Apparatus and method for detecting a phase change in a liquid

Abstract

This invention relates to an apparatus and method for detecting liquid phase change. The apparatus for detecting liquid phase change includes: a sample placement area for placing a liquid sample to be tested and completing the phase change process of the liquid in the sample placement area for detection; a pulse module for applying pulsed pressure to the sample to be tested; a detection module for detecting pressure changes in a pipe on one side of the detection module; and a pipe having an inlet and an outlet for the sample to enter and exit. The pulse module and the detection module are disposed on opposite sides of the sample placement area. Detecting pressure changes in the pipe on one side of the detection module means that the detection module detects the pressure change over time of the pressure applied to the sample by the pulse module and transmitted through the sample to the detection module, and outputs this pressure change over time as a signal.

Description

Technical Field

[0001] This application is a divisional application of Chinese Invention Patent Application No. 201711210942.2 (titled "Apparatus and Method for Detecting Liquid Phase Change", filed on November 28, 2017). The present invention relates to an apparatus for detecting liquid phase change and a method for detecting liquid phase change using the apparatus. Background Technology

[0002] It is well known that blood clotting within a living heart or blood vessels can form thrombi and cause thrombotic diseases, such as acute myocardial infarction (AMI), cerebral thrombosis, deep vein thrombosis (DVT), and disseminated intravascular coagulation (DIC). Conversely, blood spilling outside blood vessels can lead to bleeding and hemorrhagic diseases, such as allergic purpura, thrombocytopenic purpura, hemophilia, and bleeding due to liver disease. To effectively prevent these diseases, it is necessary to regularly monitor the patient's blood for thrombosis.

[0003] Currently, for whole blood systems, the common method is to use a thromboelastometer to measure thromboelastography (TEG) to detect blood coagulation and thrombus formation. Thromboelastography (TEG) is an indicator reflecting the dynamic changes in blood coagulation (including the rate of fibrin formation, dissolution state, and the strength and elasticity of the coagulated substance). A thromboelastogram is a graph plotted by the thromboelastometer. The main components of a typical thromboelastometer include: an automatically regulated, temperature-controlled (37°C) stainless steel blood collection cup, a small stainless steel cylinder inserted into the cup, and a sensor that connects to the cylinder. The blood collection cup is placed on a reaction chamber that can rotate at a 4°45' angle, with blood contained between the cup wall and the cylinder. When the blood sample is liquid, the back-and-forth rotation of the cup cannot move the cylinder. The signal reflected by the sensor on the tracing paper is a straight line. When the blood begins to coagulate, resistance is generated between the cup and the cylinder due to the adhesion of fibrin. The rotation of the cup moves the cylinder at the same time. As the amount of fibrin increases, the resistance also increases, and the movement of the cup and the cylinder changes accordingly. This signal is drawn by the sensor onto the tracing paper to form a thromboelastography map.

[0004] In addition, many other liquid phase transition processes also need to be detected or monitored, such as the coagulation process of some polymer solutions, such as protein solutions, protein curds, gelatin, and polymer polymerization. Summary of the Invention

[0005] As mentioned above, thromboelastography is commonly used in this field to determine blood coagulation and thrombus formation. However, thromboelastography often requires a large amount of blood, necessitating the extraction of a significant amount of blood from the patient. This places a heavy burden on the patient and imposes higher operational demands on clinicians.

[0006] Therefore, if blood coagulation detection could be performed using only small amounts of samples, such as microliters, it would significantly reduce the burden on patients and the risks associated with blood collection. Furthermore, since blood coagulation detection requires minimizing interference from the external environment during the testing process, a detection device is also needed that minimizes the impact on the collected blood throughout the entire testing process.

[0007] JP2007-271323A discloses a method for simultaneously detecting blood viscosity and thrombus formation in a short time and at low cost. This patent document relates to a blood holding container with a capillary tube connected to its opening, a pressurizing device for draining blood from the blood holding container through the capillary tube at a certain flow rate, and a detection device for detecting blood viscosity and thrombus formation.

[0008] CN102762991A discloses a microchip for platelet detection and a platelet detection device using the microchip. The microchip disclosed in this patent document measures platelet function by inducing platelet aggregation through blood flow in a flow path. The microchip has an internal flow path, which is at least partially coated with collagen for platelet adhesion. Multiple walls extend along the direction of blood flow in the flow path, dividing the width of the flow path to form flow path partitions. The walls are treated to have a surface roughness (Ra) of 10–200 nm. Using this device, platelet detection of blood can be achieved using a small amount of blood.

[0009] CN101292161A discloses a device for monitoring thrombosis and a method for detecting thrombosis. The device includes a thrombosis cavity in which a thrombosis-inducing agent is provided at least a portion; an inlet tube connected to the thrombosis cavity through which blood flows; and a drug tube connected to the inlet tube through which an anticoagulant or blood-clotting-promoting drug is supplied. The method includes flowing anticoagulated blood into the thrombosis cavity, providing the thrombosis-inducing agent in at least a portion of the thrombosis cavity, and simultaneously releasing the anticoagulant or blood-clotting-promoting drug, thereby monitoring thrombosis.

