CN115876989A - Magnetoelastic sensor-based thromboelastogram detection chip and detection method - Google Patents

Abstract

The invention discloses a thrombelastogram detection chip based on a magnetoelastic sensor, which belongs to the field of medical instruments, wherein two ends of a microchannel flow path of a main body are respectively communicated with a sample inlet and an exhaust port, the microchannel flow path can provide capillary force required by fluid flow to enable fluid entering from the sample inlet to flow along the microchannel flow path, the fluid is mixed with a reagent in the microchannel flow path when flowing, a cavity collects the fluid mixed with the reagent, the magnetoelastic sensor is positioned in the cavity, peripheral parts such as a pump valve, a pipeline and the like are not needed by the thrombectomy detection chip adopting the microfluidic technology, and through the integrated functional design of self-driving, self-mixing and reagent pre-loading in a chip, the operation is greatly simplified, and the thrombelastogram detection chip has the characteristics of low blood sampling amount, low cost, high sensitivity and high efficiency. The application also comprises a thrombelastogram detection method implemented by adopting the thrombelastogram detection chip based on the magnetoelastic sensor.

Description

Magnetoelastic sensor-based thromboelastogram detection chip and detection method

Technical Field

The invention relates to the field of medical instruments, in particular to a magnetoelastic sensor-based thromboelastogram detection chip and a detection method.

Background

Among the applications of medical health detection, the detection of blood coagulation function is an important part of the diagnosis and treatment fields of diabetes, hyperlipidemia, cardiovascular and cerebrovascular diseases and the like. Thromboelastography (TEG), invented by Hartert in 1948, is a whole blood viscoelasticity measurement method. The dynamic change of blood coagulation is reflected by the change of blood viscoelasticity of a whole blood sample in a simulated human body internal environment, and the process from the activation of a coagulation factor to the formation of platelet-fibrin, the aggregation of the platelet, the formation of a stable blood clot to the dissolution of the fibrin is monitored by using a physical principle so as to reflect the rate, the strength and the stability (fibrinolysis level) of the formation of the blood clot, so that the whole process of the coagulation and the fibrinolysis is functionally evaluated. The TEG can continuously reflect the whole blood coagulation process in which all blood components except blood vessel factors participate in real time, so as to judge the risk of bleeding and thrombus of a patient. The thromboelastogram not only can contain all the problems reflected by the detection of clinical end-point methods such as activated blood coagulation time, prothrombin time, activated partial thromboplastin time, thrombin time, fibrinogen, D-dimer and the like, but also has 20 related parameters to support the detection of the whole blood coagulation process. All these parameters are consistent in baseline and unified in standards, and have been well accepted by the international academia. In addition, the TEG can more sensitively and comprehensively evaluate the abnormal state of blood coagulation, predict the risk of bleeding and death of a patient, is beneficial to a clinician to clearly and definitely make a blood transfusion strategy, guide reasonable medication, resist thrombus and other clinical treatments, and can effectively control the death rate of the patient.

Developed to date, the measurement technology based on the thromboelastogram measurement method mainly includes: a suspension wire method, a simple harmonic oscillation method, a rotary probe method, an ultrasonic resonance method and the like. There are two mainstream commercial measurement devices for detecting blood coagulation function based on the measurement technology of thromboelastogram (thromboelastogram system)

Usa) and the rotary thromboelastosis system (@ sang)>

Tem Innovations, germany). Wherein it is present>

Series of latest products

6s (US 2007/0237677A 1) develops a 4-channel reagent card box through simple harmonic oscillation and optical detection methods and based on a microfluidic technology, has the advantages of convenience in operation, small influence of vibration and the like, and has the defects of high manufacturing cost, complex structure and the like. />

sigma (US 2016/0091516 A1) is a mode and realizes automatic blood viscoelasticity measurement through the principle of mechanical rotation and optical detection, and is combined with a microfluidic technology to realize a 4-channel double-cartridge, so that the stability is high, but the blood sampling amount reaches 2.7mL.

Disclosure of Invention

In order to overcome the defects of the prior art, the invention aims to provide a magnetoelastic sensor-based thromboelastogram detection chip which is simple in structure, convenient to operate, less in blood sampling amount and high in sensitivity.

