CN111855732B - Device and method for detecting phase change of liquid - Google Patents
Device and method for detecting phase change of liquid Download PDFInfo
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- CN111855732B CN111855732B CN201910350919.6A CN201910350919A CN111855732B CN 111855732 B CN111855732 B CN 111855732B CN 201910350919 A CN201910350919 A CN 201910350919A CN 111855732 B CN111855732 B CN 111855732B
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- G—PHYSICS
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Abstract
The invention provides a device for detecting a phase change of a liquid, comprising: the detection area is used for placing a liquid sample to be detected and completing the phase change process of the liquid in the detection area so as to detect the liquid sample; 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, and the pulse module and the detection module are arranged at one side of the detection area; a conduit having a first sample port and a second sample port for passing the sample into and out of the detection zone; the pressure release end is used for releasing the pressure of the detection area and is positioned at the other side of the detection area opposite to the pulse module and the detection module; 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 fed back to the detection module, and outputs the time-dependent pressure change as a signal.
Description
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 from the external environment as much as possible during the detection, there is also a need for a detection device that can achieve very little influence on the collected blood during the entire 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; a first sample port tube connected to the thrombotic chamber and through which blood flows into the thrombotic chamber; and a drug tube connected to the first sample port tube and supplied therethrough to release the anticoagulant-treated drug to be removed or to promote blood coagulation. 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 detection area is used for placing a liquid sample to be detected and completing the phase change process of the liquid in the detection area so as to detect the liquid sample;
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, and the pulse module and the detection module are arranged at one side of the detection area;
a conduit having a first sample port and a second sample port for passing the sample into and out of the detection zone;
the pressure release end is used for releasing the pressure of the detection area and is positioned at the other side of the detection area opposite to the pulse module and the detection module;
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 fed back to the detection module, and outputs the time-dependent pressure change as a signal.
2. The device of item 1, wherein the first sample port is located between the pulse module and the detection zone and the second sample port is located between the detection zone and the pressure relief end.
3. The device of item 1, wherein the pulse module, the detection module, and the detection zone are in fluid communication.
4. The device of item 1, wherein one of the first or second sample port is connected to a sample module for sample introduction, the other of the first or second sample port is in communication with a liquid sample to be tested in a sample container to be tested, preferably the pressure relief port is a valve.
5. The device of any one of claims 1-4, wherein the cross-sectional shape of the detection zone satisfies the following condition:
the maximum width of the detection area in the sample injection direction of the sample to be detected is D1, the maximum width of the detection area in the direction perpendicular to the sample injection direction of the sample to be detected is D2, and D1 is more than or equal to D2;
the detection area is basically symmetrical along the sample injection direction of the sample to be detected; and
the shape of one side of the detection area along the sample introduction direction of the sample to be detected is basically outwards convex arc.
6. The device of item 5, wherein the cross-sectional shape of the detection zone 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.
7. The device of item 6, wherein the cross-sectional shape of the detection zone further satisfies the following condition:
When the inner diameters of the pipelines of the first sample port and the second sample port for leading in and out the sample are 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.
8. The device of any one of claims 1-4, wherein the transverse base shape of the detection zone further satisfies the following condition: the shape of one side of the detection 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.
9. The device of item 8, wherein the cross-sectional shape of the detection zone further satisfies the following condition:
the detection area is basically symmetrical along the direction perpendicular to the sample introduction direction of the sample to be detected.
10. The device according to any one of claims 1 to 4, 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.
11. The device of any one of claims 1-4, wherein the detection zone, pulse module, detection module, and conduit are in fluid communication.
12. The device according to any one of items 1 to 4, 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 detection zone, a pulse module, a detection module, a pressure relief port, and a conduit, comprising the steps of:
the pressure release end is closed,
the liquid sample to be detected is injected into the detection area through the pipeline and the first injection port or the second injection port,
the pressure release end is opened up,
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 feeding back the pressure to the detection module, and outputting the time-dependent change of the pressure as a signal,
the pulse module and the detection module are arranged on one side of the detection area.
