CN109142452B - Blood viscoelastic force measuring device and method based on piezoresistive micro-suspension bridge sensor - Google Patents
Blood viscoelastic force measuring device and method based on piezoresistive micro-suspension bridge sensor Download PDFInfo
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- CN109142452B CN109142452B CN201811261649.3A CN201811261649A CN109142452B CN 109142452 B CN109142452 B CN 109142452B CN 201811261649 A CN201811261649 A CN 201811261649A CN 109142452 B CN109142452 B CN 109142452B
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Abstract
The invention provides a blood viscoelastic force measuring device and method based on a piezoresistive micro-suspension bridge sensor, which comprises a microfluidic device, wherein the microfluidic device comprises a substrate, a microchannel is carved on the upper surface of the substrate, the input end of the microchannel is a double port, the output end of the microchannel is a single port, the piezoresistive micro-suspension bridge sensor is arranged in the microchannel, and liquid flows in through the two input ends, is converged, then flows out from the output end through the piezoresistive micro-suspension bridge sensor; the permanent magnets are arranged on two sides of the micro-fluid device and used for providing a constant magnetic field for the piezoresistive micro-suspension bridge sensor; and the signal excitation detection circuit is connected with the piezoresistive micro-suspension bridge sensor and is used for measuring the viscoelastic force change in the blood coagulation process. This device can carry out quick accurate measurement to the viscoelastic power of blood sample under the condition that uses less blood volume, satisfies the demand of clinical blood coagulation detection analysis now.
Description
Technical Field
The invention relates to a measurement technology for rapidly detecting the viscoelastic force of blood, in particular to a viscoelastic force measurement device and method of a trace blood sample based on a piezoresistive micro-suspension bridge sensor.
Background
Blood coagulation is the process by which flowing blood becomes a coagulated state, and its essence is the process by which soluble fibrinogen in plasma changes to insoluble fibrin. The detection of the blood coagulation function is very important for predicting the risk of blood loss after operation, judging the bleeding reason, guiding the implementation of hemostasis measures and the like, and especially is very important for operations with large bleeding amount, such as cardiovascular surgery, obstetrical surgery, orthopedic surgery and the like.
Currently, methods commonly used for blood coagulation detection include platelet counting, fibrinogen concentration, Thromboelastometry (TEG), rotational thromboelastometry (ROTEM), and electromagnetic sensor-based thromboelastometry. The time for counting blood platelets and detecting the concentration of fibrinogen is long, and generally 45-60 minutes is needed. The thrombelastogram appearance is difficult to keep upright when putting into the cup body with the cup head, leads to the probe difficult alignment when inserting in the cup head, is unfavorable for going up the cup operation. The method has low sensitivity and requires a large amount of blood for each detection, so that the requirement of clinical blood coagulation detection and analysis is difficult to meet.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a device and a method for measuring the viscoelastic force of blood based on a piezoresistive micro-suspension bridge sensor by combining the prior art and starting from practical application, so that the viscoelastic force of a blood sample can be quickly and accurately measured under the condition of using less blood volume, and the requirements of clinical coagulation detection and analysis at present are met.
The technical scheme of the invention is as follows:
blood viscoelastic power measuring device based on little suspension bridge sensor of piezoresistive formula includes:
the micro-fluid device comprises a substrate, wherein a micro-channel is carved on the upper surface of the substrate, the input end of the micro-channel is a double port, the output end of the micro-channel is a single port, a piezoresistive micro-suspension bridge sensor is arranged in the micro-channel, and liquid flows in through the two input ends, is converged, then flows out from the output end through the piezoresistive micro-suspension bridge sensor;
the permanent magnets are arranged on two sides of the micro-fluid device and used for providing a constant magnetic field for the piezoresistive micro-suspension bridge sensor;
and the signal excitation detection circuit is connected with the piezoresistive micro-suspension bridge sensor and is used for measuring the viscoelastic force change in the blood coagulation process.
The piezoresistive micro-suspension bridge sensor comprises a silicon substrate, wherein U-shaped piezoresistive sensors with openings facing outwards and an electrified lead with an independent channel are arranged at two ends of the silicon substrate, and two end heads of the piezoresistive sensors and two end heads of the electrified lead are connected with bonding pads deposited on the silicon substrate.