[0010] CN101874208A discloses a microfilm and a blood observation device. The microfilm includes: a first flow path through which a first liquid flows, selected from whole blood, platelet-rich plasma, or their pharmaceutically treated solutions; a second flow path connected to the first flow path through which a second liquid flows, the second liquid containing a reagent capable of reacting with the first liquid; and a confluence flow path extending from the connection between the first and second flow paths. The microfilm is characterized by a stirring section provided in the confluence flow path, the stirring section having a stirring element for mixing the first and second liquids. This device enables the efficient mixing of trace amounts of blood and a reagent to detect the reactivity of the blood.

[0011] CN102099676A discloses a cup-based device for measuring and testing blood coagulation. The device includes a blood clot detection instrument and a cup for the instrument. The cup includes a blood sample receiver inlet and a channel structure comprising: at least one test channel for measuring blood clotting time; a sampling channel having at least one hydrophilic surface portion communicating with the blood sample receiver inlet and the at least one test channel; a waste channel having at least one hydrophilic surface portion communicating with the sampling channel; and a vent opening communicating 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 blood sample into the at least one test channel.

[0012] The above information is provided merely to enhance understanding of the background of this invention and may therefore contain information that does not constitute prior art known to those skilled in the art. Various complex devices with intricate structures have been employed in the aforementioned patent applications and prior art to detect trace amounts of blood. Furthermore, the aforementioned devices often require coagulation inhibition treatment of the surfaces of components in contact with blood, for example, using heparin, polyacetyllactone, or poly-2-phosphonomethoxyethyladenine.

[0013] In addition, similar issues exist for other liquid samples besides blood samples. It is desirable to be able to perform the detection using a very small volume, and to avoid external interference and influence on the liquid sample throughout the entire process of detecting liquid coagulation.

[0014] Furthermore, it is hoped that continuous, rapid, and efficient detection can be achieved for different liquid samples, and that there is no mutual interference or contamination between different samples.

[0015] In view of the above, the present invention aims to provide a liquid phase change detection device with a simple structure that can rapidly detect liquid phase change processes to quickly obtain information on liquid phase change, such as thrombosis, and can detect only trace amounts of liquid samples, as well as a method for detecting liquid phase change using the device.

[0016] The objective of this invention is achieved through the following technical solutions.

[0017] 1. An apparatus for detecting liquid phase change, comprising:

[0018] The sample placement area is used to place the liquid sample to be tested and to complete the phase transition process from liquid to solid in the sample placement area for detection.

[0019] A pulse module is used to apply pulsed pressure to the sample to be tested;

[0020] The detection module is used to detect changes in pressure in the pipeline on one side of the detection module;

[0021] It has inlet and outlet pipes for allowing samples to enter and exit;

[0022] The pulse module and the detection module are located on both sides of the sample placement area. Detecting the pressure change in the pipe on one side of the detection module means that the detection module detects the pressure change over time that is applied to the sample by the pulse module and transmitted through the sample to the detection module, and outputs this pressure change over time as a signal.

[0023] 2. The apparatus according to claim 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 injection is D1, and the maximum width of the sample placement area in the direction perpendicular to the direction of sample injection is D2, and D1≥D2.

[0025] The sample placement area is substantially symmetrical along the injection direction of the sample to be tested; and

[0026] The sample placement area is shaped as an outwardly convex arc on one side along the direction of sample injection.

[0027] 3. The apparatus 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] Preferred value 1 < D1 / D2 ≤ 7

[0030] Further optimization is to select 1 < D1 / D2 ≤ 6.

[0031] Further optimization is to select 1 < D1 / D2 ≤ 5.

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

[0033] When the inner diameter of the inlet and outlet pipes for sample entry and exit is R,

[0034] The condition 2 ≤ D1 / R ≤ 24 is satisfied.

[0035] Preferably, 2 ≤ D1 / R ≤ 20.

[0036] Further optimization is to select 2≤D1 / R≤16.

[0037] 5. The apparatus according to item 1, wherein the shape of the transverse base surface of the sample placement area further satisfies the following condition: the shape of the sample placement area on one side along the direction of sample injection is a substantially outwardly convex arc shape and there is no obvious depression on the arc shape.

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

[0039] The sample placement area is substantially symmetrical along the direction perpendicular to the direction of sample injection.

[0040] 7. The apparatus according to any one of claims 1 to 6, wherein the conduit is a microchannel with an inner diameter of 10 micrometers to 5 millimeters, preferably 50 micrometers to 4 millimeters, more preferably 100 micrometers to 3 millimeters, more preferably 200 micrometers to 2 millimeters, and more preferably 300 micrometers to 1 millimeter.

