CN113967486A - Centrifugal micro-fluidic chip - Google Patents
Centrifugal micro-fluidic chipDownload PDFInfo
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- CN113967486A CN113967486ACN202010713364.XACN202010713364ACN113967486ACN 113967486 ACN113967486 ACN 113967486ACN 202010713364 ACN202010713364 ACN 202010713364ACN 113967486 ACN113967486 ACN 113967486A
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- B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
- B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
- B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
- B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
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Abstract
Translated fromChinese
Description
Technical Field
The invention relates to the technical field of biological detection, in particular to a centrifugal micro-fluidic chip.
Background
The microfluidic chip is also called a Lab-on-a-chip (Lab-on-a-chip), and is characterized in that basic operation units related to the fields of biology, chemistry, medicine and the like, such as sample preparation, reaction, separation, detection and the like, are integrated on a chip with a micro-channel with a micron scale, and the whole process of reaction and analysis is automatically completed. The analysis and detection device based on the microfluidic chip has the advantages that: the sample dosage is less, the analysis speed is fast, the portable instrument is convenient to manufacture, and the method is very suitable for real-time and on-site analysis. When the centrifugal micro-fluidic chip is used as one branch of the centrifugal micro-fluidic chip, when driving chips such as a motor and the like rotate, reagents pre-embedded in the chip and added samples finish flowing, mixing and reacting in the chip, the whole process is finished in the closed chip, and cross contamination is avoided. Meanwhile, the centrifugal microfluidic chip has the advantages of simplicity and convenience in operation, simplicity in training and the like.
Chemiluminescence immunoassay, also known as luminescence, refers to the light radiation generated by chemical reactions without any excitation by light, heat or electric field, which combines highly sensitive chemiluminescence detection techniques with highly specific antigen-antibody immunoreactions to detect the content of antigen or antibody in the test subject. Because an external excitation light source is not needed, background interference can be avoided and the signal-to-noise ratio can be greatly improved. Can be used for detecting various antigens, antibodies, hormones, enzymes, fatty acids, vitamins, medicines and the like, can be used as a substitute of radioimmunoassay and enzyme-linked immunoassay, and is an important development direction of immunoassay. Chemiluminescence immunoassay comprises two main components, namely an immunoreaction system and a chemiluminescence analysis system. The immune reaction system is based on the basic principle of antigen-antibody reaction, and the luminescent substance is directly marked on the antigen or the antibody, or the enzyme is used for a luminescent substrate; the chemiluminescence analysis system utilizes chemiluminescence substance to form an excited state through catalysis of a catalyst and oxidation of an oxidant, when unstable excited state molecules return to a stable ground state, energy is released to emit photons, and a photon signal detector is utilized to measure the luminous intensity of a luminous reaction, so that the content of a substance to be measured is calculated.
The chemiluminescent immunoassay step is cumbersome and time consuming: firstly, capture antibody, antigen, detection antibody linked with enzyme, cleaning solution and substrate are added in sequence. And (II) incubation and washing steps are required among all the steps. And thirdly, the clinical sample (whole blood) needs to be subjected to sample pretreatment in advance, and serum is taken out after high-speed centrifugation so as to carry out the experiment. Therefore, it is an important subject to integrate the method into a simple and fast detection method.
Disclosure of Invention
The invention provides a centrifugal microfluidic chip to solve at least one of the disadvantages of the related art.
In order to achieve the above object, an embodiment of the present invention provides a centrifugal microfluidic chip, which at least includes a set of detection structures, where each set of detection structures at least includes:
a first microfluidic channel within the substrate and/or cover plate, the first microfluidic channel comprising a first section having an outlet and a second section having an inlet;
and a first movable member having a first state and a second state; when the first movable part is positioned in the first state, a closed space is formed among the first movable part, the outlet of the first section and the inlet of the second section so as to conduct the first microfluidic channel; when the first movable part is located in the second state, the first movable part respectively seals off the outlet of the first section and the inlet of the second section so as to cut off the first micro-flow channel.
Optionally, the first movable component is an elastic film layer.
Optionally, the centrifugal microfluidic chip further comprises a first magnetic material body and a first magnetizable material body, and one of the first magnetic material body and the first magnetizable material body is close to the other one of the first magnetic material body and the first magnetizable material body and presses the elastic film layer to deform, so that the elastic film layer is in the second state.
Optionally, the first microfluidic channel is located in the substrate, and the first movable element is disposed on the cover plate.
Optionally, the outlet of the first section and the inlet of the second section are located within the cover plate.
Optionally, each group of the detection structures further includes: the first reaction cavity and the first waste liquid cavity are connected through the first micro-flow channel.
Optionally, magnetic beads coated with antibodies are buried in the first reaction cavity; each set of detection structures further includes: and the second reaction cavity is internally embedded with an enzyme-labeled antibody.
Optionally, the first reaction chamber, the first waste liquid chamber, the first microfluidic channel and the first movable element are respectively provided with a plurality of chambers, and each first reaction chamber is embedded with magnetic beads coated with antibodies; the coated antibodies bound by the magnetic beads buried in different first reaction cavities are different.
