Apparatus and method for detecting a phase change in a liquid

Abstract

The present application relates to a kind of detecting liquid phase change device and method, wherein the device for detecting liquid phase change includes: sample placement area, for placing the liquid sample to be detected and completing the phase change process of liquid in the sample placement area to detect;Pulse module, for applying pulsed pressure to the sample to be detected;Detection module, for detecting the change of pressure in the pipeline on the side of detection module;With the inlet and outlet of sample inlet and outlet;Wherein, the pulse module and detection module are arranged on the two sides of sample placement area, and the change of pressure in the pipeline on the side of detection module is detected, that is, the detection module detects the change of pressure with time that pulse module applies to the sample to be detected and transmits to the side of detection module through sample, and the change of pressure with time is output as signal.

Description

TECHNICAL FIELD

[0001] This application is a divisional application of Chinese Patent Application No. 201711210942.2, filed on November 28, 2017, entitled "Device and method for detecting liquid phase change". The present invention relates to a device for detecting liquid phase change and a method for detecting liquid phase change using the device. BACKGROUND

[0002] It is well known that blood coagulation in the heart or blood vessels of a living body can form thrombus and cause thrombotic diseases, such as acute myocardial infarction (AMI), cerebral thrombosis, deep vein thrombosis (DVT), disseminated intravascular coagulation (DIC), and the like; and blood overflow outside the blood vessels can cause bleeding and cause hemorrhagic diseases, such as allergic purpura, thrombocytopenic purpura, hemophilia, and liver disease bleeding, and the like. In order to effectively inhibit these diseases, it is necessary to regularly detect the thrombosis of the patient's blood.

[0003] At present, for the whole blood system, the general method is to use a thromboelastograph to detect blood coagulation and thrombus formation by determining a thromboelastogram. The thromboelastogram is an index reflecting the dynamic changes of blood coagulation, including the formation speed of fibrin, the dissolution state and the firmness of the coagulation, and the elasticity. The thromboelastogram is a graph drawn by a thromboelastograph. The main components of the thromboelastograph generally include: an automatically adjusted stainless steel blood containing cup with a constant temperature (37°C), a small cylindrical body of stainless steel inserted into the cup, and a sensor that can be connected to the cylindrical body. The blood containing cup is placed on a reaction pool that can rotate back and forth at an angle of 4°45', and the blood is contained between the cup wall and the cylindrical body. When the blood sample is in a liquid state, the back and forth rotation of the cup cannot drive the cylindrical body, and the signal reflected to the drawing paper by the sensor is a straight line. When the blood begins to coagulate, the resistance between the cup and the cylindrical body is generated due to the adhesion of fibrin, and the cup drives the cylindrical body to move simultaneously. With the increase of fibrin, the resistance also increases, and the movement of the cylindrical body driven by the cup also changes. This signal is drawn to the drawing paper by the sensor to form a thromboelastogram.

[0004] In addition, many other processes of liquid phase change also need to be detected or paid attention to, such as the coagulation process of some high molecular solution, such as protein solution, protein curd, gelatin, and high molecular polymerization process. SUMMARY

[0005] As described above, in the art, a thromboelastograph is generally used to determine blood coagulation and thrombus formation. However, when using a thromboelastograph for detection, a large amount of blood is often required, and a large amount of blood needs to be extracted from the patient for detection, which will bring a great burden to the patient and higher requirements for the operation of the clinician.

[0006] Therefore, in the art, if the detection of blood coagulation can be realized by a small amount, for example, a micro-liter amount of micro-sample, the burden of the patient and the risk existing in the blood sampling process will be greatly reduced. In addition, since the detection of blood coagulation needs to avoid the interference of the external environment as much as possible during the detection process, a detection device which can realize very small influence on the collected blood during the whole detection process is also needed.

[0007] JP2007-271323A discloses a measuring method capable of simultaneously detecting blood viscosity and thrombus formation amount in a short time and at a low cost. In this patent document, a blood holding container connected with a capillary tube at an opening portion, a pressurizing device for discharging blood in the blood holding container from the capillary tube at a certain flow rate, and a detection device for detecting blood viscosity and thrombus formation amount are involved.

[0008] CN102762991A discloses a microchip for platelet detection and a platelet detection device using the microchip. The microchip disclosed in this patent document is a microchip for measuring platelet function by flowing blood in a flow path to induce platelet aggregation, the microchip has a flow path provided inside, at least a part of the flow path is coated with collagen for adhesion with platelets, a plurality of walls extend along the direction of blood flow in the flow path and separate the width of the flow path to form flow path separation portions, and the walls are subjected to a treatment to have a surface roughness (Ra) of 10-200 nm. By using this device, the detection of platelet function of blood using a small amount of blood can be realized.

[0009] CN101292161A discloses a device for monitoring thrombus formation and a method for detecting thrombus formation. The device includes a thrombus formation chamber, a thrombus inducer provided in at least a part of the thrombus formation chamber for inducing thrombus formation, an inlet tube connected with the thrombus formation chamber and through which blood flows into the thrombus formation chamber, and a drug tube connected with the inlet tube and through which a drug for releasing an anti-coagulation treatment or promoting blood coagulation is supplied. The method includes flowing an anti-coagulation blood into the thrombus formation chamber, providing a thrombus inducer in at least a part of the thrombus formation chamber for inducing thrombus formation, and releasing an anti-coagulation treatment or promoting blood coagulation, thereby monitoring thrombus formation.

