CN112756018A - Micro-fluidic chip and in-vitro detection system - Google Patents

Micro-fluidic chip and in-vitro detection system Download PDF

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Publication number
CN112756018A
CN112756018A CN201911001358.5A CN201911001358A CN112756018A CN 112756018 A CN112756018 A CN 112756018A CN 201911001358 A CN201911001358 A CN 201911001358A CN 112756018 A CN112756018 A CN 112756018A
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CN
China
Prior art keywords
cavity
microfluidic chip
microchannel
sample
waste liquid
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CN201911001358.5A
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Chinese (zh)
Inventor
白孟斌
万惠芳
冷杰
苗再奎
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Guangzhou Wondfo Biotech Co Ltd
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Guangzhou Wondfo Biotech Co Ltd
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Priority to CN201911001358.5A priority Critical patent/CN112756018A/en
Priority to PCT/CN2019/126900 priority patent/WO2021077591A1/en
Publication of CN112756018A publication Critical patent/CN112756018A/en
Pending legal-status Critical Current

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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
    • 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
    • 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
    • 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
    • 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
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • 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
    • 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 discloses a micro-fluidic chip and an in-vitro detection system containing the same. After adding sample solution in the application of sample cavity to micro-fluidic chip, through rotatory centrifugation, sample solution gets into quantitative cavity and first waste liquid cavity via first connection microchannel to fill up first waste liquid cavity and quantitative cavity gradually, unnecessary sample solution gets into in the second waste liquid cavity via overflow microchannel overflow, can separate solid impurity etc. and the solution that awaits measuring in the sample solution through further centrifugation, solid impurity etc. are by centrifugal precipitation to first waste liquid cavity in, the solution that awaits measuring is stayed in the quantitative cavity that is close to the heart end, thereby realize separation and the ration to sample solution. After the sample solution is added into the micro-fluidic chip, the separation and quantification of impurities in the sample solution and the target solution to be detected 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 sample processing efficiency is obviously improved.

Description

Micro-fluidic chip and in-vitro detection system
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 system.
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, there is a need for a microfluidic chip capable of improving sample processing efficiency and an in vitro detection system including the microfluidic chip.
A micro-fluidic chip is provided with a separation and quantification unit, wherein the separation and quantification unit comprises a sample adding cavity, a first connecting micro-channel, a quantification cavity, a first waste liquid cavity, an overflow micro-channel and a second waste liquid cavity; the sample adding cavity is provided with a sample adding hole; the quantitative cavity is communicated with the sample adding cavity through the first connecting micro-channel; the first waste liquid cavity is communicated with the quantitative cavity; the second waste liquid cavity is communicated with the quantitative cavity through the overflow micro-channel;
the separation and quantification unit has a proximal end close to the rotation center during centrifugation; the sample adding cavity is closer to the proximal end than the quantitative cavity; the quantitative cavity is closer to the proximal end than the first waste liquid cavity; when the quantitative cavity is filled with liquid, redundant liquid can enter the second waste liquid cavity through the overflow micro-channel, and the distance from the whole second waste liquid cavity to the proximal end is not more than the distance from the quantitative cavity to the proximal end.
In one embodiment, the sample application hole is closer to the proximal end than the connection position of the sample application cavity and the first connection microchannel.
In one embodiment, the sample-adding cavity further has a first air vent, and the first air vent is closer to the proximal end than a connection position of the sample-adding cavity and the first connecting micro channel.
In one embodiment, the connection between the sample-adding cavity and the first connecting microchannel is funnel-shaped.
In one embodiment, the microfluidic chip further comprises a quality control cavity, the quality control cavity is communicated with the second waste liquid cavity, and the quality control cavity is far away from the proximal end compared with the second waste liquid cavity.
In one embodiment, the microfluidic chip further comprises a second connecting microchannel communicated with the second waste liquid cavity, the second connecting microchannel gradually extends from one end connected with the second waste liquid cavity to a direction close to the proximal end, and a second air hole is formed in the other end.
In one embodiment, the microfluidic chip further comprises a third connecting microchannel, and the first waste liquid cavity is communicated with the quantitative cavity through the third connecting microchannel.