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

[0042] 9. The apparatus according to any one of claims 1 to 8, wherein the liquid sample is a blood sample, or a protein liquid sample, or other liquid sample that undergoes a phase change due to polymer polymerization, or a substance that undergoes a phase change with temperature.

[0043] 10. The apparatus according to any one of claims 1 to 9, wherein the peak value of the pulsed pressure applied by the pulse module to the module to be detected remains substantially constant.

[0044] 11. The apparatus according to any one of items 1 to 10, wherein the entire apparatus is filled with a medium before the apparatus for detecting liquid solidification is put into use.

[0045] 12. The apparatus according to any one of claims 1 to 11, wherein the liquid sample is a blood sample, or a protein liquid sample, or other liquid sample that undergoes a phase change due to polymer polymerization.

[0046] 13. A method for detecting a liquid phase change, comprising using a device including a sample placement area, a pulse module, a detection module, and a conduit, and including the following steps:

[0047] The liquid sample to be tested is introduced into the sample placement area through a pipeline in the form of a medium encapsulating the liquid sample.

[0048] The pulse module provides pulsed pressure to the liquid sample, and

[0049] The detection module detects the pressure change over time between the pressure applied to the sample by the detection pulse module and the pressure transmitted from the sample to the detection module, and outputs this pressure change as a signal.

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

[0051] 14. The method according to item 13, wherein the detection is performed using the apparatus described in any one of items 1 to 12.

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

[0053] Before conducting the test, the entire testing system is filled with the medium.

[0054] As described above, the device for detecting liquid phase transitions of the present invention 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). Furthermore, when using the detection device of the present invention, the liquid sample (e.g., blood sample) is encapsulated by a medium, thereby ensuring that the liquid sample (e.g., blood sample) is not subjected to unnecessary external interference during the detection process, and the entire phase transition process of the liquid sample can be accurately detected, such as the time when blood begins to coagulate and the intensity of coagulation (thrombus strength) after the addition of procoagulant drugs or factors.

[0055] Furthermore, the apparatus for detecting liquid phase transitions of the present invention can detect the process of a sample solidifying from a liquid to a solid, and can further detect the process of the solidified sample melting back into a liquid. Meanwhile, those skilled in the art will understand that this process from liquid to solid and back to liquid can be repeated multiple times, and the entire process repeated multiple times can be detected by the apparatus of the present invention.

[0056] The above description is merely an overview of the technical solution of the present invention. In order to make the technical means of the present invention clearer and more understandable, so that those skilled in the art can implement it according to the contents of the specification, and in order to make the above and other objects, features and advantages of the present invention more obvious and understandable, specific embodiments of the present invention are described below. Attached Figure Description

[0057] Various other advantages and benefits of the present invention will become apparent to those skilled in the art upon reading the detailed description of the preferred embodiments below. The accompanying drawings are for illustrative purposes only and are not intended to limit the invention. It is obvious that the drawings described below are merely some embodiments of the invention, and those skilled in the art can obtain other drawings based on these drawings without any inventive effort. Furthermore, the same reference numerals denote the same parts throughout the drawings.

[0058] Figure 1 A schematic diagram of one embodiment of the detection device of the present invention.

[0059] Figure 2 A schematic diagram of another embodiment of the detection device of the present invention.

[0060] Figure 3 (a) to (c) are schematic diagrams of the sample placement area and its cross-section of the detection device of the present invention.

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

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

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

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

[0065] Figure 8 Example of a test result when the score is 9.

[0066] Figure 9 Comparative Example 1 shows the cross-sectional shape of the sample placement area and the detection scoring results.

[0067] Figure 10 Comparative Example 2 shows the cross-sectional shape of the sample placement area and the detection scoring results.

[0068] Figure 11 A schematic diagram of the detection results in Example 11. Detailed Implementation

[0069] Specific embodiments of the invention will now be described in more detail with reference to the accompanying drawings. While specific embodiments of the invention are shown in the drawings, it should be understood that the invention can be implemented in various forms and should not be limited to the embodiments set forth herein. Rather, these embodiments are provided to enable a more thorough understanding of the invention and to fully convey the scope of the invention to those skilled in the art.

[0070]

[0071] The present invention provides an apparatus for detecting liquid phase transitions, comprising: a sample placement area for placing a liquid sample to be tested and completing the phase transition process of the liquid in the sample placement area for detection; a pulse module for applying pulsed pressure to the sample to be tested; a detection module for detecting pressure changes in a pipe on one side of the detection module; and a pipe having an inlet and an outlet for the sample to enter and exit. The pulse module and the detection module are disposed on opposite sides of the sample placement area. Detecting pressure changes in the pipe on one side of the detection module means that the detection module detects the pressure changes over time caused by the pulse module applying pressure to the sample to be tested and transmitted through the sample to the detection module, and outputs this pressure change over time as a signal.