[0010] CN101874208A discloses a micro-thin slice and blood observation device. The micro-thin slice includes: a first flow path, a first liquid flowing into the first flow path, the first liquid being selected from whole blood, platelet-rich plasma or a medicament-treated liquid thereof; a second flow path, a second liquid flowing into the second flow path, the second liquid containing a medicament capable of reacting with the first liquid; and a confluence flow path extending from a connection portion of the first flow path and the second flow path; and the micro-thin slice is characterized in that a stirring portion having a stirring member for mixing the first liquid and the second liquid is provided on the confluence flow path. By using the device, the reaction performance of blood can be detected by effectively mixing trace blood and a medicament.

[0011] CN102099676A discloses a cup-based device for blood clotting measurement and testing. The device includes a blood clot detection instrument and a cup for the blood clot detection instrument. The cup includes a blood sample receiver inlet and a channel structure including: at least one test channel for performing a blood clotting time measurement; a sampling channel having at least one surface portion that is hydrophilic and in communication with the blood sample receiver inlet and the at least one test channel; and a waste channel having at least one surface portion that is hydrophilic and in communication with the sampling channel; and a vent opening in communication with the sampling channel. Exposure of an optical sensor activates a pump module of the blood clot detection instrument, which draws a desired volume of the blood sample into the at least one test channel.

[0012] The above information is only used to enhance the understanding of the background of the present application, and therefore can contain information that does not constitute prior art known to those of ordinary skill in the art. The above patent applications and prior art use various complex structures to achieve detection of trace blood. In addition, in the above-mentioned devices, the surface of the part in contact with the blood often needs to be treated to inhibit clotting, such as surface treatment with heparin, polyacetyl lactone or poly-2-phosphomethoxyethyl adenine.

[0013] In addition, for other liquid samples in addition to blood samples, similar problems exist, and it is desirable to achieve detection using a small volume, and to avoid external interference and influence on the liquid sample during the entire process of detecting liquid clotting.

[0014] Further, it is also desirable to achieve continuous, rapid and efficient detection for different liquid samples, and to avoid mutual interference and contamination between different samples.

[0015] In view of the above, the present application aims to provide a liquid phase change detection device that is simple in structure, capable of rapidly detecting a phase change process of a liquid to quickly obtain information on a liquid phase change such as thrombus formation, and can achieve detection of a liquid phase change for only a small amount of liquid sample, and a method of detecting a liquid phase change using the device.

[0016] The object of the present application is achieved by the following technical solutions.

[0017] 1. A device for detecting a liquid phase change, comprising:

[0018] a sample placement area for placing a liquid sample to be detected and completing a phase change process from liquid to solid in the sample placement area for detection;

[0019] a pulse module for applying a pulsed pressure to the sample to be detected;

[0020] a detection module for detecting a change in pressure in a pipe on one side of the detection module;

[0021] a pipe having an inlet and an outlet for the sample to enter and exit;

[0022] wherein the pulse module and the detection module are arranged on both sides of the sample placement area, and the detection of the change in pressure in the pipe on one side of the detection module refers to the detection by the detection module of a change in pressure over time of the pressure applied by the pulse module to the sample to be detected and transmitted through the sample to the side of the detection module, and outputting the change in pressure over time as a signal.

[0023] 2. The device according to item 1, wherein the cross-sectional shape of the sample placement area satisfies the following condition:

[0024] the maximum width of the sample placement area in the direction of sample introduction of the sample to be detected is D1, the maximum width of the sample placement area in the direction perpendicular to the direction of sample introduction of the sample to be detected is D2, and D1≥D2;

[0025] the sample placement area is substantially symmetrical along the direction of sample introduction of the sample to be detected; and

[0026] the shape of the sample placement area on one side in the direction of sample introduction of the sample to be detected is substantially outwardly convex arc shape.

[0027] 3. The device according to item 2, wherein the cross-sectional shape of the sample placement area further satisfies the following condition:

[0028] 1 < D1 / D2 ≤ 8,

[0029] preferably 1 < D1 / D2 ≤ 7,

[0030] more preferably 1 < D1 / D2 ≤ 6,

[0031] Further preferably, 1 < D1 / D2 < 5.

[0032] 4. The device according to item 3, wherein the cross-sectional shape of the sample placement region further satisfies the following condition:

[0033] when the inner diameter of the pipe of the inlet and outlet for the sample to enter and exit is R,

[0034] 2 < D1 / R < 24 is satisfied,

[0035] preferably, 2 < D1 / R < 20 is satisfied,

[0036] further preferably, 2 < D1 / R < 16 is satisfied.

[0037] 5. The device according to item 1, wherein the cross-sectional shape of the sample placement region further satisfies the following condition: the shape of one side of the sample placement region in the direction of sample introduction to be detected is substantially outwardly convex arc shape without obvious concave.

[0038] 6. The device according to item 5, wherein the cross-sectional shape of the sample placement region further satisfies the following condition:

[0039] the sample placement region is substantially symmetrical in the direction perpendicular to the direction of sample introduction to be detected.

[0040] 7. The device according to any one of items 1 to 6, wherein the pipe is a microchannel, and the inner diameter thereof is 10 micrometers to 5 millimeters, preferably 50 micrometers to 4 millimeters, further preferably 100 micrometers to 3 millimeters, further preferably 200 micrometers to 2 millimeters, further preferably 300 micrometers to 1 millimeter.

[0041] 8. The device according to any one of items 1 to 7, wherein the sample placement region, the pulse module, the detection module, and the pipe are in fluid communication.

[0042] 9. The device according to any one of items 1 to 8, wherein the liquid sample is a blood sample, or a protein liquid sample, or other liquid sample that will undergo phase transition due to high molecular polymerization, or a substance that undergoes phase transition with temperature change.