Optionally, each group of the detection structures further includes:
the cleaning solution storage cavity and a second micro-flow channel are connected with the cleaning solution storage cavity and the first reaction cavity; the second microfluidic channel comprises a third section and a fourth section, the third section having an outlet and the fourth section having an inlet;
and a second movable member having a first state and a second state; when the second movable part is positioned in the first state, a closed space is formed among the second movable part, the outlet of the third section and the inlet of the fourth section so as to conduct the second microfluidic channel; when the second movable part is located in the second state, the second movable part respectively seals off the outlet of the third section and the inlet of the fourth section so as to cut off the second micro-flow channel.
Optionally, the second microfluidic channel is provided with a first liquid stopping pit for buffering the flow rate of the cleaning liquid.
Optionally, each group of the detection structures further includes:
the luminescent substrate storage cavity and a third microflow channel are connected with the luminescent substrate storage cavity and the first reaction cavity; the third microfluidic channel comprises a fifth section and a sixth section, the fifth section having an outlet and the sixth section having an inlet;
and a third movable member having a first state and a second state; when the third movable part is positioned in the first state, a closed space is formed among the third movable part, the outlet of the fifth section and the inlet of the sixth section so as to conduct the third microfluidic channel; when the third movable element is located in the second state, the outlet of the fifth section and the inlet of the sixth section are respectively blocked by the third movable element, so that the third micro-flow channel is cut off.
Optionally, the third microfluidic channel is provided with a second liquid blocking pit for buffering the flow rate of the luminescent substrate.
According to the above embodiment of the present invention, the centrifugal microfluidic chip at least includes a set of detection structures, each set of detection structures at least includes: the first microfluidic channel is positioned in the substrate and/or the cover plate and comprises a first section and a second section, the first section is provided with an outlet, and the second section is provided with an inlet; the first movable member has a first state and a second state; when the first movable part is positioned in the first state, a closed space is formed among the first movable part, the outlet of the first section and the inlet of the second section so as to conduct the first microflow channel; when the first movable component is located in the second state, the first movable component respectively seals off the outlet of the first section and the inlet of the second section so as to cut off the first micro-flow channel. The first movable part realizes the selective conduction and the disconnection of the first micro-flow channel, and the first micro-flow channel is always closed, thereby avoiding the cross infection. In addition, the centrifugal microfluidic chip can be combined with immunochemiluminescence, so that the fluid in the centrifugal structure is more controllable.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments consistent with the invention and together with the description, serve to explain the principles of the invention.
Fig. 1 is a schematic bottom view of a centrifugal microfluidic chip according to a first embodiment of the present invention;
FIG. 2 is an exploded view of the P region of FIG. 1;
FIG. 3 is a schematic view of the structure taken along line AA in FIG. 2;
FIG. 4 is a schematic structural diagram of a sandwich structure formed by binding of antibody-coated magnetic beads, antigen and enzyme-labeled antibody;
fig. 5 is a flowchart of a control method of a centrifugal microfluidic chip according to a first embodiment of the present invention;
FIG. 6 is a schematic bottom view of a microfluidic chip according to a second embodiment of the present invention;
fig. 7 is a schematic bottom view of a microfluidic chip according to a third embodiment of the present invention.
List of reference numerals:
centrifugal micro-fluidic chip 1, 2, 3substrate 11
Firstmovable member 14 enclosesspace 13a
The cleaningliquid storage chamber 19 and the secondmicrofluidic channel 20
First liquid-blockingpit 27 and second liquid-blocking pit 28
Exhausthole 29sealing ring 30
First body ofmagnetic material 31 first body ofmagnetizable material 32
Detailed Description
Reference will now be made in detail to the exemplary embodiments, examples of which are illustrated in the accompanying drawings. When the following description refers to the accompanying drawings, like numbers in different drawings represent the same or similar elements unless otherwise indicated. The embodiments described in the following exemplary embodiments do not represent all embodiments consistent with the present invention. Rather, they are merely examples of apparatus and methods consistent with certain aspects of the invention, as detailed in the appended claims.
Fig. 1 is a schematic bottom view of a microfluidic chip according to a first embodiment of the present invention. Fig. 2 is an exploded view of the P region of fig. 1, and fig. 3 is a view taken along line AA of fig. 2.
Referring to fig. 1 to 3, a centrifugal microfluidic chip 1 at least includes a set of detection structures, each set of detection structures at least includes:
a firstmicrofluidic channel 13 located in thesubstrate 11 and/or thecover plate 12, the firstmicrofluidic channel 13 including afirst section 131 and asecond section 132, thefirst section 131 having anoutlet 131a, thesecond section 132 having aninlet 132 b;
and a firstmovable member 14, the firstmovable member 14 having a first state and a second state; when the firstmovable member 14 is in the first state, aclosed space 13a is formed between the firstmovable member 14 and theoutlet 131a of thefirst section 131 and theinlet 132b of thesecond section 132 to communicate the firstmicrofluidic channel 13; in the second state, the firstmovable member 14 blocks theoutlet 131a of thefirst section 131 and theinlet 132b of thesecond section 132, respectively, to shut off the firstmicrofluidic channel 13.
