CN111215158A - Integrated form exosome detects chip - Google Patents
Integrated form exosome detects chip Download PDFInfo
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- CN111215158A CN111215158A CN201811423005.XA CN201811423005A CN111215158A CN 111215158 A CN111215158 A CN 111215158A CN 201811423005 A CN201811423005 A CN 201811423005A CN 111215158 A CN111215158 A CN 111215158A
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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
- B01L3/502707—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 manufacture of the container or its components
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- 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
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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
- B01L2300/0809—Geometry, shape and general structure rectangular shaped
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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
- B01L2300/0887—Laminated structure
Abstract
The invention provides an integrated exosome detection chip, and belongs to the field of exosome separation and detection. The micro-fluidic chip is divided into five units, a sample introduction unit, an exosome enrichment unit, an anti-incubation unit, a horseradish peroxidase labeling unit and a color development detection unit. The exosome enrichment unit is positioned behind the sample introduction unit, the anti-incubation unit is positioned behind the exosome enrichment unit, the horseradish peroxidase marking unit is positioned behind the anti-incubation unit, and the color development detection unit is positioned behind the horseradish peroxidase marking unit. According to the invention, the sample is introduced, the exosome is enriched, the non-exosome substance is cleaned, and the dyeing detection is concentrated on one chip, so that the exosome detection steps are optimized, the exosome detection efficiency is greatly improved, the manual operation procedure is simplified, and a better exosome detection effect is obtained.
Description
Technical Field
The invention belongs to the field of exosome separation and detection, and particularly relates to an integrated exosome detection chip.
Background
Exosome is a nano-scale vesicle which is secreted by cells and contains a plurality of substances such as lipid, protein, mRNAs and the like, the exosome is widely distributed in a human body, and most of body fluids of the human body such as urine, blood, milk, saliva and the like contain exosome. Exosomes mainly have two major functions of substance transmission and information transmission in human bodies. Research shows that exosome plays an important role in the inflammation process, adaptive immunity, embryogenesis, and the generation and development process of tumor. However, how to effectively separate exosomes from body fluid still is a great challenge, and the separation modes of ultracentrifugation, ultrafiltration and the like which are commonly used at present are time-consuming and labor-consuming, and the purity of the product is difficult to guarantee.
The microfluidic chip technology is a technology which integrates basic operation units of sample preparation, reaction, separation, detection and the like in the processes of biological, chemical and medical analysis into a micron-scale chip to automatically complete the whole analysis process. Since the concept of microfluidic chips was proposed by a.manz in the beginning of the 90 s of the 20 th century, the microfluidic technology has been developed rapidly, and the publication of Lab on a Chip in 2001, Business 2.0 in 2004, was known as "one of seven technologies for changing the future", and album of "Lab on a Chip" was introduced in Nature journal in 2006. At present, the microfluidic chip technology has been developed into a new research field crossing the disciplines of biology, chemistry, medicine, fluid, electronics, materials, machinery and the like due to its great potential in the fields of biology, chemistry, medicine and the like. Because of the advantages of miniaturization, integration and the like, the micro-fluidic chip technology also occupies a place in the field of exosome separation. However, it is still a difficult problem to efficiently obtain high-purity exosomes and perform detection and analysis on the exosomes, and further exploration is needed.
Disclosure of Invention
The invention aims to provide an integrated exosome detection chip.