In order to overcome the defects of the prior art, the invention also aims to provide a magnetoelastic sensor-based thromboelastogram detection method which is simple in structure, convenient to operate, less in blood sampling amount and high in sensitivity.

One of the purposes of the invention is realized by adopting the following technical scheme:

the utility model provides a thrombelastogram detects chip based on magnetoelastic sensor, includes the main part, the main part be equipped with the introduction port of outside intercommunication, with gas vent, microchannel flow path and the cavity of outside intercommunication, microchannel flow path both ends respectively with introduction port and gas vent intercommunication, the microchannel flow path can provide the required capillary force of fluid flow and make the fluid that the introduction port got into is followed the microchannel flow path flows, the storage has reagent in the microchannel flow path, during the fluid flow with the reagent mixes, the cavity with microchannel flow path intercommunication is located the introduction port with between the gas vent, the cavity is collected and has been mixed the fluid of reagent, thrombelastogram detects chip based on magnetoelastic sensor still includes magnetoelastic sensor, magnetoelastic sensor is located in the cavity.

Further, the chamber comprises a reaction chamber and a plurality of micro-pillars, the plurality of micro-pillars are located in the reaction chamber, and the plurality of micro-pillars support the magnetoelastic sensor.

Furthermore, the plurality of micro-columns are positioned at the bottom of the reaction chamber and are arranged in an array, and the plurality of micro-columns are used as capillary pumps to drive fluid to fill the reaction chamber.

Further, the microchannel flow path includes reagent room, mixing channel and the collection window that communicates each other, reagent room storage reagent, mixing channel is located the reagent room and between the collection window, the reagent room with the introduction port intercommunication, the collection window with the chamber intercommunication.

Further, the reagent chamber is formed by protruding the micro-channel flow path.

Further, the mixing channel has a serpentine shape.

Further, the main part includes capping layer, diaphragm layer and stratum basale, the introduction port and the gas vent set up in the capping layer, the reagent room the mixing channel and the collection window be special-shaped through-hole and set up in the diaphragm layer, the chamber set up in the stratum basale, capping layer, diaphragm layer and stratum basale laminating bonding are aimed at each other fixedly, the diaphragm layer is located the capping layer and between the stratum basale, the reagent room the mixing channel with the collection window with the lower surface of capping layer and the upper surface of stratum basale constitutes the microchannel flow path.

Further, the main part includes capping layer and stratum basale, the inlet port the gas vent the reagent room mix the passageway and the collection window set up in the capping layer, the inlet port the gas vent is the through-hole, the reagent room mix the passageway and the collection window is the recess, the capping layer with stratum basale laminating bonding mutual alignment is fixed, the reagent room mix the passageway and the collection window with the upper surface of stratum basale constitutes the microchannel flow path.

Further, the main part includes capping layer and stratum basale, the introduction port the gas vent set up in the capping layer, the introduction port the gas vent is the through-hole, the reagent room the mixing channel and the collection window set up in the stratum basale, the reagent room the mixing channel is the recess, the collection window with the cavity overlaps, the capping layer and stratum basale laminating bonding is aimed at each other fixedly, the reagent room the mixing channel and the collection window with the lower surface of capping layer constitutes the microchannel flow path.

Further, the microchannel flow path the cavity the gas vent and the quantity of magnetoelastic sensor is a plurality of, and is a plurality of the microchannel flow path is with same the introduction port intercommunication, each the microchannel flow path with one the gas vent intercommunication, each the microchannel flow path with one the cavity intercommunication, each install one in the cavity magnetoelastic sensor, it is a plurality of different reagents of microchannel flow path storage.

