CN112756017A - Micro-fluidic chip and in-vitro detection device - Google Patents
Micro-fluidic chip and in-vitro detection device Download PDFInfo
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- CN112756017A CN112756017A CN201911000623.8A CN201911000623A CN112756017A CN 112756017 A CN112756017 A CN 112756017A CN 201911000623 A CN201911000623 A CN 201911000623A CN 112756017 A CN112756017 A CN 112756017A
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- 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
- B01L3/50273—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 characterised by the means or forces applied to move the fluids
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- 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
- B01L3/502753—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 characterised by bulk separation arrangements on lab-on-a-chip devices, e.g. for filtration or centrifugation
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- 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
- B01L3/502761—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 specially adapted for handling suspended solids or molecules independently from the bulk fluid flow, e.g. for trapping or sorting beads, for physically stretching molecules
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2300/00—Additional constructional details
- B01L2300/08—Geometry, shape and general structure
- B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2400/00—Moving or stopping fluids
- B01L2400/04—Moving fluids with specific forces or mechanical means
- B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
- B01L2400/0409—Moving fluids with specific forces or mechanical means specific forces centrifugal forces
Abstract
The invention relates to a micro-fluidic chip capable of improving sample processing efficiency and an in-vitro detection device containing the micro-fluidic chip. This micro-fluidic chip is through designing the application of sample cavity, first microchannel, the second microchannel, a plurality of separation ration units, first capillary flow way and first waste liquid cavity, add the sample solution in the application of sample cavity after, through rotatory centrifugation, the sample solution can get into in the ration cavity under the centrifugal action, and fill up second waste liquid cavity and ration cavity in proper order, can further with solid waste material centrifugation such as blood cells deposit to the second waste liquid cavity with ration cavity intercommunication through the centrifugation in, realize the separation of samples such as whole blood and the ration in the ration cavity. After the sample solution is added into the micro-fluidic chip, the separation and quantification of impurities and target detection liquid in the sample solution can be realized only by one-time centrifugation without excessive centrifugal operation, so that the micro-fluidic chip is simple and convenient to operate, the waiting time is short, and the efficiency of sample treatment is obviously improved.
Description
Technical Field
The invention relates to the technical field of in-vitro diagnosis, in particular to a micro-fluidic chip and an in-vitro detection device.
Background
The In Vitro Diagnosis Industry (IVD) belongs to the pharmaceutical and biological industry, and refers to taking samples such as blood, body fluid, and tissue from human body, and detecting and checking the samples with In Vitro detection reagents, instruments, etc. to prevent, diagnose, treat, detect, later stage observe, health evaluate, and predict genetic diseases. In vitro diagnosis is divided into three major categories, biochemical diagnosis, immunological diagnosis and molecular diagnosis, and bedside rapid diagnosis POCT differentiated from biochemical, immunological and molecular diagnosis. The dry chemical reaction is one of biochemical diagnosis, and is to utilize biochemical reagent to react with specific substrate, and then to quantitatively detect the concentration of the target substance by an instrument, and to calculate some biochemical indexes of human body. The traditional biochemical diagnosis needs to be carried out on a large-scale biochemical analyzer, so that the problems of more reagent consumption, insufficient flexibility and the like are caused; the general dry biochemical POCT diagnosis mode is low in test throughput, and can test one or more samples and one or more items at a time. The microfluidic chip technology (Microfluidics) can integrate basic operation units of sample preparation, reaction, separation, detection and the like in the processes of biological, chemical and medical analysis on a chip, automatically complete the whole analysis process, greatly improve the detection efficiency, and have the advantages of miniaturization, automation and the like, so the microfluidic chip technology is more and more widely applied to the field of POCT.
In the field of biochemical detection, represented by Abaxis company in the United states, a microfluidic chip for biochemical detection is developed first, and similar microfluidic chips such as Tianjin micro-nano cores, Chengdu Simat and the like are developed in China. The chip of the traditional product is used for quantifying and distributing the whole blood sample, and the whole blood separation process and the serum quantification process are separated, so that the centrifugal separation and quantification are required for multiple times, the sample processing time is long, and the detection time is excessively prolonged.
Disclosure of Invention
In view of the above, it is desirable to provide a microfluidic chip capable of improving sample processing efficiency and an in vitro detection apparatus including the microfluidic chip.
A micro-fluidic chip is provided with a sample adding cavity, a first micro-channel, a second micro-channel, a separation quantification unit, a first capillary channel and a first waste liquid cavity; the sample adding cavity is provided with a sample adding hole and is communicated with the second micro-channel through the first micro-channel; the micro-fluidic chip is provided with a rotation center, and the second micro-channel is arranged around the rotation center; the first waste liquid cavity is communicated with the liquid outlet end of the second micro flow channel through the first capillary flow channel; the separation quantitative unit is provided with a plurality of separation quantitative units, each separation quantitative unit comprises a third micro-channel, a quantitative cavity and a second waste liquid cavity, the quantitative cavity is communicated with the second micro-channel through the third micro-channel, the second waste liquid cavity is communicated with the quantitative cavity, and the separation quantitative units are distributed around the second micro-channel on the inner side of the second micro-channel;
the first capillary channel is connected with the second micro channel, extends towards the direction close to the rotation center, bends and extends towards the direction far away from the rotation center on the inner side of the second micro channel so as to be communicated with the first waste liquid cavity; the third micro-channel extends from the second micro-channel to the direction close to the rotation center so as to be communicated with the quantitative cavity;
the distance between the connection position of the quantitative cavity and the third micro flow channel and the rotation center is not less than the distance between the bending peak position of the first capillary flow channel and the rotation center, and the second waste liquid cavity is far away from the rotation center than the quantitative cavity.