An integrated exosome detection chip mainly comprises an upper channel layer, a middle non-structural layer and a bottom magnet layer;
the upper channel layer consists of four inlets, three reaction tanks, three S-shaped mixing channels and a straight channel, wherein the four inlets are respectively a sample inlet, a buffer solution inlet, a primary antibody inlet and a horseradish peroxidase-labeled secondary antibody inlet;
the three S-shaped mixing channels are respectively a sample mixing channel, a primary antibody and sample mixing channel and a secondary antibody and sample mixing channel;
the three reaction tanks are respectively a cleaning tank, a primary antibody incubation tank and a secondary antibody incubation and color development tank;
the bottom magnet layer mainly comprises three cylindrical magnet pits, wherein a cylindrical small magnet with the diameter of 2mm and the height of 2mm is arranged in each pit, and the positions of the three cylindrical magnet pits correspond to the positions of the three reaction tanks one by one;
the sample inlet and the sample buffer solution inlet are intersected in a Y shape and connected with the sample mixing channel, and the lower part of the sample mixing channel is connected with the cleaning pool; the first anti inlet surrounds the sample inlet and the sample buffer solution inlet from two sides respectively through the channel and is connected with the first anti and sample mixing channel in a cross shape, the first anti and sample mixing channel is connected with the cleaning pool at the upper part and is connected with the first anti incubation pool at the lower part; the second antibody inlet surrounds the second antibody incubation and color development pool from two sides through the channel respectively and is connected with the second antibody and the sample mixing channel in a cross shape, the second antibody and sample mixing channel is connected with the first antibody incubation pool, and the second antibody incubation and color development pool is connected below the second antibody incubation and color development pool.
The height of the top channel layer is 100-1 mm, the diameters of the three reaction tanks are 3-8 mm, the secondary antibody incubation and the color development tank are communicated upwards, and the widths of other channels are 250-1 mm.
The microfluidic chip is prepared according to the following steps: drawing a mask by using autoCAD software, preparing an upper channel layer template by using SU8 glue, performing reverse molding by using mixed PDMS (PDMS: initiator is 5:1-20:1), and sealing the upper channel layer and the middle non-structural layer by using oxygen plasma equipment; taking a blank PDMS with the thickness of more than 2mm, punching a round hole with the diameter of 2mm at the position of a contrast reaction tank, and placing a small magnet in the round hole; and finally, placing the sealed upper channel and the middle non-structural layer chip on the blank PDMS, and aligning the position of the magnet with the position of the reaction tank.
An application of an integrated exosome detection chip.
The method comprises the steps of placing the chip in a vacuum drier for vacuumizing for at least 15min, adding hexadecane containing 2-5% of octadecyl trichlorosilane into all channels, and incubating for 3-6 min at room temperature; and (3) sucking liquid in the channel, cleaning the channel for at least 5min by using ethanol and water sequentially, and placing the chip in an oven at 80 ℃ for more than 1h for later use.
When the microfluidic chip is used, the exosome needs to be captured by the immunomagnetic beads and then separated and detected, and the streptavidin immunomagnetic beads need to be modified before being captured, wherein the modification steps are as follows: biotinylated EpCAM of 2. mu.g/ml to 10. mu.g/ml is mixed with immunomagnetic beads, incubated overnight at 4 ℃, removed and washed three times or more with PBS, and then mixed with the sample to be detected and incubated for one hour or more at 4 ℃ for later use.
When the micro-fluidic chip is used, the flow speed in all channels is 1-10 mu L/min.
The invention has the advantages that:
1. the invention introduces a sample, enriches exosomes, cleans non-exosome substances, and concentrates dyeing detection on one chip, thereby optimizing an exosome detection process.
2. The invention adsorbs the magnetic beads through the magnet, simplifies the manual operation, reduces the error and realizes the space-time resolution which is difficult to realize by the traditional method.
3. The invention can finally observe by means of TMB color reaction, and the experimental result can be seen by naked eyes without other equipment, thereby being convenient and fast.
Drawings
FIG. 1 is a mask schematic of an integrated exosome detection chip;
FIG. 2 is a 3D schematic of an integrated exosome detection chip;
wherein: 1. a primary antibody inlet 2, a sample inlet 3, a buffer solution inlet 4, a sample mixing channel 5, a sample and primary antibody mixing channel 6, a sample and secondary antibody mixing channel 7, a horseradish peroxidase-labeled secondary antibody inlet 8, a cleaning pool 9, a primary antibody incubation pool 10, a secondary antibody incubation and color development pool 11, a small magnet
A. Exosome capturing unit B, primary antibody incubation unit C, secondary antibody incubation unit D, developing unit.
FIG. 3 is a schematic diagram of the detection of an integrated exosome detection chip;
FIG. 4 shows the capture rate of magnetic beads by a magnet at different flow rates of the integrated exosome detection chip;
FIG. 5 shows the escape rates of magnetic beads captured at different flow rates after the magnetic beads are captured by the integrated exosome detection chip.