The silicon substrate is I-shaped, supporting seats are arranged at two ends of the silicon substrate, and silicon dioxide is deposited on the uppermost layer of the silicon substrate.
The micro-channel direction is perpendicular to the suspension bridge direction of the piezoresistive micro-suspension bridge sensor, and the magnetic force line direction of the permanent magnet is perpendicular to the micro-channel direction.
The piezoresistive micro-suspension bridge sensor is characterized in that the size range of the piezoresistive micro-suspension bridge sensor is the length of a micro-suspension bridge: 200-300 μm, width: 20-30 μm, thickness: 1-5 microns, the height of the silicon substrate supporting seats at two ends of the piezoresistive micro-suspension bridge sensor is higher than the thickness of the silicon substrate in the middle, the bit width of the micro-channel at the piezoresistive micro-suspension bridge sensor part is 200-300 microns, the depth is 5-50 microns, the bit width of the rest part is 1-200 microns, and the length is 1-10 cm.
The signal excitation detection circuit comprises a signal generator, a Wheatstone bridge, a differential amplifier, a multiplier, a low-pass filter, an analog-to-digital converter and a microcontroller, wherein the microcontroller is connected with the signal generator, the microcontroller controls the signal generator to generate sine and cosine signals, and the signal generator connects a generated sine excitation signal source to a bonding pad corresponding to a power-on wire of the piezoresistive micro-suspension bridge sensor.
The Wheatstone bridge is composed of two fixed resistors and two piezoresistive sensors at two ends of a piezoresistive micro-suspension bridge sensor, the output voltages of two arms of the Wheatstone bridge are connected to the input end of a differential amplifier, the amplification factor of the differential amplifier is controlled by an external resistor, the output of the differential amplifier is connected to two multipliers, sine and cosine signals output by a signal generator are respectively connected to the two multipliers, the output signals of the two multipliers are sent to a microcontroller for processing after low-pass filtering and analog-to-digital conversion, the amplitude and the phase are obtained, and the viscoelastic force in the blood coagulation process is obtained.
The substrate of the microfluid device is divided into an upper substrate and a lower substrate, the lower substrate is made of glass, the upper substrate is made of polydimethylsiloxane and is engraved with a microchannel, and the upper substrate is bonded with the lower substrate together after being bombarded by ions.
The input and the output of microchannel are the same cylinder type hole in aperture to connect the silica gel hose respectively, the silica gel hose connection trace injection syringe of two inputs, the silica gel hose connection waste liquid collection container of output.
A measurement method of the blood viscoelastic force measurement device based on the piezoresistive micro-suspension bridge sensor comprises the following steps:
step 3, pushing a micro sample injection injector by using an injection pump to simultaneously inject the blood sample and the blood coagulation activating reagent into the micro channel, and stopping pushing the injection pump when the blood sample and the blood coagulation activating reagent are pushed to the position of the piezoresistive micro-suspension bridge sensor;
and 4, as the blood sample is activated by the activating reagent, the viscoelastic force of the blood changes, the resonance characteristic of the piezoresistive micro-suspension bridge sensor changes, the amplitude and the phase of the voltage detected by the signal excitation detection circuit change, and the change of the viscoelastic force of the blood is obtained through the detected voltage value and phase.
The invention has the beneficial effects that:
1. the piezoresistive micro-suspension bridge sensor is adopted as a main testing element to measure the viscoelastic force of blood, the piezoresistive micro-suspension bridge sensor and the micro-channel template can be manufactured by adopting an MEMS (micro electro mechanical System) processing technology, the batch cost is low, meanwhile, the sensor can be made to be very small, when the detection is realized in the micro-channel, the test can be finished only by trace blood, at least 1ul is needed, and the piezoresistive micro-suspension bridge sensor can be widely applied to the related field of the detection of the viscoelastic force of the blood.
2. The piezoresistive micro-suspension bridge sensor adopted by the invention can ensure better consistency of the sensor when the MEMS is processed, the detection precision is ensured, and meanwhile, the micro-suspension bridge structure ensures high sensitivity of detection.
3. In the detection process, the micro-solidification time is short, and the method is suitable for rapid detection.
4. The invention can adopt a plurality of piezoresistive micro-suspension bridge sensors and a + micro-fluid device to realize array detection, thereby realizing synchronous detection of different reagents and further improving the detection efficiency.