Referring to fig. 2 and 3, in the present embodiment, thecover plate 12 has two holes aligned with thefirst section 131 and thesecond section 132 of thesubstrate 11, respectively. In other words, theoutlet 131a of thefirst section 131 and theinlet 132b of thesecond section 132 are disposed on thecover plate 12. In some embodiments, theoutlet 131a of thefirst section 131 and theinlet 132b of thesecond section 132 may also be disposed on thesubstrate 11. Compared with the latter embodiment, the former embodiment can increase the length of thefirst section 131 and thesecond section 132, so that the flow speed can be buffered while the liquid flows through, and the gas in the liquid can be discharged to prevent the flow interruption.
Still referring to fig. 2 and 3, thecover plate 12 has a receiving hole that receives the firstmovable member 14. In this embodiment, the firstmovable member 14 may be an elastic membrane secured within the receiving hole with aseal ring 30. The sealingring 30 can be made of soft materials such as rubber, silica gel, PE film material and the like, and the thickness can be 0.1 mm-1 mm. Preferably, theseal ring 30 is a silicone sheet having a thickness of 0.5 mm. The sealingring 30 may be in interference fit or may be adhered to the elastic film layer and thecover plate 12 by using an adhesive. The side of the sealingring 30 remote from thebase 11 is provided with afirst body 31 of magnetic material, for example a magnet. Correspondingly, the side of thesubstrate 11 facing away from thecover plate 12 is provided with afirst body 32 of magnetizable material, for example an iron block.
When the firstmagnetic material body 31 approaches the firstmagnetizable material body 32, the two bodies attract each other, and the elastic film layer is pressed to be in the second state.
The firstmagnetic material body 31 is receivable in a receiving hole in thecover plate 12 that receives the firstmovable member 14. Thesubstrate 11 may have a receiving hole that receives the firstmagnetic material body 31.
In some embodiments, a side of theseal ring 30 remote from thebase 11 is provided with a first body ofmagnetizable material 32, for example an iron block. Accordingly, afirst body 31 of magnetic material, for example a magnet, is arranged on the side of the base 11 remote from thecover plate 12.
In some embodiments, firstmovable member 14 may be a rigid body that is mechanically driven to assume a first state and a second state.
In some embodiments, the firstmicrofluidic channel 13 may be disposed in thecover plate 12, and the firstmovable element 14 may be disposed on thesubstrate 11.
Referring to fig. 1, the set of detection structures further includes: thefirst reaction chamber 15 and the firstwaste liquid chamber 16, and the firstmicrofluidic channel 13 connects thefirst reaction chamber 15 and the firstwaste liquid chamber 16.
In addition, the set of detection structures may further include: asample cavity 17, asecond reaction cavity 18, a cleaningsolution storage cavity 19, a secondmicrofluidic channel 20, a luminescentsubstrate storage cavity 21 and a third microfluidic channel 22.
Wherein thesample chamber 17 is adapted to receive a sample to be tested. The opening of thesample chamber 17, i.e. the sample port, is located in thecover plate 12. Referring to fig. 1, in the present embodiment, the sample to be tested dropped into thesample chamber 17 through the sample port is blood. Thesample chamber 17 is connected to a bloodcell accommodating chamber 23. After blood is dropped into the sample port, the centrifugal microfluidic chip 1 is subjected to high-speed centrifugation, blood cells in the blood enter the bloodcell accommodating chamber 23, and serum is retained in thesample chamber 17.
In some embodiments, the sample to be tested that is dripped into thesample chamber 17 through the sample port may be serum. In this case, the centrifugation step and the bloodcell accommodating chamber 23 are omitted.
A variety of antigens are contained in serum.
Thesample chamber 17 is connected to thesecond reaction chamber 18 by a first siphon 24.
The serum in the first siphontube 24 will undergo a capillary phenomenon. That is, when the centrifugal rate of the centrifugal microfluidic chip 1 is low or at rest, the serum infiltrates the inner wall of the first siphontube 24 under the action of surface tension until the boundary between the first siphontube 24 and thesecond reaction chamber 18 stops.
To generate the capillary phenomenon, the cross-sectional area of the first siphontube 24 is much smaller than the cross-sectional area of thesecond reaction chamber 18 at the interface of the first siphontube 24 and thesecond reaction chamber 18. Preferably, the ratio of the two may be 1: 10 to 1: 10000.
In order to prevent the serum and the blood cells from being centrifuged into thesecond reaction chamber 18 during the separation process, the first siphontube 24 includes a bending part, and the bending part is close to the rotation axis of the centrifugal microfluidic chip 1 (in this embodiment, the center of the centrifugal microfluidic chip 1) relative to the connection end of the first siphontube 24 and thesample chamber 17.
The centrifugal microfluidic chip 1 is subjected to high-speed centrifugation, and serum at the junction of the first siphon 24 and thesecond reaction chamber 18 enters thesecond reaction chamber 18. The high-speed centrifugation of this step may be forward and reverse centrifugation to allow the serum to react sufficiently in thesecond reaction chamber 18.
Thesecond reaction chamber 18 is embedded with an enzyme-labeled antibody, and can be pre-embedded in a freeze-dried solid state. Enzyme-labeled antibodies refer to: the antibody binds to the enzyme. The enzyme may be alkaline phosphatase, which catalyzes the luminescence of certain chemicals. The antibody is an antibody that specifically binds to a certain antigen in serum.
After the enzyme-labeled antibody binds to the antigen in the serum, a first reaction solution is generated.