In one embodiment, the microfluidic chip further comprises a liquid outlet micro channel, one end of the liquid outlet micro channel is communicated with the quantitative 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 capillary flow channel, one end of the capillary flow channel is connected with the third connecting micro flow channel, and the other end of the capillary flow channel is provided with the permeation hole;
the capillary flow channel gradually extends from one end connected with the third connecting micro flow channel to the direction close to the proximal end, bends and then extends to the direction far away from the proximal end; the bending peak position of the capillary flow channel is closer to the proximal end than the connection position of the quantitative cavity and the first connection micro-flow channel.
In one embodiment, the liquid outlet micro-channel further comprises a fourth connecting micro-channel, one end of the fourth connecting micro-channel is connected with the third connecting micro-channel, and the other end of the fourth connecting micro-channel is connected with the capillary channel.
In one embodiment, the fourth connecting microchannel extends from the end connected to the third connecting microchannel gradually toward the proximal end to be connected to the capillary channel.
In one embodiment, each of the microfluidic chips is provided with one of the separation and quantification units.
In one embodiment, the microfluidic chip further comprises a clamping part for mounting on a centrifugal device.
In one embodiment, the snap-fit portion is located at the proximal end.
An in vitro detection system 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 in-vitro detection system further comprises a centrifugal tray for being mounted on a centrifugal device, and the centrifugal tray is provided with a mounting position for placing the microfluidic chip.
In one embodiment, the centrifugal tray has a plurality of mounting positions in the middle, and the plurality of mounting positions are arranged around the rotary mounting part.
In one embodiment, the centrifugal tray is provided with at least one observation hole for observing the state and/or detection result of the microfluidic chip at the mounting position.
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 separation and quantification unit, and the detection mechanism is embedded in each of the mounting grooves.
The separation and quantification unit of the microfluidic chip comprises a sample adding cavity, a first connecting microchannel, a quantification cavity, a first waste liquid cavity, an overflow microchannel and a second waste liquid cavity, wherein each cavity and the microchannels are matched to form a structure of a communicating vessel, after a sample solution is added into the sample adding cavity, the sample solution enters the quantification cavity and the first waste liquid cavity through the first connecting microchannel and gradually fills the first waste liquid cavity and the quantification cavity, the redundant sample solution overflows into the second waste liquid cavity through the overflow microchannel, solid impurities and the like in the sample solution can be separated from a solution to be detected through further centrifugation, the solid impurities and the like are centrifugally precipitated into the first waste liquid cavity, and the solution to be detected is left in the quantification cavity close to the core end, so that the separation and quantification of the sample solution are realized. When detection is needed, a detection mechanism can be used for detecting quantitative solution to be detected in the quantitative cavity.
After the sample solution is added into the micro-fluidic chip, the separation and quantification of impurities in the sample solution and the target solution to be detected 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 sample processing efficiency is obviously improved.
Furthermore, the micro-fluidic chip is provided with a liquid outlet micro-channel comprising a capillary channel, the capillary channel gradually extends from one end connected with the third connecting micro-channel to the direction close to the proximal end and extends to the direction far away from the proximal end after bending, and the bending peak position of the capillary channel is closer to the proximal end than the connection position of the quantitative cavity and the first connecting micro-channel, so that during the centrifugal separation and quantification of the sample solution, because the centrifugal force is greater than the capillary force in the capillary channel, the sample solution can not break through the bending peak of the capillary channel, the capillary channel can play a role in closing a valve, and subsequently, during the detection, under the condition of low-speed centrifugation, the solution to be detected in the quantitative cavity can continuously advance along the capillary channel under the action of the capillary force and break through the bending peak position of the capillary channel, the valve is opened, and under the siphon action, the solution to be detected continues to advance and seeps out of the permeation hole to the detection mechanism to be detected.
The capillary flow channel is used as a valve for controlling the contact reaction of the sample and the detection mechanism, and can replace the 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 favorably reduced.
