CN111289556B

CN111289556B - Device and method for detecting phase change of liquid

Info

Publication number: CN111289556B
Application number: CN201811486535.9A
Authority: CN
Inventors: 苏楠; 和建伟
Original assignee: Beijing Bicheng Biotechnology Co ltd
Current assignee: Beijing Jushu Biotechnology Co ltd
Priority date: 2018-12-06
Filing date: 2018-12-06
Publication date: 2023-06-23
Anticipated expiration: 2038-12-06
Also published as: CN111289556A

Abstract

The invention provides a device for detecting a phase change of a liquid, comprising: the sample placing area is used for placing a liquid sample to be detected and completing a phase change process of the liquid in the sample placing area for detection; the pulse module is used for applying pulse pressure to the sample to be detected; the detection module is used for detecting the pressure change in the pipeline at one side of the detection module; the adjusting area is used for adjusting the intensity of the signal fed back from the sample to be detected, which is detected by the detecting module; a conduit having an inlet and an outlet for ingress and egress of a sample; the pulse module and the detection module are arranged on two sides of the sample placing area, the detection of the pressure change in the pipeline on one side of the detection module means that the detection module detects the time-dependent pressure change applied to the sample to be detected by the pulse module and transmitted to one side of the detection module through the sample, the time-dependent pressure change is used as a signal output, and the adjustment area is located between the detection module and the sample placing area.

Description

Device and method for detecting phase change of liquid

Technical Field

The invention relates to a device for detecting liquid phase change and a method for detecting liquid phase change by using the device.

Background

It is well known that coagulation of blood in a living heart or blood vessel causes thrombosis and thrombotic diseases, for example, acute Myocardial Infarction (AMI), cerebral thrombosis, deep Vein Thrombosis (DVT), disseminated Intravascular Coagulation (DIC), and the like; extravasation of blood out of the blood vessel can lead to bleeding and cause hemorrhagic diseases such as allergic purpura, thrombocytopenic purpura, hemophilia and liver bleeding. In order to effectively inhibit these diseases, it is necessary to periodically detect the thrombotic condition of the patient's blood.

Currently, in the whole blood system, a general method is to measure a Thromboelastography (TEG), which is an index reflecting dynamic changes of blood coagulation (including the formation rate of fibrin, the dissolution state and the firmness of coagulation, and the elasticity), by using a thromboelastometer to detect blood coagulation and thrombus formation. The thromboelastography is the graph plotted by the thromboelastometer. The main components of a typical thromboelastometer include: automatically adjusting a stainless steel blood cup with constant temperature (37 ℃) and a small stainless steel cylinder and a sensor which can be connected with the cylinder, wherein the small stainless steel cylinder is inserted into the cup. The blood cup is arranged on the reaction tank which can rotate back and forth at an angle of 4 degrees 45', and the middle of the cup wall and the cylinder is used for containing blood. When the blood sample is in liquid state, the back and forth rotation of the cup can not drive the cylinder, the signal reflected to the tracing paper by the sensor is a straight line, when the blood starts to solidify, resistance is generated between the cup and the cylinder due to the adhesiveness of fibrin, the rotation of the cup drives the cylinder to move simultaneously, the resistance is also increased along with the increase of fibrin, the movement of the cup driving the cylinder is also changed along with the increase of fibrin, and the signal is traced to a thromboelastography formed on the tracing paper by the sensor.

In addition, many other processes for liquid phase change are also needed for detection or attention, for example, some processes for coagulation of polymer solutions, such as processes for protein solutions, protein curds, gelatin, and polymer polymerization.

Disclosure of Invention

As mentioned above, thromboelastography is commonly used in the art to determine blood coagulation and thrombus formation. However, when the thromboelastometer is used for the test, a large amount of blood is often required, and a large amount of blood is required to be drawn from the patient for the test, which places a great burden on the patient and places a higher requirement on the operation of the clinician.

Thus, if the detection of blood coagulation can be achieved in the art with a small amount of a micro-sample, e.g. in the order of a microliter, the burden on the patient and the risks present during blood collection will be greatly reduced. In addition, since the detection of blood coagulation requires avoidance of interference of external environment as much as possible in the detection process, there is also a need for a detection device that can realize very little influence on collected blood in the whole detection process.

JP2007-271323A discloses a measurement method capable of simultaneously detecting blood viscosity and thrombus formation in a short time at low cost. This patent document relates to a blood holding container in which a capillary is connected to an opening, a pressurizing device for discharging blood in the blood holding container from the capillary at a constant flow rate, and a detecting device for detecting the viscosity of blood and the amount of thrombus formation.

CN102762991a discloses a microchip for detecting platelets and a platelet detecting device using the microchip. The microchip disclosed in this patent document is a microchip for measuring platelet function by flowing blood through a channel to induce platelet aggregation, and has a channel provided therein, wherein collagen is at least partially coated in the channel for adhesion to platelets, a plurality of walls extend along the direction of blood flow in the channel, and the width of the channel is partitioned to form a channel partition, and the walls are subjected to a treatment in which the surface roughness (Ra) becomes 10 to 200 nm. By using the device, platelet function of blood can be detected using a minute amount of blood.

A device for monitoring thrombosis and a method of detecting thrombosis are disclosed in CN101292161 a. Providing a thrombus inducing agent in at least a portion of the device that induces thrombus formation; an inlet tube connected to the thrombotic chamber and through which blood flows into the thrombotic chamber; and a drug tube connected to the inlet tube and through which a drug for releasing the anticoagulation treatment to remove or promote blood coagulation is supplied. The method includes flowing anticoagulated blood into a thrombotic chamber, providing a thrombogenic agent that induces thrombosis in at least a portion of the thrombotic chamber, while releasing the anticoagulation treatment or promoting blood clotting, thereby monitoring thrombosis.

CN101874208A discloses a microchip and a blood monitoring device. The microchip comprises: a first flow path into which a first liquid is flowed, the first liquid being selected from whole blood, platelet-rich plasma, and a drug-treated liquid thereof; a second flow path connected to the first flow path, into which a second liquid containing a chemical capable of reacting with the first liquid flows; and a merged channel extending from the connection portion of the first channel and the second channel; the microchip is characterized in that a stirring section is provided in the confluent flow path, and the stirring section has a stirring element for mixing the first liquid and the second liquid. By using the device, the reaction performance of blood can be detected by effectively mixing trace blood and medicament.

A cup-based device for blood coagulation measurement and testing is disclosed in CN102099676 a. The device comprises 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, the channel structure comprising: at least one test channel for performing a measurement of blood clotting time; a sampling channel having at least one surface portion of hydrophilic nature 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 of hydrophilic nature in communication with the sampling channel; and a vent opening in communication with the sampling channel. The exposure of the optical sensor activates the pump module of the blood clot detection instrument, which draws a desired volume of blood sample into at least one test channel.

