candidate value is determined. Judgment can be made and the phase change value can be estimated. Thereby, the measurable phase range can be expanded from ⁇ 180 ° to 180 °.
- the second measurement signal since the fourth signal is shifted by 90 ° with respect to the first to third signals, the second measurement signal has the highest sensitivity when the first measurement signal has the lowest sensitivity. Since it becomes an area
- the reference signal is branched to the third signal and the fourth signal by shifting the phase, but the detection signal may be branched to the third signal and the fourth signal.
- the example which shifted the phase of the 4th signal 90 degrees with respect to the 1st signal was demonstrated as the most effective example, as long as it is a value except 180 degrees, other than 90 degrees may be sufficient.
- noise determination can be performed by using two measurement signals (first measurement signal and second measurement signal) as described above. This is due to the following mechanism. Noise may be mixed in the detection signal and the reference signal. Usually, it is difficult to distinguish such noise from noise.
- the sample sensor 100 of the present embodiment when the measurement is correctly performed, one voltage strength of the first measurement signal and the second measurement signal is in a range between the intersection strengths Vmax and Vmin. Enter a value that falls within the range of the other. In other words, if both the first measurement signal and the second measurement signal take a value within this range or take a value outside this range, it can be determined to be noise. Since noise can be discriminated in this way, the analyte sensor 100 capable of accurate measurement without being affected by noise can be obtained.
- analyte sensor 100 that can detect the phase range having the same width as that of the quadrature modulation method with a small number of components and a small signal processing.
- the specimen sensor 100 ⁇ / b> A mainly includes a piezoelectric substrate 1 and a cover 3 in appearance.
- the cover 3 is provided with a first through hole 18 that is an inlet of the sample solution and an air hole or a second through hole 19 that is an outlet of the sample solution.
- FIG. 5 shows a perspective view of the sample sensor 100A when one half of the cover 3 is removed.
- a space 20 serving as a sample flow path for a sample (solution) is formed inside the cover 3.
- the first through hole 18 is connected to the space 20. That is, the specimen entering from the first through hole 18 flows into the space 20.
- the sample liquid that has flowed into the space 20 includes a target, and the target reacts with a detection unit made of the metal film 7 or the like formed on the piezoelectric substrate 1.
- the piezoelectric substrate 1 is made of, for example, a single crystal substrate having piezoelectricity such as lithium tantalate (LiTaO 3 ) single crystal, lithium niobate (LiNbO 3 ) single crystal, or quartz.
- the planar shape and various dimensions of the piezoelectric substrate 1 may be set as appropriate.
- the thickness of the piezoelectric substrate 1 is 0.3 mm to 1 mm.
- FIG. 6 shows a cross-sectional view of the specimen sensor 100A.
- 6A is a cross-sectional view taken along line VIa-VIa in FIG. 4
- FIG. 6B is a cross-sectional view taken along line VIb-VIb in FIG.
- FIG. 7 shows a top view of the piezoelectric substrate 1.
- a detection first IDT electrode 5a, a detection second IDT electrode 6a, a reference first IDT electrode 5b, and a reference second IDT electrode 6b are formed on the upper surface of the piezoelectric substrate 1.
- the detection first IDT electrode 5a and the reference first IDT electrode 5b are for generating a predetermined SAW
- the detection second IDT electrode 6a and the reference second IDT electrode 6b are the detection first IDT electrode 5a and the reference first IDT electrode 5b, respectively. This is for receiving the generated SAW.
- the detection second IDT electrode 6a is disposed on the propagation path of the SAW generated by the detection first IDT electrode 5a so that the detection second IDT electrode 6a can receive the SAW generated by the detection first IDT electrode 5a.
- the reference first IDT electrode 5b and the reference second IDT electrode 6b are similarly arranged.
- the detection first IDT electrode 5a and the detection second IDT electrode 6a are the same as the detection first IDT electrode 5a and the detection second IDT electrode 6a, the detection first IDT electrode 5a and the detection second IDT electrode 6a will be described below as an example. .