Furthermore, by adopting the form that the microfluidic chip is separated from the centrifugal tray, a plurality of microfluidic chips can be freely assembled on one centrifugal tray, so that free matching of detection items and detection samples is realized, and the flexibility of the in-vitro detection system is integrally improved.
Drawings
Fig. 1, 2 and 3 are schematic front, back and side views of a microfluidic chip according to an embodiment of the present invention;
FIGS. 4 and 5 are schematic diagrams of the front and back structures of a centrifugal tray matched with the microfluidic chip shown in FIG. 1;
FIG. 6 is a schematic diagram of the assembly of the microfluidic chip shown in FIG. 1 and the centrifugal picture shown in FIG. 4;
FIG. 7-1, FIG. 7-2 and FIG. 7-3 are schematic views of a process for separating and quantifying a sample solution by the microfluidic chip shown in FIG. 1, respectively, and FIG. 7-2-1 is a partially enlarged schematic view;
fig. 8-1 and 8-2 are schematic diagrams of a detection process using the microfluidic chip shown in fig. 1, respectively.
The reference numerals are explained below:
10: microfluidic chip, 11: proximal, 12: a clamping part; 13: chip body, 14: transparent cover film, 15: mounting grooves;
100: separation quantifying unit, 110: sample addition cavity, 111: wells, 112: first vent, 120: first connecting microchannel, 130: quantitative cavity, 140: first waste liquid chamber, 150: overflow microchannel, 160: second waste liquid chamber, 170: liquid outlet micro-flow channel, 171: penetration hole, 172: capillary flow channels, 172a, 172b and 172c are different locations of the capillary flow channels, 173: fourth connection microchannel, 180: quality control cavity, 190: second connection microchannel, 191: second vent, 200: thirdly, connecting a micro-channel;
20: centrifugal tray, 21: mounting position, 22: rotation mounting portion, 23: detection hole, 24: and (4) quality control holes.
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.
It will be understood that when an element is referred to as being "on" another element, it can be directly on the other element or intervening elements may also be present. When an element is referred to as being "connected" or "in communication with" another element, it can be directly connected or intervening elements may also be present.
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 2, an embodiment of the invention provides a microfluidic chip 10 having a separation and quantification unit 100. The separation and quantification unit 100 includes a sample application chamber 110, a first connection microchannel 120, a quantification chamber 130, a first waste liquid chamber 140, an overflow microchannel 150, and a second waste liquid chamber 160.
Sample addition chamber 110 has sample addition well 111. Sample solution can be added from the sample addition well 111 to the sample addition chamber 110. The quantitative cavity 130 is communicated with the sample adding cavity 110 through the first connecting microchannel 120. The quantitative cavity 130 is used for realizing the quantitative determination of the solution to be measured. The first waste chamber 140 communicates with the dosing chamber 130. The first waste liquid chamber 140 is used to fill the surplus sample solution and the separated fixed impurities precipitate, etc. The second waste chamber 160 is in communication with the dosing chamber 130 via the overflow microchannel 150. The second waste chamber 160 is used to fill with excess sample solution.
In the present embodiment, the separation and quantification unit 100 has a proximal end 11 that is near the center of rotation at the time of centrifugation. Sample application chamber 110 is closer to proximal end 11 than dosing chamber 130. The dosing chamber 130 is closer to the proximal end 11 than the first waste chamber 140. After the quantitative cavity 130 is filled with liquid, the excess liquid can enter the second waste liquid cavity 160 through the overflow micro channel 150, and the distance from the whole second waste liquid cavity 160 to the proximal end 11 is not greater than the distance from the quantitative cavity 130 to the proximal end 11.
After the sample solution is added into the sample adding cavity 110, through the spin centrifugation, the sample solution can enter the quantitative cavity 130 and the first waste liquid cavity 140 through the first connecting microchannel 120, and gradually fill the first waste liquid cavity 140 and the quantitative cavity 130, the redundant sample solution overflows into the second waste liquid cavity 160 through the overflow microchannel 150, the solid impurities and the like in the sample solution can be separated from the solution to be measured (for example, blood cells and serum (plasma) in the whole blood sample) through the further centrifugation, the solid impurities and the like are centrifugally precipitated into the first waste liquid cavity 140, and the solution to be measured is left in the quantitative cavity 130 close to the proximal end 11, so that the separation and the quantification of the sample solution are realized. When detection is required, the detection mechanism can be used to detect the quantitative solution to be detected in the quantitative cavity 130.