The second purpose of the invention is realized by adopting the following technical scheme:

a detection method adopting any one of the magnetoelastic sensor-based thromboelastogram detection chips comprises the following steps:

preparing a blood sample: performing fingertip blood sampling with a blood collection needle or using anticoagulated whole blood prepared in advance;

adding a blood sample: blood is dripped into a sample inlet of a thromboelastogram detection chip based on a magnetoelastic sensor, the blood can enter a micro-channel flow path under the driving of capillary force, the blood is mixed with a reagent in the micro-channel flow path and then enters a cavity, and the magnetoelastic sensor is immersed;

and (3) blood coagulation detection: the chip loaded with the blood sample is immediately placed into corresponding measuring equipment, the magnetoelastic sensor generates high-frequency vibration under the excitation of an alternating magnetic field of the measuring equipment, when the magnetoelastic sensor works in blood which is continuously coagulated, the resonance frequency and the impedance amplitude of the magnetoelastic sensor are continuously reduced along with the continuous increase of the viscoelasticity of the blood, and a relation curve of the resonance frequency and the impedance amplitude of the magnetoelastic sensor which are respectively continuously changed along with time can be obtained through the circuit detection module and the data processing module, so that the blood viscoelasticity measurement of the whole blood coagulation process is realized by using two modes of frequency and impedance amplitude, and finally the thrombelastogram is obtained.

Compared with the prior art, the magnetoelastic sensor-based thromboelastogram detection chip has the following advantages:

1. the thrombus elastogram detection chip of the magnetoelastic sensor realizes the on-site rapid blood coagulation detection with easy operation, low consumption and low cost;

2. the magnetoelastic sensor-based thromboelastogram detection method is different from the traditional electrochemical, optical, suspension wire, rotary and other means, and has the advantages of passive wireless performance, high sensitivity, low power consumption and easiness in preparation;

3. the thrombelastogram detection chip based on the microfluidic technology does not need peripheral parts such as pump valves, pipelines and the like, greatly simplifies the operation through the integrated functional design of self-driving, self-mixing and reagent preassembling in the chip, and has the characteristics of low blood sampling amount, low cost and high efficiency;

4. the multichannel design of the thromboelastogram detection chip realizes simultaneous detection of multiple blood coagulation items, obtains relevant clinical indexes of the thromboelastogram, and is favorable for popularization and use in bedside detection in the future.

Drawings

FIG. 1 is a perspective view of a magnetoelastic sensor-based thromboelastography detection chip according to a first embodiment of the present invention;

FIG. 2 is an exploded view of the magnetoelastic sensor-based thromboelastogram detection chip of FIG. 1;

FIG. 3 is a perspective view of a membrane layer of the magnetoelastic sensor-based thromboelastography detection chip of FIG. 2;

FIG. 4 is a partial perspective view of the substrate layer of the magnetoelastic sensor-based thromboelastography detection chip of FIG. 2;

FIG. 5 is a schematic diagram of the internal structure of the magnetoelastic sensor-based thromboelastogram detection chip in FIG. 1;

FIG. 6 is an enlarged view of the magnetoelastic sensor-based thromboelastography detection chip of FIG. 5 at A;

FIG. 7 is a perspective view of a magnetoelastic sensor-based thromboelastography detection chip in a second embodiment of the present invention;

FIG. 8 is a schematic diagram showing the internal structure of the magnetoelastic sensor-based thromboelastogram detection chip of FIG. 7;

FIG. 9 is a graph of the impedance frequency of a magnetoelastic sensor in an air environment;

FIG. 10 is a graph of the change in resonant frequency of a magnetoelastic sensor in blood over time;

FIG. 11 is a graph of the magnitude of the magneto-elastic sensor's impedance in blood versus time;

fig. 12 is a graph showing the results of TEG measurement using a conventional commercial instrument.

In the figure: 10. a capping layer; 11. a sample inlet; 12. an exhaust port; 20. a separator layer; 21. a flow channel; 210. an inlet; 211. a reagent chamber; 212. a mixing channel; 213. a collection window; 214. an outlet; 30. a base layer; 31. a chamber; 310. a front end portion; 311. a reaction chamber; 312. a rear end portion; 32. a microcolumn; 40. a magneto-elastic sensor; 50. and (3) a reagent.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

It will be understood that when an element is referred to as being "secured to" another element, it can be directly on the other element or intervening elements may also be present, secured by intervening elements. When a component is referred to as being "connected" to another component, it can be directly connected to the other component or intervening components may also be present. When a component is referred to as being "disposed on" another component, it can be directly disposed on the other component or intervening components may also be present. The terms "vertical," "horizontal," "left," "right," and the like as used herein are for illustrative purposes only.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.