In one embodiment, the sample adding cavity is disposed around the rotation center, one end of the sample adding cavity is provided with the sample adding hole, and the other end of the sample adding cavity is connected with the first microchannel.
In one embodiment, the sample-adding cavity is further provided with a first air vent at one end connected with the first micro channel, and the first air vent is closer to the rotation center than the connection position of the sample-adding cavity and the first micro channel.
In one embodiment, the microfluidic chip further comprises a fifth micro channel, one end of the fifth micro channel is connected to the first waste liquid cavity, and the other end of the fifth micro channel is provided with a second air hole, and the second air hole is closer to the rotation center than the first waste liquid cavity.
In one embodiment, the first waste chamber is disposed around the center of rotation outside of the second microchannel; and/or
And the radial size of a section of the fifth micro-channel connected with the first waste liquid cavity is larger than that of a section close to the second air hole.
In one embodiment, each separation quantification unit further comprises a sixth micro-channel, and the quantification cavity is communicated with the third micro-channel through the sixth micro-channel;
the connection position of the sixth micro-channel and the third micro-channel is closer to the rotation center than the quantitative cavity; the distance between the connection position of the sixth micro flow channel and the third micro flow channel and the rotation center is not less than the distance between the bending peak position of the first capillary flow channel and the rotation center.
In one embodiment, the microfluidic chip further comprises a gas-permeable micro-channel, the gas-permeable micro-channel is communicated with the sixth micro-channel of each quantitative cavity, and a third gas hole is formed in the gas-permeable micro-channel;
the air-permeable micro flow channel is closer to the rotation center than the connection position of the sixth micro flow channel and the third micro flow channel.
In one embodiment, the air-permeable micro flow channel is annularly arranged around the rotation center inside the separation and quantification units, the third air holes are multiple, and the third air holes are distributed around the air-permeable micro flow channel.
In one embodiment, one end of the sixth microchannel is connected to the air-permeable microchannel, the other end is connected to the quantitative cavity, and the third microchannel is connected to the middle of the sixth microchannel.
In one embodiment, each of the separation and quantification units further comprises a seventh microchannel, and the second waste liquid cavity is communicated with the quantification cavity through the seventh microchannel.
In one embodiment, the separation and quantification unit further comprises a liquid outlet micro-channel, one end of the liquid outlet micro-channel is communicated with the quantification cavity, and the other end of the liquid outlet micro-channel is provided with a permeation hole.
In one embodiment, the liquid outlet micro flow channel comprises a second capillary flow channel, one end of the second capillary flow channel is communicated with the seventh micro flow channel, and the other end of the second capillary flow channel is provided with the permeation hole;
the second capillary channel extends from the direction close to the rotation center after being connected with the seventh micro-channel, bends and extends from the direction far away from the rotation center;
the distance between the connection position of the quantitative cavity and the third micro flow channel and the rotation center is larger than the distance between the bending peak position of the second capillary flow channel and the rotation center, and the distance between the bending peak position of the first capillary flow channel and the rotation center is larger than the distance between the bending peak position of the second capillary flow channel and the rotation center.
In one embodiment, the liquid outlet micro-channel further comprises an eighth micro-channel connected with the seventh micro-channel, and the second capillary channel is communicated with the seventh micro-channel through the eighth micro-channel.
In one embodiment, the microfluidic chip comprises a chip body and a transparent cover film covering the chip body, and the chip body and the transparent cover film are matched to form each cavity structure and each flow channel structure of the microfluidic chip.
In one embodiment, the transparent cover film is a transparent pressure sensitive adhesive film.
An in vitro detection device comprises the microfluidic chip and a detection mechanism in any embodiment, wherein the detection mechanism is communicated with the quantitative cavity and is used for detecting a sample in the quantitative cavity.
In one embodiment, the detection mechanism is a dry chemical strip.
In one embodiment, the dry chemical test paper comprises a support layer, and a reaction indicating layer and a diffusion layer which are sequentially stacked on the support layer, wherein the reaction indicating layer contains a reaction reagent and an indicating reagent which can react with a target substance in a sample to be tested, and the diffusion layer faces the permeation hole through the sample inlet.
In one embodiment, the microfluidic chip is provided with mounting grooves around the permeation holes of the respective separation and quantification units, and the detection mechanism is embedded in each of the mounting grooves.
The micro-fluidic chip is characterized in that a sample adding cavity, a first micro-channel, a second micro-channel, a plurality of separation quantitative units, a first capillary channel and a first waste liquid cavity are designed, wherein the first micro-channel, the second micro-channel, a third micro-channel of each separation quantitative unit, the first capillary channel and the like form a structure of a communicating vessel. After the sample solution is added into the sample adding cavity, the sample solution enters a second micro-channel through a first micro-channel by rotary centrifugation, and flows in the second micro-channel respectively enter a third micro-channel of each separation quantification unit, so that the sample solution can enter a quantification cavity under the action of centrifugation, and the second waste liquid cavity and the quantification cavity are sequentially filled with the sample solution, solid waste such as blood cells and the like can be further centrifugally deposited into the second waste liquid cavity communicated with the quantification cavity by centrifugation, the separation of samples such as whole blood and the like and quantification in the quantification cavity are realized, redundant sample solution enters a first capillary channel through a second micro-channel, and because the distance between the connection position of the quantification cavity in the separation quantification unit and the third micro-channel and the rotation center of the micro-fluidic chip is equal to the distance between the bending vertex position of the first capillary channel and the rotation center, the sample solution can continuously advance when reaching the bending vertex of the first micro-channel, and under the action of centrifugal force, a siphon effect is formed, and redundant sample solution is guided into the first waste liquid cavity.