[0072] Furthermore, the apparatus for detecting liquid solidification of the present invention may also include a sample injection module, which is not specifically limited to any module that can inject a sample in the form of a medium including a liquid sample.

[0073] Figure 1 and Figure 2 Schematic diagrams of one embodiment of the detection device of the present invention are shown. It can be seen that in the detection device of the present invention, the pulse module and the detection module need to be arranged on both sides of the sample placement area. Figure 1 and Figure 2 Two representative methods are given. It will be understood by those skilled in the art that the pulse module and the detection module do not need to be set at a 180-degree angle relative to the sample placement area; one can simply be located on one side of the sample placement area and the other on the other. That is, the pulse module is used to apply pulsed pressure to the sample to be tested, while the detection module is used to detect the pressure transmitted to the other side of the sample channel after the pulsed pressure has been absorbed by the sample. Therefore, those skilled in the art will understand that as the liquid sample changes from liquid to solid or from solid to liquid, the pressure absorbed by the sample changes, and thus the pressure transmitted to the other side of the channel also changes continuously. The device of this invention characterizes the change of the liquid sample from liquid to solid by detecting this change over time.

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

[0075] The pulse module used in the device of this invention applies pulsed pressure to the sample to be tested. Therefore, any commonly used component in the art capable of providing pulsed pressure can be used, such as a pulse pump, plunger pump, syringe pump, or a medium indirectly driven by pulsed gas pressure to provide pulsed pressure. During the detection process, the pulsed pressure applied by the pulse module to the liquid sample to be tested is a pulsed pressure with a substantially constant peak value for each applied pressure. For example, a certain pressure is applied at intervals, wherein the interval can be 1-60 seconds, preferably 2-40 seconds, more preferably 3-20 seconds; the applied pressure can be 0.1-50 kPa, preferably 0.4-24 kPa, more preferably 0.8-16 kPa, and even more preferably 1.2-12 kPa.

[0076] The peak value of the pulsed pressure applied by the pulse module to the module under test remains essentially constant. This essentially constant peak value means that the set pulsed pressure output value remains constant, but variations in the output value are allowed within the allowable error range of the instrument. Typically, this variation is ±1 kPa, preferably ±0.5 kPa, and more preferably ±0.1 kPa.

[0077] Before use, the detection device of this invention should be filled with a medium throughout the entire device. This means filling the pipes and sample placement area with the medium. Upon initial use, the liquid sample to be tested is injected into the pipes, encapsulated by the medium, and then into the sample placement area. After injection, the pulse module is activated, applying a pulsed pressure with a substantially constant peak value to the liquid sample. As the liquid sample gradually solidifies in the sample placement area, the pressure change over time in the pipes transmitted to the detection module can be detected using the detection device within the device. This pressure is typically the same as the pressure in the pipes outside the sample placement area on the detection module side. Based on the output pressure signal, the detection module records the pressure change, thus reflecting the entire process from liquid to solidification.

[0078] The pulse module applies a relatively constant peak pressure, so when there is no liquid sample in the device, the peak height of the pulse remains essentially unchanged; this peak height is the background value detected by the detection module. When the liquid sample undergoes a phase transition from liquid to solid and then back to liquid, it affects pressure transmission, causing changes in the amplitude of the signal received by the detection module. This change in amplitude can be used to describe the intensity of the phase transition. By subtracting the detected value from the background value, the phase transition intensity can be obtained. Outputting the phase transition intensity value over time yields the detection curve, which characterizes the phase transition process of the sample.

[0079] Those skilled in the art will understand that, as a liquid sample gradually changes from liquid to solid, the amplitude of the pressure pulse detected by the detection module will gradually decrease. At this time, the process of this gradual decrease in the amplitude of the pressure pulse detected by the detection module can be recorded, and the directly measured gradually decreasing pressure pulse amplitude can be subtracted from the essentially constant peak pressure of the pulse to obtain a gradually increasing pressure curve reflecting the solidification strength of the sample. This curve can then be used as the detection result. For example, see [reference needed]. Figures 4 to 10 The results of various detections are presented. Furthermore, if the detection involves a phase transition from solid to liquid, those skilled in the art will understand that the resistance to pulse pressure weakens as the sample changes from solid to liquid. Therefore, as the pulse amplitude detected by the phase transition detection module continuously increases, the gradually increasing pressure pulse amplitude measured directly is subtracted from the essentially constant pulse pressure peak value to obtain a gradually decreasing pressure curve reflecting the degree of sample liquefaction, which is then used as the detection result.

[0080] The detection module used in the device of the present invention, as described above, can be any pressure sensor capable of detecting changes in pressure within the pipeline; there are no limitations. It can be any pressure sensor applicable to the field of microfluidics, such as a miniature pneumatic sensor or a miniature hydraulic sensor.