After the sample solution is added into the micro-fluidic chip 10, the separation and quantification of impurities in the sample solution and the target solution to be detected can be realized only by one-time centrifugation without excessive centrifugal operation, so that the operation is simple and convenient, the waiting time is short, and the efficiency of sample treatment is obviously improved.
In one embodiment, the sample application hole 111 is closer to the proximal end 11 than the connection position of the sample application chamber 110 and the first connection microchannel 120, so as to prevent the sample solution from flowing back from the sample application hole 111 during the centrifugation operation.
In one specific example, the sample application cavity 110 further has a first air vent 112, and the first air vent 112 is closer to the proximal end 11 than the connection position of the sample application cavity 110 and the first micro flow channel 120. Through setting up first bleeder vent 112, when the application of sample, can be in time effectively with the air escape in application of sample cavity 110, guarantee going on smoothly of application of sample.
In one embodiment, the connection between the sample application cavity 110 and the first connecting microchannel 120 is funnel-shaped, which is more favorable for guiding the sample solution in the sample application cavity 110 to the quantitative cavity 130 through the first connecting microchannel 120.
In one embodiment, the microfluidic chip 10 further includes a quality control cavity 180. The quality control cavity 180 is communicated with the second waste liquid cavity 160, and the quality control cavity 180 is far away from the proximal end 11 than the second waste liquid cavity 160. The sample solution entering the second waste liquid cavity 160 flows in after the quantitative cavity 130 is filled with the sample, the redundant sample solution further flows into the quality control cavity 180 far away from the proximal end 11 in the second waste liquid cavity 160, and whether the quantitative cavity 130 is filled with the sample solution can be judged by observing whether the quality control cavity 180 contains the liquid or not.
In a specific example, the microfluidic chip 10 further includes a second connecting microchannel 190 communicated with the second waste liquid chamber 160, the second connecting microchannel 190 gradually extends from one end connected with the second waste liquid chamber 160 to a direction close to the proximal end 11, and a second air hole 191 is formed at the other end. Through set up second bleeder vent 191 in the one side of being close to heart end 11 of second waste liquid cavity 160, can be when sample solution overflows to second waste liquid cavity 160, in time with the air escape in second waste liquid cavity 160, guarantee going on smoothly of overflow.
In a specific example, the microfluidic chip 10 further includes a third connecting microchannel 200, and the first waste liquid chamber 140 is communicated with the quantitative chamber 130 through the third connecting microchannel 200. By providing the third connecting microchannel 200, the first waste liquid chamber 140 can be separated from the quantitative chamber 130, so that impurities deposited in the first waste liquid chamber 140 can be prevented from entering the quantitative chamber 130.
In one specific example, the microfluidic chip 10 further includes a liquid outlet microchannel 170. One end of the liquid outlet micro-channel 170 is communicated with the quantitative cavity 130, and the other end is provided with a penetration hole 171. The liquid outlet micro channel 170 is used for guiding the quantitative solution to be detected in the quantitative cavity 130 out of the permeation hole 171 to the detection mechanism.
Further, the outlet microchannel 170 includes a capillary channel 172. One end of the capillary channel 172 is connected to the third connecting microchannel 200, and the other end is provided with a permeation hole 171. Further, the capillary channel 172 gradually extends from the end connected to the third connecting microchannel 200 toward the proximal end 11, bends and then extends away from the proximal end 11. The bending peak of the capillary channel 172 is closer to the proximal end 11 than the connection position of the quantitative cavity 130 and the first connecting microchannel 120. By arranging the capillary flow channel 172, the capillary flow channel 172 can play a role of a valve, when the sample solution is separated and quantified, the valve is closed, and the sample solution to be measured cannot break through the bent top of the capillary flow channel 172 and permeate out of the permeation hole 171; during subsequent detection, under the action of the capillary force of the capillary channel 172, in cooperation with low-speed centrifugation, a fixed amount of the solution to be detected in the quantitative cavity 130 continuously advances along the capillary channel 172 under the action of siphon, and can be detected by seepage from the seepage hole 171.