After the sample solution is added into the micro-fluidic chip, the separation and quantification of impurities and target detection liquid in the sample solution can be realized only by one-time centrifugation without excessive centrifugal operation, so that the micro-fluidic chip is simple and convenient to operate, the waiting time is short, and the efficiency of sample treatment is obviously improved.
Furthermore, the micro-fluidic chip is also provided with a liquid outlet micro-channel comprising a second capillary channel, one end of the second capillary channel is communicated with a seventh micro-channel, the other end of the second capillary channel is provided with a permeation hole, the second capillary channel extends from the direction close to the rotation center after being connected with the seventh micro-channel, and extends from the direction far away from the rotation center after being bent, and the distance from the connection position of the quantitative cavity and the third micro-channel to the rotation center is greater than the distance from the bent vertex position of the second capillary channel to the rotation center, so that during centrifugal treatment, because the centrifugal force is greater than the capillary suction force, the sample solution cannot break through the bent position of the second capillary channel, and the second capillary channel can play the role of a valve to close the sample solution in the quantitative cavity and cannot flow out; after the subsequent centrifugation is finished, the liquid in the second capillary flow channel moves forwards along the second capillary flow channel under the action of capillary force, the valve is opened, and the liquid can seep out of the permeation hole after continuously flowing to the permeation hole. Preferably, the detection of the sample can be completed by matching with low-speed centrifugation and continuously seeping liquid from the permeation hole to the detection mechanism under the siphon action.
The second capillary flow channel is used as a valve for controlling the contact reaction of the sample and the detection mechanism, and can replace traditional delay opening mechanisms such as a water-soluble film or a valve, so that the sample introduction detection process is more stable and reliable, the chip assembly process is simplified, and the production cost is reduced.
Drawings
Fig. 1, fig. 2 and fig. 3 are schematic diagrams of front, back and side structures of a microfluidic chip according to an embodiment of the present invention.
Fig. 4-1, 4-2, 4-3, and 4-4 are schematic diagrams of the flow of separating and quantifying the sample solution by the microfluidic chip shown in fig. 1, respectively, and fig. 4-3-1 and 4-3-2 are schematic diagrams of partial enlargement.
Fig. 5-1 and 5-2 are schematic diagrams of a detection flow of the microfluidic chip shown in fig. 1, respectively, and fig. 5-1-1 is a schematic diagram of a partial enlargement.
Description of reference numerals:
10: microfluidic chip, 101: rotation center, 102: mounting portion, 103: chip body, 104: transparent cover film, 11: sample addition cavity, 111: wells, 112: first vent, 12: first micro flow channel, 13: second microchannel, 14: separation quantifying unit, 141: third microchannel, 142: quantitative cavity, 143: second waste liquid chamber, 144: liquid outlet micro-flow channel, 145: penetration hole, 146: sixth microchannel, 147: seventh micro flow channel, 148: second capillary flow passage, 148a, 148b and 148c are different locations on the second capillary flow passage, 149: eighth micro flow channel, 15: first capillary flow passage, 15a, 15b and 15c are different positions on the first capillary flow passage, 16: first waste liquid chamber, 17: fourth microchannel, 18, fifth microchannel, 181: second vent, 19: air-permeable microchannel, 191: third air hole, 20: and (4) mounting the groove.
Detailed Description
To facilitate an understanding of the invention, the invention will now be described more fully with reference to the accompanying drawings. Preferred embodiments of the present invention are shown in the drawings. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
Referring to fig. 1 and fig. 2, an embodiment of the present invention provides a microfluidic chip 10, which has a sample application cavity 11, a first microchannel 12, a second microchannel 13, a separation and quantification unit 14, a first capillary channel 15, and a first waste liquid cavity 16.
The sample addition chamber 11 has a sample addition hole 111. The sample solution can be added from the sample addition well 111 to the sample addition chamber 11. The sample adding cavity 11 is communicated with the second micro-channel 13 through the first micro-channel 12. The microfluidic chip 10 has a rotation center 101, and the microfluidic chip 10 rotates around the rotation center 101 during rotational centrifugation. The second microchannel 13 is disposed around the rotation center 101. The first waste liquid cavity 16 is communicated with the liquid outlet end of the second micro flow channel 13 through the first capillary flow channel 15.
The separation and quantification unit 14 is plural. Each of the separation and quantification units 14 includes a third microchannel 141, a quantification chamber 142, and a second waste liquid chamber 143. The quantitative cavity 142 is communicated with the second microchannel 13 through the third microchannel 141, and the second waste liquid cavity 143 is communicated with the quantitative cavity 142. A plurality of separation and quantification units 14 are distributed around the second microchannel 13 inside the second microchannel 13. Preferably, the plurality of separation and quantification units 14 are evenly spaced around the second microchannel 13.