The above information is only used to enhance understanding of the background of the invention and thus may contain information that does not form the prior art that is well known to a person of ordinary skill in the art. The above-mentioned patent applications and prior art use various devices of relatively complex construction to achieve the detection of minute amounts of blood. In the above-mentioned devices, it is often necessary to perform coagulation inhibition treatment on the surface of the member in contact with blood, for example, surface treatment with heparin, polyacetyl lactone, poly-2-phosphonomethoxyethyl adenine, or the like.

In addition, there are similar problems with other liquid samples than blood samples, it is desirable that detection can be achieved with a small amount of volume, and that interference and influence of the liquid sample on the outside can be avoided throughout the detection of coagulation of the liquid.

Further, it is also desirable to achieve continuous, rapid, efficient detection of different liquid samples, and to achieve that there is no mutual interference and contamination between the different samples.

In view of the above, the present invention is intended to provide a liquid phase change detection device which has a simple structure, can rapidly detect a phase change process of a liquid to rapidly obtain information of liquid phase change, such as thrombosis, and can detect only a trace amount of a liquid sample, and a method of detecting liquid phase change using the device.

The aim of the invention is achieved by the following technical scheme.

1. An apparatus for detecting a phase change of a liquid, comprising:

the sample placing area is used for placing a liquid sample to be detected and completing a phase change process of the liquid in the sample placing area for detection;

the pulse module is used for applying pulse pressure to the sample to be detected;

the detection module is used for detecting the pressure change in the pipeline at one side of the detection module;

the adjusting area is used for adjusting the intensity of the signal fed back from the sample to be detected, which is detected by the detecting module;

a conduit having an inlet and an outlet for ingress and egress of a sample;

wherein the pulse module and the detection module are arranged at two sides of the sample placing area, the detection of the pressure change in the pipeline at one side of the detection module means that the detection module detects the time-dependent pressure change which is applied to the sample to be detected by the pulse module and transmitted to one side of the detection module through the sample, and outputs the time-dependent pressure change as a signal,

the conditioning zone is located between the detection module and the sample placement zone.

2. The device of item 1, wherein the cross-sectional shape of the sample placement region satisfies the following condition:

The maximum width of the sample placement area in the sample introduction direction of the sample to be detected is D1, the maximum width of the sample placement area in the direction perpendicular to the sample introduction direction of the sample to be detected is D2, and D1 is more than or equal to D2;

the sample placement area is basically symmetrical along the sample injection direction of the sample to be detected; and

the shape of one side of the sample placement area along the sample introduction direction of the sample to be detected is basically outwards convex arc.

3. The device of item 2, wherein the cross-sectional shape of the sample placement region further satisfies the following condition:

1＜D1/D2≤8，

preferably 1 < D1/D2.ltoreq.7,

further preferably 1 < D1/D2.ltoreq.6,

more preferably 1 < D1/D2.ltoreq.5.

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

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

satisfies the requirement that D1/R is less than or equal to 2 and less than or equal to 24,

preferably 2.ltoreq.D1/R.ltoreq.20,

further preferably 2.ltoreq.D1/R.ltoreq.16.

5. The device of item 1, wherein the transverse base shape of the sample placement zone further satisfies the following condition: the shape of one side of the sample placement area along the sample introduction direction of the sample to be detected is basically outwards convex arc, and no obvious concave is arranged on the arc.

6. The device of item 5, wherein the cross-sectional shape of the sample placement area further satisfies the following condition:

The sample placement area is basically symmetrical along the direction perpendicular to the sample introduction direction of the sample to be detected.

7. The device according to any one of claims 1 to 6, wherein the conduit is a microchannel having 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, more preferably 300 micrometers to 1 millimeter.

8. The device of any one of claims 1-7, wherein the sample placement zone, pulse module, detection module, and conduit are in fluid communication.

9. The apparatus according to item 8, wherein,

in the case where the volume of the adjustment region is Vo and the volume of the sample placement region is Vs,

when the pulse pressure applied by the pulse module is more than 100Pa and less than or equal to 1000Pa, the range of Vo/Vs satisfies the following conditions: 1001. more preferably 500 or more, more preferably 100 or more, more preferably 50 or more, more preferably 10 or more, vo/Vs;

when the pulse pressure applied by the pulse module is more than 1000Pa and less than or equal to 10KPa, the range of Vo/Vs satisfies the following conditions: 101. more preferably 50 or more, more preferably 10 or more, more preferably 5 or more, more preferably 2 or more, than or equal to Vo/Vs;

When the pulse pressure applied by the pulse module is more than 10KPa and less than or equal to 100KPa, the range of Vo/Vs satisfies the following conditions: 11. more preferably 5.gtoreq.vo/Vs, further preferably 2.gtoreq.vo/Vs, further preferably 1.gtoreq.vo/Vs, further preferably 0.8.gtoreq.vo/Vs;

when the pulse pressure applied by the pulse module is greater than 100KPa, the range of Vo/Vs satisfies the following conditions: 2. more preferably 1.gtoreq.vo/Vs, still more preferably 0.8.gtoreq.vo/Vs, still more preferably 0.6.gtoreq.vo/Vs, still more preferably 0.4.gtoreq.vo/Vs.

10. The device of any one of claims 1-9, wherein the conditioning zone is provided by a communication conduit between the detection module and the sample placement zone.

11. The device of any one of claims 1-9, wherein the regulated volume region is provided by a separately disposed region between the detection module and the sample placement region.

12. The device according to any one of claims 1 to 11, wherein the liquid sample is a blood sample, a protein liquid sample, or another liquid sample in which phase change occurs due to polymerization of a polymer, or a substance in which phase change occurs with a change in temperature.

13. A method for detecting a phase change of a liquid using an apparatus comprising a sample placement area, a pulse module, a conditioning area, a detection module, and a conduit, and comprising the steps of:

The liquid sample to be detected is injected into the sample placing area through a pipeline in the form of medium wrapping the liquid sample,

providing pulsed pressure to a liquid sample by a pulse module

The detection module is used for detecting the time-dependent change of the pressure applied to the sample to be detected by the detection pulse module and transmitted to one side of the detection module through the sample, and outputting the time-dependent change of the pressure as a signal,

the pulse module and the detection module are arranged on two sides of the sample placing area, and the adjusting area is positioned between the detection module and the sample placing area.

14. The method of claim 13, wherein during the detection, the conduit is filled with a medium selected from the group consisting of oil and gas, the conditioning zone is filled with a gas, preferably the oil is mineral oil and the gas is air.

15. The method according to item 13, which is performed by the device according to any one of items 1 to 12.

As described above, the device for detecting phase change of a liquid according to the present invention is simple in structure, and can detect the coagulation time and coagulation state of a liquid (e.g., blood) in a minute amount of the liquid sample (e.g., blood sample). In addition, when the detection device is used, the liquid sample (for example, blood sample) is wrapped by the medium, so that the liquid sample (for example, blood sample) is ensured not to be unnecessarily disturbed by the outside in the detection process, and the whole phase change process of the liquid sample, such as the time when blood starts to coagulate after the procoagulant medicine and the factor are added and the strength (thrombus strength) during the coagulation, can be accurately detected.