[0043] 10. The device according to any one of items 1 to 9, wherein the pulse pressure applied by the pulse module to the detection module has a substantially constant pressure peak value.

[0044] 11. The device according to any one of items 1 to 10, wherein the entire device is filled with medium before the device for detecting liquid coagulation is used.

[0045] 12. The device according to any one of items 1 to 11, wherein the liquid sample is a blood sample, or a protein liquid sample, or other liquid sample that will undergo phase transition due to high molecular polymerization.

[0046] 13. A method for detecting liquid phase transition, which uses the device comprising a sample placement area, a pulse module, a detection module, and a pipe, and comprises the following steps:

[0047] feeding the liquid sample to be detected in the form of a liquid sample wrapped by a medium through the pipe to the sample placement area,

[0048] providing a pulsed pressure to the liquid sample by the pulse module, and

[0049] detecting the change of the pressure applied to the sample to be detected by the pulse module and transmitted to the side of the detection module over time by the detection module, and outputting the change of the pressure over time as a signal,

[0050] wherein the pulse module and the detection module are arranged on both sides of the sample placement area.

[0051] 14. The method according to item 13, which uses the device according to any one of items 1 to 12.

[0052] 15. The method according to item 13, which further comprises the following steps:

[0053] filling the entire detection system with the medium before detection.

[0054] As described above, the device for detecting liquid phase transition of the present application has a simple structure, and can detect the coagulation time and coagulation state of a liquid (e.g., blood) with a small amount of liquid sample (e.g., blood sample). In addition, when the detection device of the present application is used, the liquid sample (e.g., blood sample) is wrapped by a medium, so that the liquid sample (e.g., blood sample) is not disturbed by unnecessary external factors during detection, and the entire process of the phase transition of the liquid sample, such as the time when blood starts to coagulate after the addition of a blood coagulation promoting drug or factor, and the strength of coagulation (the strength of the thrombus) can be accurately detected.

[0055] In addition, the device for detecting liquid phase transition of the present application can detect the process of the sample from liquid to solid, and can further detect the process of the solid coagulated again to liquid. At the same time, those skilled in the art can understand that the process from liquid to solid to liquid can be repeated many times, and the entire process repeated many times can be detected by the device of the present application.

[0056] The above description is only a summary of the technical solutions of the present application. In order to make the technical solutions of the present application more clear and understandable, to the extent that a person skilled in the art can implement the content of the description, and in order to make the above and other purposes, features and advantages of the present application more obvious and understandable, the following will be illustrated by specific embodiments of the present application. BRIEF DESCRIPTION OF DRAWINGS

[0057] Various other advantages and benefits of the present application will become apparent to those of ordinary skill in the art, upon reading the following detailed description of the preferred embodiments. The accompanying drawings are included to provide a description of the preferred embodiments, and are not meant to limit the present application. Obviously, the drawings described below are only some embodiments of the present application, and other drawings can be obtained from these drawings by those of ordinary skill in the art without creative labor. Moreover, the same reference numerals are used to represent the same components throughout the drawings.

[0058] Figure 1 Schematic diagram of one embodiment of the detection device of the present application.

[0059] Figure 2 Schematic diagram of another embodiment of the detection device of the present application.

[0060] Figure 3 (a)-(c) Schematic diagram of the sample placement area of the detection device of the present application and its cross section.

[0061] Figure 4 Example of detection results when the score is 5.

[0062] Figure 5 Example of detection results when the score is 6.

[0063] Figure 6 Example of detection results when the score is 7.

[0064] Figure 7 Example of detection results when the score is 8.

[0065] Figure 8 Example of detection results when the score is 9.

[0066] Figure 9 Cross-sectional shape of the sample placement area used in Comparative Example 1 and the detection score results.

[0067] Figure 10 Cross-sectional shape of the sample placement area used in Comparative Example 2 and the detection score results.

[0068] Figure 11 Schematic diagram of the detection results of Example 11. DETAILED DESCRIPTION

[0069] Specific embodiments of the present application will now be described in greater detail with reference to the accompanying drawings. In the drawings, specific embodiments of the application are illustrated, however, it will be understood that the application can be carried out in various forms and should not be limited to those illustrated and described herein. Rather, these embodiments are provided so that this disclosure will convey the full scope of the application to skilled artisans.

[0070] <Device for detecting phase change of liquid>

[0071] The device for detecting phase change of liquid of the present application comprises: a sample placement area for placing a liquid sample to be detected and completing the phase change process of the liquid in the sample placement area for detection; a pulse module for applying a pulsed pressure to the sample to be detected; a detection module for detecting the change of pressure in the pipeline on the side of the detection module; a pipeline with an inlet and an outlet for sample in and out; wherein the pulse module and the detection module are arranged on both sides of the sample placement area, and the detection of the change of pressure in the pipeline on the side of the detection module refers to the detection of the change of pressure with time by the detection module after the pulsed pressure applied by the pulse module to the sample to be detected and transmitted through the sample to the side of the detection module, and the change of pressure with time is output as a signal.

[0072] In addition, the device for detecting liquid solidification of the present application can also comprise a sample injection module, which is a module capable of injecting in the form of medium including a liquid sample, without specific limitation.

[0073] Figure 1 and Figure 2 respectively show the schematic diagram of an embodiment of the detection device of the present application. As can be seen, in the detection device of the present application, the pulse module and the detection module need to be arranged on both sides of the sample placement area, Figure 1 and Figure 2 respectively give two representative ways, of course, those skilled in the art can understand that the pulse module and the detection module do not need to be arranged at an angle of 180 degrees relative to the sample placement area, as long as one is located on one side of the sample placement area and the other is located on the other side of the sample placement area, i.e. the pulse module is used to apply a pulsed pressure to the sample to be detected, and the detection module is used to detect the pressure that can be transmitted to the pipeline on the other side of the sample after the absorption of the pulsed pressure by the sample. Thus, those skilled in the art can understand that as the liquid sample to be detected changes from liquid to solid or from solid to liquid, the pressure value absorbed by the sample will change, and the pressure in the pipeline on the other side that can be transmitted will also change constantly, and the device of the present application detects this change with time to represent the change of the liquid sample to be detected from liquid to solid.