Example one

Fig. 1 to 6 show a magnetoelastic sensor-based thromboelastogram detection chip according to a first embodiment of the present invention, in which the magnetoelastic sensor-based thromboelastogram detection chip includes a main body, a magnetoelastic sensor 40, and a reagent 50.

The body comprises a capping layer 10, a membrane layer 20, a base layer 30.

The capping layer 10 is provided with a sample inlet 11 and an exhaust port 12, wherein the sample inlet 11 is used for adding fluid (blood in the embodiment), and the exhaust port 12 is used for exhausting air in the chip, so that the fluid can flow in the chip. Preferably, the shape of the capping layer 10 is rectangular, and the material is polymer plastic, such as any one of PET, PVC, PE, and PP. The capping layer 10 is 0.1-0.5mm thick. The injection port 11 and the exhaust hole 12 of the capping layer 10 are circular in shape and have diameters of 3-5mm and 2-4mm, respectively. Preferably, the diameter of the injection port 11 is 4mm, and the diameter of the exhaust hole 12 is 3mm. The capping layer 10 is formed by laser cutting, die cutting, or the like.

The membrane layer 20 is provided with a flow channel 21, and the flow channel 21 includes an inlet 210, a reagent chamber 211, a mixing channel 212, a collection window 213, and an outlet 214, which are sequentially connected. The inlet 210, reagent chamber 211, mixing channel 212, collection window 213 and outlet 214 are all shaped through holes. When the membrane layer 20 is fixed to the capping layer 10 and the base layer 30, the flow channels 21 form micro-channel flow paths with the lower surface of the membrane layer 20 and the upper surface of the capping layer 10, and the micro-channel flow paths can provide capillary force required by fluid flow to drive the fluid to flow in the set channels. Specifically, the reagent chamber 211 is used to store the reagent 50 and the mixing channel 212 is a serpentine channel that slows the flow of fluid while promoting adequate mixing of the blood sample with the reagent 50. Preferably, the membrane layer 20 is rectangular in shape, and is made of polymer plastic, such as any one of PET, PVC, PE, and PP. The membrane layer 20 has a thickness of 50-200 μm. The membrane layer 20 has a channel aspect ratio of 1. In addition, the membrane layer 20 may provide a desired capillary driving force through the structure (e.g., porous structure) or hydrophilicity and hydrophobicity of the material. The membrane layer 20 is processed by laser cutting, die cutting, or the like.

The substrate layer 30 is provided with a chamber 31 and a micro-column 32 located in the chamber 31. The chamber 31 includes a front end 310, a reaction chamber 311, and a rear end 312, the reaction chamber 311 being located between the front end 310 and the rear end 312. The front end 311 and back end 312 may be trapezoidal, rectangular, or other irregular shapes in order to mitigate abrupt changes in the geometry between the microchannel flow path and the reaction chamber 311. The front end 311 serves to introduce the fluid flowing out of the mixing channel 212 into the reaction chamber 311 of the substrate layer, and the rear end 312 serves to guide the excess fluid in the reaction chamber 311 to the outlet 214. Reaction chamber 311 is used to collect blood and to load magnetoelastic sensor 40. The microcolumn 32 is located at the bottom of the chamber 31 and is used to support the magnetoelastic sensor 40 and avoid excessive friction between the magnetoelastic sensor 40 and the bottom of the chamber 31. The micro-pillars 32 are uniformly distributed at the bottom of the reaction chamber 311 and arranged in an array. The microcolumn 32 may also act as a capillary pump, driving blood to fill the entire chamber 31.

The substrate layer 30 is rectangular in shape and made of hydrophilic material such as glass or PMMA plastic. The thickness of the substrate layer 30 is 0.4-2mm. The reaction chamber 311 of the substrate layer 30 has the same shape as the magnetoelastic sensor 40, and the length and width of the reaction chamber 311 should match the size of the magnetoelastic sensor 40. The reaction chamber 311 has a length and width of 4-20mm and 1-8mm, respectively. Preferably, the reaction chamber 311 has a length and a width of 10.1mm and 4.1mm, respectively. The depth of the reaction chamber 311 is 0.1 to 1mm. The micro-column 32 is in the shape of a cylinder, an elliptic cylinder, a rhombic cylinder, etc., and has a width of 0.05-0.5mm. The microcolumns 32 in the reaction chamber 311 of the substrate layer 30 are uniformly distributed. The micro-pillars 32 are spaced apart by 0.05-0.5mm to drive the flow of blood in the reaction chamber 311. In addition, the reaction chamber 311 may also provide power for driving blood by the structure (such as porous structure) of the material or hydrophilicity and hydrophobicity, and the substrate layer 30 is formed by laser engraving, chemical etching, or the like.