The term "encircling" as used herein may or may not be a closed loop, e.g. may encircle a sector having an angle of more than 180 °.
In the present embodiment, the first capillary channel 15 extends from the inside of the second microchannel 13 to the direction close to the rotation center 101 (may be a direction gradually close to the rotation center 101, such as but not limited to a radial direction toward the rotation center 101) after connecting with the second microchannel 13, and bends to extend to the direction away from the rotation center 101 (may be a direction gradually away from the rotation center 101, such as but not limited to a radial direction away from the rotation center 101) to communicate with the first waste liquid chamber 16. The third microchannel 141 is located inside the second microchannel 13, and the third microchannel 141 extends from the second microchannel 13 to the direction close to the rotation center 101 to communicate with the quantitative cavity 142.
Further, in this embodiment, the distance from the connection position of the quantitative cavity 142 and the third micro flow channel 141 to the rotation center 101 is not less than the distance from the bending peak position of the first capillary flow channel 15 to the rotation center 101, and the second waste liquid cavity 143 is farther from the rotation center 101 than the quantitative cavity 142.
By designing the micro-fluidic chip 10 with the structure, the sample solution can be separated and quantified by one-time centrifugation, and is distributed to the plurality of separation and quantification units 14, so that the consistency is good, the integration level is high, and the flux of single detection is obviously improved.
In a specific example, the sample adding cavity 11 is disposed around the rotation center 101, one end of the cavity is provided with a sample adding hole 111, and the other end is connected to the first microchannel 12, and preferably, the sample adding cavity 11 gradually widens from the end provided with the sample adding hole 111 to the other end, so that the added sample solution can smoothly flow to the first microchannel 12. Further, the end of the sample application chamber 11 connected to the first microchannel 12 extends toward the direction away from the rotation center 101, and is connected to the first microchannel 12 at the bottom, so as to introduce the sample solution into the first microchannel 12 during centrifugation.
Furthermore, the sample-adding cavity 11 is further provided with a first air vent 112 at the end connected with the first microchannel 12, and the first air vent 112 is closer to the rotation center 101 than the connection position of the sample-adding cavity 11 and the first microchannel 12. Through setting up first bleeder vent 112, when adding sample solution to application of sample cavity 11, can in time derive gas, be convenient for sample solution's interpolation.
In one specific example, the second microchannel 13 is connected to the first microchannel 12 at one end and extends around the center of rotation 101 to the other end to be connected to the first capillary channel 15.
In a specific example, the microfluidic chip 10 further comprises a fourth microchannel 17. The first capillary channel 15 is connected to the second microchannel 13 via a fourth microchannel 17, and the fourth microchannel 17 extends from the second microchannel 13 toward the rotation center 101 to be connected to the first capillary channel 15.
Further, in one particular example, the microfluidic chip 10 also includes a fifth microchannel 18. One end of the fifth micro flow channel 18 is connected to the first waste liquid chamber 16, and the other end has a second vent 181. The second vent hole 181 is closer to the rotation center 101 than the first waste liquid chamber 16. Preferably, the fifth microchannel 18 extends from the connection with the first waste chamber 16 in a direction close to the centre of rotation 101.
In the illustrated specific example, the first waste chamber 16 is provided around the rotation center 101 at the periphery of the second microchannel 13, and the volume of the entire first waste chamber 16 is ensured to be large enough to sufficiently contain the excess sample solution. Preferably, the radial dimension of the section of the fifth micro flow channel 18 connected to the first waste liquid chamber 16 is greater than the radial dimension of the section near the second vent 181, so as to prevent the liquid from entering the fifth micro flow channel 18 and blocking the fifth micro flow channel 18, which may result in untimely venting.
In one particular example, each separation and quantification unit 14 further includes a sixth micro fluidic channel 146. The quantitative cavity 142 is communicated with the third microchannel 141 through the sixth microchannel 146.
The connection position of the sixth microchannel 146 and the third microchannel 141 is closer to the rotation center 101 than the quantitative cavity 142. The distance from the connection position of the sixth micro flow channel 146 and the third micro flow channel 141 to the rotation center 101 is not less than the distance from the bending peak position of the first capillary flow channel 15 to the rotation center 101.
Further, the microfluidic chip 10 further includes a gas-permeable microchannel 19. The air-permeable microchannel 19 is communicated with the sixth microchannel 146 of each quantitative cavity 142. The air-permeable micro-channel 19 is provided with a third air-permeable hole 191. The air-permeable micro flow channel 19 is located closer to the rotation center 101 than the connection position of the sixth micro flow channel 146 and the third micro flow channel 141.
In the illustrated specific example, the air-permeable microchannels 19 are arranged in a ring shape around the rotation center 101 inside the plurality of separation quantifying units 14. Preferably, the third vent 191 has a plurality of third vents 191, and the plurality of third vents 191 are distributed around the airing channel 19. Through the arrangement of the plurality of air holes 191, the air in each separation quantitative unit 14 can be discharged in time by matching with the plurality of separation quantitative units 14, so that the introduction of the sample solution is facilitated.
In the illustrated embodiment, one end of the sixth microchannel 146 is connected to the air-permeable microchannel 19, the other end is connected to the quantitative cavity 142, and the third microchannel 141 is connected to the middle of the sixth microchannel 146. The "central portion" as used herein may be, but is not limited to, a geometric center or midpoint, and may be a location near the center or midpoint, preferably a non-end location.