[0074] In a preferred embodiment, the pulse module and the detection module are placed at 180 degrees ± 20 degrees, preferably at 180 degrees ± 10 degrees, and further preferably at 180 degrees ± 5 degrees, relative to the sample placement area.

[0075] The pulse module used in the device of the present application applies a pulse pressure to the sample to be detected, and therefore any means commonly used in the art that can provide a pulse pressure can be used, such as a pulse pump, a plunger pump, a syringe pump, or a pulse pressure provided indirectly by pushing the medium with a pulse gas pressure, etc. The pulse pressure applied by the pulse module to the liquid sample to be detected during the detection process is a pulse pressure with a substantially constant peak value of the pressure applied each time, such as a certain pressure applied at intervals, wherein the interval time can be 1-60 seconds, preferably 2-40 seconds, and further preferably 3-20 seconds; the applied pressure can be 0.1-50 KPa, preferably 0.4-24 KPa, further preferably 0.8-16 KPa, and further preferably 1.2-12 KPa.

[0076] The peak value of the pressure of the pulse pressure applied by the pulse module to the sample to be detected is substantially constant. The substantially constant peak value means that the output value of the pulse pressure is kept constant, but a variation in the output value within the error range allowed by the instrument is allowed, and generally the variation is ± 1 KPa, preferably ± 0.5 KPa, and preferably ± 0.1 KPa of the output pressure value.

[0077] The detection device of the present application should be filled with a medium throughout the device before use, and the filling of the medium throughout the device means that the medium fills the pipe and the sample placement area. When the detection device is used, the liquid sample to be detected is injected into the pipe in the form of a liquid sample wrapped by the medium, and enters the sample placement area through the pipe. After the injection is completed, the pulse module is opened, and a pulse pressure with a substantially constant peak value of the pressure is applied to the liquid sample to be detected. As the liquid sample in the sample placement area gradually solidifies from a liquid state to a solid state, the change in the pressure in the pipe on the side of the detection module, which is generally the pressure in the pipe on the side of the detection module outside the sample placement area, can be detected by the detection device in the device, and the change in the pressure is recorded by the detection module according to the output pressure signal, thereby reflecting the entire state from the liquid to the solidification.

[0078] The pulse module applies a peak pressure which is substantially constant, so when there is no liquid sample in the device, the peak of the pulse is substantially constant, and this peak is the background value detected by the detection module. When the liquid sample undergoes a phase change from liquid to solid, and then undergoes a phase change from solid to liquid, the transmission of pressure is affected, so the amplitude of the signal received by the detection module changes, and the amount of this amplitude change can be used to describe the strength of the phase change, and by subtracting the detection value from the background value, the value of the phase change strength can be obtained, and the output of the phase change strength value over time is the detection curve, which can represent the phase change process of the sample.

[0079] Those skilled in the art can understand that, as the liquid sample gradually changes from liquid to solid, the amplitude of the pressure pulse detected by the detection module gradually decreases, and at this time, the process of the gradually decreasing amplitude of the pressure pulse detected by the detection module can be recorded, and the gradually decreasing amplitude of the directly measured pressure pulse is subtracted from the substantially constant peak value of the pulse pressure, thereby obtaining a gradually increasing pressure curve reflecting the solidification strength of the sample, and taking it as the detection result. For example, various detection results are given in Figures 4-10 Meanwhile, if it is to detect the phase change process from solid to liquid, those skilled in the art can understand that the solid sample becomes liquid, and the effect of hindering the pulse pressure becomes weak, so as the phase change occurs, the amplitude of the pulse detected by the detection module continuously increases, and the gradually increasing amplitude of the directly measured pressure pulse is subtracted from the substantially constant peak value of the pulse pressure, thereby obtaining a gradually decreasing pressure curve reflecting the liquefaction degree of the sample, and taking it as the detection result.

[0080] The detection module used in the device of the present application, as described above, can detect the change of pressure in the pipeline, and there is no limitation, which can be any pressure sensor that can be used in the field of microfluidics. For example, a micro air pressure sensor, a micro hydraulic pressure sensor.

[0081] The sample placement area in the device of the present application is used to place the liquid sample to be detected and complete the phase change process of the liquid in the sample placement area for detection. The shape of the sample placement area is generally not limited as long as it can achieve this process. Preferably, the cross-sectional shape of the sample placement area of the present application meets some limited conditions.

[0082] In addition, when using the device of the present application, the sample enters in liquid form, but after entering the sample placement area, the process of the sample solidifying from liquid to solid can be detected, and the process of the sample melting from solid to liquid can also be detected. Similarly, it can be known that the phase change process can be repeated many times, and the multiple phase change processes can be detected.

[0083] Figure 3 A schematic diagram of the cross section of the sample placement area is given. Figure 3(a) and (b) show schematic perspective views of the device of the present invention, where the cuboids on both sides can represent the pulse module and the detection module, respectively, and the ellipsoidal or cylindrical shape in the middle schematically represents the sample placement area. Those skilled in the art should understand that... Figure 3 The shapes shown in (a) and (b) are merely schematic diagrams illustrating the sample placement area and its cross-section, and are not intended to limit the shape of the sample placement area. Furthermore, Figure 3 (a) and (b) show two different solid shapes, which are exemplary, and any solid shape that satisfies the shape of its cross section can be used.