- the detection first IDT electrode 5a and the detection second IDT electrode 6a have a pair of comb electrodes (see FIG. 7). Each comb electrode has two bus bars facing each other and a plurality of electrode fingers extending from each bus bar to the other bus bar side. The pair of comb electrodes are arranged so that a plurality of electrode fingers mesh with each other.
- the detection first IDT electrode 5a and the detection second IDT electrode 6a constitute a transversal IDT electrode.
- the detection first IDT electrode 5a and the detection second IDT electrode 6a are connected to the pad 9 through the wiring 8, respectively.
- a signal is input from the outside to the detection first IDT electrode 5a through the pad 9 and the wiring 8, and a signal is output to the outside from the detection second IDT electrode 6a.
- the detection first IDT electrode 5a, the detection second IDT electrode 6a, the reference first IDT electrode 5b, the reference second IDT electrode 6b, the wiring 8 and the pad 9 are made of, for example, aluminum (Al), an alloy of aluminum and copper (Cu), or the like. . These electrodes may have a multilayer structure. In the case of a multilayer structure, for example, the first layer is made of titanium (Ti) or chromium (Cr), and the second layer is made of aluminum or an aluminum alloy.
- the detection first IDT electrode 5a, the detection second IDT electrode 6a, the reference first IDT electrode 5b, and the reference second IDT electrode 6b are covered with a protective film 4.
- the protective film 4 contributes to preventing oxidation of each electrode and wiring.
- the protective film 4 is made of silicon oxide, aluminum oxide, zinc oxide, titanium oxide, silicon nitride, silicon (Si), or the like.
- silicon dioxide (SiO 2 ) is used as the protective film 4.
- the protective film 4 is formed over the entire top surface of the piezoelectric substrate 1 so as to expose the pads 9.
- the detection first IDT electrode 5a and the detection second IDT electrode 6a are covered with the protective film 4. Thereby, it can suppress that an IDT electrode corrodes.
- the thickness of the protective film 4 is, for example, 100 nm to 10 ⁇ m.
- the detection first IDT electrode 5a is accommodated in the first vibration space 11a
- the detection second IDT electrode 6a is accommodated in the second vibration space 12a. Accordingly, the detection first IDT electrode 5a and the detection second IDT electrode 6a are isolated from the outside air and the sample liquid, and the detection first IDT electrode 5a and the detection second IDT electrode 6a can be protected from corrosive substances such as moisture. Further, by securing the first vibration space 11a and the second vibration space 12a, the detection first IDT electrode 5a and the detection second IDT electrode 6a can be brought into a state in which the excitation of the SAW is not significantly hindered.
- the first vibration space 11a and the second vibration space 12a can be formed by joining the plate-like body 2 having a recess for forming these vibration spaces to the piezoelectric substrate 1.
- the reference first IDT electrode 5b and the reference second IDT electrode 6b are also provided with a first vibration space 11b and a second vibration space 12b.
- a through portion that is a portion penetrating the plate-like body 2 in the thickness direction is formed.
- This penetrating portion is provided to form the metal film 7a on the SAW propagation path. That is, when the plate-like body 2 is bonded to the piezoelectric substrate 1, at least a part of the SAW propagation path propagating from the detection first IDT electrode 5 a to the detection second IDT electrode 6 a is exposed from the through portion in plan view. A metal film 7a is formed on the exposed portion.
- the plate-like body 2 having such a shape can be formed using, for example, a photosensitive resist.
- the metal film 7a exposed from the penetrating part of the plate-like body 2 constitutes a specimen liquid detection part.
- the metal film 7a has a two-layer structure of, for example, chromium and gold formed on the chromium.
- an aptamer made of nucleic acid or peptide is immobilized on the surface of the metal film 7a.
- the mass of the metal film 7a monotonously increases as the specimen binds and adsorbs to the aptamer.
- the mass increases monotonously according to the detection of the specimen.
- the mass of the metal film 7a monotonously increases only while the specimen is continuously supplied onto the metal film 7a. For example, when the buffer solution is supplied continuously with the sample supply before and after the sample solution is supplied, the sample passes over the metal film 7a, and the mass is reduced due to the separation of the sample and the aptamer. There is no problem.