Drawings
FIG. 1 is a schematic diagram of a piezoresistive micro-suspension bridge sensor.
FIG. 2 is a schematic cross-sectional view of a piezoresistive micro-suspension bridge sensor.
FIG. 3 is a schematic diagram of a viscoelastic force measuring device based on a piezoresistive micro-suspension bridge sensor for a trace blood sample.
Fig. 4 is a block diagram of a signal stimulus detection circuit.
FIG. 5 is a graph showing the variation of output voltage during the viscoelastic force test of a trace amount of blood sample.
Fig. 6 is a graph showing the output phase change during the viscoelastic force testing of a trace amount of blood sample.
Reference numerals shown in the drawings:
1 sensor silica surface
2 sensor silicon substrate
21. 22 sensor silicon substrate supporting seat
31. 32 sensor power-on lead
41. 42U-shaped piezoresistive sensing device
5 sensor suspension bridge
A1+, A1-, A2+, A2-, B1+, B1-, B2+, B2-pads
6 straight section of sensor electrified lead
7 piezoresistive sensing normal section
8 microfluidic device
81 micro-channel
82 piezoresistive micro suspension bridge sensor
831. 832 piezoresistive micro suspension bridge sensor lead-out wire
84 PDMS (polydimethylsiloxane) substrate as upper layer
85 lower glass substrate
861. 862 microchannel access holes
863 micro-channel outlet hole
871. 872, 873 silica gel hose
881. 882 filling pump
8810. 8820 microsample injection syringe
89 waste liquid collecting container
9 permanent magnet
91 permanent magnet N pole
92 permanent magnet S pole
93 magnetic force line of permanent magnet with N pole pointing to S pole
10 signal excitation detection circuit
Detailed Description
The invention is further described with reference to the accompanying drawings and specific embodiments. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, it should be understood that various changes or modifications of the present invention may be made by those skilled in the art after reading the teaching of the present invention, and these equivalents also fall within the scope of the present application.
As shown in fig. 1 and 2, a schematic structural diagram of a piezoresistive micro-suspension bridge sensor 82 used in the present invention is shown.
The substrate of the piezoresistive micro-suspension bridge sensor 82 is an I-shaped silicon substrate 2, energizing leads 31 and 32 of independent channels and U-shaped piezoresistive sensors 41 and 42 are deposited on the silicon substrate 2, and the energizing leads 31 and 32 are made of aluminum (Al). The same current conducting wires 31 and 32, piezoresistive sensors 41 and 42 are respectively arranged at two ends of the piezoresistive micro-suspension bridge sensor 82. The energizing leads 31, 32 are connected to aluminum pads A1+ and A1-, A2+ and A2-, respectively, deposited on the silicon substrate. The U-shaped piezoresistive sensors 41, 42 are connected to aluminum pads B1+ and B1-, B2+ and B2-, respectively, deposited on the silicon substrate. The piezoresistive micro-suspension bridge sensor 82 has silicon dioxide 1 deposited on the uppermost layer.
Piezoresistive micro-suspension bridge sensor 82, its size range: the micro suspension bridge is long: 200-300 μm, width: 20-30 μm, thickness: 1 to 5 μm. The height of the silicon substrate supporting seats 21 and 22 at the two ends of the piezoresistive micro-suspension bridge sensor 82 is higher than the thickness of the silicon substrate 2.
Fig. 3 is a schematic diagram of the overall structure of the measuring device of the present invention. The piezoresistive micro-suspension bridge sensor blood viscoelastic force measuring device comprises: microfluidic device 8, permanent magnet 9, signal excitation detection circuit 10.
The micro-fluid device 8 is divided into an upper substrate 84 and a lower substrate 85, the lower substrate 84 is made of glass, the upper substrate 85 is made of PDMS (polydimethylsiloxane) and is provided with micro-channels 81, and the upper substrate 84 is bonded with the lower substrate 85 after being bombarded by ions.
The micro-channel 81 has a piezoresistive micro-suspension bridge sensor 82 sandwiched therebetween, the width of the micro-channel 81 at the portion of the piezoresistive micro-suspension bridge sensor 82 is 200-300 μm, the depth is 5-50 μm, the width of the rest portion is 1-200 μm, the depth is 5-50 μm, and the length is 1-10 cm.