14. The method of claim 13, wherein the tubing is filled with a gas, preferably air or other gas that does not biochemically interact with the sample during the detection process.
15. The method according to item 13 or 14, which is performed using 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.
FIG. 3 is a schematic diagram of yet another embodiment of the detection apparatus of the present invention.
FIGS. 4 (a) to (c) are schematic diagrams of detection areas and cross sections thereof of the detection device of the present invention.
Fig. 5 shows an example of the detection result scored at 5 time slots.
Fig. 6 shows an example of the detection result with a score of 6 minutes.
Fig. 7 shows an example of the detection result scored at 7 time slots.
Fig. 8 is an example of a test result scored at 8 time slots.
Fig. 9 shows an example of the detection result with a score of 9 minutes.
Fig. 10 shows the cross-sectional shape of the detection region used in comparative example 1 and the detection scoring result.
Fig. 11 is a cross-sectional shape of the detection region employed in comparative example 2 and a detection scoring result.
FIG. 12 is a schematic diagram of the detection result of example 10.
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 >
As described in fig. 1 to 3, the apparatus for detecting phase change of a liquid of the present invention includes: the detection area is used for placing a liquid sample to be detected and completing the phase change process of the liquid in the detection area so as to detect the liquid sample; 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, and the pulse module and the detection module are arranged at one side of the detection area; a conduit having a first sample port and a second sample port for passing the sample into and out of the detection zone; the pressure release end is used for releasing the pressure of the detection area and is positioned at the other side of the detection area opposite to the pulse module and the detection module; 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 fed back to the detection module, 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 introduction module, and the sample introduction module is not particularly limited as long as it is a module capable of transporting a liquid sample to a detection area. Preferably, the sample injection module is selected from a negative pressure air source or a plunger pump.
In a specific embodiment of the invention, a first sample port is located between the pulse module and the detection zone, and a second sample port is located between the detection zone and the pressure relief end.
Fig. 1 shows a schematic diagram of an embodiment of the detection device of the present invention. It can be seen that, in the detection device of the present invention, the pulse module and the detection module need to be disposed at one side of the detection area, i.e. the pulse module is used for applying the pulse pressure to the sample to be detected, and the detection module is used for detecting the pressure of the pulse pressure after the absorption of the sample, and the pressure can be fed back to the pipeline at the same side. Thus, as will be appreciated by those skilled in the art, as the liquid sample to be tested changes from liquid to solid or from solid to liquid, the pressure value absorbed by the sample will change, and thus the pressure in the conduit that can be fed back to the same side will also change continuously, and the device of the present invention will characterize the change in liquid sample to be tested from liquid to solid by detecting this change over time.
As shown in fig. 1, a pulse module is located between the detection module and the detection zone. The invention is not limited thereto as long as fluid communication is ensured between the pulse module, the detection module and the detection zone, and two further variants are shown in fig. 2 and 3, respectively.
As shown in fig. 2, the first sample port is located between the pulse module and the detection area, the second sample port is located between the detection area and the pressure release end, and the pulse module, the detection module and the detection area are in fluid communication, so that the pulse module can apply pulse pressure to the sample to be detected, and the detection module is used for detecting the pressure of the pulse pressure, after the absorption of the sample, can be fed back to the same side pipeline. Thus, as will be appreciated by those skilled in the art, as the liquid sample to be tested changes from liquid to solid or from solid to liquid, the pressure value absorbed by the sample will change, and thus the pressure in the conduit that can be fed back to the same side will also change continuously, and the device of the present invention will characterize the change in liquid sample to be tested from liquid to solid by detecting this change over time.