In addition, the device for detecting the phase change of the liquid can detect the process of solidifying the sample from the liquid to the solid, and can further detect the process of solidifying to the solid and melting again to the liquid. Also, it will be appreciated by those skilled in the art that this liquid-to-solid-to-liquid process may be repeated a number of times, the entire process being repeated a number of times for detection by the apparatus of the present invention.

The foregoing description is only an overview of the technical solutions of the present invention, to the extent that it can be implemented according to the content of the specification by those skilled in the art, and to make the above-mentioned and other objects, features and advantages of the present invention more obvious, the following description is given by way of example of the present invention.

Drawings

Various other advantages and benefits of the present invention will become apparent to those of ordinary skill in the art upon reading the following detailed description of the preferred embodiments. The drawings are only for purposes of illustrating the preferred embodiments and are not to be construed as limiting the invention. It is evident that the figures described below are only some embodiments of the invention, from which other figures can be obtained without inventive effort for a person skilled in the art. Also, like reference numerals are used to designate like parts throughout the figures.

FIG. 1 is a schematic diagram of one embodiment of the detection apparatus of the present invention.

FIG. 2 is a schematic diagram of another embodiment of the detection device of the present invention.

FIGS. 3 (a) to (c) are schematic diagrams of sample placement areas and cross sections thereof of the detection device of the present invention.

Fig. 4 shows an example of the detection result with a score of 5 minutes.

Fig. 5 shows an example of the detection result with a score of 6 minutes.

Fig. 6 shows an example of the detection result scored at 7 time minutes.

Fig. 7 is an example of a test result scored at 8 time slots.

Fig. 8 shows an example of the detection result with a score of 9 minutes.

FIG. 9 is a cross-sectional shape of the sample placement area used in comparative example 1 and the result of detection scoring.

Fig. 10 is a cross-sectional shape of the sample placement area used in comparative example 2 and the result of detection scoring.

FIG. 11 is a schematic diagram of the detection result of example 10.

FIG. 12 is a schematic view of yet another embodiment of the detection device of the present invention.

FIG. 13 is a schematic diagram of a variant 1 of yet another embodiment of the detection device of the present invention.

FIG. 14 is a schematic diagram of a variation 2 of yet another embodiment of the detection device of the present invention.

Fig. 15 is a schematic diagram of a variant 2 of still another embodiment of the detection device of the present invention when the detection is performed in the presence of an oily medium.

Fig. 16 is a schematic diagram of the detection result of embodiment 11, in which Vo/vs=0 indicates the case where no regulatory region exists.

Fig. 17 is a schematic diagram of a variant 2 of still another embodiment of the detection device of the present invention when the detection is performed using air as a medium.

FIG. 18 is a schematic diagram of the detection result of example 12.

Detailed Description

Specific embodiments of the present invention will be described in more detail below with reference to the accompanying drawings. While specific embodiments of the invention are shown in the drawings, it should be understood that the invention may be embodied in various forms and should not be limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.

< device for detecting phase transition of liquid >

The device for detecting the phase change of the liquid comprises: the sample placing area is used for placing a liquid sample to be detected and completing a phase change process of the liquid in the sample placing area for detection; the pulse module is used for applying pulse pressure to the sample to be detected; the detection module is used for detecting the pressure change in the pipeline at one side of the detection module; a conduit having an inlet and an outlet for ingress and egress of a sample; the pulse module and the detection module are arranged on two sides of the sample placing area, and the detection of the pressure change in the pipeline on one side of the detection module means that the detection module detects the time-dependent pressure change applied to the sample to be detected by the pulse module and transmitted to one side of the detection module through the sample, and outputs the time-dependent pressure change as a signal.

The device for detecting solidification of a liquid according to the present invention may further include a sample injection module, and the sample injection module is not particularly limited as long as it can perform sample injection in the form of a medium including a liquid sample.

Fig. 1 and 2 show schematic diagrams of an embodiment of the detection device of the present invention, respectively. It will be appreciated that in the detection device of the present invention, the pulse module and the detection module need to be disposed on both sides of the sample placement area, and two representative ways are shown in fig. 1 and 2, respectively, although those skilled in the art will appreciate that the pulse module and the detection module need not be disposed at an angle of 180 degrees with respect to the sample placement area, as long as one is located on one side of the sample placement area and one is located on the other side of the sample placement area, i.e., the pulse module is used to apply a pulse pressure to the sample to be detected, and the detection module is used to detect the pressure that can be transferred to the pipe on the other side of the sample after the pulse pressure is absorbed by the sample. Thus, as will be appreciated by those skilled in the art, as the liquid sample to be measured changes from liquid to solid or from solid to liquid, the pressure value absorbed by the sample changes, and thus the pressure in the conduit on the other side that can be passed on also changes continuously, and the device of the present invention characterizes the change in liquid sample to be measured from liquid to solid by detecting this change over time.

In a preferred manner, the pulse module and the detection module are positioned 180 degrees.+ -. 20 degrees, preferably 180 degrees.+ -. 10 degrees, and more preferably 180 degrees.+ -. 5 degrees relative to the sample placement area.

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

The peak value of the pressure of the pulse pressure applied by the pulse module to the module to be detected is basically unchanged. The peak value is substantially unchanged, meaning that the pressure output value of the set pulse pressure is kept constant, but a variation in the output value is allowed to exist within a range allowed by an error of the instrument, and typically this variation is an output pressure value of ±1KPa, preferably ±0.5KPa, preferably ±0.1KPa.

The test device of the present invention should be filled with medium throughout the device prior to use, meaning that the tubing and sample placement area are filled with medium. When the detection device is started to be used, a liquid sample to be detected is injected into the pipeline in a mode of wrapping the liquid sample by a medium, and enters the sample placement area through the pipeline. After the sample injection is finished, the pulse module is opened, and the pulse pressure with basically constant pressure peak value is applied to the liquid sample to be detected. As the liquid sample gradually solidifies from a liquid state to a solid state in the sample placement area, the change in pressure over time in the conduit to the side of the detection module, which is typically the pressure in the conduit to the side of the detection module outside the sample placement area, can be detected by the detection means in the device. Based on the output signal of pressure, the detection module records the change of pressure to reflect the whole state from liquid to solidification.

The peak of the pulse applied by the pulse module is at a substantially constant pressure so that in the absence of a liquid sample in the device, the peak height of the pulse is substantially constant, this peak height being the background value detected by the detection module. When the liquid sample changes phase from liquid phase to solid phase and changes phase from solid phase to liquid phase again, the transmission of pressure is affected, so that the amplitude of the signal received by the detection module changes, the amplitude change amount can be used for describing the intensity of the phase change, the value of the phase change intensity can be obtained by subtracting the detection value from the background value, and a detection curve can be obtained by outputting the phase change intensity value which changes with time, and the curve can represent the phase change process of the sample.