Piezoresistive micro-suspension bridge sensor pads A1+, A1-, B1+ and B1-are led out of the microfluidic device 8 through lead-out wires 831, piezoresistive micro-suspension bridge sensor pads A2+, A2-, B2+ and B2-are led out of the microfluidic device 8 through lead wires 832, and the direction of the microchannel 81 is perpendicular to the direction of the sensor suspension bridge 2.
The input end of the micro-channel 81 is a double port, namely an input end 861 and an input end 862, and the output end is a single port, namely an output end 863. The liquid flows in and joins through the input ends 861 and 862, passes through the piezoresistive micro-suspension bridge sensor 82, and then flows out of the output end 863. The input end 861, the input end 862 and the output end 863 of the micro-channel are all cylindrical holes with the same aperture and are respectively connected with silica gel hoses 871, 872 and 873. The silica gel hoses 871, 872 and 873 led out from the microchannel 81 are respectively connected with the micro-injection syringe 8810, the micro-injection syringe 8820 and the waste liquid collecting container 89, and the micro-injection syringe 8810 and the micro-injection syringe 8820 are respectively fixed on the injection pump 881 and the injection pump 882.
As shown in the drawing, the permanent magnets 9 are placed at two ends of the microfluidic device 8, the permanent magnet N pole 91 points to the magnetic line 93 of the permanent magnet S pole 92 and is perpendicular to the direction of the microchannel 81, and the magnetic field generated by the permanent magnets 9 is a constant magnetic field.
As shown in fig. 4, the signal excitation detecting circuit 10 includes a signal generator S1, a wheatstone bridge B, a differential amplifier IC1, multipliers M1 and M2, low pass filters LPF1 and LPF2, analog-to-digital conversion (a/D), and a Microcontroller (MCU).
The MCU is connected to the signal generator S1, and the MCU controls the signal generator S1 to generate sine and cosine signals. The signal generator S1 connects the generated sine excitation signal source to the bonding pads A1+, A2+, A1-, A2-corresponding to the piezoresistive micro-suspension bridge sensor power-on wires and the power ground.
The Wheatstone bridge B consists of two fixed resistors R1 and R2, and a piezoresistive sensor 41 and a piezoresistive sensor 42 which are arranged at two ends of the piezoresistive micro-suspension bridge sensor, wherein the corresponding resistors at two ends of a bonding pad B1+ and a bonding pad B1-are Rsen1, and the corresponding resistors at two ends of a bonding pad B2+ and a bonding pad B2-are Rsen 2. One end of R1 is connected with power supply + VS1, the other end is connected with Rsen1, one end of Rsen2 is connected with power supply + VS1, the other end is connected with R2, and the other ends of Rsen1 and R2 are simultaneously connected with power ground.
The output voltages V1 and V2 of the two arms of the Wheatstone bridge B are connected to the input end of the differential amplifier IC 1. The amplification of the differential amplifier IC1 is controlled by a resistor Rg. The output of the differential amplifier IC1 is connected to multipliers M1 and M2, and the sine and cosine signals output by the signal generator S1 are connected to multipliers M1 and M2, respectively. The output signals of the multipliers M1 and M2 are connected to the low pass filters LPF1 and LPF2, the filtered output signals are connected to the A/D analog-to-digital converter and then sent to the MCU for processing to obtain the amplitude and the phase, and the viscoelastic force in the blood coagulation process is obtained.
The invention relates to a viscoelastic force measuring method for measuring trace blood samples, which comprises the following steps:
1. setting a measuring device, putting the measuring device into a temperature control box, and preheating the temperature of the temperature control box to reach a temperature value required by detection.
2. After the blood sample and the Prothrombin Time (PT) detection reagent are preheated to reach the test temperature, the blood sample and the PT detection reagent are respectively sucked into the micro sample injection syringes 8810 and 8820, and the amount of the blood sample and the PT detection reagent is 1-10 ul.
3. The micro sample injection syringes 8810, 8820 are respectively pushed by the syringe pumps 881, 882, and the blood sample and the PT detection reagent are simultaneously injected into the micro channel 81, and the push of the syringe pumps 881, 882 is stopped when the blood sample and the PT detection reagent are pushed to the position of the piezoresistive micro suspension bridge sensor 82.