In one specific example, each separation and quantification unit 14 further comprises a seventh microchannel 147. The second waste liquid chamber 143 communicates with the quantification chamber 142 via a seventh microchannel 147. The liquid outlet micro-channel 144 is connected with the seventh micro-channel 147.
In one specific example, the separation and quantification unit 14 further comprises a liquid outlet microchannel 144. One end of the liquid outlet micro-channel 144 is communicated with the quantitative cavity 142, and the other end is provided with a permeation hole 145. The sample solution quantified in the quantification chamber 142 can be leaked out through the permeation hole 145.
Further, the outlet microchannel 144 includes a second capillary channel 148. One end of the second capillary flow channel 148 is communicated with the seventh micro flow channel 147, and the other end is provided with a permeation hole 145. In this specific example, the second capillary channel 148 extends from the connection with the seventh microchannel 147 to a direction close to the rotation center 101 and extends from the connection to the third microchannel 141 to a direction away from the rotation center 101, and the distance from the connection position of the quantitative cavity 142 and the third microchannel 141 to the rotation center 101 is greater than the distance from the bending vertex position of the second capillary channel 148 to the rotation center 101, and the distance from the bending vertex position of the first capillary channel 15 to the rotation center 101 is greater than the distance from the bending vertex position of the second capillary channel 148 to the rotation center 101. Thus, in centrifugation, the sample solution after the separation of impurities flows along the second capillary flow channel 148, but because the centrifugal force is greater than the capillary force, the sample solution does not flow to the bent vertex of the second capillary flow channel 148, and thus the second capillary flow channel 148 can function as a valve, and the effect of closing the sample solution in separation and quantification is achieved.
Further, in one specific example, the outlet microchannel 144 further includes an eighth microchannel 149. The eighth microchannel 149 is connected to the middle of the seventh microchannel 147, and the second capillary channel 148 is connected to the seventh microchannel 147 through the eighth microchannel 149.
The middle part of the microfluidic chip 10 is also provided with a mounting part 102. The center of the mounting portion 102 is the rotation center 101 of the microfluidic chip 10.
The capillary flow channels described herein are flow channel structures that are smaller than the dimensions (e.g., width and/or depth) of the micro flow channels. In one specific example, the first capillary flow passage 15 and the second capillary flow passage 148 have a V-shape, and a bent portion thereof is close to the rotation center 101. Preferably, the width of the first capillary flow channel 15 and the second capillary flow channel 148 is 0.1mm to 0.2mm, and the depth is 0.1mm to 0.2 mm; or the width of the first capillary flow passage 15 and the second capillary flow passage 148 is 0.2mm to 0.5mm, and the depth is 0.2mm to 0.5 mm. When the widths of the first capillary flow channel 15 and the second capillary flow channel 148 are 0.1mm to 0.2mm and the depths thereof are 0.1mm to 0.2mm, surface treatment is not required, and when the widths of the first capillary flow channel 15 and the second capillary flow channel 148 are 0.2mm to 0.5mm and the depths thereof are 0.2mm to 0.5mm, the channel walls of the first capillary flow channel 15 and the second capillary flow channel 148 are preferably surface-treated with PEG 4000. Further preferably, the width of the first capillary flow channel 15 and the second capillary flow channel 148 is 0.2mm, and the depth is also 0.2 mm. The first capillary channel 15 and the second capillary channel 148 allow the sample solution to flow to the other end thereof by capillary action after the sample solution enters. It is further preferable that the first capillary flow passage 15 and the second capillary flow passage 148 have different sizes at different sections, for example, the width of the first capillary flow passage 15 and the second capillary flow passage 148 at the bent portion is 0.2mm, the depth thereof is also 0.2mm, and the width thereof at the other portion is 0.5mm, and the depth thereof is also 0.2mm, so as to facilitate the liquid flow and the siphon and capillary action locally.
The PEG4000 surface treatment can be, but is not limited to, adding 1 wt% PEG4000 solution into a capillary flow channel, and naturally drying to form the PEG4000 surface treatment. The PEG4000 surface treatment is beneficial to increasing the capillary force of the capillary flow channel, and the PEG4000 belongs to an inert substance in a reaction system and generally does not react with a sample, a detection reagent and the like, so that the detection result is not influenced.
As shown in fig. 3, in a specific example, the microfluidic chip 10 includes a chip body 103 and a transparent cover film 104 covering the chip body 103. The chip body 103 and the transparent cover film 104 cooperate to form each cavity structure and flow channel structure. Specifically, the grooves of the cavity structures and the flow channel structures are preformed on the chip body 103, as shown in fig. 2, the holes are opened on the back of the chip body 103, the grooves of the cavity structures and the flow channel structures are opened on the front of the chip body 103, and the cavity structures and the flow channel structures are subsequently packaged by covering and sealing the transparent cover film 12 on the front of the chip body 11, so as to form complete cavity structures and flow channel structures.
The transparent cover film 104 may be, but not limited to, a transparent adhesive tape or a transparent pressure-sensitive adhesive, and the like, and is matched with the chip body 103 to form the whole microfluidic chip 10, so that the assembly is simple, a complex and expensive ultrasonic welding technology is not required, the bonding is performed directly, and the manufacturing cost can be reduced remarkably. It is understood that in other specific examples, the microfluidic chip 10 may be formed by welding using a costly ultrasonic welding technique or integrally formed by using a 3D printing technique.