It will be appreciated by those skilled in the art that as the liquid sample gradually changes from liquid to solid, the pressure pulse amplitude detected by the detection module will gradually decrease, at which point the process of detecting the gradual decrease in the pressure pulse amplitude by the detection module may be recorded and the direct measured gradual decrease in the pressure pulse amplitude subtracted from the substantially constant pulse pressure peak value, thereby obtaining a progressively greater pressure curve reflecting the solidification strength of the sample and using this as a detection result, for example, various detected results may be shown in fig. 4 to 10. Meanwhile, if the phase change process from solid to liquid is detected, it will be understood by those skilled in the art that the effect of the pulse-blocking force on the solid to liquid sample becomes weak, so that the pulse amplitude detected by the phase change occurrence detection module is continuously increased, and the directly measured progressively larger pressure pulse amplitude is subtracted from the substantially constant pulse pressure peak value, so that a progressively smaller pressure curve reflecting the liquefaction degree of the sample is obtained and taken as a detection result.

The detection module used in the device of the present invention is not limited as long as it can detect a change in pressure in a pipe as described above, and may be any pressure sensor that can be used in the field of microfluidics. Such as miniature air pressure sensors, miniature hydraulic pressure sensors.

The sample placing area in the device is used for placing a liquid sample to be detected and completing the phase change process of the liquid in the sample placing area for detection. The shape of the sample placement area is not generally limited as long as it can achieve this. Preferably, the cross-sectional shape of the sample placement area of the present invention satisfies certain constraints.

In addition, when using the device of the present invention, the sample is introduced in liquid form, but after entering the sample placement area, the solidification of the sample from liquid to solid may be detected, or the melting of the sample from solid to liquid may be detected again. Similarly, it is known that the phase change process can be repeated multiple times and multiple phase change processes can be detected.

Fig. 3 presents a schematic view of a cross-section of the sample placement area. Fig. 3 (a) and (b) show schematic perspective views of the device of the present invention, the cuboid at both sides can represent a pulse module and a detection module, respectively, and the ellipsoid or cylinder in the middle schematically represents a sample placement area. It will be understood by those skilled in the art that the shapes shown in fig. 3 (a) and (b) are merely illustrative of the sample placement area, and schematic illustrations of the cross-section thereof, and are not intended to limit the shape of the sample placement area. In addition, fig. 3 (a) and (b) show two different three-dimensional shapes, which are also exemplary, and any three-dimensional shape may be employed as long as it satisfies the shape of the cross section thereof.

The cross section of the sample placement area refers to a cross section obtained by cutting the center of the sample placement area with a rectangular plane shown in fig. 3 (a) or (b) in the direction of the sample flow, and a hatched portion shown by oblique lines in fig. 3 (a) or (b), that is, a cross section of the sample placement area referred to herein. Fig. 3 (c) shows a schematic plan view of the entire cross section after cutting, in which a hatched portion indicated by oblique lines, i.e., a cross section of the sample placement area. In fig. 3, the dotted line indicates the sample introduction direction of the sample.

In the device of the present invention, it is preferable that the cross-sectional shape of the sample-placing section satisfies the following condition: the maximum width of the sample placement area in the sample introduction direction of the sample to be detected is D1 (shown in fig. 3 (c)), the maximum width of the sample placement area in the direction perpendicular to the sample introduction direction of the sample to be detected is D2 (shown in fig. 3 (c)), and D1 is more than or equal to D2; the sample placement area is basically symmetrical along the sample injection direction of the sample to be detected; and the shape of one side of the sample placement area along the sample introduction direction of the sample to be detected is basically outwards convex arc.

In the above condition, the sample placement area is substantially symmetrical along the sample introduction direction of the sample to be measured, that is, the area of the upper portion and the lower portion is substantially the same and the shape is substantially symmetrical with respect to the cross section of the sample placement area along the dotted line in the schematic diagram of fig. 3 (b) as the center line. For example, the area of the upper part of the broken line and the area of the lower part of the broken line differ by 20%, more preferably 15%, still more preferably 10%, still more preferably 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% and 1%.

The shape of one side of the sample placement area along the sample introduction direction of the sample to be detected is basically outwards convex arc. An arc is the shape of a portion of a circle or ellipse. A substantially convex arc is a shape in which the arc protrudes outward from the broken line in fig. 3, and an arc is a part of a circle or ellipse as a whole, and is not required to be a completely smooth arc.

In the device of the present invention, it is further preferable that the cross-sectional shape of the sample-placing section satisfies the following condition: 1 < D1/D2.ltoreq.8, preferably 1 < D1/D2.ltoreq.7, more preferably 1 < D1/D2.ltoreq.6, even more preferably 1 < D1/D2.ltoreq.5. That is, the cross section of the sample placement region of the present invention preferably has a shape of a major axis and a minor axis, wherein the direction of introduction is the major axis and the direction of treatment with the direction of introduction is the minor axis.

In the device of the present invention, it is further preferable that the cross-sectional shape of the sample-placing section satisfies the following condition: when the inner diameters of the pipelines of the inlet and the outlet for the sample to enter and exit are R, the D1/R is more than or equal to 2 and less than or equal to 24, preferably the D1/R is more than or equal to 2 and less than or equal to 20, and further preferably the D1/R is more than or equal to 2 and less than or equal to 16. I.e. the volume of the sample receiving zone of the invention and the dimensions of the conduit preferably satisfy the above-mentioned relationship.

In the device of the present invention, it is further preferable that the shape of the lateral base surface of the sample placement region also satisfies the following condition: the shape of one side of the sample placement area along the sample introduction direction of the sample to be detected is basically outwards convex arc, and no obvious concave is arranged on the arc. By concave is meant herein a cross-sectional shape of a sample placement area such as in examples 6 to 8 described below, such as where a trough occurs in an arc shape, for example. Examples 6 and 8 had one distinct depression in the arc on one side in the sample introduction direction and example 7 had two distinct depressions in the arc on one side in the sample introduction direction.

In the device of the present invention, it is further preferable that the cross-sectional shape of the sample-placing section also satisfies the following condition: the sample placement area is basically symmetrical along the direction perpendicular to the sample introduction direction of the sample to be detected.

In another specific embodiment of the present invention, an apparatus for detecting a phase change of a liquid comprises: the sample placing area is used for placing a liquid sample to be detected and completing a phase change process of the liquid in the sample placing area for detection; the pulse module is used for applying pulse pressure to the sample to be detected; the detection module is used for detecting the pressure change in the pipeline at one side of the detection module; the adjusting area is used for adjusting the intensity of the signal fed back from the sample to be detected, which is detected by the detecting module, wherein the intensity of the detection signal is improved when the volume of the adjusting area is increased; the intensity of the detection signal decreases when the volume of the adjustment area becomes smaller; a conduit having an inlet and an outlet for ingress and egress of a sample; the pulse module and the detection module are arranged on two sides of the sample placing area, the detection of the pressure change in the pipeline on one side of the detection module means that the detection module detects the time-dependent pressure change applied to the sample to be detected by the pulse module and transmitted to one side of the detection module through the sample, the time-dependent pressure change is used as a signal output, and the adjustment area is located between the detection module and the sample placing area.