- the metal film 7b exposed from the other penetrating portion of the plate-like body 2 constitutes a reference portion.
- the metal film 7b has, for example, a two-layer structure of chromium and gold formed on the chromium. It is assumed that an aptamer immobilized on the metal film 7a is not attached to the surface of the metal film 7a so as not to be reactive with the specimen. Furthermore, a surface treatment may be performed so as to stabilize the sample solution by reducing its reactivity.
- a predetermined voltage (signal) is applied to the detection first IDT electrode 5a from the external measuring device via the pad 9 and the wiring 8. Then, the surface of the piezoelectric substrate 1 is excited in the formation region of the detection first IDT electrode 5a, and SAW having a predetermined frequency is generated. Part of the generated SAW passes through the region between the detection first IDT electrode 5a and the detection second IDT electrode, and reaches the detection second IDT electrode 6a.
- the aptamer immobilized on the metal film 7a binds to a specific target substance in the sample, and the weight of the metal film 7a changes by the amount of the binding, so it passes under the metal film 7a.
- a voltage corresponding to the SAW is generated in the detection second IDT electrode 6a. This voltage is output to the outside as a detection signal of an AC signal through the wiring 8 and the pad 9, and is processed through the branching unit 130 and the calculating unit 140 shown in FIG. be able to.
- the detection element 110 ⁇ / b> A is configured by the piezoelectric substrate 1, the metal film 7 a as a detection unit formed on the piezoelectric substrate 1, and the detection first IDT electrode 5 a and the detection second IDT electrode 6 a.
- a signal from the reference first IDT electrode 5b is input, and an AC signal output from the reference second IDT electrode 6b is converted to a temperature characteristic or the like.
- Reference signal used for calibration of signal fluctuation due to environmental changes such as humidity and humidity.
- the piezoelectric substrate 1, the metal film 7b as a reference portion formed on the piezoelectric substrate 1, and the reference first IDT electrode 5b and the reference second IDT electrode 6b constitute a reference element 120A.
- the detection element 110A and the reference element 120A share the same piezoelectric substrate 1, but the detection element substrate (first substrate) and the reference element substrate (second substrate) may be separated. Good.
- the cover 3 is made of, for example, polydimethylsiloxane.
- polydimethylsiloxane By using polydimethylsiloxane as the material of the cover 3, the cover 3 can be formed into an arbitrary shape. Moreover, if polydimethylsiloxane is used, the ceiling part and side wall of the cover 3 can be formed comparatively easily. The thickness of the ceiling part and the side wall of the cover 3 is, for example, 1 mm to 5 mm.
- one of the pair of comb-like electrodes constituting each of the detection first IDT electrode 5a, the detection second IDT electrode 6a, the reference first IDT electrode 5b, and the reference second IDT electrode 6b is a reference potential line. 31 is connected.
- the reference potential line 31 is connected to the pad 9G and becomes a reference potential.
- an electrode on the side connected to the reference potential is selected. It is arranged on the side where the reference potential line 31 is arranged. In other words, the electrode on the inner side of the pair of comb-like electrodes is connected to the reference potential.
- the wiring 8 can be easily routed between the detection element 110A and the reference element 120A, and the lengths of the wirings 8 can be made uniform. As a result, the reference signal from the reference element 120A becomes more accurate as a reference signal.
- the example in which signals from the detection element 110 and the reference element 120 are directly used has been described.
- the sample sensor 100B according to the second embodiment shown in FIG. 8 between the detection element 110 and the first branch part 131 and between the reference element 120 and the second branch part 132, respectively.
- the low noise amplifier 133 (first low noise amplifier 133a, second low noise amplifier 133b) may be arranged.
- the SAW sensor when the sensitivity is high, the change of the amplitude characteristic becomes large. Therefore, if the thickness of the protective film 4 is adjusted to increase the sensitivity, the loss may increase and accurate measurement may not be possible. However, high detection accuracy is obtained by interposing the low noise amplifier 133. be able to. On the other hand, if the signal input to the calculation unit 140 is small, noise may increase and the detection accuracy may be lowered. However, by providing a low noise amplifier 133 in the input path to the calculation unit 140, high detection accuracy may be achieved. Obtainable.
