CN113492024B - Microfluidic chip with self-driving unit, microfluidic method and application of microfluidic chip - Google Patents
Microfluidic chip with self-driving unit, microfluidic method and application of microfluidic chip Download PDFInfo
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- CN113492024B CN113492024B CN202111053025.4A CN202111053025A CN113492024B CN 113492024 B CN113492024 B CN 113492024B CN 202111053025 A CN202111053025 A CN 202111053025A CN 113492024 B CN113492024 B CN 113492024B
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- 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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- 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
Abstract
The invention discloses a micro-fluidic chip with a self-driving unit, a micro-fluidic method and application thereof, and belongs to the technical field of micro-fluidic chips. The micro-fluidic chip with the self-driving unit comprises: the device comprises a reaction cavity, a self-driving unit and a fluid pipeline; according to the fluid flowing direction, a plurality of reaction cavities are arranged along the upstream, the midstream and the downstream; the self-driving unit can be communicated with the midstream reaction cavity through a fluid pipeline and is positioned at the upstream of the upstream reaction cavity; the upstream reaction cavity can be communicated with the midstream reaction cavity through a fluid pipeline; the middle-stream reaction cavity can be communicated with the downstream reaction cavity through a fluid pipeline; a quantitative flow distribution mechanism is arranged on the midstream reaction cavity; compressed air may be generated within the self-driven unit. The micro-fluidic chip and the micro-fluidic method thereof can be suitable for detection experiments in various biological or other fields, and have the advantages of convenient operation, simplicity and easy implementation and wide application range.
Description
Technical Field
The invention relates to the technical field of microfluidic chips, in particular to a microfluidic chip with a self-driving unit, a microfluidic method and application thereof.
Background
The microfluidic chip technology integrates basic operations such as sample preparation, separation, reaction and detection in various biological, chemical or medical analysis processes on a chip with the size of several square centimeters to dozens of square centimeters, and is widely applied to the fields of biochemical detection, nucleic acid analysis, immunoassay, cell sorting, environmental detection, food safety and the like at present due to the characteristics of integration, automation, small sample and reagent consumption and the like. However, since biochemical, immunological and nucleic acid detection requires multi-step fluid operation reactions, transfer of the reaction products to a microfluidic chip requires complicated fluid operations such as multi-step addition or discharge of reaction liquids. The conventional micro-fluidic chip needs an external pipeline and is connected with an external pump valve, so that the operation is complex and pollution is easily caused.
Therefore, how to provide a chip capable of simply realizing multi-step fluid operation is a problem to be solved by those skilled in the art.
Disclosure of Invention
Based on the above needs in the art, the present invention aims to provide a microfluidic chip with a self-driving unit, a microfluidic method and applications thereof, wherein the self-driving unit built in the chip is used in combination with an external force to realize a multi-step progressive flow direction and flow control of the fluid in the chip, and smoothly complete each step of reaction.
The technical scheme of the invention is as follows:
a microfluidic chip with a self-driving unit, comprising: the device comprises a reaction cavity, a self-driving unit and a fluid pipeline; according to the fluid flowing direction, a plurality of reaction cavities are arranged along the upstream, the midstream and the downstream;
the self-driving unit can be communicated with the midstream reaction cavity through a fluid pipeline and is positioned at the upstream of the upstream reaction cavity;
the upstream reaction cavity can be communicated with the midstream reaction cavity through a fluid pipeline; the middle-stream reaction cavity can be communicated with the downstream reaction cavity through a fluid pipeline; a quantitative flow distribution mechanism is arranged on the midstream reaction cavity;
compressed air may be generated within the self-driven unit.
The quantitative distribution mechanism is an opening with adjustable height and is arranged on the wall of the midstream reaction chamber;
preferably, the height-adjustable opening is: the opening bottom is provided with an opening and closing door or a sliding door which can slide radially and is matched with the cavity wall corresponding to the periphery of the opening in shape and size and is in sealing contact with the cavity wall; preferably, the height adjustable opening is in communication with a fluid line.
The micro-fluidic chip with the self-driving unit further comprises: a ventilation unit; the ventilation unit comprises a ventilation pipe; the cavity wall of the reaction cavity far away from the downstream end of the chip is provided with an air vent communicated with an air pipe;
preferably, the vent pipe on the upstream reaction chamber, the vent pipe on the midstream reaction chamber and the vent pipe on the downstream reaction chamber are communicated with each other;
more preferably, the joint where the air pipes are communicated with each other extends and bends in the direction away from the downstream end of the chip.