[0081] The sample placement area in the device of the present invention is used to place the liquid sample to be tested and to 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 allows this process to be achieved. Preferably, the cross-sectional shape of the sample placement area of ​​the present invention meets certain limiting conditions.

[0082] Furthermore, when using the apparatus of the present invention, 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, as can the process of the sample melting back from solid to liquid. Similarly, it can be understood that this phase transition process can be repeated multiple times, and multiple phase transition processes can be detected.

[0083] Figure 3 A schematic diagram of the cross-section of the sample placement area is provided. 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 diagram 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 sample injection direction, 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 shape of the dotted line protruding outwards, the arc shape refers to the overall shape that looks like part of a circle or ellipse, and does not need to be a completely smooth arc shape.

[0088] In the apparatus of the present invention, it is further preferred that the cross-sectional shape of the sample placement area satisfies the following conditions: 1 < D1 / D2 ≤ 8, preferably 1 < D1 / D2 ≤ 7, further preferably 1 < D1 / D2 ≤ 6, and even more preferably 1 < D1 / D2 ≤ 5. That is, the cross-section of the sample placement area of ​​the present invention preferably has a major axis and a minor axis, wherein the sample injection direction is the major axis and the direction of disposal relative to the sample injection direction is the minor axis direction.

[0089] In the apparatus of the present invention, it is further preferred that the cross-sectional shape of the sample placement area satisfies the following condition: when the inner diameter of the inlet and outlet pipes for the sample is R, 2≤D1 / R≤24, preferably 2≤D1 / R≤20, and more preferably 2≤D1 / R≤16. That is, the volume of the sample placement area and the size of the pipes of the present invention preferably satisfy the above relationship.

[0090] In the apparatus of the present invention, the transverse base shape of the sample placement area is further preferably satisfied with the following condition: the shape of the sample placement area on one side along the sample injection direction is a substantially outwardly convex arc shape with no obvious depressions on the arc shape. In this text, a depression refers to, for example, a trough on the arc shape, such as the cross-sectional shape of the sample placement area in Examples 6-8 described below. Examples 6 and 8 have one obvious depression on one side of the arc in the injection direction, and Example 7 has two obvious depressions on one side of the arc in the injection direction.

[0091] In the apparatus of the present invention, the cross-sectional shape of the sample placement area is further preferably satisfied with the following condition: the sample placement area is substantially symmetrical along the direction perpendicular to the injection direction of the sample to be tested.

[0092] Table 1, which shows the embodiments and comparative examples of the present invention, illustrates the cross-sectional shapes that can and cannot be used. Those skilled in the art will fully understand that Table 1 merely lists illustrative cross-sections, and any shape other than those shown in Table 1 can be used, or may be used more preferably, as long as it meets the aforementioned limitations of the present invention.

[0093] In the device of the present invention, the channel is a microchannel with an inner diameter of 10 micrometers to 5 millimeters, preferably 50 micrometers to 4 millimeters, more preferably 100 micrometers to 3 millimeters, more preferably 200 micrometers to 2 millimeters, and more preferably 300 micrometers to 1 millimeter.

[0094] In this invention, there are no limitations on the material of the pipe, as long as it is a material that allows the liquid sample to be encapsulated by the medium through the operation of this invention. Examples include: polymer materials such as polytetrafluoroethylene (PTFE), polymethyl methacrylate (PMMA), and polypropylene (PP), glass, and metal materials such as stainless steel, titanium alloy, copper, platinum, and gold.

[0095] In this invention, a certain amount of the liquid sample to be tested needs to be injected into the sample placement area. The certain amount of the liquid sample to be tested refers to the quantity of the liquid sample to be tested in this invention. There is no specific limitation on this certain amount. Those skilled in the art know how to select an appropriate amount based on the subsequent sample processing or testing to determine the solidification process of the liquid sample. For example, the following can be listed: 0.1 to 200 μL, 0.5 to 150 μL, 1 to 100 μL, 2 to 80 μL, 3 to 60 μL, etc. Specifically, it can be 200 μL, 150 μL, 100 μL, 80 μL, 60 μL, 40 μL, 20 μL, 10 μL, 8 μL, 6 μL, 4 μL, 2 μL, 1 μL, 0.1 μL, etc.

[0096] In this invention, as described above, the liquid sample is a blood sample or a polymer solution such as a protein solution, gelatin solution, protein curd, or polymer material solution.

[0097] The medium used in this invention is typically an oleophilic medium, and various oil-based substances commonly used in the art can be used, such as mineral oil, low-temperature paraffin, and vegetable oil.