- the low noise amplifier 133 is preferably provided on the side close to the elements 110 and 120 in the input path to the calculation unit 140.
- the signals input to the detection element 110 and the reference element 120 are increased, there is a possibility that the input signals of each other or these input signals and other signals may have an adverse effect such as crosstalk. Further, by interposing the low noise amplifier 133 in the output path from the reference element 120, it is possible to suppress the above-described crosstalk and obtain high detection accuracy. Furthermore, when the signals input to the detection element 110 and the reference element 120 are increased, there is a possibility that the input signals of each other, or these input signals and other signals may leak to the outside as electromagnetic waves. By interposing the low noise amplifier 133 in the output path from the reference element 120, leakage of electromagnetic waves as described above can be suppressed and high detection accuracy can be obtained.
- sample solution supply process First, a sample solution supplying step for supplying a sample containing a target to the detection unit of the detection element whose mass changes in accordance with the target adsorption or the reaction with the target and the reference unit of the reference element that does not adsorb or react with the target. Do.
- the phase of the fourth signal can be appropriately selected as long as it is a value excluding ⁇ 180 ° relative to the phase of the first signal, but is preferably ⁇ 90 °.
- a first measurement signal is obtained from the first signal and the third signal by a heterodyne method.
- the third signal may be subtracted from the first signal, or the first signal may be subtracted from the third signal.
- a second measurement signal is obtained from the second signal and the fourth signal by a heterodyne method.
- the fourth signal may be subtracted from the second signal, or the second signal may be subtracted from the fourth signal, as in the first calculation step described above.
- phase change candidate values are calculated from the first measurement signal
- two second phase change candidate values are calculated from the second measurement signal
- two first phase change candidate values and two second phase change values are calculated.
- the phase change candidate values the one that forms the smallest combination is defined as a first phase change value and a second phase change value.
- the intensity of two intersection points of the trajectory of the first measurement signal and the second measurement signal is obtained in advance, and the first measurement signal and the second measurement signal that are located between the above two intersection intensity values are obtained. Select as measurement signal. Similarly, the first phase change value and the second phase change value corresponding to this measurement signal are selected as the phase change value.
- the detection amount of the specimen is calculated from the phase change value selected in the selection step.
- the amount of detected sample can be measured.
- the present invention is not limited to the above embodiment, and can be implemented in various modes.
- the intensity of two intersections of the trajectory of the first measurement signal and the second measurement signal is obtained in advance, and the first measurement signal and the second measurement are obtained.
- a signal and a signal positioned between two intersection strengths are selected as measurement signals.
- the signal output value for example, V1, V2
- the phase change value may be selected as the phase change value.
- the reference value for example, the midpoint of the two intersection strengths described above, or 0 (zero) can be set.
- the midpoint of the two intersection strengths that are reference values is zero.
- the reference value is not limited to the midpoint between the two intersection strengths, and is set to an appropriate value so that a highly sensitive measurement signal can be obtained in consideration of the first measurement signal and the second measurement signal. Good.
- the third signal has the same phase as the first signal, and the fourth signal is derived from the first signal.
- the phase is shifted by 90 °.
- the setting of the phases of the first to fourth signals is not limited to this, and the first measurement signal and the second measurement signal may be set so as to have a phase difference excluding ⁇ 180 °.
- the first signal and the second signal have the same phase
- the third signal is shifted by ⁇ 45 ° from the first signal
- the fourth signal is changed to the first signal.
- the phase may be shifted by + 45 ° with respect to the angle. Even in this case, the same effects as those of the sample sensor according to the above-described embodiment can be obtained.
- the first branching unit 131 and the second branching unit 132 are branched into two signals, respectively.
- the unit 131 and the second branch unit 132 may be set to branch into three or more signals, respectively.
- two of the obtained signals are used to each other by a heterodyne method.
- the sensitivity of the three measurement signals is higher than that of the three measurement signals even if the region with a small inclination is wide, in other words, the region where each measurement signal can be measured with high sensitivity. Since it can set so that the measurement signal which has an area
- one detection element 110 and one reference element 120 are provided, and one detection element 110 and the first branch portion 131 are connected.