As shown in fig. 3, the first sample port is located between the pulse module and the detection area, the second sample port is located between the detection area and the pressure release end, and the pulse module, the detection module and the detection area are in fluid communication, so that the pulse module can apply pulse pressure to the sample to be detected, and the detection module is used for detecting the pressure of the pulse pressure, after the absorption of the sample, can be fed back to the same side pipeline. Thus, as will be appreciated by those skilled in the art, as the liquid sample to be tested changes from liquid to solid or from solid to liquid, the pressure value absorbed by the sample will change, and thus the pressure in the conduit that can be fed back to the same side will also change continuously, and the device of the present invention will characterize the change in liquid sample to be tested from liquid to solid by detecting this change over time.
The pulse module used in the device applies pulse pressure to the sample to be detected, and the pulse module is connected with the pipeline in an airtight manner. In the use process of the device, the pulse module, the detection module and the sample to be detected can seal a certain amount of gas in the pipeline; the pulse module can push and reset the sealed certain amount of gas by a fixed volume amount or pull and reset the sealed certain amount of gas by a fixed volume amount; this will cause a periodic pressure change in the sealed volume of gas and be registered by the detection module.
In a specific embodiment, the pulse module may be a syringe pump, a plunger pump, or the like, but is not limited thereto, as long as the above-described functions can be achieved. Such as syringe pumps, plunger pumps, rubber balloons, sealed metal cartridges that deform sufficiently, and the like. The pulse module provides a volume pulse Vo, where the pulse volume is the amount of push or pull of the pulse module to the sealed fixed volume of gas within the structure, such as, but not limited to, using a syringe pump as the pulse module, the syringe pump pushes a volume of gas into the sealed structure, and then resets to pull the same volume of gas back into the syringe pump, thus cycling back and forth to form periodic pulses. In the present invention, vo may range from 0.01 to 800. Mu.l, preferably from 0.01 to 400. Mu.l, more preferably from 0.01 to 200. Mu.l, still more preferably from 0.01 to 100. Mu.l, still more preferably from 0.01 to 60. Mu.l; the pulse period may be 1 to 60 seconds, preferably 2 to 40 seconds, and more preferably 3 to 20 seconds.
The detection device of the present invention should be filled with gas, which may be air or other gas that does not biochemically interact with the sample, prior to use, and the filling of the entire device with gas refers to filling of the tubing and detection zone with gas. When the detection device is started to be used, the pressure release end is closed, and the liquid sample to be detected is injected into the detection area through the pipeline and the first injection port or the second injection port under the action of the injection module. After the sample injection is finished, the sample injection port is closed, the pressure release end is opened, the pulse module is opened, and a volume compression pulse with basically constant volume change 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 detection zone, the pressure in the conduit fed back to the detection module side, which is typically the pressure in the conduit on the detection module side outside the detection zone, can be detected over time 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.
More specifically, after the sample injection is completed, a valve at the pressure release end is opened, and the pulse module is started to start detection. In the detection process, after the pulse module pushes a certain volume Vo, the sample moves a certain volume Vx towards the pressure release end, wherein Vx is smaller than Vo, at the moment, a certain amount of gas sealed at the pulse end is compressed by a certain volume Vt, vt=vo-Vx is larger than 0, and the pressure of the sealed gas after the volume compression is increased; after the pulse module resets the Vo volume, the sample moves Vx' to one end of the pulse module; because the detection area has a limiting effect on the movement of the sample, the moving volume Vx '< Vo, a certain amount of gas sealed at the pulse end can be released by a certain volume Vt', and Vt '=vo-Vx' > 0, and the pressure of the sealing gas can be reduced after the volume is increased; thereby completing one cycle of detection. When the sample is in a liquid state, the limiting effect of the detection area on the movement of the sample is weak, the movement amount of the sample is large, namely the Vt and Vt' volumes are close to the Vo volumes, so that the volume scaling of a certain amount of gas with a sealed pulse end is small, and the pressure fluctuation is small. When the sample gradually becomes solid, the limiting effect of the detection area on the movement of the sample is enhanced, the movement amount of the sample is reduced, namely the difference between the Vt and Vt' volumes and the Vo volume is increased, so that the volume scaling of a certain amount of gas with a sealed pulse end is increased, and the pressure fluctuation is increased; this increased pressure reflects the extent to which the sample solidifies.