The micro-fluidic chip with the self-driving unit further comprises: a liquid storage unit; the liquid storage unit is positioned at the upstream of the upstream reaction cavity and is communicated with the midstream reaction cavity through a fluid pipeline;
at least 2 midstream reaction chambers are arranged; a check mechanism is arranged between the interconnected midstream reaction chambers, which can prevent the fluid from flowing back to the upstream reaction chamber;
preferably, anti-contact mechanisms are further arranged between the interconnected midstream reaction chambers and between the midstream reaction chamber and the downstream reaction chamber; the anti-contact mechanism is a bending structure which extends from the fluid pipeline towards the direction far away from the downstream end and is higher than the top of the midstream reaction cavity;
preferably, the non-return mechanism means that the pipe diameter of the fluid pipeline between the midstream reaction chambers is larger than that between the midstream reaction chambers and the upstream reaction chambers.
The fluid line is preferably a siphon;
preferably, each reaction cavity is internally provided with a dry reaction reagent;
preferably, the reaction reagents comprise: nucleic acid extraction reagent, nucleic acid releaser, primer, enzyme required for nucleic acid amplification, amplification buffer solution and dNTP;
preferably, the microfluidic chip is selected from a disc-type structure or a fan-shaped structure.
The microfluidic chip with the self-driving unit further comprises a chip fixing mechanism, wherein the chip fixing mechanism is used for fixing the chip in the fluid flow driving device or connecting the chip with the fluid flow driving device; the chip fixing mechanism is a chip fixing groove;
in some preferred embodiments, the microfluidic chip is a disc-shaped structure; the microfluidic chip includes: the device comprises a sample pool, a transfer pool, a mixing pool, an air pool, a distribution pipeline and a reaction hole;
a sample adding port is arranged on the wall of the sample cell as the upstream reaction cavity;
the transfer pool and the mixing pool are used as a midstream reaction cavity and are communicated through a fluid pipeline; the transfer pool is positioned at the upstream of the blending pool according to the fluid flowing direction; the self-driving unit comprises an air pool and a gas pipeline, and the pool wall at the top of the transfer pool is communicated with the air pool through the gas pipeline; the air pool is located upstream of the sample pool; the fluid flowing direction is the direction from the circle center to the circumference of the disc;
the distribution pipeline and the reaction holes as the downstream reaction cavity are positioned on the inner side of the edge of the chip;
preferably, the liquid storage unit is communicated with a mixing pool of the midstream reaction cavity through a fluid pipeline;
preferably, a quantitative flow dividing mechanism A is arranged on the side wall of the side, close to the mixing pool, of the transfer pool of the midstream reaction cavity, and a quantitative flow dividing mechanism B is arranged on the side wall, far from the transfer pool, of the mixing pool of the midstream reaction cavity;
the fluid quantity q which can be divided by the quantitative flow dividing mechanism A1Satisfies the following relation: q. q.s1=Q1-s1h1，
The height of the opening B of the quantitative flow distribution mechanism B with adjustable height is h2Satisfies the following relation: (Q)2+q1)/s2＞h2＞q1/s2，
Wherein: q. q.s1For the total amount of fluid entering the interior of the transfer tank, Q2The amount of fluid in the reservoir unit, h1The height, s, of the opening a is adjustable for the height of the quantitative distribution mechanism A1To transfer the area of the pool bottom, s2The area of the bottom of the mixing pool;
a fluid pipeline between the transfer pool and the sample pool is a first connecting pipeline, a circumferential fluid pipeline between the transfer pool and the blending pool is a third connecting pipeline, and a radial fluid pipeline is a first siphon pipeline; the first connecting pipeline is communicated with the third connecting pipeline, the third connecting pipeline is communicated with the first siphon pipeline, and the inner diameters of the first siphon pipeline and the second siphon pipeline are both larger than the inner diameter of the first connecting pipeline and the inner diameter of the second connecting pipeline, so that a non-return mechanism is formed;
the check mechanism is preferably: the inner diameter of the first siphon pipeline is 2-3 times of the inner diameter of the first connecting pipeline;
preferably, the reaction holes are multiple and are respectively communicated with the distribution pipeline; a fluid pipeline between the blending pool and the distribution pipeline is a second siphon pipeline;
preferably, the front projection character of the blending pool is L-like;
preferably, the first siphon pipeline and the second siphon pipeline extend out of a bending structure higher than the L-shaped top of the mixing pool towards the center direction of the disc to form the anti-contact mechanism;
preferably, the plurality of reaction holes are uniformly distributed along the distribution pipeline and are all positioned at the downstream side of the distribution pipeline; reaction reagents are arranged in the reaction holes;
preferably, an aluminum foil liquid sac is arranged in the liquid storage unit and is communicated with the blending pool; the aluminum foil liquid bag is easy to crush, so that the fluid in the liquid bag flows into the blending pool through a fluid pipeline;
preferably, the chip fixing groove is provided at the center of the disk.