In the present invention, the regulation region may be formed of any structure as long as its volume is greater than 0. Fig. 12 shows a schematic view of an apparatus for detecting phase change of a liquid including a regulating region, and it will be understood by those skilled in the art that the position of the regulating region is shown only schematically in fig. 12, and there is no limitation on the shape and size thereof.

In another specific embodiment, the conditioning zone is provided by a communication conduit between the detection module and the sample placement zone, as shown in FIG. 13. Furthermore, although the conditioning zone is formed by expanding the tubing in fig. 13, it will be appreciated by those skilled in the art that the space between the sample and the detection module can be used as the conditioning zone.

In another specific embodiment, the regulated volume region is provided by a separately disposed region between the detection module and the sample placement region, as shown in fig. 14. It will also be appreciated by those skilled in the art that fig. 14 is also merely a schematic representation of the adjustment zone as a separately disposed area and that fig. 14 is not intended to limit the shape and size of the adjustment zone.

Further, in the present invention, in the case where the volume of the adjustment region is Vo and the volume of the sample placement region is Vs, when the pulse pressure applied by the pulse module is greater than 100Pa and equal to or less than 1000Pa, the range of Vo/Vs satisfies: 1001. more preferably 500 or more, more preferably 100 or more, more preferably 50 or more, more preferably 10 or more, vo/Vs; when the pulse pressure applied by the pulse module is more than 1000Pa and less than or equal to 10KPa, the range of Vo/Vs satisfies the following conditions: 101. more preferably 50 or more, more preferably 10 or more, more preferably 5 or more, more preferably 2 or more, than or equal to Vo/Vs; when the pulse pressure applied by the pulse module is more than 10KPa and less than or equal to 100KPa, the range of Vo/Vs satisfies the following conditions: 11. more preferably 5.gtoreq.vo/Vs, further preferably 2.gtoreq.vo/Vs, further preferably 1.gtoreq.vo/Vs, further preferably 0.8.gtoreq.vo/Vs; when the pulse pressure applied by the pulse module is greater than 100KPa, the range of Vo/Vs satisfies the following conditions: 2. more preferably 1.gtoreq.vo/Vs, still more preferably 0.8.gtoreq.vo/Vs, still more preferably 0.6.gtoreq.vo/Vs, still more preferably 0.4.gtoreq.vo/Vs. By controlling the size of the adjusting area, the strength of the signal fed back by the sample to be detected and detected by the detecting module can be effectively adjusted, so that the detection of the phase change process of the sample to be detected can be better realized. By properly increasing the signal strength through the conditioning region, a higher detection resolution can be provided, as compared to detection accomplished without the conditioning region, which is more clearly described for the overall phase change process, and which may even exhibit some variation details that are masked at lower signal strengths.

The cross-sectional shapes that can be used and that cannot be used are shown in table 1 of the examples and comparative examples of the present invention. It will be fully understood by those skilled in the art that the exemplary cross-sections are listed in Table 1, and that other than the shapes shown in Table 1, either may be used or may be more preferably used so long as the above-described limitations of the present invention are met.

In the device of the present invention, the conduit is a microchannel having an inner diameter of 10 micrometers to 5 millimeters, preferably 50 micrometers to 4 millimeters, more preferably 100 micrometers to 3 millimeters, still more preferably 200 micrometers to 2 millimeters, still more preferably 300 micrometers to 1 millimeter.

In the present invention, the material of the pipe is not limited as long as it is a material that can achieve the wrapping of the liquid sample with the medium by the operation of the present invention. Examples may include: high polymer materials such as Polytetrafluoroethylene (PTFE), polymethyl methacrylate (PMMA), polypropylene (PP), glass, and metal materials such as stainless steel, titanium alloy, copper, platinum, gold, etc.

In the present invention, a certain amount of the liquid sample to be measured is required to be introduced into the sample placement area, and the certain amount of the liquid sample to be measured in the present invention is not particularly limited, and a person skilled in the art knows how to select an appropriate amount according to the processing or detection of the subsequent sample, so as to determine the solidification process of the liquid sample, and examples thereof include: 0.1 to 200 microliters, 0.5 to 150 microliters, 1 to 100 microliters, 2 to 80 microliters, 3 to 60 microliters, etc., and may be specifically 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., for example.

In the present invention, as described above, the liquid sample is a blood sample or a polymer solution such as a protein solution, a gelatin solution, a protein curd, a polymer material solution, or the like.

The medium used in the present invention is usually a lipophilic medium, and various oil substances commonly used in the art can be used. Such as mineral oil, low temperature paraffin, vegetable oil.

< method for detecting phase transition of liquid >

The invention also provides a method for detecting a phase change of a liquid using a device comprising a sample placement area, a pulse module, a detection module and a conduit, and comprising the steps of: the method comprises the steps of injecting a liquid sample to be detected into a sample placement area through a pipeline in a mode of wrapping the liquid sample by a medium, providing pulse pressure for the liquid sample through a pulse module, detecting the change of the pressure applied to the sample to be detected by the pulse module and transmitted to one side of the detection module through the sample by using 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 two sides of the sample placement area.

The invention also provides a method for detecting a phase change of a liquid using a device comprising a sample placement area, a pulse module, a conditioning area, a detection module and a conduit, and comprising the steps of: the method comprises the steps of injecting a liquid sample to be detected into a sample placement area through a pipeline in a mode of wrapping the liquid sample with a medium, providing pulse pressure for the liquid sample through a pulse module, detecting the time-dependent change of the pressure applied to the sample to be detected by the pulse module and transmitted to one side of the detection module through the sample by using the detection module, and outputting the time-dependent change of the pressure as a signal, wherein the pulse module and the detection module are arranged on two sides of the sample placement area, and the adjustment area is positioned between the detection module and the sample placement area. The conditioning zone is as described above.

In the present invention, during the detection, the conduit is filled with a medium selected from the group consisting of oil and gas, and the conditioning zone is filled with a gas, preferably the oil is mineral oil and the gas is air.

The apparatus used in the method of the invention is the apparatus of the invention described above.

Furthermore, the method of the present invention further comprises: the entire assay system is filled with medium prior to performing the assay.

As described above, the device for detecting phase change of a liquid of the present invention is simple in structure, and can detect the coagulation time and coagulation state of a liquid (e.g., blood) in a minute amount of a liquid sample (e.g., blood sample). In addition, when the detection device is used, the liquid sample (for example, blood sample) is wrapped by the medium, so that the liquid sample (for example, blood sample) is ensured not to be disturbed by the outside unnecessary in the detection process, the whole solidification process of the liquid sample can be accurately detected, for example, the time for starting solidification of blood after the procoagulant medicine and the factor are added is shortened, and the strength at solidification is increased (the strength of thrombus).

In addition, in the case of blood samples, there is a possibility that the sample will liquefy over a period of time after coagulation, and this change indicates that the coagulated blood is fibrinolytic, medically called hyperfibrinolysis; patients with hyperfibrinolysis have a high risk of internal bleeding, and if a patient needs to perform an operation, medical measures must be taken to improve their clotting ability, otherwise, the patients may have a great deal of bleeding during or after the operation, and even be life threatening. The device can detect the process and realize the detection of the hyperfibrinolysis process.