As will be appreciated by those skilled in the art, as the liquid sample gradually changes from a liquid to a solid, the pressure detected by the detection module fluctuates, and the process of increasing the pressure detected by the detection module may be recorded at this time, so that a pressure curve reflecting the increasing of the solidification strength of the sample is obtained, and as a result of the detection, various detected results may be given, for example, with reference to fig. 4 to 10. Meanwhile, if the phase change process from solid to liquid is detected, those skilled in the art can understand that when the solid is changed into liquid sample, the mobility of the sample increases along with the phase change, the restriction of the detection area on the sample is weakened, the movement amount of the sample is increased, namely the difference between the Vt and Vt' volume and the Vo volume is reduced, so that the volume scaling of a certain amount of gas with the pulse end sealed is reduced, and the pressure fluctuation is reduced; the pressure fluctuation detected by the detection module is continuously weakened; taking the pressure fluctuation value of the sample when the sample is completely liquid as a base line, subtracting the base line from the detected pressure to obtain a pressure curve reflecting the gradual decrease of the liquefaction degree of the sample, and taking the pressure curve 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 detection 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 detection area so as to detect. The shape of the detection zone is generally not limited as long as it can achieve this. Preferably, the cross-sectional shape of the detection zone 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 detection zone, the solidification of the sample from liquid to solid can be detected, or the melting of the sample from solid to liquid again can be detected. Similarly, it is known that the phase change process can be repeated multiple times and multiple phase change processes can be detected.
Fig. 2 gives a schematic representation of a cross section of the detection zone. Fig. 2 (a) and (b) show schematic perspective views of the device of the present invention, the cuboid on both sides may represent a pulse module and a detection module, respectively, and the ellipsoid or cylinder in the middle schematically represents the detection zone. It will be appreciated by those skilled in the art that the shapes shown in fig. 2 (a) and (b) are merely illustrative of the detection zone, and schematic illustrations of the cross-section thereof, and are not intended to limit the shape of the detection zone. In addition, fig. 2 (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 detection area refers to a cross section obtained by cutting the center of the detection area with a rectangular plane shown in fig. 2 (a) or (b) in the direction of the sample flow, and a hatched portion shown by oblique lines in fig. 2 (a) or (b), that is, a cross section of the detection area referred to herein. Fig. 2 (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 detection 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 detection region satisfies the following condition: the maximum width of the detection area in the sample introduction direction of the sample to be detected is D1 (shown in fig. 2 (c)), the maximum width of the detection area in the direction perpendicular to the sample introduction direction of the sample to be detected is D2 (shown in fig. 2 (c)), and D1 is more than or equal to D2; the detection area is basically symmetrical along the sample injection direction of the sample to be detected; and the shape of one side of the detection area along the sample introduction direction of the sample to be detected is basically outwards convex arc.
In the above condition, the detection region being substantially symmetrical along the sample injection direction of the sample to be detected means that the area of the upper portion and the area of the lower portion are substantially the same and the shape is substantially symmetrical with respect to the cross section of the detection region along the dotted line in the schematic diagram of fig. 2 (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 detection 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. 2, and an arc is a shape that appears to be a part of a circle or an 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 detection region 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 detection region of the present invention preferably has a shape of a major axis and a minor axis, wherein the direction of injection is the major axis and the direction of treatment with the direction of injection is the minor axis.
In the device of the present invention, it is further preferable that the cross-sectional shape of the detection region satisfies the following condition: when the inner diameters of the pipelines of the first sample port and the second sample port for inputting and outputting the sample 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 detection zone of the invention and the size of the conduit preferably satisfy the above relation.
In the device of the present invention, it is further preferable that the shape of the transverse basal plane of the detection region also satisfies the following condition: the shape of one side of the detection 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. A depression in this context refers to a cross-sectional shape of a detection zone, for example in the form of an arc, where, for example, a trough occurs, for example in examples 6 to 8 described below. 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 detection region also satisfies the following condition: the detection area is basically symmetrical along the direction perpendicular to the sample introduction direction of the sample to be detected.