[0084] The cross-section of the sample placement area refers to the area along the direction of sample flow. Figure 3 The cross-section obtained by cutting the center of the sample placement area with the rectangular plane shown in (a) or (b), as shown in the figure. Figure 3 The shaded area indicated by the diagonal line in (a) or (b) is the cross-section of the sample placement area as referred to in this paper. Figure 3 (c) shows a planar schematic of the entire cross-section after cutting, where the shaded area indicated by the diagonal line represents the cross-section of the sample placement area. Figure 3 The dashed line indicates the direction of sample injection.

[0085] In the apparatus of the present invention, the preferred cross-sectional shape of the sample placement area satisfies the following condition: the maximum width of the sample placement area in the direction of sample injection is D1 (e.g., ...). Figure 3 (c) shows that the maximum width of the sample placement area in the direction perpendicular to the sample injection direction is D2 (as shown in the figure). Figure 3 (c) as shown), and D1≥D2; the sample placement area is basically symmetrical along the injection direction of the sample to be tested; and the shape of the sample placement area on one side along the injection direction of the sample to be tested is a basically outwardly convex arc.

[0086] In the above conditions, the condition that the sample placement area is basically symmetrical along the injection direction of the sample to be tested means that, in terms of the cross-section of the sample placement area, along... Figure 3 (b) The dotted line in the schematic diagram is the center line. The areas of the upper and lower parts are basically the same, and the shapes are basically symmetrical. For example, the area of ​​the upper part above the dotted line and the area of ​​the lower part below the dotted line differ by 20%, more preferably by 15%, more preferably by 10%, and even more preferably by 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, and 1%.

[0087] The sample placement area, on one side along the direction of sample injection, has a substantially outward-convex arc shape. An arc is a portion of a circle or ellipse. A substantially outward-convex arc means that the arc... Figure 3The arc shape means that the shape as a whole looks like a part of a circle or an ellipse, and does not require a completely smooth arc shape.

[0088] In the device of the present application, it is further preferred that the cross-sectional shape of the sample placement zone satisfies the following condition: 1 < D1 / D2 < 8, preferably 1 < D1 / D2 < 7, further preferably 1 < D1 / D2 < 6, further preferably 1 < D1 / D2 < 5. That is, the cross-section of the sample placement zone of the present application preferably has the shape of an ellipse having a major axis and a minor axis, wherein the direction of sample introduction is the major axis and the direction perpendicular to the direction of sample introduction is the minor axis.

[0089] In the device of the present application, it is further preferred that the cross-sectional shape of the sample placement zone satisfies the following condition: when the inner diameter of the pipe of the inlet and outlet for the introduction and discharge of the sample is R, 2 < D1 / R < 24, preferably 2 < D1 / R < 20, further preferably 2 < D1 / R < 16. That is, the volume of the sample placement zone and the size of the pipe of the present application preferably satisfy the above relationship.

[0090] In the device of the present application, it is further preferred that the cross-sectional shape of the sample placement zone satisfies the following condition: the shape of the sample placement zone on one side in the direction of sample introduction of the sample to be measured is an arc shape substantially convex outward and there is no significant depression on the arc shape. In this context, a depression means, for example, a part such as a wave trough appearing on the arc shape, for example, the cross-sectional shape of the sample placement zone in Examples 6 to 8 described below. Example 6 and 8 have one significant depression on the arc on one side in the direction of sample introduction, and Example 7 has two significant depressions on the arc on one side in the direction of sample introduction.

[0091] In the device of the present application, it is further preferred that the cross-sectional shape of the sample placement zone satisfies the following condition: the sample placement zone is substantially symmetrical in the direction perpendicular to the direction of sample introduction of the sample to be measured.

[0092] The cross-sectional shapes that can be used and cannot be used are shown in Table 1 of the examples and comparative examples of the present application. Those skilled in the art can fully understand that Table 1 only lists illustrative cross-sectional shapes, and in addition to the shapes in Table 1, as long as the above-mentioned defined conditions of the present application are satisfied, they can be used, or can be more preferably used.

[0093] In the device of the present application, the pipe is a microchannel, and the inner diameter thereof is 10 micrometers to 5 millimeters, preferably 50 micrometers to 4 millimeters, further preferably 100 micrometers to 3 millimeters, further preferably 200 micrometers to 2 millimeters, further preferably 300 micrometers to 1 millimeter.

[0094] In the present application, the material of the tube is not limited, as long as it is a material that can realize the wrapping of the liquid sample by the medium through the operation of the present application. For example, high molecular materials such as polytetrafluoroethylene (PTFE), polymethyl methacrylate (PMMA), polypropylene (PP), glass, and metal materials such as stainless steel, titanium alloy, copper, platinum, and gold can be listed.

[0095] In the present application, a certain amount of the liquid sample to be tested is required to be introduced into the sample placement area. The amount of the liquid sample to be tested refers to the amount of the liquid sample to be tested in the present application. The amount is not specifically limited, and those skilled in the art know how to select an appropriate amount according to the subsequent processing or detection of the sample to determine the coagulation process of the liquid sample. For example, 0.1-200 microliters, 0.5-150 microliters, 1-100 microliters, 2-80 microliters, 3-60 microliters, etc. can be listed. For example, 200 microliters, 150 microliters, 100 microliters, 80 microliters, 60 microliters, 40 microliters, 20 microliters, 10 microliters, 8 microliters, 6 microliters, 4 microliters, 2 microliters, 1 microliter, 0.1 microliters, etc. can be specifically listed.