Detailed Description
The invention will now be further illustrated by the following specific examples, which are not intended to be limiting thereof.
Example 1
Preparation of integrated exosome detection chip
Drawing a mask pattern shown in FIG. 1 by using autocAD software, preparing an upper channel layer template by using SU8 glue, performing reverse molding by using mixed PDMS (PDMS: initiator: 10:1), and sealing the upper channel layer and the middle non-structural layer by using an oxygen plasma device; taking a blank PDMS with the thickness of 2mm, punching a round hole with the diameter of 2mm at the position of a contrast reaction tank, and placing a small magnet in the round hole; and finally, placing the sealed upper channel and the middle non-structural layer chip on the blank PDMS, and aligning the position of the magnet and the position of the reaction tank for later use.
The microfluidic chip mainly comprises an upper channel layer, a middle non-structural layer and a bottom magnet layer as shown in fig. 1 and 2;
the upper channel layer consists of four inlets, three reaction tanks, three S-shaped mixing channels and a straight channel, wherein the four inlets are a sample inlet 2, a buffer solution inlet 3, a primary antibody inlet 1 and a horseradish peroxidase-labeled secondary antibody inlet 7 respectively; the three S-shaped mixing channels are a sample mixing channel 4, a primary antibody and sample mixing channel 5 and a secondary antibody and sample mixing channel 6 respectively; the three reaction tanks are respectively a cleaning tank 8, a primary antibody incubation tank 9 and a secondary antibody incubation and color development tank 10;
the bottom magnet layer is mainly composed of three cylindrical magnet pits, a cylindrical small magnet with the diameter of 2mm and the height of 2mm is arranged in each pit,
wherein the positions of the three cylindrical magnet pits correspond to the positions of the three reaction tanks one by one; the sample inlet 2 and the sample buffer solution inlet 3 are intersected in a Y shape and connected with the sample mixing channel 4, and the lower part of the sample mixing channel 4 is connected with the cleaning pool 8; the primary antibody inlet 1 surrounds the sample inlet 2 and the sample buffer solution inlet 3 from two sides through channels respectively and is connected with a primary antibody and sample mixing channel 5 in a cross shape, the primary antibody and sample mixing channel 5 is connected with a cleaning pool 8 at the upper part and is connected with a primary antibody incubation pool 9 at the lower part; the second antibody inlet 7 surrounds the second antibody incubation and color development pool 10 from two sides through a channel respectively and is connected with the second antibody and the sample mixing channel 6 in a cross shape, the second antibody and sample mixing channel 6 is connected with the first antibody incubation pool 9 at the upper part, and the second antibody incubation and color development pool 10 at the lower part.
The height of the top channel layer channel is 250 μm, the diameters of the three reaction pools are 5mm, wherein the secondary antibody incubation and the color development pool are opened upwards, and the widths of other channels are 300 μm.
Example 2
Application of integrated exosome detection chip
The chips prepared in example 1 were incubated with 5% octadecyltrichlorosilane in hexadecane at room temperature for three minutes. And (3) sucking the liquid in the channel, washing the channel for 5min by using ethanol and water sequentially, and placing the chip in an oven at 80 ℃ for 1 h.