The invention further provides an in vitro detection device which comprises the microfluidic chip 10 and a detection mechanism. The detection mechanism is in communication with the dosing chamber 142, for example, but not limited to, may be in communication with the dosing chamber 142 through a permeate hole 145. The detection mechanism is used for detecting the sample in the quantitative cavity 142.
In one particular example, the detection mechanism is a dry chemical strip. More specifically, the dry chemical test paper may include a support layer, and a reaction indicating layer and a diffusion layer sequentially stacked on the support layer, the reaction indicating layer contains a reaction reagent and an indicating reagent capable of reacting with a target substance in a sample to be tested, and the diffusion layer faces the permeation hole 145 through the sample inlet. It is understood that in other specific examples, the detection mechanism is not limited to dry chemical test strips, but may be various other test strips or reactors.
In a specific example, as shown in fig. 2, the microfluidic chip 10 is provided with mounting grooves 20 around the permeation holes 145 of the respective separation and quantification units 14, and the detection mechanism is embedded in each of the mounting grooves 20.
The micro-fluidic chip 10 can separate and quantify impurities in a sample solution through one-time centrifugation, such as separating blood cells and serum (plasma) of a whole blood sample and quantifying serum, and can realize synchronous sample loading detection of different separation and quantification units 14 through the valve action of the second capillary flow channel 148. Therefore, the in-vitro detection device using the microfluidic chip 10 can realize detection of different indexes or repeated detection of the same index of a sample by one-time sample loading. Each separation quantification unit 14 is arranged around the rotation center 101, the integration level is high, and the consistency, the accuracy and the reliability of the detection result can be improved by using the in-vitro detection device.
Specifically, taking the specific microfluidic chip 10 shown in fig. 1 as an example, in the separation of impurities in the sample solution and the quantification of the solution to be detected, reference may be made to the following procedures, but the procedures are not limited to the following:
as shown in FIG. 4-1, a certain amount of sample solution is added into the sample adding cavity 11 from the sample adding hole 111, and air in the sample adding cavity 11 can be exhausted from the first air vent 112. After the sample solution is added, the microfluidic chip 10 is installed in an instrument with a rotation centrifugation function through the installation part 102, the instrument is started, and the microfluidic chip 10 is rotated centrifugally at the rotation speed not limited to 4000 and 6000 rpm.
As shown in FIG. 4-2, under the action of centrifugal force, the sample solution starts to flow from one end of the sample application chamber 11 to the other end, and enters the second micro flow channel 13 in a ring shape through the first micro flow channel 12.
As shown in fig. 4-3, with the sample solution flowing in, the sample solution enters the third microchannel 141, the sixth microchannel 146, the quantitative cavity 142, the seventh microchannel 147, the second waste liquid cavity 143, the eighth microchannel 149 and the second capillary channel 148 of the separation and quantitative unit 14 in sequence, these channels and cavities form a communicating structure, and the air in the original channel and cavity is discharged from the third air hole 191 of the air-permeable microchannel 19. As shown in fig. 4-3-1, when the sample solution fills the quantitative cavity 142 and reaches the intersection point of the third micro flow channel 141 and the sixth micro flow channel 146, the sample solution enters the second capillary flow channel 148 through the eighth micro flow channel 149 and flows in the second capillary flow channel 148, under the action of the rapid centrifugation, the centrifugal force is greater than the capillary force, and when the sample solution flows to the position 148a flush with the connection point of the third micro flow channel 141 and the sixth micro flow channel 146 in the second capillary flow channel 148, the sample solution does not flow any more, because the distance between the bent part 148b of the second capillary flow channel 143 and the rotation center 101 is shorter than the distance between the connection point of the third micro flow channel 141 and the sixth micro flow channel 146 and the rotation center 101, the sample solution does not rise to the bent part 148b of the second capillary flow channel 143, and does not flow out from the permeation hole 145 after passing through the 148c segment due to the effect formed in the second capillary flow channel 143, thus, the quantification of the sample solution is completed.
As shown in fig. 4-3-2, at the same time, the sample solution enters the first capillary channel 15 through the second microchannel 13 and the fourth microchannel 17, and the sample solution continues to advance after passing through the section 15a, because the distance between the bending vertex of the first capillary channel 15 and the rotation center 101 is the same as the distance between the connection part of the third microchannel 141 and the sixth microchannel 146 and the rotation center 101, the sample solution can reach the highest point 15b, as shown in fig. 4-3, the first capillary channel 15 is filled up with the continuous flow of the sample solution, and a continuous siphon action is formed under the action of centrifugal force, and the redundant sample solution is continuously discharged into the first waste liquid cavity 16, so that the quantitative accuracy can be improved, and the cross contamination of the sample solution can be avoided.
As shown in fig. 4-4, the centrifugal rotation is continued, so that the fixed impurities (such as blood cells of the whole blood sample) in the quantitative cavity 142 can be separated from the liquid under the action of the centrifugal force, and the fixed impurities finally enter the second waste liquid cavity 143, thereby realizing the separation of the impurities in the sample solution from the solution to be tested.
The micro-fluidic chip 10 only needs one centrifugal operation in the separation of the impurities in the sample solution from the solution to be measured and the quantification process of the solution to be measured, and through the valve action of the second capillary flow channel 148, the sample solution can be closed in the quantification cavity 142 and the second waste liquid cavity 143 without flowing out during the separation and quantification of the sample solution.