The magnetoelastic sensor 40 is made of an iron-based amorphous strip, and the common components include iron, silicon, boron, nickel, molybdenum, and the like. Firstly, the thin strip is cut into different shapes including rectangle, triangle, irregular triangle, etc. by laser or mechanical cutting, the length is 4-20mm, the width is 1-8mm, and the thickness is 22-28 μm. The strip is then treated by transverse magnetic annealing to obtain a magnetoelastic sensor which can be used. In addition, the size of the magnetoelastic sensor 40 may affect the sensitivity and signal-to-noise ratio of the measurement, and in general, the aspect ratio of 2:1 to 3:1 may exhibit better electrical performance.

The reagent 50 is a lyophilized spherical solid, a sheet solid or a powder, and is filled inside the chip in the chip preparation process and located in the reagent chamber 211 near the chip inlet, so that the substance to be tested can enter and be mixed with the substance. The reagents 50 are pre-filled in the reagent chambers 211 of the chip, and each reagent chamber 211 is filled with only one reagent. When each chip comprises a plurality of sensors, different reagents such as the reagents 50 related to the ordinary cup, the rapid TEG, the heparinase detection and the platelet cup detection can be filled in the membrane layer 20 connected with each sensor, so that the detection of various coagulation items on the single chip is realized.

When the magnetoelastic sensor-based thromboelastography detection chip is assembled, the reagent 50 is filled in the reagent chamber 211 of the chip, the magnetoelastic sensor 40 is placed in the reaction chamber 311, and the capping layer 10, the diaphragm layer 20 and the substrate layer 30 are mutually aligned and fixed through bonding by a laminating method, wherein the bonding mode comprises but is not limited to laminating, plasma bonding, thermal compression bonding and cold compression bonding. The collection window 213 of the membrane layer 20 is aligned with the reaction chamber 311 of the base layer 30, and the sample inlet 11 and the exhaust 12 of the capping layer 10 are aligned with the inlet 210 and the outlet 214 of the membrane layer 20. The assembled complete chip is ready for addition of blood and measurement in coagulation equipment.

Example two

With reference to fig. 7 to 8, a second embodiment of the magnetoelastic sensor-based thromboelastogram detecting chip according to the present invention is shown, in which the structure of the magnetoelastic sensor-based thromboelastogram detecting chip is substantially the same as that of the first embodiment, and the difference is: the number of the micro-channel flow paths, the chambers 31, the exhaust port 12 and the magnetoelastic sensor 40 is multiple, the micro-channel flow paths are communicated with the same sample inlet 11, each micro-channel flow path is communicated with the exhaust port 12, each micro-channel flow path is communicated with one chamber 31, one magnetoelastic sensor 40 is installed in each chamber 31, and the micro-channel flow paths store different reagents 50, such as reagents related to common cups, rapid TEG, heparinase detection and platelet cup detection, so that the detection of various coagulation items on a single chip is realized.

Specifically, in the second embodiment, the thromboelastography detection chip of the magnetoelastic sensor includes 4 microchannel flow paths, i.e., the chip has 4 channels. The distribution mode of the 4 channels may be 2 × 2 or 1 × 4, and in order to reasonably utilize the space, the present embodiment adopts a 2 × 2 layout mode. The structure, function and processing mode of each layer of four-channel blood coagulation detection chip are the same as those of a single-channel blood coagulation detection chip, and are not repeated here. Each channel is an independent detection unit containing 4 magnetoelastic sensors 40. Blood samples are added from the sample inlet 11 of the chip, and the blood coagulation detection of 4 channels can be realized simultaneously. When 4 channels contain different reagents 50, 4 coagulation tests of common cups, rapid TEG, heparinase test and platelet cups can be simultaneously realized.