[0096] In the present application, as described above, the liquid sample is a blood sample or a high molecular solution such as a protein solution, a gelatin solution, a protein curd, and a polymer material solution.

[0097] The medium used in the present application is generally oleophilic, and various oil substances commonly used in the art can be used. For example, mineral oil, low-temperature paraffin, and vegetable oil.

[0098] <Method for detecting phase change of liquid>

[0099] The present application also provides a method for detecting the phase change of a liquid, which uses a device comprising a sample placement area, a pulse module, a detection module, and a tube to detect, and comprises the following steps: introducing a liquid sample to be tested into the sample placement area through the tube in the form of being wrapped by a medium, providing a pulse pressure to the liquid sample by the pulse module, and detecting the change of the pressure applied to the sample to be tested by the pulse module and transmitted to the side of the detection module with time by the detection module, and outputting the change of the pressure with time as a signal, wherein the pulse module and the detection module are arranged on both sides of the sample placement area.

[0100] The device used in the method of the present application is the device of the present application described above.

[0101] In addition, the method of the present application further comprises: filling the medium in the entire detection system before detection.

[0102] As described above, the device for detecting the phase change of liquid of the present application is simple in structure, and can detect the coagulation time and coagulation state of liquid (e.g. blood) with a small amount of liquid sample (e.g. blood sample). In addition, when the detection device of the present application is used, the liquid sample (e.g. blood sample) is wrapped with a medium, so that the liquid sample (e.g. blood sample) is not disturbed by the outside world during the detection, and the whole process of coagulation of the liquid sample can be accurately detected, for example, the time of blood coagulation after the addition of a blood coagulation promoting drug or factor is shortened, and the strength of coagulation (the strength of thrombus) is increased.

[0103] In addition, for blood samples, the sample may be liquefied after coagulation for a period of time, which indicates that the coagulated blood has fibrinolysis, which is medically referred to as hyperfibrinolysis. Patients with hyperfibrinolysis have a higher risk of internal bleeding, and if a patient needs surgery, medical means must be taken to improve the coagulation ability of the patient, otherwise the patient may bleed a lot during or after the operation, and even endanger life. The device of the present application can detect the above process and realize the detection of the hyperfibrinolysis process.

[0104] In addition, since the device of the present application uses the given sample introduction module described below, different liquid samples can be continuously introduced to realize continuous and one-time processing of a large number of different liquid samples. The liquid samples introduced each time can be properly isolated from each other and not contaminated and affected by each other, so that continuous introduction and effective detection of a plurality of liquid samples can be realized.

[0105] Embodiments

[0106] The detection device used in the following embodiments is basically constructed in the manner of Figure 2 .

[0107] The pulse module is composed of a constant pressure gas source and a time-controlled electromagnetic valve. A KLP01 diaphragm pump from Carkon Fluid Technology (Shanghai) Co., Ltd. is used, a DP-101 gas pressure sensor switch module from Shenzhen Chuangfeng Instrument & Meter Co., Ltd. is used, a 2L volume stainless steel gas storage tank is used, and a constant pressure gas source is formed. The gas source is positive pressure; a TM-06 two-position three-way high-frequency electromagnetic valve from Ningbo Suno Industrial Automation Equipment Co., Ltd. is used, a DTM01 time relay module from Shenzhen Qin Yuansheng Electronics Co., Ltd. is used, and a time-controlled electromagnetic valve is formed.

[0108] Wherein, solenoid valve normally closed port connection constant pressure gas source, normally open port connection with detection zone fluid communication pulse pipe, pipe filled with medium, solenoid valve another port and the outside air communication. When solenoid valve does not act, pulse channel through solenoid valve and outside air communication, the pressure detected by the detection module at this time is 0 Pa; when solenoid valve act, solenoid valve and constant pressure gas source communication, the pressure detected by the detection module at this time is greater than zero and less than or equal to a certain pressure value of constant pressure gas source. The action time and interval time of solenoid valve are controlled by time relay module.

[0109] At the same time, the same components and methods are used to make a constant pressure gas source. It is used for sample injection operation of the sample to be tested.

[0110] In the following examples, the medium uses mineral oil, and the gas source pressure is controlled at 12 KPa.

[0111] The pipe has an inner diameter of 0.6 mm x 0.6 mm, and the material of the pipe is polymethyl methacrylate (PMMA).

[0112] The sample placement area is made of polymethyl methacrylate (PMMA) material. In the examples, a cylindrical structure is used, as shown in Figure 3 (b), and the shape and parameters of the cross section used in each example are listed in Table 1 below.

[0113] The detection module uses a micro gas-liquid universal pressure sensor (XGZP6847 type pressure sensor module purchased from Wuhu Xinggan Zhi Sensor Technology Co., Ltd.), which outputs a 0-5V voltage signal and has a range of 0-20KPa.

[0114] The materials used in the following examples 1-9 and comparative examples 1-4 are as follows:

[0115] Sheep plasma (heparin sodium titer detection) was purchased from Shandong Cangshan Xiangming Biochemical Auxiliary Factory, stored at a temperature below -18℃, and thawed at 4℃ before the experiment, and activated at 37℃ for 1 hour.

[0116] Calcium chloride solution was purchased from Hisun Biotech (Wuxi) Co., Ltd., with a calcium ion concentration of 0.02 mol / L. After preparation at the above concentration, it was stored at 4℃ and preheated to room temperature before use. The calcium ion is used to promote the coagulation reaction of sheep plasma.