Thesecond reaction chamber 18 is connected to thefirst reaction chamber 15 by a second siphon 25.
The first reaction liquid in the second siphon 25 is subject to a capillary phenomenon. That is, when the centrifugal rate of the centrifugal microfluidic chip 1 is low or at rest, the first reaction liquid infiltrates the inner wall of the second siphon 25 under the action of surface tension until the boundary between the second siphon 25 and thefirst reaction chamber 15 stops.
In order to generate the capillary phenomenon, the cross-sectional area of the second siphontube 25 is much smaller than that of thefirst reaction chamber 15 at the interface of the second siphontube 25 and thefirst reaction chamber 15. Preferably, the ratio of the two may be 1: 10 to 1: 10000.
In order to prevent the first reaction liquid from being centrifuged into thefirst reaction chamber 15 during the forward and backward centrifugation for sufficiently reacting the serum in thesecond reaction chamber 18, the second siphon 25 includes a bent portion which is close to the rotation axis of the microfluidic chip 1 (the center of the microfluidic chip 1 in this embodiment) with respect to the connection end of the second siphon 25 and thesecond reaction chamber 18. In order to prevent the first reaction liquid from being centrifuged into thesample chamber 17 during the forward and backward centrifugation for sufficiently reacting the serum in thesecond reaction chamber 18, the bent portion of the first siphontube 24 is close to the rotation axis of the microfluidic chip 1 (the center of the microfluidic chip 1 in this embodiment) with respect to the connection end of the first siphontube 24 and thesecond reaction chamber 18.
In this embodiment, thesecond reaction chamber 18 is close to the rotation axis of the centrifugal microfluidic chip 1 (in this embodiment, the center of the centrifugal microfluidic chip 1), and thefirst reaction chamber 15 is far from the rotation axis of the centrifugal microfluidic chip 1 (in this embodiment, the center of the centrifugal microfluidic chip 1).
And (3) carrying out high-speed centrifugation on the centrifugal microfluidic chip 1, and enabling the first reaction liquid at the junction of the second siphon 25 and thefirst reaction chamber 15 to enter thefirst reaction chamber 15. The high-speed centrifugation in this step may be forward and reverse centrifugation to allow the first reaction solution to react sufficiently in thefirst reaction chamber 15.
In some embodiments, in order to ensure sufficient first reaction liquid, the centrifugal microfluidic chip 1 is centrifuged at high speed, and a part of the first reaction liquid at the interface of the second siphon 25 and thefirst reaction chamber 15 enters thefirst reaction chamber 15, and the rest enters the secondwaste liquid chamber 26.
Thefirst reaction chamber 15 is embedded with magnetic beads for coating antibodies, and may be embedded in a freeze-dried solid state. The magnetic beads coated with the antibody refer to: the antibody is bound to the magnetic beads. The magnetic beads may be particles of a magnetic material or particles of a magnetizable material, which may attract the magnetizable material to be attracted by the magnetic material. The magnetic beads coated with the antibody are used for reacting with the first reaction liquid to generate a second reaction liquid, and in the second reaction liquid, the magnetic beads coated with the antibody are combined with a combination of an enzyme-labeled antibody and an antigen to form a sandwich structure.
FIG. 4 is a schematic diagram of a sandwich structure formed by binding of antibody-coated magnetic beads, antigen, and enzyme-labeled antibody. Referring to fig. 4, the antibody-coated magnetic beads can be combined with the conjugates of the enzyme-labeled antibody and the antigen to form a sandwich structure by the specific binding of the antibody and the antigen.
And combining the magnetic beads coated with the antibody with a conjugate of an enzyme-labeled antibody and an antigen to generate a second reaction solution.
In order to prevent the first reaction liquid from flowing into thefirst reaction chamber 15, the volume of thesecond reaction chamber 18 may be much larger than the volume of thefirst reaction chamber 15, in other words, thesecond reaction chamber 18 is a mixing chamber.Second reaction chamber 18 may be connected to avent 29 to release gas from the liquid insecond reaction chamber 18 to prevent flow interruption.
It should be noted that, the centrifugal microfluidic chip 1 is subjected to forward and backward high-speed centrifugation, before the first reaction liquid enters thefirst reaction chamber 15 for reaction, the firstmagnetic material body 31 is controlled to be close to the firstmagnetizable material body 32, and the extrusion elastic film layer is in the second state.
After the forward and reverse high-speed centrifugation is finished, namely the second reaction liquid is generated, the second magnetic material body or the second magnetic material body is controlled to be close to thefirst reaction cavity 15 so as to adsorb magnetic beads. Then, the firstmagnetic material body 31 is controlled to be away from the firstmagnetizable material body 32, so that the elastic membrane layer is in the first state, the centrifugal microfluidic chip 1 is subjected to high-speed centrifugation, and the enzyme-labeled antibody and antigen conjugate which is not bound to the antibody-coated magnetic beads in the second reaction solution and the liquid enter the firstwaste liquid chamber 16.
In this embodiment, the firstwaste liquid chamber 16 is far from the rotation axis of the centrifugal microfluidic chip 1 (the center of the centrifugal microfluidic chip 1 in this embodiment) relative to thefirst reaction chamber 15.
Then, the firstmagnetic material body 31 is controlled to be close to the firstmagnetizable material body 32, and the elastic film layer is pressed to be in the second state.