The modified chip is firstly rinsed by PBS (phosphate buffer solution), so that the channel is filled with liquid, then the four inlets are respectively connected into corresponding injectors through polytetrafluoroethylene tubes, and the flow rate of the injectors is controlled by using injection pumps. Firstly, opening the injection pump corresponding to the sample inlet, closing the other three injection pumps, and enabling the mixture of the magnetic beads and the exosomes to completely enter the chip at the flow rate of 5 mu L/min, as shown in A in figure 3, in the process, the exosomes and the magnetic beads are continuously mixed, so that the capture efficiency can be improved, when the magnetic beads pass through the cleaning pool, the magnetic beads are captured by the magnet at the bottom, and the impure proteins and other substances in the sample are washed away;
then turning on the buffer solution injection pump, turning off the other three pumps, injecting the buffer solution into the chip at the flow rate of 5 mu L/min, and washing for about 10 min; then, gently taking down the magnet at the bottom of the washing tank, starting an injection pump corresponding to the primary antibody, and injecting the primary antibody solution into the chip at a flow rate of 5 muL/min for about 10min, wherein in the process, the magnetic beads in the washing tank are taken away by the primary antibody solution and enter an anti-incubation tank to be captured, as shown in B in FIG. 3;
all syringe pumps were turned off and incubated at room temperature for 20 min; opening a buffer solution injection pump, closing the other three pumps, injecting the buffer solution into the chip at the flow rate of 5 mu L/min, washing for about 10min, and removing waste liquid in the developing pool by using a liquid transfer gun; gently taking down a magnet at the bottom of the primary anti-incubation pool, opening a corresponding injection pump of a secondary antibody marked by horseradish peroxidase, injecting a secondary antibody solution into the chip at the flow rate of 5 mu L/min for 10min, and taking away the magnetic beads in the primary anti-incubation pool by the secondary antibody solution in the process, and allowing the magnetic beads to enter a developing pool to be captured, as shown in C in figure 3;
all syringe pumps were turned off and incubated at room temperature for 20 min; gently sucking away the secondary antibody in the developing pool by using a pipette, and not sucking the secondary antibody to the bottom magnetic beads; opening a buffer solution injection pump, closing the other three pumps, injecting the buffer solution into the chip at the flow rate of 5 mu L/min, washing for 10min, removing the buffer solution in the developing pool by using a pipette, and washing by using the buffer solution for three times continuously; the liquid in the color development pool is slightly sucked, 50 mu L of TMB substrate is added, the color development pool is protected from light for 20min, then 1M sulfuric acid is added to stop the reaction, and the detection result can be observed, in the process, the TMB substrate can be reacted with the horseradish peroxidase to turn blue, the solution is yellow after the stop solution is added, the depth of the yellow is related to the concentration of the horseradish peroxidase, and therefore the amount of exosomes in the sample can be reacted, and the process is shown as D in figure 3.
Example 3
Capture rate of magnetic beads by magnet under different flow rates of integrated exosome detection chip
The chip prepared in example 1 was injected into the injection port at a flow rate of 1 μ L/min to give a 10 μ L injection with a concentration of 5X 104And (4) closing the rest inlets of the magnetic beads, and measuring the concentration of the magnetic beads in the upper layer liquid in the secondary antibody incubation and color development pool. After that, the sample was rinsed clean and the above experiment was repeated again at a flow rate of 2. mu.L/min, 3. mu.L/min, 4. mu.L/min up to 10. mu.L/min. The experimental results are shown in FIG. 4, and it can be seen from the results that the capture rate of the magnetic beads by the magnet decreases with the increase of the flow rate, and the capture rate is lower than 80% when the flow rate is higher than 10 μ L/min.
Example 4
Escape rate of magnetic beads captured by integrated exosome detection chip at different flow rates
The chip prepared in example 1 was injected into the injection port at a flow rate of 1 μ L/min to give a 10 μ L injection with a concentration of 5X 104And (4) closing the rest inlets of the magnetic beads per milliliter, measuring the concentration of the magnetic beads in the secondary antibody incubation and upper layer liquid in the color development pool, and calculating to obtain the concentration of the captured magnetic beads. Then 1. mu.L/min from the buffer inletInjecting 10 mu L of PBS at the flow rate, and measuring the concentration of the magnetic beads in the upper layer liquid in the secondary antibody incubation and color development pool; the sample was then rinsed clean and the experiment repeated again at a flow rate of 2. mu.L/min, 3. mu.L/min up to 10. mu.L/min. As shown in FIG. 5, it can be seen that the magnetic bead escape rate is less than 10% when the fluid flow rate is within 10. mu.L/min after the magnetic beads are captured by the magnet.
The integrated exosome detection chip can meet different purposes by changing the antibody of the modified magnetic bead and the antibody used for detection. If it is desired to detect a particular protein, the corresponding protein can be used for detection, thereby obtaining the relative amounts of exosomes expressing the protein.