- one reference element 120 and the second branch part 132 are connected.
- two or more detection elements and reference elements are used, and the two or more detection elements 110a and 110b and the first branch portion 131 are connected, and 2 Two or more reference elements 120a, 120b and the second branch part 132 may be connected.
- the first branch unit 131 can be selectively connected to one of the two or more detection elements 110a and 110b by the switch 136a
- the second branch unit can be two or more reference elements by the switch 136b.
- each of the first branch unit and the second branch unit can be connected to both the detection element and the reference element. be able to.
- three detection elements and one reference element may be used. In this case, as long as one of the first branch part and the second branch part is connected to the reference element, there is no particular limitation on which of the three detection elements is connected to the other. It can be set as appropriate according to the type and number.
- the detection element 110A and the reference element 120A have been described using an example in which a substrate having piezoelectricity is shared, but the element substrate for the detection element 110A and the reference element The second substrate for the element 120A may be separated. In this case, crosstalk between the detection element 110A and the reference element 120A can be suppressed. In such a case, a separate substrate for holding the element substrate and the second substrate may be provided.
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Abstract
Description
(第1実施形態)
(検体センサ100)
図1は、検体センサ100の原理を説明するための概略図である。
検出素子110は、検体中に存在する標的が吸着する、またはこの標的との反応に応じて質量が変化する検出部111を有する。この検出部111は、例えば、検体の導電率などの電気的性質の影響を受けない金(Au)の膜に、標的を特異的に吸着させるような反応性を有する反応基を固定化することで実現できる。なお、標的自体を吸着させなくてもよい。例えば、Auの膜に、標的に対して反応し、検体中に存在する標的以外の物質と反応しないような特性を有する反応基を固定化してもよい。なお、このAu膜は電気的に接地されていることが望ましい。このような構成により、標的の量に応じて検出部111の質量が変化するものとなる。
リファレンス素子120は、標的を吸着しない、または標的と反応しないリファレンス部121を有する。このリファレンス部121は、例えば、検体中に存在する標的に対して特異的に吸着させたり、構造変化を生じて検体中の物質と置換反応を起こしたりするような反応性を有さないものである。具体的には、上述の反応基を固定化していないAuの膜や、上述の反応基と同程度の物質量を有し、ランダムな塩基配列を有するDNA,RNA等をAu膜上に固定化したものを用いることができる。このような構成により、リファレンス部121が標的の量に依存して質量変化を生じることを抑制できる。