[0098] <Methods for detecting liquid phase transitions>

[0099] The present invention also provides a method for detecting liquid phase change, which uses a device including a sample placement area, a pulse module, a detection module, and a pipeline for detection, and includes the following steps: injecting the liquid sample to be tested into the sample placement area through the pipeline in the form of a liquid sample encapsulated by a medium; providing pulsed pressure to the liquid sample through the pulse module; and using the detection module to detect the pressure applied to the sample by the pulse module and transmitted to the detection module side over time, and outputting the pressure change over time as a signal, wherein the pulse module and the detection module are disposed on opposite sides of the sample placement area.

[0100] The apparatus used in the method of the present invention is the apparatus of the present invention described above.

[0101] Furthermore, the method of the present invention also includes filling the entire detection system with a medium before detection.

[0102] As described above, the device for detecting liquid phase transitions according to the present invention 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). Furthermore, when using the detection device of the present invention, the liquid sample (e.g., blood sample) is encapsulated by a medium, thereby ensuring that the liquid sample (e.g., blood sample) is not subjected to unnecessary external interference during the detection process, and the entire coagulation process of the liquid sample can be accurately detected. For example, after the addition of procoagulant drugs or factors, the time for blood to begin coagulation will be shorter and the intensity of coagulation will be greater (thrombus strength).

[0103] Furthermore, blood samples may liquefy after coagulation, indicating fibrinolysis, a condition medically termed hyperfibrinolysis. Patients with hyperfibrinolysis have a higher risk of internal bleeding. If surgery is required, medical interventions must be implemented to improve coagulation; otherwise, massive bleeding during or after surgery may occur, potentially endangering their lives. The device of this invention can detect this process, enabling the detection of hyperfibrinolysis.

[0104] Furthermore, since the apparatus of the present invention employs the given sample introduction module described below, different liquid samples can be continuously introduced, thereby enabling the continuous, one-time processing of a large number of different liquid samples. Each injected liquid sample can be appropriately isolated from each other to prevent cross-contamination and interference, thus enabling continuous injection and effective detection of multiple liquid samples.

[0105] Example

[0106] The detection devices used in the following embodiments are constructed in accordance with the basic principles of... Figure 2 In this way.

[0107] The pulse module consists of a constant pressure air source and a time-controlled solenoid valve. A constant pressure air source is constructed using a Kamer KLP01 diaphragm pump (purchased from Kachuaner Fluid Technology (Shanghai) Co., Ltd.), a Panasonic DP-101 pressure sensor switch module (purchased from Shenzhen Chuangfeng Instrument Co., Ltd.), and a 2L stainless steel air tank. The air source is positive pressure. A time-controlled solenoid valve is constructed using a Sonuo Tiangong TM-06 two-position three-way high-frequency solenoid valve (purchased from Ningbo Sonuo Industrial Automation Equipment Co., Ltd.) and a DTM01 time relay module (purchased from Shenzhen Qinyuansheng Electronics Co., Ltd.).

[0108] The solenoid valve has a normally closed port connected to a constant-pressure air source, and a normally open port connected to a pulse pipeline that is fluidly connected to the detection area. This pipeline is filled with a medium, and the other port of the solenoid valve is connected to the outside air. When the solenoid valve is not activated, the pulse channel is connected to the outside air through the solenoid valve, and the pressure detected by the detection module is 0 Pa. When the solenoid valve is activated, it is connected to the constant-pressure air source, and the pressure detected by the detection module is a specific pressure value that is greater than zero and less than or equal to the constant-pressure air source pressure. The activation time and interval of the solenoid valve are controlled by a time relay module.

[0109] Simultaneously, using the same components and methods as those used to create a constant-pressure gas source, a negative-pressure constant-pressure gas source is constructed. This is used for sample injection.

[0110] In the following embodiments, mineral oil is used as the medium, and the gas source pressure is controlled at 12 kPa.

[0111] The pipe has an inner diameter of 0.6mm × 0.6mm and is made of polymethyl methacrylate (PMMA).

[0112] The sample placement area is made of polymethyl methacrylate (PMMA). In this example, the sample placement area has a cylindrical three-dimensional structure, such as... Figure 3 As shown in (b), Table 1 below lists the specific cross-sectional shapes and parameters used in each embodiment.

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

[0114] The materials used in Examples 1-9 and Comparative Examples 1-4 below:

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

[0116] The calcium chloride solution purchased from Sysmex Biotechnology (Wuxi) Co., Ltd. has a calcium ion concentration of 0.02 mol / L. After preparation at the above concentration, it is stored at 4°C and preheated to room temperature before use. This calcium ion is used to promote the coagulation reaction of sheep plasma.

[0117] After the experimental materials are prepared, take the activated sheep plasma, add calcium chloride and start timing (this is taken as 0 seconds). At this time, the sample is in the centrifuge tube. Inject the sample into the sample placement area and start detection at the 100-second mark.