EXAMPLE III

In the third embodiment, the structure of a magnetoelastic sensor-based thromboelastography detection chip is substantially the same as that of the first embodiment, except that: the main body comprises a sealing layer 10 and a substrate layer 30, a sample inlet 11 and an exhaust port 12 are arranged on the sealing layer 10, the sample inlet 11 and the exhaust port 12 are through holes, a reagent chamber 211, a mixing channel 212 and a collecting window 213 are arranged on the substrate layer 30, the reagent chamber 211 and the mixing channel 212 are grooves, the collecting window 213 is overlapped with a cavity 31, the sealing layer 10 and the substrate layer 30 are laminated and bonded to be aligned and fixed with each other, and the reagent chamber 211, the mixing channel 212 and the collecting window 213 form a micro-channel flow path with the lower surface of the sealing layer 10.

Example four

In the fourth embodiment, the structure of a magnetoelastic sensor-based thromboelastography detection chip is substantially the same as that of the first embodiment, except that: the main body comprises a sealing layer 10 and a substrate layer 30, a sample inlet 11, an exhaust port 12, a reagent chamber 211, a mixing channel 212 and a collecting window 213 are arranged on the sealing layer 10, the sample inlet 11 and the exhaust port 12 are through holes, the reagent chamber 211, the mixing channel 212 and the collecting window 213 are grooves, the sealing layer 10 and the substrate layer 30 are laminated and bonded to be aligned and fixed with each other, and the reagent chamber 211, the mixing channel 212 and the collecting window 213 form a micro-channel flow path with the upper surface of the substrate layer 30.

When the magnetoelastic sensor-based thromboelastogram detection chip is used, blood is collected by a fingertip with a blood collection needle, or anticoagulated whole blood prepared in advance is used, the blood is dripped into the sample inlet 11 of the chip, and the blood can enter a flow channel under the driving of capillary force. First, the blood mixes with the dry chemistry reagents in the reagent chamber 211 and enters the serpentine mixing channel 212 for thorough mixing; then, the blood continues to flow to the front end 310 of the cavity of the substrate layer 30, and then the capillary force generated in the reaction chamber 311 drives the blood to flow continuously until the reaction chamber is full of the blood, so that the magnetoelastic sensor 40 is immersed by the blood; finally, the blood in the reaction chamber 311 flows out through the micro-channels of the rear end portion 312, and the excess blood is discharged from the outlet 214. Therefore, the operation of the chip is very simple, and the chip loaded with the blood sample is immediately put into corresponding measuring equipment only by the step of manually adding the sample, so that the blood coagulation detection can be started.

The invention also relates to a thromboelastogram detection method implemented by the thromboelastogram detection chip based on the magnetoelastic sensor, which comprises the following steps of:

preparing a blood sample: performing fingertip blood collection with a blood collection needle or anticoagulated whole blood prepared in advance;

adding a blood sample: blood is dripped into a sample inlet 11 of a magnetoelastic sensor-based thromboelastography detection chip, the blood enters a micro-channel flow path under the driving of capillary force, the blood is mixed with a reagent 50 in the micro-channel flow path and then enters a cavity 31, and meanwhile, the magnetoelastic sensor 40 is immersed;

and (3) blood coagulation detection: the chip loaded with the blood sample is immediately placed into corresponding measuring equipment, the magnetoelastic sensor 40 generates high-frequency vibration under the excitation of an alternating magnetic field of the measuring equipment, when the magnetoelastic sensor 40 works in blood which is continuously coagulated, the resonance frequency and the impedance amplitude of the magnetoelastic sensor 40 are continuously reduced along with the continuous increase of the viscoelasticity of the blood, and a relation curve that the resonance frequency and the impedance amplitude of the magnetoelastic sensor 40 respectively change along with the continuous change of time can be obtained through a circuit detection module and a data processing module, so that the blood viscoelasticity measurement in the whole blood coagulation process is realized through two modes of frequency and impedance amplitude, and finally the thromboelastogram is obtained.