In a specific example, the outlet microchannel 170 further includes a fourth connecting microchannel 173. One end of the fourth connecting microchannel 173 is connected to the third connecting microchannel 200, and the other end is connected to the capillary channel 172. By providing the fourth connecting micro-channel 173, the solution to be measured in the quantitative cavity 130 can be more conveniently guided into the capillary channel 172 during the measurement. Preferably, the fourth connecting microchannel 173 gradually extends from the end connected to the third connecting microchannel 200 toward the proximal end 11 to be connected to the capillary channel 172.
During centrifugal separation and quantification of the sample solution, since the centrifugal force is greater than the capillary suction force in the capillary flow channel 172, the sample solution does not break through the bent vertex of the capillary flow channel 172, the capillary flow channel 172 can play a role in closing the valve, and subsequently, during detection, under the condition of low-speed centrifugation, the solution to be detected in the quantification cavity 130 continuously advances along the capillary flow channel 172 under the action of the capillary suction force and breaks through the bent vertex of the capillary flow channel 172, the valve is opened, and under the action of siphoning, the solution to be detected continuously advances and the permeation hole 171 is permeated to the detection mechanism to be detected.
The capillary flow channel 172 is used as a valve for controlling the contact reaction of the sample and the detection mechanism, and can replace the 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 favorably reduced.
In a specific example, each microfluidic chip 10 is provided with a separate quantification unit 100. The microfluidic chip 10 may be, but not limited to, a fan-shaped structure as a whole, and may be mounted on a centrifugal tray or other devices to realize single-item detection of a sample.
Further, in a specific example, the microfluidic chip 10 further has a clamping portion 12 for mounting on a centrifugal device. The clamping portion 12 is used for clamping an external centrifugal tray and other devices, and has the functions of positioning and stable assembly.
More specifically, in one example, the snap 12 may be located, but is not limited to, at the proximal end 11 of the microfluidic chip 10.
As shown in fig. 3, in a specific example, the microfluidic chip 10 includes a chip body 13 and a transparent cover film 14 covering the chip body 13. The chip body 13 and the transparent cover film 14 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 13, as shown in fig. 2, the holes are opened on the back of the chip body 13, the grooves of the cavity structures and the flow channel structures are opened on the front of the chip body 13, and the cavity structures and the flow channel structures are packaged by covering and sealing the transparent cover film 12 on the front of the chip body 11 to form complete cavity structures and flow channel structures.
The transparent cover film 14 can be, but is not limited to, a transparent adhesive tape or a transparent pressure-sensitive adhesive, and the like, and is matched with the chip body 13 to form the whole microfluidic chip 10, so that the assembly is simple, a complex and expensive ultrasonic welding technology is not required, the direct bonding is only required, and the manufacturing cost can be obviously reduced. 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 system, which comprises the microfluidic chip 10 and a detection mechanism, wherein the detection mechanism is communicated with the quantitative cavity 130 through a penetration hole 171, and is used for detecting a sample in the quantitative cavity 130.
In one particular example, the detection mechanism is a dry chemical strip. More specifically, the dry chemical test paper includes a support layer, and a reaction indicating layer and a diffusion layer that are sequentially stacked on the support layer, the reaction indicating layer contains a reaction reagent and an indicating reagent that can react with a target substance in a sample to be tested, and the diffusion layer faces the penetration hole 171 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 15 around the penetration holes 171 of the separation and quantification unit 100, and the detection mechanism is embedded in each mounting groove 15.
In one particular example, as shown in fig. 4, 5 and 6, the extracorporeal detection system still further includes a centrifuge tray 20 for mounting on a centrifuge device. The centrifugal tray 20 is provided with a mounting position 21 for placing the microfluidic chip 10.
More specifically, the centrifugal tray 20 has a rotation mounting portion 22 at the middle thereof. The mounting positions 21 are plural, and the plural mounting positions 21 are provided around the rotation mounting portion 22.