[0118] Before injection, the pulse port is closed. The sample outlet pipe is connected to a negative pressure constant pressure gas source via a valve, and the system is filled with the medium. During injection, the pipe connected to the sample inlet is inserted into the centrifuge tube containing the sample. The valve connecting the sample outlet pipe to the negative pressure constant pressure gas source is opened, and the sample is drawn into the sample placement area through the inlet. Once the sample placement area is full, the valve connecting the sample outlet pipe to the negative pressure constant pressure gas source is closed, the centrifuge tube containing the sample to be tested is removed, and the sample inlet is closed. At this point, the injection is complete.

[0119] After sample injection, the pulse port opens, and the pulse channel is fluidly connected to the pulse module. The time relay module is activated, causing the pulse module's solenoid valve to actuate intermittently, thus applying pulse pressure to the sample and initiating the detection. The pulse cycle is 5 seconds of applied pressure followed by 5 seconds of interval. The positive pressure constant pressure source of the pulse module is 12 kPa, and the negative pressure constant pressure source is -6 kPa. The detection duration is 12-20 minutes.

[0120] Figures 4-8 Examples of scoring for different test results when using the detection device of the present invention are shown, in Examples 1 to 9 below. Figures 4-8 The examples are used to score the implementation. From Figure 4 It can be seen that the example rated 5 points can basically describe the complete phase transition process, but the detailed description of the phase transition process is relatively limited, and the main characteristics of the phase transition are not fully reflected. From Figure 5 It can be seen that the example rated 6 points can describe the complete phase transition process. Although the detailed description of the phase transition process is not accurate enough, it can basically reflect the main characteristics of the phase transition. From Figure 6 It can be seen that the example with a score of 7 can describe the complete phase transition process. Although the description of the local details of the phase transition process is not accurate enough, it can already reflect the main characteristics of the phase transition. From Figure 7 It can be seen that the example with a score of 8 accurately and completely describes the entire phase transition process, with only minor local data deviations, but these do not significantly affect the accuracy of the description of the phase transition process. From Figure 8 As can be seen, the example with a score of 9 can accurately and completely describe the entire phase transition process. Only a few data points have slight fluctuations, but this does not affect the accuracy of the description of the phase transition process.

[0121] Example 10

[0122] Using the same apparatus as in Examples 1-9, the cross-section of the sample placement area was exactly the same as in Example 3. The sample placement area was placed in a constant temperature incubator and fluidly connected to the pulse module and detection module placed outside the incubator via a 0.6 mm inner diameter polytetrafluoroethylene (PTFE) flexible tube. A Blue Leopard LRH-150 constant temperature incubator purchased from Shanghai Yiheng Technology Co., Ltd. was used. Tianmeihua brand baking animal butter purchased from Hohhot Tianmeihua Dairy Food Co., Ltd. was used as the sample. This sample was a soft solid at 28-34℃ and a liquid state above 34℃.

[0123] Before the experiment, the sample placement area and the sample were preheated at 40°C for 20 minutes until the sample was completely melted into a liquid state. Using the same injection method as in Examples 1-9, the liquid sample was injected into the sample placement area, and then the detection began, with the detection start time recorded as 0 seconds. One minute after the start of the detection, the temperature of the constant temperature incubator was set to 25°C. As the temperature decreased, the liquid sample gradually turned into a solid. After 12 minutes of detection, the sample had fully solidified, and the incubator temperature was set back to 40°C. As the temperature increased, the solid sample gradually returned to a liquid state. The detection module completely recorded the process of the sample changing from liquid to solid and then back to liquid. Specific results are as follows: Figure 11 As shown.

[0124] In Comparative Examples 1 and 2, the shape of the transverse base surface of the sample placement area is such that the length in the sample injection direction is less than the length in the direction perpendicular to the sample injection direction. When the shape is such that the ratio of the sample direction to the direction perpendicular to the sample direction is 1:1.5, the results can only provide a limited response to the phase transition and cannot describe the process itself. Figure 9 The cross-sectional shapes and results of the sample placement areas used in Comparative Example 1 and Comparative Example 2 are shown. From Figure 9 It can be seen that sample placement areas that do not meet the above condition D1≥D2 cannot obtain satisfactory detection curves.

[0125] In Comparative Examples 3 and 4, if the shape of the transverse base surface of the sample placement area is asymmetrical along the sample injection direction, such as... Figure 10 As shown, when the shape is of the first asymmetric type, the results can only provide a limited response to the phase transition and cannot fully describe the process; while with the second asymmetric shape, the results can basically describe the occurrence of the phase transition, but cannot describe the complete process, and the detection is unstable in the later stages. Figure 10 It can be seen that a sample placement area that does not meet the conditions of being basically symmetrical along the injection direction of the sample to be tested and having a basically outwardly convex arc shape on one side along the injection direction of the sample to be tested cannot obtain a satisfactory detection curve.

[0126] The average score of the three tests conducted in Examples 1 to 9 was at least 5 points, which can achieve the purpose of detecting the liquid phase change process.