分岐部130は、第1分岐部131と第2分岐部132とを含む。第1分岐部131は、検出素子110に接続されて、検出素子110の検出部111の質量変化に応じた検出信号を第1信号と第2信号とに分岐する。ここで、第1信号と第2信号とは位相の同じ信号である。すなわち、検出信号を2つの同一信号Aに分岐するものである。
計算部140は、第1計算部141と第2計算部142とを有する。
計測部150は、第1計測信号から2つの第1位相変化候補値を算出し、そのうちの一方を第1位相変化値と判断する。同様に、第2計測信号から2つの第2位相変化候補値を算出し、そのうち一方を第2位相変化値と判断する。
選択部160は、第1計測信号と第2計測信号との2つから、一方をその後の検出量算出部170で用いる計測信号として選択する。同様に、計測信号として選択されたものが第1計測信号の場合には第1位相変化値を、第2計測信号の場合には第2位相変化値をそれぞれ位相変化値として選択する。
V1<V2,かつV2>Vmax・・・計測信号としてV1を採用
V1<V2,かつV1<Vmin・・・計測信号としてV2を採用
V1>V2,かつV2<Vmin・・・計測信号としてV1を採用
仮にV1=V2の場合は、どちらを計測信号として採用してもよい。このようにして選択した計測信号の軌跡を図3(b)に示す。
次に、検出量算出部170において、上述の過程を経て選択した位相変化値を用いて検体の検出量を算出する。検出量算出部170は、選択部160に接続されている。
次に、図4を用いて、検体センサ100の原理を具体化した、本発明の第1実施形態に係る検体センサ100Aの構成について説明する。
次に、本発明の第2実施形態に係る検体センサ100Bについて、図8を参照しつつ説明する。
本発明の実施形態に係る検体センシング方法について説明する。
まず標的を含む検体を、標的の吸着または標的との反応に応じて質量が変化する検出素子の検出部と、標的を吸着しないまたは反応しないリファレンス素子のリファレンス部とに供給する検体溶液供給工程を行なう。
次に、検出部の質量変化に応じた交流信号である検出信号およびリファレンス部から、交流信号である上述のリファレンス信号のうち一方の信号を、2つの同じ位相の第1信号と第2信号とに分岐し、他方の信号を、第1信号と同じ位相の第3信号と、位相を180°を除く値だけずらした第4信号とに分岐する。
次に、第1信号と第3信号とからヘテロダイン方式によって第1計測信号を得る。
同様に、第2信号と第4信号とからヘテロダイン方式によって第2計測信号を得る。
次に、第1計測信号から2つの第1位相変化候補値を算出し、第2計測信号から2つの第2位相変化候補値を算出し、2つの第1位相変化候補値と2つの第2位相変化候補値とのうち最も値が小さい組合せを成すものを第1位相変化値および第2位相変化値とする。
さらに、第1計測信号と第2計測信号との軌跡の2つの交点の強度を予め求め、第1計測信号と第2計測信号とのうち、上述の2つの交点強度の間に位置するものを計測信号として選択する。同様に、第1位相変化値と第2位相変化値とのうち、この計測信号に対応するものを位相変化値として選択する。
選択工程にて選択した位相変化値から検体の検出量を算出する。
2・・・板状体
3・・・カバー
4・・・保護膜
5a・・・検出第1IDT電極
5b・・・リファレンス第1IDT電極
6a・・・検出第2IDT電極
6b・・・リファレンス第2IDT電極
7a,7b・・・金属膜
8・・・配線
9・・・パッド
11a,11b・・・第1振動空間
12a,12b・・・第2振動空間
20・・・空間
31・・・基準電位線
100,100A,B,C,D,E・・・検体センサ
110・・・検出素子
111・・・検出部
120・・・リファレンス素子
121・・・リファレンス部
130・・・分岐部
131・・・第1分岐部
132・・・第2分岐部
133・・・ローノイズアンプ
135a,b,c,d・・・素子側スイッチ
136a,b・・・分岐部側スイッチ
140・・・計算部
141・・・第1計算部
142・・・第2計算部
150・・・計測部
160・・・選択部
170・・・検出量算出部
Claims (9)
- 検体に含まれる標的の吸着または前記標的との反応に応じて質量が変化する検出部を有し、前記検出部の質量変化に応じた交流信号である検出信号を出力する検出素子と、
前記標的を吸着しないまたは前記標的と反応しないリファレンス部を有し、前記検出信号に対する交流信号であるリファレンス信号を出力するリファレンス素子と、
前記検出信号および前記リファレンス信号のうち一方の信号を、第1信号と第2信号とに分岐し、他方の信号を第3信号と第4信号とに分岐する分岐部と、
前記第1信号と前記第3信号とからヘテロダイン方式によって第1計測信号を得る第1計算部と、