Further, the centrifuge tray 20 is provided with at least one observation hole for observing the state and/or detection result of the microfluidic chip 10 at the mounting position 21. For example, in the illustrated embodiment, the centrifugal tray 20 is provided with a detection hole 23 corresponding to the detection mechanism, and a quality control hole 24 for observing the state of the quality control chamber 180.
The following will take the specific microfluidic chip shown in fig. 1 and the centrifugal tray shown in fig. 4 as an example to perform the whole blood sample detection, and further describe the separation and quantification of the sample solution and the detection process in detail. The centrifugal tray 20 can be provided with a plurality of micro-fluidic chips 10, a corresponding number of micro-fluidic chips 10 can be installed according to specific detection project requirements and sample requirements, and blank micro-fluidic chips 10 can be used for filling up the missing situation so as to ensure the basic balance of each position of the centrifugal tray 20.
The microfluidic chip 10 can be used for separating and quantifying the whole blood sample by referring to, but not limited to, the following:
as shown in fig. 7-1, the whole blood sample is loaded into the loading chamber 110 through the loading hole 111, the centrifuge tray 20 is mounted on the detection apparatus having the centrifugation function, the apparatus is turned on, and the centrifuge tray 20 is rotated.
As shown in fig. 7-2, with the progress of centrifugation, the whole blood sample in the sample application cavity 110 enters the quantitative cavity 130 and the first waste liquid cavity 140 through the first connecting microchannel 120, and the redundant whole blood sample enters the quality control cavity 180 and the second waste liquid cavity 160 through the overflow microchannel 150, and when the whole blood sample is detected in the quality control cavity 180, the quantitative cavity 13 is filled with the whole blood sample. As shown in FIG. 7-2-1, since the bending peak of the capillary channel 172 is located closer to the proximal end 11 than the uppermost position of the quantitative cavity 130, the whole blood sample solution will enter only the section 172a of the capillary channel 172 and will not flow to the section 172c through the bending peak 172b of the capillary channel 172 due to the centrifugal force greater than the capillary force in the capillary channel 172 during high-speed centrifugation (e.g. 4000-.
As shown in fig. 7-3, the whole blood sample filled in the quantitative cavity 130 will be separated from the blood serum (blood plasma) and deposited in the first waste liquid cavity 140 by continuing the centrifugation process, so as to realize the separation and quantitative determination of the whole blood sample.
The detection process of the whole blood sample by using the microfluidic chip 10 can refer to, but is not limited to, the following:
after the whole blood sample is quantified, as shown in fig. 8-1 and 8-2, the rotation of the centrifugal tray 20 is suspended, and the serum (plasma) quantified in the quantification cavity 130 continuously advances along the capillary channel 172 under the capillary force of the capillary channel 172 and breaks through the bending peak 172b of the capillary channel 172, preferably, the device is opened for low-speed centrifugation (such as 1000 + 2500rpm), the serum (plasma) seeps out of the permeation hole 171 from the section 172c of the capillary channel 172, and the serum (plasma) in the quantification cavity 130 is continuously discharged under the siphon force until the whole blood sample is completely emptied and detected.
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 (21)

1. A micro-fluidic chip is characterized by comprising a separation quantification unit, wherein the separation quantification unit comprises a sample adding cavity, a first connecting micro-channel, a quantification cavity, a first waste liquid cavity, an overflow micro-channel and a second waste liquid cavity; the sample adding cavity is provided with a sample adding hole; the quantitative cavity is communicated with the sample adding cavity through the first connecting micro-channel; the first waste liquid cavity is communicated with the quantitative cavity; the second waste liquid cavity is communicated with the quantitative cavity through the overflow micro-channel;
the separation and quantification unit has a proximal end close to the rotation center during centrifugation; the sample adding cavity is closer to the proximal end than the quantitative cavity; the quantitative cavity is closer to the proximal end than the first waste liquid cavity; when the quantitative cavity is filled with liquid, redundant liquid can enter the second waste liquid cavity through the overflow micro-channel, and the distance from the whole second waste liquid cavity to the proximal end is not less than the distance from the quantitative cavity to the proximal end.