In the detection, reference may be made to, but not limited to, the following procedures:
as shown in fig. 5-1, 5-2 and 5-1-1, when the solution to be measured is quantified, the centrifugation is stopped, and the solution to be measured in the second capillary flow channel 148 continuously advances under the capillary force, and passes through the highest point 148b to enter the 148c section of the second capillary flow channel 148, and finally reaches the permeation hole 145. At this time, the low-speed centrifugation can be started, for example, the low-speed centrifugation is rotated at the rotation speed of 1000-.
The micro-fluidic chip 10 is a valve for controlling the contact reaction of the sample and the detection mechanism through the second capillary flow channel 148, and can replace the traditional delay opening mechanism such as a water-soluble film or a valve, so that the sample injection detection process is more stable and reliable, the chip assembly process is simplified, and the production cost is reduced.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (19)
1. A micro-fluidic chip is characterized by comprising a sample adding cavity, a first micro-channel, a second micro-channel, a separation quantitative unit, a first capillary channel and a first waste liquid cavity; the sample adding cavity is provided with a sample adding hole and is communicated with the second micro-channel through the first micro-channel; the micro-fluidic chip is provided with a rotation center, and the second micro-channel is arranged around the rotation center; the first waste liquid cavity is communicated with the liquid outlet end of the second micro flow channel through the first capillary flow channel; the separation quantitative unit is provided with a plurality of separation quantitative units, each separation quantitative unit comprises a third micro-channel, a quantitative cavity and a second waste liquid cavity, the quantitative cavity is communicated with the second micro-channel through the third micro-channel, the second waste liquid cavity is communicated with the quantitative cavity, and the separation quantitative units are distributed around the second micro-channel on the inner side of the second micro-channel;
the first capillary channel is connected with the second micro channel, extends towards the direction close to the rotation center, bends and extends towards the direction far away from the rotation center on the inner side of the second micro channel so as to be communicated with the first waste liquid cavity; the third micro-channel extends from the second micro-channel to the direction close to the rotation center so as to be communicated with the quantitative cavity;
the distance between the connection position of the quantitative cavity and the third micro flow channel and the rotation center is not less than the distance between the bending peak position of the first capillary flow channel and the rotation center, and the second waste liquid cavity is far away from the rotation center than the quantitative cavity.
2. The microfluidic chip according to claim 1, wherein the sample application chamber is disposed around the rotation center, and has one end provided with the sample application hole and the other end connected to the first microchannel.
3. The microfluidic chip according to claim 2, wherein the sample loading cavity further comprises a first air vent at an end connected to the first microchannel, and the first air vent is closer to the rotation center than a connection position of the sample loading cavity and the first microchannel.
4. The microfluidic chip according to claim 1, further comprising a fifth microchannel, wherein one end of the fifth microchannel is connected to the first waste chamber and the other end of the fifth microchannel has a second vent closer to the rotation center than the first waste chamber.
5. The microfluidic chip of claim 4, wherein the first waste chamber is disposed around the center of rotation outside of the second microchannel; and/or
And the radial size of a section of the fifth micro-channel connected with the first waste liquid cavity is larger than that of a section close to the second air hole.
6. The microfluidic chip according to any one of claims 1 to 5, wherein each of the separation quantification units further comprises a sixth microchannel, and the quantification chamber is communicated with the third microchannel through the sixth microchannel;
the connection position of the sixth micro-channel and the third micro-channel is closer to the rotation center than the quantitative cavity; the distance between the connection position of the sixth micro flow channel and the third micro flow channel and the rotation center is not less than the distance between the bending peak position of the first capillary flow channel and the rotation center.
7. The microfluidic chip according to claim 6, further comprising a gas-permeable microchannel, wherein the gas-permeable microchannel is communicated with the sixth microchannel of each of the quantitative cavities, and a third gas-permeable hole is formed in the gas-permeable microchannel;
the air-permeable micro flow channel is closer to the rotation center than the connection position of the sixth micro flow channel and the third micro flow channel.
8. The microfluidic chip according to claim 7, wherein the gas-permeable microchannel is arranged in a ring shape around the rotation center inside the plurality of separation quantifying units, and the third gas-permeable holes are plural and distributed around the gas-permeable microchannel.
9. The microfluidic chip according to claim 7, wherein one end of the sixth microchannel is connected to the gas-permeable microchannel, the other end of the sixth microchannel is connected to the quantitative chamber, and the third microchannel is connected to a middle portion of the sixth microchannel.
10. The microfluidic chip according to any of claims 1 to 5 and 7 to 9, wherein each of the separation and quantification units further comprises a seventh microchannel, and the second waste liquid chamber is communicated with the quantification chamber through the seventh microchannel.
11. The microfluidic chip according to claim 10, wherein the separation and quantification unit further comprises a liquid outlet microchannel, one end of the liquid outlet microchannel is communicated with the quantification chamber, and the other end of the liquid outlet microchannel is provided with a permeation hole.