The impedance frequency curve of the magnetoelastic sensor 40 in an air environment is shown by a solid line in fig. 9, and at a certain frequency point, the impedance amplitude reaches the maximum, and the frequency is the resonance frequency of the sensor. When the magnetoelastic sensor 40 is operated in a liquid environment, the viscoelasticity of the liquid damps the resonance of the magnetoelastic sensor, and the magnetic flux generated inside the sensor changes. When the viscosity of the liquid is increased continuously, the vibration frequency of the sensor is reduced, namely, the impedance-frequency curve is translated; when the elastic modulus of the liquid is increased, the vibration amplitude of the sensor is reduced, namely the peak value of the impedance-frequency curve is reduced. The impedance frequency curve of the magnetoelastic sensor 40 in a liquid environment is shown by the dashed line in fig. 9. Therefore, when magnetoelastic sensor 40 is operated in blood with coagulation, the resonant frequency and the impedance amplitude of magnetoelastic sensor 40 are decreased as the viscoelasticity of blood is increased. The relationship curve of the resonance frequency and the impedance amplitude of the magnetoelastic sensor 40 which respectively change along with the time can be obtained through the external circuit detection module and the data processing module, so that the blood viscoelasticity measurement in the whole blood coagulation process is realized through two modes of the frequency and the impedance amplitude, and finally the thrombelastogram is obtained. The invention takes two electrical parameters of resonance frequency and impedance amplitude as characterization parameters of the thrombelastogram. Taking the ordinary cup coagulation measurement as an example, the measurement results are shown in fig. 10 to 11, in which fig. 10 is a graph showing the results of the resonance frequency variation with time, and fig. 11 is a graph showing the results of the impedance amplitude variation with time. Comparing the result curve measured by the existing commercial instrument TEG, as shown in fig. 12, it can be seen that the impedance amplitude measurement result obtained by the magnetoelastic sensor 40 is very similar to the half curve in TEG, and when the measurement result of the magnetoelastic sensor 40 is normalized and the data curve is mirrored, the curve effect same as TEG can be obtained, so that the analysis of relevant parameters, such as parameters of blood coagulation time R, blood clot forming time K, blood clot rate α, blood clot strength MA, blood coagulation index CI, etc., can be performed.

The thrombus elastogram detection chip realizes the on-site rapid blood coagulation detection with easy operation, low consumption and low cost. Firstly, the magnetoelastic sensor-based thromboelastogram detection method is different from traditional electrochemical, optical, suspension wire, rotary and other means, and has the advantages of being passive and wireless, high in sensitivity, low in power consumption and easy to prepare; secondly, the coagulation detection chip based on the microfluidic technology does not need peripheral parts such as a pump valve, a pipeline and the like, greatly simplifies the operation through the integrated functional design of self-driving, self-mixing and reagent pre-filled in the chip, and has the characteristics of low blood sampling amount, low cost and high efficiency; finally, the multichannel design of the thromboelastogram detection chip realizes simultaneous detection of multiple blood coagulation items, obtains relevant clinical indexes of the thromboelastogram, and is favorable for popularization and use in bedside detection in the future.

The above examples only show some embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for those skilled in the art, variations and modifications can be made without departing from the spirit of the invention, and all equivalent modifications and changes can be made to the above embodiments according to the essential technology of the invention, which falls into the protection scope of the invention.

Claims (11)

1. The utility model provides a thrombelastogram detects chip based on magnetoelastic sensor, includes the main part, its characterized in that: the main part be equipped with the introduction port of outside intercommunication, with gas vent, microchannel flow path and the cavity of outside intercommunication, microchannel flow path both ends respectively with introduction port and gas vent intercommunication, the microchannel flow path can provide the required capillary force of fluid flow and make the fluid that the introduction port got into is followed the microchannel flow path flows, the microchannel flow path is internal to be stored with reagent, during the fluid flow with the reagent mixes, the cavity with microchannel flow path intercommunication is located the introduction port with between the gas vent, the cavity is collected and is mixed the fluid of reagent, the thrombus elasticity picture based on magnetoelasticity sensor detects the chip and still includes magnetoelasticity sensor, magnetoelasticity sensor is located in the cavity.

2. The magnetoelastic sensor-based thromboelastography detection chip of claim 1, wherein: the chamber comprises a reaction chamber and a plurality of micro-columns, the micro-columns are positioned in the reaction chamber, and the micro-columns support the magnetoelastic sensor.