The cleaning solution stored in the cleaningsolution storage chamber 19 is used to wash the unbound enzyme-labeled antibody attached to the sandwich structure. After the cleaning liquid is released from the cleaningliquid storage cavity 19, when the centrifugal rate of the centrifugal microfluidic chip 1 is low or the centrifugal microfluidic chip is static, the cleaning liquid can infiltrate to the junction between the first siphon 24 and thesecond reaction cavity 18 by utilizing the capillary phenomenon in the first siphon 24 and stop. And (3) carrying out high-speed centrifugation on the centrifugal microfluidic chip 1 to enable the cleaning solution to enter thesecond reaction cavity 18. The centrifugal speed of the centrifugal microfluidic chip 1 is low or static, and the cleaning solution can infiltrate into the boundary between the second siphon 25 and thefirst reaction chamber 15 to stop by utilizing the capillary phenomenon in the second siphon 25. And (3) carrying out high-speed centrifugation on the centrifugal microfluidic chip 1 to enable the cleaning solution to enter thefirst reaction cavity 15. The washing solution washes unbound enzyme-labeled antibody attached to the sandwich structure. And controlling the firstmagnetic material body 31 to be far away from the firstmagnetizable material body 32, enabling the elastic film layer to be in a first state, carrying out high-speed centrifugation on the centrifugal micro-fluidic chip 1, and enabling the enzyme-labeled antibody under washing to enter the firstwaste liquid cavity 16.
In this embodiment, the cleaningsolution storage chamber 19 is close to the rotation axis of the centrifugal microfluidic chip 1 (the center of the centrifugal microfluidic chip 1 in this embodiment) relative to thesecond reaction chamber 18.
In some embodiments, the centrifugal microfluidic chip 1 may further include a second movable part. The secondmicrofluidic channel 20 includes a third section having an outlet and a fourth section having an inlet. The second movable member has a first state and a second state; when the second movable part is in the first state, a closed space is formed among the second movable part, the outlet of the third section and the inlet of the fourth section so as to conduct the secondmicrofluidic channel 20; when the second movable element is in the second state, the second movable element blocks the outlet of the third section and the inlet of the fourth section respectively to cut off the secondmicrofluidic channel 20. In other words, the release of the cleaning liquid is performed by controlling the second movable member to conduct the secondmicro flow path 20.
The specific structure and the arrangement method of the second movable member can be referred to the specific structure and the arrangement method of the firstmovable member 14.
In some embodiments, the cleaningsolution storage chamber 19 may release the cleaning solution by a release method known in the related art.
In some embodiments, the cleaningsolution storage chamber 19 may be connected to thefirst reaction chamber 15 through a secondmicrofluidic channel 20.
In other embodiments, the secondmicrofluidic channel 20 may be provided with a firstliquid stopping pit 27 for buffering the flow rate of the cleaning liquid to prevent bubbles from being generated and causing flow interruption.
The firstwaste liquid chamber 16 is used for collecting the conjugate of the enzyme-labeled antibody and the antigen that is not bound to the antibody-coated magnetic beads in the second reaction liquid, the enzyme-labeled antibody washed by the washing liquid, and the liquid in the second reaction liquid.
The luminescent substrate stored in the luminescentsubstrate storage chamber 21 is catalyzed by the labeled enzyme in the sandwich structure to emit light for detecting the antigen in the sandwich structure. After the luminescentsubstrate storage cavity 21 releases the luminescent substrate, when the centrifugal rate of the centrifugal microfluidic chip 1 is low or the centrifugal microfluidic chip is static, the luminescent substrate can be infiltrated to the junction of the first siphonpipe 24 and thesecond reaction cavity 18 by utilizing the capillary phenomenon in the first siphonpipe 24 to stop. The centrifugal microfluidic chip 1 is centrifuged at high speed to make the luminescent substrate enter thesecond reaction chamber 18. The centrifugal speed of the centrifugal microfluidic chip 1 is low or static, and the luminescent substrate can be infiltrated to the junction of the second siphonpipe 25 and thefirst reaction chamber 15 to stop by utilizing the capillary phenomenon in the second siphonpipe 25. The centrifugal microfluidic chip 1 is subjected to high-speed centrifugation, so that the luminescent substrate enters thefirst reaction chamber 15. The enzyme catalysis luminescence substrate in the sandwich structure emits light and can be used for detecting the antigen in the sandwich structure.
In this embodiment, the luminescentsubstrate storage chamber 21 is close to the rotation axis of the microfluidic chip 1 (in this embodiment, the center of the microfluidic chip 1) relative to thesecond reaction chamber 18.
In some embodiments, the centrifugal microfluidic chip 1 may further include a third movable part. The third microfluidic channel 22 includes a fifth section having an outlet and a sixth section having an inlet. The third movable member has a first state and a second state; when the third movable element is in the first state, a closed space is formed between the third movable element and the outlet of the fifth section and the inlet of the sixth section so as to conduct the third microfluidic channel 22; when in the second state, the third movable element blocks the outlet of the fifth section and the inlet of the sixth section respectively to cut off the third microfluidic channel 22. In other words, the release of the luminescent substrate is achieved by controlling the third movable element to render the third microfluidic channel 22 conductive.