4. As the blood sample is activated by the PT detection reagent, the viscoelastic force of the blood changes, and the resonance characteristic of the piezoresistive micro-suspension-bridge sensor 82 changes, resulting in a change in the amplitude and phase of the voltage detected by the signal excitation detection circuit 10. And obtaining the change of the blood viscoelasticity through the measured voltage value and the measured phase.
Fig. 5 and 6 are test curves as general data references for this embodiment.
As shown in fig. 5, the graph is the output voltage variation curve during the viscoelastic force test of the trace blood sample.
And in the stage of not adding the blood sample and the PT detection reagent in the time period of 0-2 seconds, the piezoresistive micro-suspension bridge sensor resonates in the air.
The stage of adding a blood sample and a PT detection reagent is carried out within a time period of 2-8 seconds, the piezoresistive micro-suspension bridge sensor is converted from resonance in air to resonance in liquid, and voltage fluctuates during continuous input of the liquid in the process.
The 8 ~ 20 second time quantum is activated by PT detection reagent for the blood sample, and the blood sample begins to condense, and piezoresistive micro-suspension bridge sensor receives the influence of blood coagulation, and resonance damping grow, and resonance amplitude diminishes, and the decline appears in the voltage.
In the 20-28 second time period, the blood sample is coagulated and accelerated, the resonance amplitude is reduced rapidly, and the voltage is reduced rapidly.
In the 28-32 second time period, most of the blood sample is coagulated, so the coagulation speed is reduced.
After a period of 32 seconds, the blood sample has substantially finished coagulating, and the piezoresistive micro-suspension bridge sensor resonant frequency tends to be flat, meaning that the detection is complete.
As shown in fig. 6, the graph is an output phase variation curve during the viscoelastic force test of the trace blood sample.
The stage of adding no blood sample and PT detection reagent is 0-2 seconds, the piezoresistive micro-suspension bridge sensor resonates in the air, and the phase position does not change obviously.
And 2-8 seconds is a stage of adding a blood sample and a PT detection reagent, the piezoresistive micro-suspension bridge sensor is converted from resonance in air to a resonance process in liquid, and the phase of the liquid fluctuates during continuous input in the process.
The 8 ~ 20 second time quantum is activated by PT detection reagent for the blood sample, and the blood sample begins to condense, and piezoresistive micro-suspension bridge sensor receives the influence of blood coagulation, and resonance damping grow, and resonance amplitude diminishes, and the phase place begins to reduce.
In the 20-28 second time period, the blood sample is coagulated and accelerated, the resonance amplitude is rapidly reduced, and the phase is rapidly reduced.
In the 28-32 second time period, most of the blood sample is coagulated, so the coagulation speed is reduced.
After a period of 32 seconds, the blood sample has substantially finished coagulating, and the piezoresistive micro-suspension bridge sensor resonant frequency tends to be flat, meaning that the detection is complete.
Claims (8)
1. Blood viscoelastic power measuring device based on piezoresistive type micro-suspension bridge sensor, its characterized in that: comprises that
The micro-fluid device comprises a substrate, wherein a micro-channel is carved on the upper surface of the substrate, the input end of the micro-channel is a double-port, the output end of the micro-channel is a single-port, a piezoresistive micro-suspension bridge sensor is installed in the micro-channel, liquid flows in through the two input ends and is converged, then flows out from the output end through the piezoresistive micro-suspension bridge sensor, the piezoresistive micro-suspension bridge sensor comprises a silicon substrate, U-shaped piezoresistive sensors with openings facing outwards and power-on conducting wires with independent channels are arranged at the two ends of the silicon substrate, and the two ends of the piezoresistive sensors and the two ends of the power-on conducting wires are connected with bonding pads deposited;
the permanent magnets are arranged on two sides of the micro-fluid device and used for providing a constant magnetic field for the piezoresistive micro-suspension bridge sensor;
and the signal excitation detection circuit is connected with the piezoresistive micro-suspension bridge sensor and is used for measuring the viscoelastic force change in the blood coagulation process.