[0127] Table 1 summarizes the cross-sectional shapes of the sample placement areas in Examples 1 to 9 and the results of the three tests. Figures 4-8 The scoring results are based on the scoring examples.

[0128]

[0129] The results from the above embodiments demonstrate that the device of the present invention can effectively detect the time of liquid solidification and the intensity of liquid solidification.

[0130] This application accepts various modifications and alternatives, and specific embodiments have been shown in the accompanying drawings with the aid of examples and have been described in detail herein. However, this application is not intended to be limited to the specific forms disclosed. Rather, this application is intended to include all modifications, equivalents, and alternatives within the scope of this application, which is defined by the appended claims and their legal equivalents.

[0131] The numerical ranges listed in this invention include the data at both ends of the numerical range, as well as each specific value in the numerical range, and the values ​​can be arbitrarily combined with the endpoints to form new smaller ranges.

Claims

1. An apparatus for detecting liquid phase change, comprising: The sample placement area is used to place the liquid sample to be tested and to complete the phase change process of the liquid in the sample placement area for detection. A pulse module is used to apply pulsed pressure to the sample to be tested; The detection module is used to detect changes in pressure in the pipeline on one side of the detection module; It has inlet and outlet pipes for allowing samples to enter and exit; The pulse module and the detection module are located on both sides of the sample placement area. Detecting the pressure change in the pipe on one side of the detection module means that the detection module detects the pressure change over time that is applied to the sample by the pulse module and transmitted through the sample to the detection module, and outputs this pressure change over time as a signal.

2. The apparatus according to claim 1, wherein, The 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, and the maximum width of the sample placement area in the direction perpendicular to the direction of sample injection is D2, and D1≥D2. The sample placement area is basically symmetrical along the injection direction of the sample to be tested; as well as The sample placement area has a generally outwardly convex arc shape on one side along the direction of sample injection.

3. The apparatus according to claim 2, wherein, The cross-sectional shape of the sample placement area also satisfies the following conditions: 1 < D1 / D2 ≤ 8, Preferred value 1 < D1 / D2 ≤ 7 Further optimization is to select 1 < D1 / D2 ≤ 6. Further optimization is to select 1 < D1 / D2 ≤ 5.

4. The apparatus according to claim 3, wherein, The cross-sectional shape of the sample placement area also satisfies the following conditions: When the inner diameter of the inlet and outlet pipes for sample entry and exit is R, The condition 2 ≤ D1 / R ≤ 24 is satisfied. Preferably, 2 ≤ D1 / R ≤ 20. Further optimization is to select 2≤D1 / R≤16.

5. The apparatus according to claim 1, wherein, The shape of the transverse base surface of the sample placement area also satisfies the following condition: the shape of the sample placement area on one side along the direction of sample injection is a basically outwardly convex arc shape with no obvious depression on the arc shape.

6. The apparatus according to claim 5, wherein, The cross-sectional shape of the sample placement area also satisfies the following conditions: The sample placement area is substantially symmetrical along the direction perpendicular to the direction of sample injection.

7. The apparatus according to any one of claims 1 to 6, wherein, The channel is a microchannel with an inner diameter of 10 micrometers to 5 millimeters, preferably 50 micrometers to 4 millimeters, more preferably 100 micrometers to 3 millimeters, more preferably 200 micrometers to 2 millimeters, and more preferably 300 micrometers to 1 millimeter.

8. The apparatus according to any one of claims 1 to 7, wherein, The sample placement area, pulse module, detection module, and pipeline are fluidly connected.

9. The apparatus according to any one of claims 1 to 8, wherein, The liquid sample is a blood sample, a protein liquid sample, or other liquid sample that undergoes a phase change due to polymer polymerization, or a substance that undergoes a phase change with temperature.

10. The apparatus according to any one of claims 1 to 9, wherein, The peak value of the pulsed pressure applied by the pulse module to the module under test remains basically constant.

11. The apparatus according to any one of claims 1 to 10, wherein, Before using the device for detecting liquid solidification, fill the entire device with the medium.

12. The apparatus according to any one of claims 1 to 11, wherein, The liquid sample is a blood sample, a protein liquid sample, or other liquid sample that may undergo a phase change due to polymer polymerization.

13. A method for detecting a liquid phase change, comprising using a device including a sample placement area, a pulse module, a detection module, and a conduit, and including the following steps: The liquid sample to be tested is introduced into the sample placement area through a pipeline in the form of a medium encapsulating the liquid sample. The pulse module provides pulsed pressure to the liquid sample, and The detection module detects the change in pressure over time applied to the sample by the detection pulse module and transmitted through the sample to the detection module. This change in pressure over time is then output as a signal. The pulse module and the detection module are located on opposite sides of the sample placement area.

14. The method according to claim 13, wherein the detection is performed using the apparatus of any one of claims 1 to 12.

15. The method of claim 13, further comprising the step of: Before conducting the test, the entire testing system is filled with the medium.

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