12. The microfluidic chip according to claim 11, wherein the liquid outlet microchannel comprises a second capillary channel, one end of the second capillary channel is connected to the seventh microchannel, and the other end is provided with the permeation hole;
the second capillary channel extends from the direction close to the rotation center after being connected with the seventh micro-channel, bends and extends from the direction far away from the rotation center;
the distance between the connection position of the quantitative cavity and the third micro flow channel and the rotation center is larger than the distance between the bending peak position of the second capillary flow channel and the rotation center, and the distance between the bending peak position of the first capillary flow channel and the rotation center is larger than the distance between the bending peak position of the second capillary flow channel and the rotation center.
13. The microfluidic chip according to claim 12, wherein the liquid outlet microchannel further comprises an eighth microchannel, the eighth microchannel is connected to the seventh microchannel, and the second capillary channel is connected to the seventh microchannel through the eighth microchannel.
14. The microfluidic chip according to any one of claims 1 to 5, 7 to 9 and 11 to 13, wherein the microfluidic chip comprises a chip body and a transparent cover film covering the chip body, and the chip body and the transparent cover film cooperate to form each cavity structure and each flow channel structure of the microfluidic chip.
15. The microfluidic chip of claim 14, wherein the transparent cover film is a transparent pressure sensitive adhesive film.
16. An in vitro detection device, comprising the microfluidic chip according to any one of claims 1 to 15 and a detection mechanism, wherein the detection mechanism is communicated with the quantitative cavity, and the detection mechanism is used for detecting a sample in the quantitative cavity.
17. The in vitro test device of claim 16, wherein the test mechanism is a dry chemical strip.
18. The in-vitro detection device according to claim 17, wherein the dry chemical test paper comprises a support layer, and a reaction indication layer and a diffusion layer which are sequentially stacked on the support layer, the reaction indication layer contains a reaction reagent and an indication reagent which can react with a target substance in a sample to be detected, and the diffusion layer faces the permeation hole through the sample inlet.
19. The in vitro detection device according to any one of claims 16 to 18, wherein the microfluidic chip is provided with mounting grooves around the permeation hole of each of the separation and quantification units, and the detection mechanism is embedded in each of the mounting grooves.
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| CN201911000623.8A CN112756017A (en) | 2019-10-21 | 2019-10-21 | Micro-fluidic chip and in-vitro detection device |
| PCT/CN2019/126899 WO2021077590A1 (en) | 2019-10-21 | 2019-12-20 | Microfluidic control chip and in vitro detection apparatus |
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| CN113600250A (en) * | 2021-07-21 | 2021-11-05 | 华中科技大学 | Chip for micro-channel assisted high-throughput reagent quantitative distribution and analysis |
| CN114433259A (en) * | 2021-12-24 | 2022-05-06 | 广州万孚生物技术股份有限公司 | Homogeneous phase test micro-fluidic chip and detection system |
| WO2023236787A1 (en) * | 2022-06-09 | 2023-12-14 | 安图实验仪器(郑州)有限公司 | Centrifugal microfluidic analysis chip |
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| DE102005016508A1 (en) * | 2005-04-09 | 2006-10-12 | Boehringer Ingelheim Microparts Gmbh | Apparatus for assaying a liquid sample comprises reaction chambers containing immobilized reagents, each connected to an assay chamber so that liquid can be transferred by centrifugal force |
| KR101722548B1 (en) * | 2010-01-29 | 2017-04-03 | 삼성전자주식회사 | Centrifugal Micro-fluidic Device and Method for detecting analytes from liquid specimen |
| CN103464230B (en) * | 2013-09-25 | 2015-02-18 | 中国科学院长春光学精密机械与物理研究所 | Centrifugal whole blood analysis micro-fluidic chip, preparation method as well as application method thereof |
| US10166541B2 (en) * | 2014-12-10 | 2019-01-01 | The Regents Of The University Of California | Centrifugal microfluidic platform for automated media exchange |
| CN105562130A (en) * | 2015-12-11 | 2016-05-11 | 中国科学院苏州生物医学工程技术研究所 | Micro-fluidic chip and method for detecting endotoxins by using micro-fluidic chip |
| CN205379906U (en) * | 2016-02-19 | 2016-07-13 | 博奥生物集团有限公司 | Multipurpose micro -fluidic chip |
| CN106179549B (en) * | 2016-08-15 | 2020-11-17 | 南京大学 | Micro-fluidic chip and application thereof |
| CN108490197B (en) * | 2018-03-07 | 2020-11-06 | 清华大学 | Multi-index analysis chip with pre-reaction function and use method thereof |
| CN109030813A (en) * | 2018-07-19 | 2018-12-18 | 东莞东阳光科研发有限公司 | A kind of chemiluminescence immunoassay detection micro-fluidic chip, detector and detection method |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113600250A (en) * | 2021-07-21 | 2021-11-05 | 华中科技大学 | Chip for micro-channel assisted high-throughput reagent quantitative distribution and analysis |
| CN113600250B (en) * | 2021-07-21 | 2023-03-10 | 华中科技大学 | Chip for micro-channel assisted high-throughput reagent quantitative distribution and analysis |
| CN114433259A (en) * | 2021-12-24 | 2022-05-06 | 广州万孚生物技术股份有限公司 | Homogeneous phase test micro-fluidic chip and detection system |
| CN114433259B (en) * | 2021-12-24 | 2023-12-26 | 广州万孚生物技术股份有限公司 | Homogeneous phase test micro-fluidic chip and detection system |
| WO2023236787A1 (en) * | 2022-06-09 | 2023-12-14 | 安图实验仪器(郑州)有限公司 | Centrifugal microfluidic analysis chip |
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