3. The magnetoelastic sensor-based thromboelastography detection chip of claim 2, wherein: the micro columns are positioned at the bottom of the reaction chamber and are arranged in an array, and the micro columns are used as capillary pumps to drive fluid to fill the reaction chamber.

4. The magnetoelastic sensor-based thromboelastography detection chip of claim 1, wherein: the microchannel flow path includes reagent room, mixing channel and the collection window of mutual intercommunication, reagent room storage reagent, mixing channel is located the reagent room and between the collection window, the reagent room with the introduction port intercommunication, the collection window with the cavity intercommunication.

5. The magnetoelastic sensor-based thromboelastography detection chip of claim 4, wherein: the reagent chamber is formed by a microchannel flow path projection.

6. The magnetoelastic sensor-based thromboelastography detection chip of claim 4, wherein: the mixing channel is serpentine in shape.

7. The magnetoelastic sensor-based thromboelastography detection chip of claim 4, wherein: the main part includes capping layer, diaphragm layer and stratum basale, the introduction port with the gas vent set up in the capping layer, reagent room, mixing channel and the collection window be special-shaped through-hole and set up in the diaphragm layer, the cavity set up in the stratum basale, capping layer, diaphragm layer and stratum basale laminating bonding are aimed at each other fixedly, the diaphragm layer is located between capping layer and the stratum basale, reagent room, mixing channel and the collection window with the lower surface of capping layer and the upper surface of stratum basale constitute the microchannel flow path.

8. The magnetoelastic sensor-based thromboelastography detection chip of claim 4, wherein: the main part includes capping layer and stratum basale, the introduction port the gas vent the reagent room the mixing channel and the collection window set up in the capping layer, the introduction port the gas vent is the through-hole, the reagent room the mixing channel with the collection window is the recess, the capping layer with stratum basale laminating bonding aligns fixedly each other, the reagent room the mixing channel with the collection window with the upper surface on stratum basale constitutes the microchannel flow path.

9. The magnetoelastic sensor-based thromboelastography detection chip of claim 4, wherein: the main part includes capping layer and stratum basale, the introduction port the gas vent set up in the capping layer, the introduction port the gas vent is the through-hole, the reagent room the mixing channel and the collection window set up in the stratum basale, the reagent room the mixing channel is the recess, the collection window with the cavity overlaps, the capping layer and stratum basale laminating bonding aligns fixedly each other, the reagent room the mixing channel and the collection window with the lower surface of capping layer constitutes the microchannel flow path.

10. The magnetoelastic sensor-based thromboelastography detection chip of claim 1, wherein: the microchannel flow path the cavity the gas vent and magnetoelastic sensor's quantity is a plurality of, and is a plurality of the microchannel flow path is with same the introduction port intercommunication, each the microchannel flow path with one the gas vent intercommunication, each the microchannel flow path with one the cavity intercommunication, each install one in the cavity magnetoelastic sensor, it is a plurality of different reagents of microchannel flow path storage.

11. A detection method using the magnetoelastic sensor-based thromboelastography detection chip of any one of claims 1-10, characterized by comprising the following steps:

preparing a blood sample: performing fingertip blood sampling with a blood collection needle or using anticoagulated whole blood prepared in advance;

adding a blood sample: blood is dripped into a sample inlet of a thromboelastogram detection chip based on a magnetoelastic sensor, the blood can enter a micro-channel flow path under the driving of capillary force, the blood is mixed with a reagent in the micro-channel flow path and then enters a cavity, and the magnetoelastic sensor is immersed;

and (3) blood coagulation detection: the chip loaded with the blood sample is immediately placed into corresponding measuring equipment, the magnetoelastic sensor generates high-frequency vibration under the excitation of an alternating magnetic field of the measuring equipment, when the magnetoelastic sensor works in blood which is continuously coagulated, the resonance frequency and the impedance amplitude of the magnetoelastic sensor are continuously reduced along with the continuous increase of the viscoelasticity of the blood, and a relation curve of the resonance frequency and the impedance amplitude of the magnetoelastic sensor which are respectively continuously changed along with time can be obtained through the circuit detection module and the data processing module, so that the blood viscoelasticity measurement of the whole blood coagulation process is realized by using two modes of frequency and impedance amplitude, and finally the thrombelastogram is obtained.

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