前記第2信号と前記第4信号とからヘテロダイン方式によって、前記第1計測信号と位相差が異なる(±180°を除く)第2計測信号を得る第2計算部と、
前記第1計測信号から2つの第1位相変化候補値を算出し、前記第2計測信号から2つの第2位相変化候補値を算出し、前記2つの第1位相変化候補値と前記2つの第2位相変化候補値とのうち最も値が近い組合せを成すものを第1位相変化値および第2位相変化値とする計測部と、
前記第1位相変化値と前記第2位相変化値とのうち信号の出力値が基準値に近い方を位相変化値として選択する選択部と、を備える検体センサ。 - 検体に含まれる標的の吸着または前記標的との反応に応じて質量が変化する検出部を有し、前記検出部の質量変化に応じた交流信号である検出信号を出力する検出素子と、
前記標的を吸着しないまたは前記標的と反応しないリファレンス部を有し、前記検出信号に対する交流信号であるリファレンス信号を出力するリファレンス素子と、
前記検出信号および前記リファレンス信号のうち一方の信号を、2つの同じ位相の第1信号と第2信号とに分岐し、他方の信号を、前記第1信号の位相と同じ第3信号と、前記第1信号と位相が異なる(±180°を除く)第4信号とに分岐する分岐部と、
前記第1信号と前記第3信号とからヘテロダイン方式によって第1計測信号を得る第1計算部と、
前記第2信号と前記第4信号とからヘテロダイン方式によって第2計測信号を得る第2計算部と、
前記第1計測信号から2つの第1位相変化候補値を算出し、前記第2計測信号から2つの第2位相変化候補値を算出し、前記2つの第1位相変化候補値と前記2つの第2位相変化候補値とのうち最も値が近い組合せを成すものを第1位相変化値および第2位相変化値とする計測部と、
前記第1計測信号と前記第2計測信号との軌跡の2つの交点の強度を予め求め、前記第1計測信号と前記第2計測信号とのうち、前記2つの交点の強度の間に位置するものを計測信号として選択し、前記第1位相変化値と前記第2位相変化値とのうち前記計測信号に対応するものを位相変化値として選択する選択部と、を備える検体センサ。 - 前記第4信号は、前記第3信号と位相が90°異なる、請求項2に記載の検体センサ。
- 前記検出素子は、圧電性を有する第1基板と、前記第1基板上にそれぞれ配置された、前記検出部と、前記検出部に向かって弾性波を発生させる検出第1IDT電極と、前記検出部を通過した前記弾性波を受ける検出第2IDT電極とを有し、
前記リファレンス素子は、圧電性を有する第2基板と、前記第2基板上にそれぞれ配置された、前記リファレンス部と、前記リファレンス部に向かって弾性波を発生させるリファレンス第1IDT電極と、前記リファレンス部を通過した前記弾性波を受けるリファレンス第2IDT電極とを有し、
前記検出信号は、前記検出部を通過した前記弾性波を前記検出第2IDT電極で受けて得られた交流信号であり、
前記リファレンス信号は、前記リファレンス部を通過した前記弾性波を前記リファレンス第2IDT電極で受けて得られた交流信号である、請求項1~3のいずれかに記載の検体センサ。 - 前記検出素子と前記分岐部との間に位置し、前記検出素子からの前記検出信号を増幅する第1ローノイズアンプと、
前記リファレンス素子と前記分岐部との間に位置し、前記リファレンス素子からの前記リファレンス信号を増幅する第2ローノイズアンプと、をさらに備える、請求項1~4のいずれかに記載の検体センサ。 - 標的を備えた検体を含む検体溶液を、前記標的の吸着または前記標的との反応に応じて質量が変化する、検出素子の検出部、および前記標的を吸着しないまたは前記標的と反応しない、リファレンス素子のリファレンス部に供給する検体溶液供給工程と、
前記検体検出素子から出力される前記検出部の質量変化に応じた交流信号である検出信号、および前記リファレンス素子から出力される前記リファレンス部の質量に応じた交流信号であるリファレンス信号のうち一方の信号を、第1信号と第2信号とに分岐し、他方の信号を第3信号と第4信号とに分岐する分岐工程と、
前記第1信号と前記第3信号とからヘテロダイン方式によって第1計測信号を得る第1計算工程と、
前記第2信号と前記第4信号とからヘテロダイン方式によって、前記第1計測信号と位相差が異なる(±180°を除く)第2計測信号を得る第2計算工程と、
前記第1計測信号から2つの第1位相変化候補値を算出し、前記第2計測信号から2つの第2位相変化候補値を算出し、前記2つの第1位相変化候補値と前記2つの第2位相変化候補値とのうち最も値が近い組合せを成すものを第1位相変化値および第2位相変化値とする計測工程と、
前記第1計測信号と前記第2計測信号とのうち信号の出力値が基準値に近い方を位相変化値として選択する選択工程と、を備える、検体センシング方法。 - 標的を備えた検体を含む検体溶液を、前記標的の吸着または前記標的との反応に応じて質量が変化する、検出素子の検出部、および前記標的を吸着しないまたは前記標的と反応しない、リファレンス素子のリファレンス部に供給する検体溶液供給工程と、