The specific structure and the arrangement method of the third movable member can refer to those of the firstmovable member 14.
In some embodiments, the luminogenicsubstrate storage chamber 21 may release luminogenic substrate using release methods known in the relevant art.
In some embodiments, the luminogenicsubstrate storage chamber 21 may be connected to thefirst reaction chamber 15 by a third microfluidic channel 22.
In other embodiments, the third microfluidic channel 22 is provided with a second liquid blocking pit 28 for buffering the flow rate of the luminescent substrate to prevent bubbles from being generated and causing flow interruption.
Thesample chamber 17, thesecond reaction chamber 18, the first siphontube 24, thefirst reaction chamber 15, the second siphontube 25, the cleaningsolution storage chamber 19, the secondmicrofluidic channel 20, the firstwaste solution chamber 16, the firstmicrofluidic channel 13, the luminescentsubstrate storage chamber 21, and the third microfluidic channel 22 may be located on thesubstrate 11, and the firstmovable member 14 may be located on thecover plate 12.
Fig. 5 is a flowchart of a control method of a centrifugal microfluidic chip according to a first embodiment of the present invention. Referring to fig. 5, the control method includes:
step S1: monitoring whether thesample cavity 17 receives a sample to be detected in real time;
if yes, go to step S2: sequentially setting a first time period when the centrifugal micro-fluidic chip 1 is in a low-speed centrifugal mode or a static mode, a second time period when the centrifugal micro-fluidic chip 1 is in a positive and negative high-speed centrifugal mode, a third time period when the centrifugal micro-fluidic chip 1 is in the low-speed centrifugal mode or the static mode, controlling the first movable part 14 to be in the second state, setting the first movable part 14 to be in the positive and negative high-speed centrifugal mode, setting the centrifugal micro-fluidic chip 1 to be in the high-speed centrifugal mode, releasing the cleaning solution, setting the centrifugal micro-fluidic chip 1 to be in the low-speed centrifugal mode or the static mode, setting the centrifugal micro-fluidic chip 1 to be in the twelfth time period when the centrifugal micro-fluidic chip is in the positive and negative high-speed centrifugal mode, setting the centrifugal micro-fluidic chip 1 to be in the low-speed centrifugal mode or the static mode, controlling the first movable part 14 to be in the second state, setting the centrifugal micro-fluidic chip 1 to be in the positive and negative high-speed centrifugal mode, setting the seventh time period when the centrifugal micro-fluidic chip 1 is in the positive and negative high-speed centrifugal mode, The fixed magnetic beads are positioned in the first reaction chamber 15, the first movable part 14 is controlled to be in the first state, the centrifugal microfluidic chip 1 is set to be in a high-speed centrifugation mode for the eighth time period, the luminescent substrate is released, the centrifugal microfluidic chip 1 is set to be in a low-speed centrifugation mode or a rest mode for the thirteenth time period, the centrifugal microfluidic chip 1 is set to be in a forward and reverse high-speed centrifugation mode for the fourteenth time period, the centrifugal chip is set to be in a low-speed centrifugation mode or a rest mode for the ninth time period, the first movable part 14 is controlled to be in the second state, and the centrifugal microfluidic chip 1 is set to be in a forward and reverse high-speed centrifugation mode for the tenth time period;
if not, the process returns to step S1: thesample chamber 17 is monitored in real time for the receipt of the sample to be tested.
After step S1, the following steps may be performed: step S11, it is detected whether the amount of the sample to be detected is larger than a predetermined amount. If yes, go to step S2; if not, the process returns to step S11, and it is detected whether the amount of the sample to be detected is larger than a predetermined amount. In some embodiments, when returning to step S11, an alarm is also provided to indicate that the amount of sample to be tested is too small.
Step S2 may include steps S211 to S233.
Step S211: when the centrifugal microfluidic chip 1 is in the low-speed centrifugation mode or the static mode for the first time period, the serum infiltrates the inner wall of the first siphon 24 under the action of the surface tension until the junction of the first siphon 24 and thesecond reaction chamber 18 stops.
When the sample to be detected dropped into thesample chamber 17 is blood, step S210 is further executed before step S211: the centrifugal microfluidic chip 1 is set in a high-speed centrifugation mode for a fifteenth period of time to separate blood into serum and blood cells.
Step S212: when the centrifugal micro-fluidic chip 1 is in the forward and reverse high-speed centrifugation mode for the second time period, the serum at the junction of the first siphon 24 and thesecond reaction cavity 18 enters thesecond reaction cavity 18, and the antigen in the serum is combined with the enzyme-labeled antibody buried in thesecond reaction cavity 18 to generate the first reaction liquid.
Step S213: when the centrifugal microfluidic chip 1 is in the low-speed centrifugal mode or the static mode for the third time period, the first reaction liquid infiltrates the inner wall of the second siphon 25 under the action of surface tension until the boundary between the second siphon 25 and thefirst reaction chamber 15 stops.
Step S214: the firstmovable element 14 is controlled to be in the second state to shut off the firstmicrofluidic channel 13.
Step S215: when the centrifugal micro-fluidic chip 1 is in the forward and reverse high-speed centrifugation mode for the fourth time period, the first reaction liquid at the junction of the second siphon 25 and thefirst reaction cavity 15 enters thefirst reaction cavity 15, and the conjugate of the antigen and the enzyme-labeled antibody in the first reaction liquid is combined with the magnetic beads embedded in thefirst reaction cavity 15 and coated with the antibody to form a sandwich structure, so that the second reaction liquid is generated.