2. The microfluidic chip according to claim 1, wherein the sample application well is closer to the proximal end than the connection position of the sample application chamber and the first connecting microchannel.
3. The microfluidic chip according to claim 1, wherein the sample application chamber further comprises a first vent closer to the proximal end than a connection position of the sample application chamber and the first connecting microchannel.
4. The microfluidic chip according to claim 1, wherein the connection between the sample application chamber and the first connecting microchannel is funnel-shaped.
5. The microfluidic chip of claim 1, further comprising a quality control cavity, wherein the quality control cavity is in communication with the second waste liquid cavity, and the quality control cavity is further from the proximal end than the second waste liquid cavity.
6. The microfluidic chip according to claim 1, further comprising a second connecting microchannel in communication with the second waste chamber, the second connecting microchannel extending from one end connected to the second waste chamber in a direction gradually closer to the proximal end and having a second vent at the other end.
7. The microfluidic chip according to any one of claims 1 to 6, further comprising a third connecting microchannel, wherein the first waste liquid chamber is communicated with the quantification chamber through the third connecting microchannel.
8. The microfluidic chip according to claim 7, further comprising a liquid outlet microchannel, wherein one end of the liquid outlet microchannel is connected to the quantitative cavity, and the other end of the liquid outlet microchannel has a permeation pore.
9. The microfluidic chip according to claim 8, wherein the liquid outlet microchannel comprises a capillary channel, one end of the capillary channel is connected to the third connecting microchannel, and the other end of the capillary channel is provided with the permeation hole;
the capillary flow channel gradually extends from one end connected with the third connecting micro flow channel to the direction close to the proximal end, bends and then extends to the direction far away from the proximal end; the bending peak position of the capillary flow channel is closer to the proximal end than the connection position of the quantitative cavity and the first connection micro-flow channel.
10. The microfluidic chip according to claim 9, wherein the liquid outlet microchannel further comprises a fourth connecting microchannel, one end of the fourth connecting microchannel is connected to the third connecting microchannel, and the other end of the fourth connecting microchannel is connected to the capillary channel.
11. The microfluidic chip according to claim 10, wherein the fourth connecting microchannel extends from the end connected to the third connecting microchannel gradually toward the proximal end to be connected to the capillary channel.
12. The microfluidic chip according to any one of claims 1 to 6 and 8 to 11, wherein each microfluidic chip is provided with one separation quantification unit.
13. The microfluidic chip of claim 12, wherein the microfluidic chip further comprises a clamping portion for mounting on a centrifuge.
14. The microfluidic chip of claim 13, wherein the snap-fit portion is located at the proximal end.
15. An in vitro detection system, comprising the microfluidic chip according to any one of claims 1 to 14 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.
16. The in vitro detection system of claim 15, further comprising a centrifuge tray for mounting on a centrifuge apparatus, wherein the centrifuge tray is provided with mounting locations for placing the microfluidic chips.
17. The in vitro testing system of claim 16, wherein the centrifuge tray has a plurality of mounting locations in a central portion thereof, the plurality of mounting locations being disposed about the rotational mounting portion.
18. The in vitro test system of claim 16, wherein the centrifuge tray is provided with at least one observation hole at the mounting position for observing the state and/or test result of the microfluidic chip.
19. The in vitro test system of claim 15, wherein the test mechanism is a dry chemical strip.
20. The in-vitro detection system according to claim 19, wherein 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, the reaction indicating layer contains a reaction reagent and an indicating 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.
21. The in vitro detection system according to any one of claims 15 to 20, wherein the microfluidic chip is provided with mounting grooves around the permeation hole of the separation and quantification unit, and the detection mechanism is embedded in each mounting groove.
CN201911001358.5A 2019-10-21 2019-10-21 Micro-fluidic chip and in-vitro detection system Pending CN112756018A (en)

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CN114453037A (en) * 2021-12-24 2022-05-10 广州万孚生物技术股份有限公司 Homogeneous test micro-fluidic chip and detection system
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