[0117] After the experimental materials were prepared, the activated sheep plasma was taken, calcium chloride was added, and the timing started at this time (0 seconds at this time). At this time, the sample was placed in the centrifugal tube; the sample was injected into the sample placement area, and the detection started at the 100 second time point.

[0118] Before sample injection, the pulse port is closed, the sample outlet pipeline is connected to the negative constant pressure gas source through the valve, and the system is filled with medium. When injecting the sample, the pipeline connected to the sample inlet is inserted into the centrifugal tube containing the sample, the valve connected to the sample outlet pipeline is opened, the sample is sucked into the sample placement area through the inlet, and when the sample placement area is filled, the valve connected to the sample outlet pipeline is closed, the centrifugal tube containing the sample to be tested is removed, and the sample inlet is closed. At this time, the sample injection is completed.

[0119] After the sample injection is completed, the pulse port is opened, and the pulse channel is in fluid communication with the pulse module. The time relay module is started, so that the pulse module electromagnetic valve intermittently acts, thereby exerting a pulse pressure on the sample to be tested, and the detection is started. The pulse cycle is 5s of pressure application and 5s of interval, the pressure of the positive constant pressure gas source of the pulse module is 12KPa, and the pressure of the negative constant pressure gas source is -6KPa. The detection time is 12-20min.

[0120] Figures 4-8 The score examples of different test results when the detection device of the application is used for detection are shown, and the examples are scored according to the examples of Figures 4-8 From Figure 4 it can be seen that the example scored 5 points can basically describe the complete phase change process, but the description of the details of the phase change process is limited, and the main features of the phase change are not fully reflected. From Figure 5 it can be seen that the example scored 6 points can describe the complete phase change process, although the description of the details of the phase change process is not accurate enough, but the main features of the phase change can be basically reflected. From Figure 6 it can be seen that the example scored 7 points can describe the complete phase change process, although the description of the local details of the phase change process is not accurate enough, but the main features of the phase change can be reflected. From Figure 7 it can be seen that the example scored 8 points can accurately and completely describe the entire phase change process, only a small data deviation exists in a part, but basically does not affect the accuracy of the description of the phase change process. From Figure 8 it can be seen that the example scored 9 points can accurately and completely describe the entire phase change process, only a small fluctuation exists in an individual data point, but does not affect the accuracy of the description of the phase change process.

[0121] Example 10

[0122] The same device as in Examples 1-9 was used, the cross section of the sample placement zone was exactly the same as in Example 3, the sample placement zone was placed in a constant temperature incubator, and was in fluid communication with the pulse module and detection module placed outside the constant temperature incubator through a polytetrafluoroethylene hose with an inner diameter of 0.6 mm. A blue LRH-150 type constant temperature incubator purchased from Shanghai Yiheng Scientific Instrument Co., Ltd. was used. Animal butter for baking purchased from Hohhot Tianmeihua Dairy Food Co., Ltd. was used as the sample, which was in a soft solid state at 28-34°C and was in a liquid state above 34°C.

[0123] The device sample placement zone and the sample were preheated at 40°C for 20 minutes before the experiment, and the sample was completely melted into a liquid state. The same sample injection method as in Examples 1-9 was used, the liquid sample was injected into the sample placement zone, and then the detection was started, the detection start time was counted as 0 seconds. After 1 minute of detection start, the temperature of the constant temperature incubator was set to 25°C, and as the temperature decreased, the liquid sample began to gradually change into a solid; after 12 minutes of detection, the sample had fully solidified, and the incubator temperature was set to 40°C again, and as the temperature increased, the solid sample gradually changed back to a liquid state. The detection module completely recorded the change process of the sample from liquid to solid and from solid to liquid, and the specific results are shown in Figure 11 .

[0124] In Comparative Examples 1 and 2, the shape of the cross section of the sample placement zone was that the length in the sample injection direction was less than the length in the direction perpendicular to the sample injection direction. When the shape was two kinds of shapes with a ratio of 1:1.5 in the sample direction to the direction perpendicular to the sample direction, the results could only make a limited response to the occurrence of phase change, and could not describe the process, Figure 9 The cross-sectional shape of the sample placement zone used in Comparative Example 1 and Comparative Example 2 and the results are shown in Figure 9 It can be seen that the sample placement zone that does not meet the condition D1≥D2 above cannot obtain a satisfactory detection curve.

[0125] In Comparative Examples 3 and 4, if the shape of the cross section of the sample placement zone is asymmetric along the sample injection direction. As Figure 10 shown, when the shape is the first asymmetric, the result can only make a limited response to the occurrence of phase change, and cannot completely describe the process; and when the shape is the second asymmetric, the result can basically describe the occurrence of phase change, but cannot describe the complete process, and is unstable in the later detection. From Figure 10 It can be seen that the sample placement zone that does not meet the condition that the sample placement zone is substantially symmetric along the sample injection direction of the sample to be detected and the shape of one side of the sample placement zone along the sample injection direction of the sample to be detected is substantially an outward convex arc cannot obtain a satisfactory detection curve.

[0126] The average of the results of the three detections of each of Examples 1 to 9 is at least 5 points, and the purpose of detecting the phase change of the liquid can be achieved.

[0127] Table 1 summarizes the cross-sectional shape of the sample placement area of Examples 1 to 9 and the results of the three detections scored according to the scoring example of Figures 4-8

[0129] According to the results of the above examples, it can be shown that the device of the present application can effectively detect the time of the liquid solidification and the strength of the reaction liquid solidification.

[0130] The present application is susceptible to modifications and alternative forms, specific embodiments having been shown by way of example in the drawings and being described in detail herein. However, it should be understood that the application is not to be limited to the particular arrangements, apparatus, methods shown. It will be apparent to one skilled in the art that numerous modifications, equivalent processes and alternative forms can be employed without departing from the scope of the present application as set forth in the claims.