Claims (7)
1. An integrated exosome detection chip, characterized in that: the micro-fluidic chip mainly comprises an upper channel layer, a middle non-structural layer and a bottom magnet layer;
the upper channel layer consists of four inlets, three reaction tanks, three S-shaped mixing channels and a straight channel, wherein the four inlets are respectively a sample inlet, a buffer solution inlet, a primary antibody inlet and a horseradish peroxidase-labeled secondary antibody inlet; the three S-shaped mixing channels are respectively a sample mixing channel, a primary antibody and sample mixing channel and a secondary antibody and sample mixing channel; the three reaction tanks are respectively a cleaning tank, a primary antibody incubation tank and a secondary antibody incubation and color development tank;
the bottom magnet layer is mainly composed of three cylindrical magnet pits, a cylindrical small magnet with the diameter of 2mm and the height of 2mm is arranged in each pit,
wherein the positions of the three cylindrical magnet pits correspond to the positions of the three reaction tanks one by one; the sample inlet and the sample buffer solution inlet are intersected in a Y shape and connected with the sample mixing channel, and the lower part of the sample mixing channel is connected with the cleaning pool; the first anti inlet surrounds the sample inlet and the sample buffer solution inlet from two sides respectively through the channel and is connected with the first anti and sample mixing channel in a cross shape, the first anti and sample mixing channel is connected with the cleaning pool at the upper part and is connected with the first anti incubation pool at the lower part; the second antibody inlet surrounds the second antibody incubation and color development pool from two sides through the channel respectively and is connected with the second antibody and the sample mixing channel in a cross shape, the second antibody and sample mixing channel is connected with the first antibody incubation pool, and the second antibody incubation and color development pool is connected below the second antibody incubation and color development pool.
2. The integrated exosome detection chip according to claim 1, characterized in that: the height of the top channel layer is 100-1 mm, the diameters of the three reaction tanks are 3-8 mm, the secondary antibody incubation and the color development tank are communicated upwards, and the widths of other channels are 250-1 mm.
3. The method for preparing an integrated exosome detection chip according to claim 1, characterized in that: the method comprises the following steps: drawing a mask by using autoCAD software, preparing an upper channel layer template by using SU8 glue, performing reverse molding by using mixed PDMS (PDMS: initiator is 5-20:1), and sealing the upper channel layer and the middle layer non-structural layer by using oxygen plasma equipment; taking a blank PDMS with the thickness of more than 2mm, punching a round hole with the diameter of 2mm at the position of a contrast reaction tank, and placing a small magnet in the round hole; and finally, placing the sealed upper channel and the middle non-structural layer chip on the blank PDMS, and aligning the position of the magnet with the position of the reaction tank.
4. Use of an integrated exosome detection chip as claimed in claim 1.
5. Use of an integrated exosome detection chip according to claim 1, characterised in that: before use, hydrophobic modification is needed, the method is that the chip is placed in a vacuum drier for vacuumizing for at least 15min, then hexadecane containing 2% -5% of octadecyl trichlorosilane is added into all channels, and the incubation is carried out for 3-6 min at room temperature; and (3) sucking liquid in the channel, cleaning the channel for at least 5min by using ethanol and water sequentially, and placing the chip in an oven at 80 ℃ for more than 1h for later use.
6. Use of an integrated exosome detection chip according to claim 1, characterised in that: when in use, the exosome needs to be captured by the immunomagnetic beads and then separated and detected, and the streptavidin immunomagnetic beads need to be modified before being captured, wherein the modification steps are as follows: biotinylated EpCAM of 2. mu.g/ml to 10. mu.g/ml is mixed with immunomagnetic beads, incubated overnight at 4 ℃, removed and washed three times or more with PBS, and then mixed with the sample to be detected and incubated for one hour or more at 4 ℃ for later use.
7. Use of an integrated exosome detection chip according to claim 1, characterised in that: when in use, the flow rate in all channels is 1-10 mu L/min.
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| CN117085751A (en) * | 2023-07-26 | 2023-11-21 | 湖南瑞生科生物科技有限公司 | Microfluidic chip and exosome separation and detection method based on microfluidic chip |
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| CN117085751B (en) * | 2023-07-26 | 2024-04-02 | 湖南瑞生科生物科技有限公司 | Microfluidic chip and exosome separation and detection method based on microfluidic chip |
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