Furthermore, since the device of the present invention employs a given sample introduction module as described below, different liquid samples can be introduced continuously to achieve continuous, one-time processing of a large number of different liquid samples. The liquid samples of each sample injection can be properly isolated from each other and are not polluted and influenced, so that continuous sample injection of various liquid samples can be realized and detection can be effectively carried out.

Examples

The detection device used in the embodiments described below is constructed substantially in the manner of fig. 2.

The pulse module consists of a constant pressure air source and a time control electromagnetic valve. The method comprises the steps of adopting a karmer brand KLP01 diaphragm pump purchased from karman fluid technology (Shanghai) limited company, and a pine brand DP-101 air pressure sensor switch module purchased from Shenzhen Chuang instruments and meters limited company, wherein a set of constant-pressure air source is formed by a 2L volume stainless steel air storage tank, and the air source is positive pressure; a time control electromagnetic valve is formed by adopting a Sonolian brand TM-06 two-position three-way high-frequency electromagnetic valve purchased from Ningbo Sorbon industrial automatic control equipment Co., ltd, and a DTM01 type time relay module purchased from Shenzhen Qin Shengyuan electronic Co., ltd.

The normally closed port of the electromagnetic valve is connected with a constant pressure air source, the normally open port of the electromagnetic valve is connected with a pulse pipeline which is in fluid communication with the detection area, the pipeline is filled with medium, and the other port of the electromagnetic valve is communicated with the outside air. When the electromagnetic valve does not act, the pulse channel is communicated with the outside air through the electromagnetic valve, and the pressure detected by the detection module is 0Pa; when the electromagnetic valve acts, the electromagnetic valve is communicated with the constant pressure air source, and the pressure detected by the detection module is a specific pressure value which is greater than zero and less than or equal to the pressure of the constant pressure air source. The action time and the interval time of the electromagnetic valve are controlled by a time relay module.

And meanwhile, the same parts and methods for manufacturing the constant-pressure air source are adopted to manufacture the negative-pressure constant-pressure air source. The method is used for sample injection operation of the sample to be detected.

The medium used in the examples below was mineral oil and the air supply pressure was controlled at 12KPa.

A pipe with an inner diameter of 0.6mm×0.6mm, wherein the pipe is made of polymethyl methacrylate (PMMA);

the sample placement area, which is made of polymethyl methacrylate (PMMA) material, was a columnar structure in the three-dimensional structure, as shown in fig. 3 (b), and the shape and parameters of the cross section specifically employed in each of the examples are listed in table 1 below.

The detection module uses a miniature gas-liquid universal pressure sensor (an XGZP6847 type pressure sensor module purchased from the Utility model lake core sensor technology Co., ltd.) to output a 0-5V voltage signal with the measuring range of 0-20KPa.

The materials used in examples 1-9 and comparative examples 1-4 below:

sheep plasma (for heparin sodium titer detection) was purchased from litsea cubeba to Ming Biochemical auxiliary factory, cryopreserved at a temperature below-18 ℃ and thawed at 4 ℃ and activated at 37 ℃ for 1 hour before the experiment.

A calcium chloride solution purchased from Hizihikang Biotechnology (tin-free) Co., ltd.) at a concentration of 0.02mol/L calcium ion was prepared at the above concentration, stored at a low temperature of 4℃and preheated to room temperature when used. The calcium ion is used for promoting coagulation reaction of sheep plasma.

Taking the activated sheep blood plasma after the experimental materials are prepared, adding calcium chloride, and starting timing (0 seconds at the moment), wherein the sample is positioned in a centrifuge tube; samples were introduced into the sample placement area and detection was started at the 100 second time point.

The pulse port is closed before sample injection, the sample outlet pipeline is connected with a negative pressure constant pressure air source through a valve, and the system is filled with medium. During sample injection, a pipeline connected with a sample inlet extends into a centrifuge tube filled with a sample, a valve of a sample outlet pipeline connected with a negative pressure constant pressure air source is opened, the sample is sucked into a sample placing area through the inlet, the sample placing area is filled with the sample, the valve of the sample outlet pipeline connected with the negative pressure constant pressure air source is closed, the centrifuge tube filled with the sample to be detected is removed, and the sample inlet is closed, so that sample injection is completed.

After the sample injection is completed, the pulse port is opened, and the pulse channel is in fluid communication with the pulse module. And starting the time relay module to enable the pulse module electromagnetic valve to intermittently act, so that pulse pressure is applied to the sample to be detected, and detection is started. The pulse period is 5S intervals of 5S of the applied pressure, the pressure of the positive pressure constant pressure air source of the pulse module is 12KPa, and the pressure of the negative pressure constant pressure air source is negative 6KPa. The detection time is 12-20min.

Fig. 4 to 8 show examples of scoring of different test results when detected by the detection device of the present invention, and examples 1 to 9 below score examples according to the examples of fig. 4 to 8. As can be seen from fig. 4, the example of scoring 5 can describe substantially the complete phase change process, but the detailed description of the phase change process is relatively limited, and the main features of the phase change are not fully reflected. As can be seen from fig. 5, the example of score 6 may describe a complete phase change process, although the detailed description of the phase change process is not yet accurate enough, but may already substantially reflect the main features of the phase change occurring. As can be seen from fig. 6, the 7 point scoring example may describe a complete phase change process, although the partial detail description of the phase change process is not yet accurate enough, but may reflect the main features of the phase change occurring. As can be seen from fig. 7, the example of 8 points can accurately and completely describe the whole phase change process, and only small data deviation exists locally, but the accuracy of the description of the phase change process is not basically affected. As can be seen from fig. 8, the example of a score of 9 can accurately and completely describe the entire phase change process, with only small fluctuations in individual data points, but without affecting the accuracy of the phase change process description.

Example 10

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, and the sample placement area was placed in a constant temperature incubator in fluid communication with the pulse module and the detection module placed outside the incubator through a polytetrafluoroethylene hose having an inner diameter of 0.6 mm. A leopard brand LRH-150 incubator purchased from Shanghai, a constant technology Co., ltd was used. Animal butter for baking of Tianmehua milk brand purchased from Tianmehua milk food limited of hula and Happy was used as a sample, which was in a soft solid state at 28 to 34℃and in a liquid state at 34℃or higher.

The sample placement area of the device and the sample were preheated at 40 ℃ for 20 minutes before the experiment, and the sample was completely melted into a liquid state. The liquid sample was introduced into the sample placement area by the same method as in examples 1 to 9, and then the test was started with a test start time of 0 seconds. After 1 minute from the start of detection, the temperature of the constant temperature incubator was set to 25 ℃, and the liquid sample began to gradually become solid as the temperature was lowered; after the test had been carried out for 12 minutes, the sample had cured sufficiently, the incubator temperature was again set to 40 ℃, and the solid sample gradually changed back to liquid as the temperature increased. The detection module completely records the change process of the sample from liquid state to solid state and then from solid state to liquid state, and the specific result is shown in fig. 11.