前記検体検出素子から出力される前記検出部の質量変化に応じた交流信号である検出信号、および前記リファレンス素子から出力される前記リファレンス部の質量に応じた交流信号であるリファレンス信号のうち一方の信号を、2つの同じ位相の第1信号と第2信号とに分岐し、他方の信号を、前記第1信号と同じ位相の第3信号と、前記第1信号と位相が異なる(±180°を除く)第4信号とに分岐する分岐工程と、
前記第1信号と前記第3信号とからヘテロダイン方式によって第1計測信号を得る第1計算工程と、
前記第2信号と前記第4信号とからヘテロダイン方式によって第2計測信号を得る第2計算工程と、
前記第1計測信号から2つの第1位相変化候補値を算出し、前記第2計測信号から2つの第2位相変化候補値を算出し、前記2つの第1位相変化候補値と前記2つの第2位相変化候補値とのうち最も値が近い組合せを成すものを第1位相変化値および第2位相変化値とする計測工程と、
前記第1計測信号と前記第2計測信号との軌跡の2つの交点の強度を予め求め、前記第1計測信号と前記第2計測信号とのうち、前記2つの交点の強度の間に位置するものを前記計測信号として選択し、前記第1位相変化値と前記第2位相変化値とのうち前記計測信号に対応するものを位相変化値として選択する選択工程と、を備える、検体センシング方法。 - 前記分岐工程において、前記検出信号および前記リファレンス信号のそれぞれを増幅し、増幅した前記検出信号および前記リファレンス信号に基づき前記第1~前記第4信号を得る、請求項7に記載の検体センシング方法。
- 前記分岐工程において、前記第4信号の位相を前記第3信号の位相と90°異ならせる、請求項7または8に記載の検体センシング方法。
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EP14804624.6A EP3006933B1 (en) | 2013-05-30 | 2014-03-26 | Specimen sensor and specimen sensing method detecting a change in mass in response to specimen adsorption |
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WO2016137009A1 (ja) * | 2015-02-27 | 2016-09-01 | 京セラ株式会社 | 検体液の測定方法および検体液センサ |
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JP5421502B1 (ja) | 2012-01-30 | 2014-02-19 | 京セラ株式会社 | 検体センサおよび検体センシング方法 |
WO2016032008A1 (ja) | 2014-08-29 | 2016-03-03 | 京セラ株式会社 | センサ装置およびセンシング方法 |
WO2016159112A1 (ja) * | 2015-03-30 | 2016-10-06 | 京セラ株式会社 | 検体液センサおよび検体液の測定方法 |
JP6391653B2 (ja) * | 2016-11-04 | 2018-09-19 | 京セラ株式会社 | 検体センサおよび検体センシング方法 |
JP7213336B2 (ja) * | 2019-04-26 | 2023-01-26 | 京セラ株式会社 | センサ装置の製造方法、及び、センサ装置 |
WO2020241867A1 (ja) | 2019-05-31 | 2020-12-03 | 京セラ株式会社 | センサ装置 |
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EP3006933A1 (en) | 2016-04-13 |
US20180156754A1 (en) | 2018-06-07 |
CN105247360B (zh) | 2017-09-29 |
JP2015025658A (ja) | 2015-02-05 |
US10241082B2 (en) | 2019-03-26 |
EP3376218A1 (en) | 2018-09-19 |
EP3006933B1 (en) | 2018-04-25 |
CN105247360A (zh) | 2016-01-13 |
EP3006933A4 (en) | 2017-08-09 |
JP6042774B2 (ja) | 2016-12-14 |
CN107655968B (zh) | 2020-07-28 |
US9791413B2 (en) | 2017-10-17 |
US20160195498A1 (en) | 2016-07-07 |
CN107655968A (zh) | 2018-02-02 |
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