Step S216: the fixed magnetic beads are located in thefirst reaction chamber 15, and the sandwich structure can be fixed in thefirst reaction chamber 15.
Step S217: the firstmovable element 14 is controlled to be in the first state to conduct the firstmicrofluidic channel 13.
Step S218: when the centrifugal microfluidic chip 1 is in the high-speed centrifugation mode for the fifth time period, the conjugate of the enzyme-labeled antibody and the antigen, which is not bound to the antibody-coated magnetic beads, in the second reaction liquid and the liquid enter the firstwaste liquid chamber 16.
Step S219: in some embodiments, the release of the cleaning fluid may be achieved by the second movable element being in communication with the secondmicrofluidic channel 20.
Step S220: when the centrifugal microfluidic chip 1 is in the low-speed centrifugal mode or the static mode for the eleventh time period, the cleaning solution infiltrates into the junction between the first siphon 24 and thesecond reaction chamber 18 by utilizing the capillary phenomenon in the first siphon 24 and stops.
Step S221: when the centrifugal micro-fluidic chip 1 is in the forward and reverse high-speed centrifugal mode for the twelfth time period, the cleaning solution at the junction of the first siphon 24 and thesecond reaction chamber 18 enters thesecond reaction chamber 18.
Step S222: when the centrifugal microfluidic chip 1 is in the low-speed centrifugal mode or the static mode for the sixth time period, the cleaning solution infiltrates to the junction of the second siphon 25 and thefirst reaction chamber 15 by using the capillary phenomenon in the second siphon 25 and stops.
Step S223: the firstmovable element 14 is controlled to be in the second state to shut off the firstmicrofluidic channel 13.
Step S224: when the centrifugal microfluidic chip 1 is in the forward and reverse high-speed centrifugation mode in the seventh time period, the cleaning solution washes the unbound enzyme-labeled antibody attached to the sandwich structure.
Step S225: the fixed magnetic beads are located in thefirst reaction chamber 15, and the sandwich structure can be fixed in thefirst reaction chamber 15.
Step S226: the firstmovable element 14 is controlled to be in the first state to conduct the firstmicrofluidic channel 13.
Step S227: when the centrifugal micro-fluidic chip 1 is set to be in the high-speed centrifugation mode for the eighth time period, the enzyme-labeled antibody under washing enters the firstwaste liquid cavity 16.
Step S228: in some embodiments, release of the luminescent substrate may be achieved by a third movable element communicating with the third microfluidic channel 22.
Step S229: when the centrifugal microfluidic chip 1 is in the low-speed centrifugation mode or the static mode for the thirteenth time period, the luminescent substrate infiltrates into the junction between the first siphontube 24 and thesecond reaction chamber 18 by utilizing the capillary phenomenon in the first siphontube 24 and stops.
Step S230: when the centrifugal micro-fluidic chip 1 is in the forward and reverse high-speed centrifugation mode for the fourteenth time period, the luminescent substrate located at the intersection of the first siphon 24 and thesecond reaction chamber 18 enters thesecond reaction chamber 18.
Step S231: when the centrifugal micro-fluidic chip 1 is in the low-speed centrifugal mode or the static mode for the ninth time period, the luminescent substrate soaks to the boundary of the second siphonpipe 25 and thefirst reaction cavity 15 and stops by utilizing the capillary phenomenon in the second siphonpipe 25.
Step S232: the firstmovable element 14 is controlled to be in the second state to shut off the firstmicrofluidic channel 13.
Step S233: when the centrifugal microfluidic chip 1 is in the forward and reverse high-speed centrifugation mode for the tenth time period, the luminescent substrate at the junction of the second siphon 25 and thefirst reaction chamber 15 enters thefirst reaction chamber 15, and the enzyme catalysis luminescent substrate in the sandwich structure emits light and can be used for detecting the antigen in the sandwich structure.
In the centrifugal microfluidic chip 1 in which the cleaningsolution storage chamber 19 is connected to thefirst reaction chamber 15 through the secondmicrofluidic channel 20, the steps S220 and S221 are omitted in the control method.
In the centrifugal microfluidic chip 1 in which the luminescentsubstrate storage chamber 21 is connected to thefirst reaction chamber 15 through the third microfluidic channel 22, the steps S229 and S230 are omitted in the control method.
Fig. 6 is a schematic bottom view of a centrifugal microfluidic chip according to a second embodiment of the present invention. Referring to fig. 6, the centrifugal microfluidic chip 2 and the control method thereof in the second embodiment are substantially the same as the centrifugal microfluidic chip 1 and the control method thereof in the first embodiment, and the differences are only: thefirst reaction chamber 15 has a plurality of different coated antibodies bound to the magnetic beads buried in thefirst reaction chamber 15, and the coated antibodies are used for specific binding with different antigens in the sample to be detected. Accordingly, the firstwaste liquid chamber 16, the firstmicrofluidic channel 13, and the firstmovable member 14 are plural in number, respectively.