2. The piezoresistive micro-suspension bridge sensor-based blood viscoelastic force measuring device according to claim 1, wherein: the silicon substrate is I-shaped, supporting seats are arranged at two ends of the silicon substrate, and silicon dioxide is deposited on the uppermost layer of the silicon substrate.
3. The piezoresistive micro-suspension bridge sensor-based blood viscoelastic force measuring device according to claim 2, wherein: the micro-channel direction is perpendicular to the suspension bridge direction of the piezoresistive micro-suspension bridge sensor, and the magnetic force line direction of the permanent magnet is perpendicular to the micro-channel direction.
4. The piezoresistive micro-suspension bridge sensor-based blood viscoelastic force measuring device according to claim 3, wherein: the piezoresistive micro-suspension bridge sensor has the size range that the micro-suspension bridge is long: 200-300 μm, width: 20-30 μm, thickness: 1-5 microns, the height of the silicon substrate supporting seats at two ends of the piezoresistive micro-suspension bridge sensor is higher than the thickness of the silicon substrate in the middle, the bit width of the micro-channel at the piezoresistive micro-suspension bridge sensor part is 200-300 microns, the depth is 5-50 microns, the bit width of the rest part is 1-200 microns, and the length is 1-10 cm.
5. The piezoresistive micro-suspension bridge sensor-based blood viscoelastic force measuring device according to claim 1, wherein: the signal excitation detection circuit comprises a signal generator, a Wheatstone bridge, a differential amplifier, a multiplier, a low-pass filter, an analog-to-digital converter and a microcontroller, wherein the microcontroller is connected with the signal generator, controls the signal generator to generate sine and cosine signals, and connects a generated sine excitation signal source to a bonding pad corresponding to a power-on wire of the piezoresistive micro-suspension bridge sensor;
the Wheatstone bridge is composed of two fixed resistors and two piezoresistive sensors at two ends of a piezoresistive micro-suspension bridge sensor, the output voltages of two arms of the Wheatstone bridge are connected to the input end of a differential amplifier, the amplification factor of the differential amplifier is controlled by an external resistor, the output of the differential amplifier is connected to two multipliers, sine and cosine signals output by a signal generator are respectively connected to the two multipliers, the output signals of the two multipliers are sent to a microcontroller for processing after low-pass filtering and analog-to-digital conversion, the amplitude and the phase are obtained, and the viscoelastic force in the blood coagulation process is obtained.
6. The piezoresistive micro-suspension bridge sensor-based blood viscoelastic force measuring device according to claim 1, wherein: the substrate of the microfluid device is divided into an upper substrate and a lower substrate, the lower substrate is made of glass, the upper substrate is made of polydimethylsiloxane and is engraved with a microchannel, and the upper substrate is bonded with the lower substrate together after being bombarded by ions.
7. The piezoresistive micro-suspension bridge sensor-based blood viscoelastic force measuring device according to claim 1, wherein: the input and the output of microchannel are the same cylinder type hole in aperture to connect the silica gel hose respectively, the silica gel hose connection trace injection syringe of two inputs, the silica gel hose connection waste liquid collection container of output.
8. A measurement method using the piezoresistive micro-suspension bridge sensor-based blood viscoelastic force measurement device according to any one of claims 1-7, is characterized by comprising the following steps:
step 1, placing a measuring device into a temperature control box, and preheating the temperature of the temperature control box to reach a temperature value required by detection;
step 2, preheating the blood sample and the blood coagulation activating reagent to reach a test temperature, and then respectively sucking the blood sample and the blood coagulation activating reagent into a micro sample injection syringe, wherein the amount of the blood sample and the blood coagulation activating reagent is 1-10 ul;
step 3, pushing a micro sample injection injector by using an injection pump to simultaneously inject the blood sample and the blood coagulation activating reagent into the micro channel, and stopping pushing the injection pump when the blood sample and the blood coagulation activating reagent are pushed to the position of the piezoresistive micro-suspension bridge sensor;
and 4, as the blood sample is activated by the activating reagent, the viscoelastic force of the blood changes, the resonance characteristic of the piezoresistive micro-suspension bridge sensor changes, the amplitude and the phase of the voltage detected by the signal excitation detection circuit change, and the change of the viscoelastic force of the blood is obtained through the detected voltage value and phase.
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| CN109142452A (en) | 2019-01-04 |
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