[0131] The numerical ranges recited in the present application include all the data between the two endpoints of the numerical range, and also include each specific number within the numerical range, and the numbers can be combined with the endpoints to form new small ranges.​

Claims

1. A device for detecting phase change of a liquid, comprising: a sample placement area for placing a liquid sample to be detected and completing a phase change process of the liquid in the sample placement area for detection; a pulse module for applying a pulsed pressure to the liquid sample to be detected; a detection module for detecting a change in pressure in a conduit on one side of the detection module; a conduit having an inlet and an outlet for the sample to enter and exit; wherein the pulse module and the detection module are arranged on both sides of the sample placement area, the detection of the change in pressure in the conduit on one side of the detection module means that the detection module detects a change in pressure over time of the pressure applied by the pulse module to the liquid sample to be detected and transmitted through the sample to the side of the detection module and outputs the change in pressure over time as a signal; the cross-sectional shape of the sample placement area satisfies the following conditions: the maximum width of the sample placement area in the direction of sample entry of the liquid to be detected is D1, the maximum width of the sample placement area in the direction perpendicular to the direction of sample entry of the liquid to be detected is D2, and D1 ≥ D2; the sample placement area is substantially symmetrical in the direction of sample entry of the liquid to be detected; and the shape of the sample placement area on one side in the direction of sample entry of the liquid to be detected is substantially outwardly convex arc shape; the material of the conduit is selected from one of polytetrafluoroethylene, polymethyl methacrylate, polypropylene, glass, stainless steel, titanium alloy, copper, platinum, and gold. The cross-sectional shape of the sample placement area further satisfies the following conditions: 1 < D1 / D2 ≤ 8. The cross-sectional shape of the sample placement area further satisfies the following conditions: 1 < D1 / D2 ≤ 7. The cross-sectional shape of the sample placement area further satisfies the following conditions: 1 < D1 / D2 ≤ 6. The cross-sectional shape of the sample placement area further satisfies the following conditions: 1 < D1 / D2 ≤ 5. The cross-sectional shape of the sample placement area further satisfies the following conditions: 1 < D1 / D2 ≤ 5. When the inner diameter of the conduit having an inlet and an outlet for the sample to enter and exit is R, 2 ≤ D1 / R ≤ 24 is satisfied. The cross-sectional shape of the sample placement area further satisfies the following conditions: 2 ≤ D1 / R ≤ 20. The cross-sectional shape of the sample placement area further satisfies the following conditions: 2 ≤ D1 / R ≤ 16. The cross-sectional shape of the sample placement area further satisfies the following conditions: the shape of the sample placement area on one side in the direction of sample entry of the liquid to be detected is substantially outwardly convex arc shape and there is no obvious depression on the arc shape.

2. The apparatus of claim 1, wherein, The cross-sectional shape of the sample placement area further satisfies the following conditions: the sample placement area is substantially symmetrical in the direction perpendicular to the direction of sample entry of the liquid to be detected. The conduit is a microchannel with an inner diameter of 10 microns to 5 millimeters.

3. The apparatus of claim 1, wherein, The conduit is a microchannel with an inner diameter of 50 microns to 4 millimeters. The conduit is a microchannel with an inner diameter of 100 microns to 3 millimeters.

4. The apparatus of claim 1, wherein, The conduit is a microchannel with an inner diameter of 200 microns to 2 millimeters. The conduit is a microchannel with an inner diameter of 300 microns to 1 millimeter.

5. The apparatus of claim 1, wherein, The sample placement area, the pulse module, the detection module, and the conduit are in fluid communication. ​ 6. The device of any one of claims 2-5, wherein, ​ ​ ​ 7. The device of any one of claims 2-5, wherein, ​ ​ 8. The device of any one of claims 2-5, wherein, ​ ​ 9. The apparatus of claim 1, wherein, ​ 10. The apparatus of claim 9, wherein, ​ ​ 11. The apparatus of claim 1, wherein, ​ 12. The apparatus of claim 1, wherein, ​ 13. The apparatus of claim 1, wherein, ​ 14. The apparatus of claim 1, wherein, ​ 15. The apparatus of claim 1, wherein, ​ 16. The apparatus of claim 1, wherein, ​ 17. The apparatus of claim 1, wherein, The liquid sample is a blood sample, or a protein liquid sample, or other liquid sample that will undergo phase transition due to high molecular polymerization, or a substance that will undergo phase transition with temperature change.

18. The apparatus of claim 1, wherein, The pressure peak of the pulse pressure applied by the pulse module to the detection module is substantially constant.

19. The apparatus of claim 1, wherein, The entire device is filled with medium before the device for detecting liquid coagulation is used.

20. The apparatus of claim 1, wherein, The liquid sample is a blood sample, or a protein liquid sample, or other liquid sample that will undergo phase transition due to high molecular polymerization.

21. A method for detecting liquid phase transition, which uses a device comprising a sample placement area, a pulse module, a detection module, and a pipeline, and comprises the following steps: The liquid sample to be detected is fed into the sample placement area through the pipeline in the form of a liquid sample wrapped with medium, The pulse module provides pulse pressure to the liquid sample, and The detection module detects the change of pressure with time of the pressure applied by the pulse module to the sample to be detected and transmitted to the side of the detection module, and outputs the change of pressure with time as a signal, Wherein, the pulse module and the detection module are arranged on both sides of the sample placement area.

22. The method according to claim 21, which uses the device according to any one of claims 1-20.

23. The method according to claim 21, which further comprises the following steps: The entire detection system is filled with medium before detection.

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