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, one sample port, namely a first sample port and a second sample port, is respectively arranged at two sides of the detection area, wherein one of the first sample port and the second sample port is connected with the sample injection module. The other sample inlet of the first sample port and the second sample port is connected with a sample, and the sample enters the detection area through the other sample inlet under the action of the sample injection module. Those skilled in the art will appreciate that the first and second sample ports are identical and interchangeable.
The device comprises a pressure release end, a pulse module and a detection module, wherein the pressure release end is used for releasing the pressure of the detection area, and the pressure release end is positioned at the other side of the detection area opposite to the pulse module and the detection module.
Wherein, as shown in fig. 1, the other side of the detection area opposite to the pulse module and the detection module is that the port of the pressure release end and the detection module are 180 degrees + -20 degrees, preferably 180 degrees + -10 degrees, and more preferably 180 degrees + -5 degrees, relative to the sample detection area. The pressure release end in the device can be a closed cavity with the volume larger than zero or an openable and closable port. The port needs to be closed in the sample injection process and is always opened in the detection process. Valves, rubber plugs, caps, etc. may be used as the pressure release terminals, but are not limited to the above type, as long as the above functions can be achieved.
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, and any material may be used as long as it can realize sample introduction and detection 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, it is necessary to sample a certain amount of the liquid sample to be measured into the detection 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.
< method for detecting phase transition of liquid >
The invention also provides a method for detecting the phase change of the liquid, which uses a device comprising a detection area, a pulse module, a detection module, a pressure release end and a pipeline for detection, and comprises the following steps: closing the pressure release end, injecting a liquid sample to be detected to a detection area through a pipeline and a first sample injection port or a second sample injection port under the action of the sample injection module, closing the sample injection port, opening the pressure release end, providing constant volume pulse for the liquid sample through the pulse module, detecting the pressure change of the pressure applied to the sample to be detected by the detection pulse module and fed back to the detection module with the detection module, and outputting the pressure change with time as a signal, wherein the pulse module and the detection module are arranged on one side of the detection area.
In the present invention, the tubing is filled with a gas, which may be air or other gas that does not biochemically interact with the sample during the course of the assay.
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 whole detection system is filled with gas before the detection is performed.
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, with the detection device of the present invention, the liquid sample (e.g., blood sample) is almost completely sealed inside the structure, thereby ensuring that the liquid sample (e.g., blood sample) is not unnecessarily disturbed by the outside during the detection, and the whole process of coagulation of the liquid sample, such as the time for which blood starts to coagulate after the procoagulant drug or factor is added, is shortened and the strength at the time of coagulation is increased (the strength of thrombus), can be accurately detected.
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. 1.
The pulse module consists of a stepping motor sliding table and a microinjector, wherein an era supergroup type 1204 stepping motor sliding table purchased from Beijing era four-dimensional science and technology limited company is used, a 50-type microinjector purchased from Shanghai's pavilion microinjector factory is used for forming the pulse module, and the pulse intensity and the period are controlled by a stepping motor controller program; the method comprises the steps of manufacturing a detection module by adopting an XGZP6847005KPGPN type pressure sensor purchased from the UK lake core intelligent sensor technology Co., ltd, wherein the measuring range of the sensor is (-5 KPa, +5 Kpa); the pressure relief port was controlled to open and close using a Sonolian UX22-1L solenoid valve purchased from Ningbo Industrial Automation devices Co.
In examples 1 to 9 below, the inner diameter of the pipe was 0.6mm.times.0.6 mm, and the constituent material was polymethyl methacrylate (PMMA). The detection zone, which is made of polymethyl methacrylate (PMMA) material, has a columnar structure in the three-dimensional structure, as shown in fig. 2 (b), and the shape and parameters of the cross section specifically used in each of the examples are shown in table 1 below.