In comparative examples 1 and 2, the shape of the lateral base surface of the sample placement area was such that the length in the sample introduction direction was smaller than the length in the direction perpendicular to the sample introduction direction. When the shape is two shapes in which the sample direction is 1:1.5 to the direction perpendicular to the sample direction, the result is only a limited reaction to the occurrence of phase transition, and the process cannot be described, and fig. 9 shows the cross-sectional shape and result of the sample placement area used in comparative examples 1 and 2. As can be seen from FIG. 9, a satisfactory detection curve cannot be obtained in the sample placement region which does not satisfy the condition of D1. Gtoreq.D2 described above.

In comparative examples 3 and 4, if the shape of the lateral base surface of the sample placement area is asymmetric in the sample introduction direction. As shown in fig. 10, when the shape is a first asymmetry, the result is a limited response to the occurrence of a phase change and a complete description of the process is not provided; while the second asymmetric pattern of shape results in a substantially descriptive of the occurrence of the phase change, but not of the complete course, the later instability is detected. As can be seen from fig. 10, the sample placement area which does not satisfy the conditions that the sample placement area is substantially symmetrical in the sample introduction direction of the sample to be measured and the shape of the sample placement area on one side in the sample introduction direction of the sample to be measured is an arc shape which is substantially convex outward, cannot obtain a satisfactory detection curve.

The average value of the results of the three tests in examples 1 to 9 is at least 5 minutes, so that the purpose of detecting the liquid phase change process can be achieved.

Table 1 summarizes the cross-sectional shapes of the sample placement areas of examples 1 to 9 and the results of the three tests scored according to the scoring examples of fig. 4 to 8.

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Example 11

The device was constructed in the same manner as in example 3 above, except that there was only one conditioning zone between the detection module and the sample placement zone. The sample placement area adopts the same ellipse shape as in example 3, and the adjustment area is an independent area which is communicated with the pipeline between the detection module and the sample placement area through a thin pipeline; as shown in fig. 15. Before detection, the detection module is taken down, all the pipelines are filled with mineral oil, at this time, the air with a fixed volume can be sealed in the adjusting area, and then the detection module is connected, so that the integral structure of the detection module, the adjusting area, the sample placing area and the pulse module in the embodiment is formed.

After the device was assembled, the sample injection and coagulation process of the sheep plasma sample was performed in the same manner as in example 1, wherein fig. 15 shows a schematic diagram during the detection process, in which dark gray areas represent the sample, diagonal areas represent the areas filled with mineral oil, and the conditioning areas were air.

In the embodiment, the pressure of the positive pressure constant pressure air source connected with the pulse module is 12KPa, the pressure of the negative pressure constant pressure air source for sample injection is controlled to be minus 6KPa, and the detection duration is 12-20min.

The detection results of example 11 are shown in FIG. 16, and it can be seen from the graph that examples 11-1, 11-2, 11-3 with the adjustment region are stronger than those of example 3 without the adjustment region, and as the adjustment region increases, vo/Vs increases, the signal gradually increases, and the resolution of the detection process increases correspondingly after the signal increases, so the detection effect further increases.

Example 12

In the same manner as in example 11 above, the adjustment region is an independent region communicating with the conduit between the detection module and the sample placement region through the thin conduit; the whole device is air before detection. After the sample injection is finished, the volume occupied by the air sealed in the sample and the detection module is the volume of the adjusting area, and the sealed area plays a role of the adjusting area at the moment.

The difference from example 11 is only that no mineral oil was injected into the device under test, but that air was used as the medium, and fig. 17 shows a schematic diagram during the test, with dark grey areas representing the sample, except that the other spaces in the device were filled with air. As indicated by the dotted line, a part of the area included in the dotted line is the volume of gas contained in the pipeline and the communication structure between the detection module and the sample; another part is to supplement the added volumes between the detection module and the sample, which volumes as a whole constitute the volume of the conditioning zone.

In example 12, the detection zone uses the same elliptical configuration as the parameters of example 11 and other parameters are as follows:

example 12 was performed in the same manner as examples 1-9 above, except that the sample was changed to human whole blood and human venous blood was drawn into a citrated blood collection tube. Before detection, 1mL of blood sample is taken and placed in a kaolin activating reagent tube, shaking is carried out and the sample is waited for 1min, then 340 mu L of activated blood sample is taken and added with 20 mu L of calcium chloride solution (0.2 mol/L), the blood sample added with calcium chloride is injected into a sample placing area, an injection port is closed, and detection is started, and the detection result is shown in figure 18.

Because of the substantial differences in source, composition and biochemical properties between sheep plasma and human whole blood, there are large differences in signal intensity in the assay, which are mainly caused by the sample itself.

From the results of FIG. 18, it can be seen that as the volume of the conditioning zone increases, the Vo/Vs increases, and the signal increases, indicating that the conditioning zone can increase the detection effect as well in the case of air as the medium.

The results according to the above examples show that the time of solidification of the liquid, and the strength of solidification of the reaction liquid can be effectively detected by the apparatus of the present invention.

While the application is susceptible to various modifications and alternative forms, specific embodiments have been shown by way of example in the drawings and have been described in detail herein. This application is not intended to be limited to the specific form disclosed. On the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the scope of the invention as defined by the appended claims and their legal equivalents.

The recitation of numerical ranges herein are merely intended to include the data set forth between the two endpoints of the range and each specific value within the range, and the range is intended to cover a new range where the value is combined with the endpoint as desired.

Claims

1. An apparatus for detecting a phase change of a liquid, comprising:

a pulse module for applying a pulsed pressure to the liquid sample to be detected;

the adjusting area is used for adjusting the intensity of the signal fed back from the liquid sample to be detected, which is detected by the detecting module;

a conduit having an inlet and an outlet for ingress and egress of a sample;

wherein the pulse module and the detection module are arranged at two sides of the sample placing area, the detection of the pressure change in the pipeline at one side of the detection module means that the detection module detects the time-dependent pressure change of the liquid sample applied to the liquid sample to be detected by the pulse module and transmitted to one side of the detection module through the sample, and outputs the time-dependent pressure change as a signal,

The adjusting area is positioned between the detection module and the sample placing area;

the cross-sectional shape of the sample placement area satisfies the following condition:

the maximum width of the sample placement area in the sample introduction direction of the liquid sample to be detected is D1, the maximum width of the sample placement area in the direction perpendicular to the sample introduction direction of the liquid sample to be detected is D2, and D1 is more than or equal to D2;

the sample placement area is basically symmetrical along the sample injection direction of the liquid sample to be detected; and

the shape of one side of the sample placement area along the sample introduction direction of the liquid sample to be tested is basically outwards convex arc.