Because the antigens in the sample to be detected are various, the specific combination of the coating antibody combined by the magnetic beads can be utilized, and the kit is suitable for detecting different antigens by different antibodies. The centrifugal microfluidic chip 2 has more detection items.
Fig. 7 is a schematic bottom view of a microfluidic chip according to a third embodiment of the present invention. Referring to fig. 7, the centrifugal microfluidic chip 3 and the control method thereof in the third embodiment are substantially the same as the centrifugal microfluidic chips 1 and 2 and the control method thereof in the first and second embodiments, and the differences are only: the detection structures are multiple groups and are used for simultaneously detecting a plurality of samples to be detected.
After thesample cavity 17 of each group of detection structures is dripped into blood of different patients, a plurality of samples to be detected can be simultaneously detected in one detection process, and the efficiency can be improved.
It is noted that in the drawings, the sizes of layers and regions may be exaggerated for clarity of illustration. Also, it will be understood that when an element or layer is referred to as being "on" another element or layer, it can be directly on the other element or layer or intervening layers may also be present. In addition, it will be understood that when an element or layer is referred to as being "under" another element or layer, it can be directly under the other element or intervening layers or elements may also be present. In addition, it will also be understood that when a layer or element is referred to as being "between" two layers or elements, it can be the only layer between the two layers or elements, or more than one intermediate layer or element may also be present. Like reference numerals refer to like elements throughout.
In the present invention, the terms "first" and "second" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance.
Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the disclosure disclosed herein. This invention is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.
It will be understood that the invention is not limited to the precise arrangements described above and shown in the drawings and that various modifications and changes may be made without departing from the scope thereof. The scope of the invention is limited only by the appended claims.
Claims (12)
1. A centrifugal microfluidic chip, comprising at least one set of detection structures, each set of detection structures comprising at least:
a first microfluidic channel within the substrate and/or cover plate, the first microfluidic channel comprising a first section having an outlet and a second section having an inlet;
and a first movable member having a first state and a second state; when the first movable part is positioned in the first state, a closed space is formed among the first movable part, the outlet of the first section and the inlet of the second section so as to conduct the first microfluidic channel; when the first movable part is located in the second state, the first movable part respectively seals off the outlet of the first section and the inlet of the second section so as to cut off the first micro-flow channel.
2. The microfluidic centrifugal chip of claim 1, wherein the first movable part is an elastic membrane layer.
3. The centrifugal microfluidic chip of claim 2, further comprising a first body of magnetic material and a first body of magnetizable material, one of the first body of magnetic material and the first body of magnetizable material being proximate to the other to compress the elastic membrane layer to deform the elastic membrane layer to the second state.
4. The microfluidic centrifugal chip of claim 1, wherein the first microfluidic channel is located in the base, and the first movable part is disposed on the cover plate.
5. The microfluidic centrifugal chip of claim 4, wherein the outlet of the first section and the inlet of the second section are located in the cover plate.
6. The microfluidic centrifugal chip of claim 1, wherein each set of detection structures further comprises: the first reaction cavity and the first waste liquid cavity are connected through the first micro-flow channel.
7. The centrifugal microfluidic chip according to claim 6, wherein magnetic beads coated with antibodies are buried in the first reaction chamber; each set of detection structures further includes: and the second reaction cavity is internally embedded with an enzyme-labeled antibody.
8. The centrifugal microfluidic chip according to claim 6, wherein the first reaction chamber, the first waste chamber, the first microfluidic channel, and the first movable member each have a plurality of chambers, and each of the first reaction chambers has an antibody-coated magnetic bead embedded therein; the coated antibodies bound by the magnetic beads buried in different first reaction cavities are different.
9. The microfluidic centrifugal chip of claim 6, wherein each set of detection structures further comprises:
the cleaning solution storage cavity and a second micro-flow channel are connected with the cleaning solution storage cavity and the first reaction cavity; the second microfluidic channel comprises a third section and a fourth section, the third section having an outlet and the fourth section having an inlet;
and a second movable member having a first state and a second state; when the second movable part is positioned in the first state, a closed space is formed among the second movable part, the outlet of the third section and the inlet of the fourth section so as to conduct the second microfluidic channel; when the second movable part is located in the second state, the second movable part respectively seals off the outlet of the third section and the inlet of the fourth section so as to cut off the second micro-flow channel.
10. The microfluidic centrifugal chip of claim 9, wherein the second microfluidic channel is provided with a first liquid stopping pit for buffering the flow rate of the cleaning liquid.
11. The microfluidic centrifugal chip of claim 6, wherein each set of detection structures further comprises:
the luminescent substrate storage cavity and a third microflow channel are connected with the luminescent substrate storage cavity and the first reaction cavity; the third microfluidic channel comprises a fifth section and a sixth section, the fifth section having an outlet and the sixth section having an inlet;
and a third movable member having a first state and a second state; when the third movable part is positioned in the first state, a closed space is formed among the third movable part, the outlet of the fifth section and the inlet of the sixth section so as to conduct the third microfluidic channel; when the third movable element is located in the second state, the outlet of the fifth section and the inlet of the sixth section are respectively blocked by the third movable element, so that the third micro-flow channel is cut off.
12. The microfluidic centrifugal chip of claim 11, wherein the third microfluidic channel is provided with a second liquid stopping pit for buffering the flow rate of the luminescent substrate.
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