The detection module uses a miniature gas-liquid universal pressure sensor (an XGZP6847005KPGPN type pressure sensor module purchased from the Utility model of the intelligent sensor technology Co., ltd.) to output a 0-5V voltage signal, and the measuring range is-5 KPa-5KPa.
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 injected into the detection zone and detection was started at the 60 second time point.
The pressure release end is closed before sample injection, the second sample port pipeline is connected with a negative pressure constant pressure air source through a valve, and the system is filled with air. During sample injection, a pipeline connected with the first sample port extends into a centrifuge tube filled with a sample, a valve of a pipeline connected with the second sample port, which is connected with a negative pressure constant pressure air source, is opened, and the sample is sucked into a detection area through the first sample port, and the detection area to be detected is full. Closing a valve of the second sample port pipeline connected with a negative pressure constant pressure air source, removing the centrifuge tube filled with the sample to be tested, and closing the sample port, wherein the sample injection is completed.
After the sample injection is completed, the pressure release end is opened, and the pulse module is started to start detection. The pulse period was a volume compression of 5S and a volume reset of 5S, with a pulse volume (Vo) of 20 μl. 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.
In comparative examples 1 and 2, the shape of the lateral base surface of the detection zone 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 in a 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 detection region used in comparative examples 1 and 2. As can be seen from FIG. 9, a satisfactory detection curve cannot be obtained in the detection region in which the condition D1. Gtoreq.D2 is not satisfied.
In comparative examples 3 and 4, if the shape of the lateral base surface of the detection zone is asymmetric along 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, a satisfactory detection curve cannot be obtained without satisfying the detection region in which the detection region is substantially symmetrical in the sample introduction direction of the sample to be detected and the detection region has a substantially outwardly convex arc shape on one side in the sample introduction direction of the sample to be detected.
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 detection areas of examples 1 to 9 and the results of scoring the three detection results according to the scoring examples of fig. 4 to 8.
Example 10
The same device as in examples 1-9 was used, the cross section of the detection zone was exactly the same as in example 3, the inner diameter of the tube was 0.6mm×0.6mm, and the constituent material was polymethyl methacrylate (PMMA); the detection zone is placed in a constant temperature incubator in fluid communication with a pulse module and a detection module placed outside the incubator through polytetrafluoroethylene hoses. 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 device detection zone and sample were preheated at 40 ℃ for 20 minutes prior to the experiment, and the sample was completely melted to a liquid state. The same sample injection method as in examples 1 to 9 was used to inject the liquid sample into the detection zone, and then the detection was started, with a detection 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.
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 (27)
1. An apparatus for detecting a phase change of a liquid, comprising:
the detection area is used for placing a liquid sample to be detected and completing the phase change process of the liquid in the detection area so as to detect the liquid sample;
a pulse module for applying a pulsed pressure to the liquid sample to be detected;
the detection module is used for detecting the pressure change in the pipeline at one side of the detection module, and the pulse module and the detection module are arranged at one side of the detection area;
a conduit having a first sample port and a second sample port for passing the sample into and out of the detection zone;
The pressure release end is used for releasing the pressure of the detection area and is positioned at the other side of the detection area opposite to the pulse module and the detection module;
detecting 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 liquid sample to be detected by the pulse module and fed back to the detection module, and outputs the time-dependent pressure change as a signal;
the cross-sectional shape of the detection zone satisfies the following condition:
the maximum width of the detection area in the sample injection direction of the liquid sample to be detected is D1, the maximum width of the detection area in the direction perpendicular to the sample injection direction of the liquid sample to be detected is D2, and D1 is more than or equal to D2;
the detection area is basically symmetrical along the sample injection direction of the liquid sample to be detected; and
the shape of one side of the detection area along the sample introduction direction of the liquid sample to be detected is basically outwards convex arc.
2. The device of claim 1, wherein the first sample port is located between the pulse module and the detection zone and the second sample port is located between the detection zone and the pressure relief end.