2. The device of claim 1, wherein the cross-sectional shape of the sample placement area further satisfies the following condition:

1＜D1/D2≤8。

3. the device of claim 1, wherein the cross-sectional shape of the sample placement area further satisfies the following condition:

1＜D1/D2≤7。

4. the device of claim 1, wherein the cross-sectional shape of the sample placement area further satisfies the following condition:

1＜D1/D2≤6。

5. the device of claim 1, wherein the cross-sectional shape of the sample placement area further satisfies the following condition:

1＜D1/D2≤5。

6. the device of claim 2, wherein the cross-sectional shape of the sample placement area further satisfies the following condition:

satisfies the requirement that D1/R is less than or equal to 2 and less than or equal to 24.

7. The apparatus of claim 6, wherein 2.ltoreq.D1/R.ltoreq.20.

8. The apparatus of claim 6, wherein 2.ltoreq.D1/R.ltoreq.16.

9. The device of claim 1, wherein the transverse base shape of the sample placement area further satisfies the following condition: the shape of one side of the sample placement area along the sample introduction direction of the sample to be detected is basically outwards convex arc, and no obvious concave is arranged on the arc.

10. The device of claim 9, wherein the cross-sectional shape of the sample placement area further satisfies the following condition:

11. The device of any one of claims 1-10, wherein the conduit is a microchannel having an inner diameter of 10 microns to 5 millimeters.

12. The apparatus of claim 11, wherein the conduit has an inner diameter of 50 microns to 4 millimeters.

13. The apparatus of claim 11, wherein the conduit has an inner diameter of 100 microns to 3 millimeters.

14. The apparatus of claim 11, wherein the conduit has an inner diameter of 200 microns to 2 millimeters.

15. The apparatus of claim 11, wherein the conduit has an inner diameter of 300 microns to 1 millimeter.

16. The device of any one of claims 1-10, wherein the sample placement zone, the pulse module, the detection module, and the conduit are in fluid communication.

17. The apparatus of claim 16, wherein,

when the pulse pressure applied by the pulse module is more than 100Pa and less than or equal to 1000Pa, the range of Vo/Vs satisfies the following conditions: 1001. not less than Vo/Vs;

when the pulse pressure applied by the pulse module is more than 1000Pa and less than or equal to 10KPa, the range of Vo/Vs satisfies the following conditions: 101. not less than Vo/Vs;

when the pulse pressure applied by the pulse module is more than 10KPa and less than or equal to 100KPa, the range of Vo/Vs satisfies the following conditions: 11. not less than Vo/Vs;

when the pulse pressure applied by the pulse module is greater than 100KPa, the range of Vo/Vs satisfies the following conditions: 2. not less than Vo/Vs.

18. The apparatus of claim 17, wherein the range of Vo/Vs satisfies when the pulsed pressure applied by the pulsing module is greater than 100Pa and less than or equal to 1000 Pa: 500. not less than Vo/Vs.

19. The apparatus of claim 17, wherein the range of Vo/Vs satisfies when the pulsed pressure applied by the pulsing module is greater than 100Pa and less than or equal to 1000 Pa: 100. not less than Vo/Vs.

20. The apparatus of claim 17, wherein the range of Vo/Vs satisfies when the pulsed pressure applied by the pulsing module is greater than 100Pa and less than or equal to 1000 Pa: 50. not less than Vo/Vs.

21. The apparatus of claim 17, wherein the range of Vo/Vs satisfies when the pulsed pressure applied by the pulsing module is greater than 100Pa and less than or equal to 1000 Pa: 10. not less than Vo/Vs.

22. The apparatus of claim 17, wherein the range of Vo/Vs satisfies when the pulsed pressure applied by the pulsing module is greater than 1000Pa and less than or equal to 10 KPa: 50. not less than Vo/Vs.

23. The apparatus of claim 17, wherein the range of Vo/Vs satisfies when the pulsed pressure applied by the pulsing module is greater than 1000Pa and less than or equal to 10 KPa: 10. not less than Vo/Vs.

24. The apparatus of claim 17, wherein the range of Vo/Vs satisfies when the pulsed pressure applied by the pulsing module is greater than 1000Pa and less than or equal to 10 KPa: 5. not less than Vo/Vs.

25. The apparatus of claim 17, wherein the range of Vo/Vs satisfies when the pulsed pressure applied by the pulsing module is greater than 1000Pa and less than or equal to 10 KPa: 2. not less than Vo/Vs.

26. The apparatus of claim 17, wherein the range of Vo/Vs satisfies when the pulsed pressure applied by the pulsing module is greater than 10KPa and less than or equal to 100 KPa: 5. not less than Vo/Vs.

27. The apparatus of claim 17, wherein the range of Vo/Vs satisfies when the pulsed pressure applied by the pulsing module is greater than 10KPa and less than or equal to 100 KPa: 2. not less than Vo/Vs.

28. The apparatus of claim 17, wherein the range of Vo/Vs satisfies when the pulsed pressure applied by the pulsing module is greater than 10KPa and less than or equal to 100 KPa: 1. not less than Vo/Vs.

29. The apparatus of claim 17, wherein the range of Vo/Vs satisfies when the pulsed pressure applied by the pulsing module is greater than 10KPa and less than or equal to 100 KPa: 0.8 Not less than Vo/Vs.

30. The apparatus of claim 17, wherein the range of Vo/Vs satisfies when the pulsed pressure applied by the pulsing module is greater than 100 KPa: 1. not less than Vo/Vs.

31. The apparatus of claim 17, wherein the range of Vo/Vs satisfies when the pulsed pressure applied by the pulsing module is greater than 100 KPa: 0.8 Not less than Vo/Vs.

32. The apparatus of claim 17, wherein the range of Vo/Vs satisfies when the pulsed pressure applied by the pulsing module is greater than 100 KPa: 0.6 Not less than Vo/Vs.

33. The apparatus of claim 17, wherein the range of Vo/Vs satisfies when the pulsed pressure applied by the pulsing module is greater than 100 KPa: 0.4 Not less than Vo/Vs.

34. The device of any one of claims 1-10, wherein the conditioning zone is provided by a communication conduit between the detection module and the sample placement zone.

35. The device of any one of claims 1-10, wherein the conditioning zone is provided by a separately provided zone between the detection module and the sample placement zone.

36. The device of any one of claims 1-10, wherein the liquid sample is a blood sample or a protein liquid sample.

37. The device according to any one of claims 1-10, wherein the liquid sample is another liquid sample that undergoes a phase change due to polymer polymerization.

38. The device of any one of claims 1-10, wherein the liquid sample is a substance that changes phase with temperature.

39. A method for detecting a phase change of a liquid using the device of any one of claims 1 to 38, and comprising the steps of:

providing pulsed pressure to a liquid sample by a pulse module

The detection module is used for detecting the time-dependent change of the pressure applied to the liquid sample to be detected by the pulse module and transmitted to one side of the detection module through the sample, and outputting the time-dependent change of the pressure as a signal,

40. The method of claim 39, wherein during the detection, the conduit is filled with a medium selected from the group consisting of oil and gas, and the conditioning zone is filled with gas.

41. The method of claim 40, wherein in performing the detection, the oil is mineral oil.

42. The method of claim 40, wherein the gas is air during the detecting.