3. The device of claim 1, wherein the pulse module, detection module, and detection zone are in fluid communication.
4. The device of claim 1, wherein one of the first or second sample port is connected to a sample module for sample introduction, and the other of the first or second sample port is in communication with a liquid sample to be tested in a sample container to be tested.
5. The apparatus of claim 1, wherein the pressure relief end is a valve.
6. The device of claim 1, wherein the cross-sectional shape of the detection zone further satisfies the following condition:
1＜D1/D2≤8。
7. the apparatus of claim 6, wherein 1 < D1/D2.ltoreq.7.
8. The apparatus of claim 6, wherein 1 < D1/D2.ltoreq.6.
9. The apparatus of claim 6, wherein 1 < D1/D2.ltoreq.5.
10. The apparatus of claim 6, wherein the cross-sectional shape of the detection zone further satisfies the following condition:
when the inner diameters of the pipelines of the first sample port and the second sample port for leading in and out the sample are R,
satisfies the requirement that D1/R is less than or equal to 2 and less than or equal to 24.
11. The apparatus of claim 10, wherein 2.ltoreq.d1/r.ltoreq.20.
12. The apparatus of claim 10, wherein 2.ltoreq.d1/r.ltoreq.16.
13. The device of any one of claims 1-4, wherein the cross-sectional shape of the detection zone further satisfies the following condition: the shape of one side of the detection area along the sample introduction direction of the liquid sample to be detected is basically outwards convex arc, and no obvious concave is arranged on the arc.
14. The apparatus of claim 13, wherein the cross-sectional shape of the detection zone further satisfies the following condition:
the detection area is basically symmetrical along the direction perpendicular to the sample introduction direction of the sample to be detected.
15. The device of any one of claims 1-4, wherein the conduit is a microchannel having an inner diameter of 10 microns to 5 millimeters.
16. The device of any one of claims 1-4, wherein the conduit is a microchannel having an inner diameter of 50 microns to 4 millimeters.
17. The device of any one of claims 1-4, wherein the conduit is a microchannel having an inner diameter of 100 microns to 3 millimeters.
18. The device of any one of claims 1-4, wherein the conduit is a microchannel having an inner diameter of 200 microns to 2 millimeters.
19. The device of any one of claims 1-4, wherein the conduit is a microchannel having an inner diameter of 300 microns to 1 millimeter.
20. The device of any one of claims 1-4, wherein the detection zone, the pulse module, the detection module, and the conduit are in fluid communication.
21. The device of any one of claims 1-4, wherein the liquid sample is a blood sample or a protein liquid sample.
22. The device of any one of claims 1-4, wherein the liquid sample is a liquid sample that undergoes a phase change due to polymer polymerization.
23. The device of any one of claims 1-4, wherein the liquid sample is a substance that changes phase with temperature.
24. A method for detecting a phase change of a liquid using an apparatus comprising a detection zone, a pulse module, a detection module, a pressure relief port, and a conduit, comprising the steps of:
the pressure release end is closed,
the liquid sample to be detected is injected into the detection area through the pipeline and the first injection port or the second injection port,
the pressure release end is opened up,
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 feeding back the time-dependent change of the pressure to the detection module, and outputting the time-dependent change of the pressure as a signal,
the pulse module and the detection module are arranged at one side of the detection area;
the cross-sectional shape of the detection zone satisfies the following condition:
the maximum width of the detection area in the sample injection direction of the liquid sample to be detected is D1, the maximum width of the detection area in the direction perpendicular to the sample injection direction of the liquid sample to be detected is D2, and D1 is more than or equal to D2;
The detection area is basically symmetrical along the sample injection direction of the liquid sample to be detected; and
the shape of one side of the detection area along the sample introduction direction of the liquid sample to be detected is basically outwards convex arc.
25. The method of claim 24, wherein the conduit is filled with gas during the detection.
26. The method of claim 25, wherein the gas is air or other gas that does not biochemically interact with the sample.
27. The method of any one of claims 24-26, which is detected using the device of any one of claims 1-23.
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