The micro-fluidic control method with the self-driving unit is characterized in that fluid is injected into the micro-fluidic chip with the self-driving unit to control the fluid.
The microfluidic method with the self-driving unit comprises the following steps:
(1) a fluid sample enters a sample cell of an upstream reaction cavity through a sample adding hole of the microfluidic chip, the microfluidic chip is placed in the fluid flow driving device or is connected with the fluid flow driving device, and the driving force of the fluid flow driving device is adjusted to perform reaction;
(2) adjusting the driving force to enable the fluid sample in the sample cell to enter the transfer cell of the midstream reaction chamber through the fluid pipeline for reaction, and meanwhile, air in the transfer cell is forced to be compressed and enters the air cell through the gas pipeline of the self-driving unit;
(3) adjusting the driving force, expanding compressed air in the air pool to extrude the fluid in the transfer pool, enabling the fluid in the transfer pool to enter the blending pool through a fluid pipeline under the action of a check mechanism under the action of the quantitative flow dividing mechanism, breaking an aluminum foil liquid bag of the liquid storage unit through extrusion, adjusting the driving force, and enabling the fluid in the liquid storage unit to enter the blending pool through the fluid pipeline to react;
(4) adjusting the driving force, enabling the fluid in the mixing pool to enter a distribution pipeline of a downstream reaction cavity through a fluid pipeline, and adjusting the driving force to enable the fluid to enter each reaction hole respectively for reaction;
preferably, the fluid flow driving means is selected from: a centrifuge, a negative pressure pump;
preferably, the driving force is selected from: centrifugal force, pressure, gravity;
preferably, the adjusting of the driving force refers to reducing or increasing the rotation speed of the centrifugal machine, and reducing or increasing the pressure of the negative pressure pump;
preferably, the reaction is selected from: nucleic acid extraction reaction, nucleic acid release reaction, nucleic acid amplification reaction and cell culture reaction;
preferably, the fluid sample is selected from a reaction solution, or, a sample to be tested; the sample to be tested is selected from the group consisting of cell culture fluid, blood, swab rinsing fluid, cerebrospinal fluid, alveolar lavage fluid and urine; the reaction solution may be a reaction reagent in a liquid form.
The microfluidic chip with the self-driving unit and/or the microfluidic control method with the self-driving unit are/is applied to nucleic acid extraction, and/or nucleic acid release, and/or nucleic acid amplification detection, and/or environmental monitoring, and/or food detection, and/or forensic identification.
According to the invention, through the design of the upstream and downstream position relationship between the chambers and the arrangement of the pipelines and the connection relationship between the pipelines and the chambers, a self-driving unit is formed in the chip, namely, when fluid is thrown into the midstream reaction chamber through high-speed centrifugation, air in the reaction chamber can be compressed into an air pool of the self-driving unit, the centrifugal force generated during the high-speed centrifugation in the process is far greater than the pressure of the compressed air in the self-driving unit, and after the high-speed centrifugation is finished, the chip is not influenced by the centrifugal force any more, and the compressed air in the air pool at the moment generates a certain driving force to drive the fluid to flow to the next chamber. In addition, the invention also enables the chip to be internally provided with functional mechanisms such as a quantitative flow distribution mechanism, a non-return mechanism, a contact prevention mechanism and the like through a simple and ingenious structural design, can ensure that the fluid in the chip can enter a correct cavity and pipeline according to a preset reaction program, simply and conveniently realizes the comprehensive control of the flow direction and the flow of the fluid, and enables the fluid in the chip to stably, stepwisely, gradually and quantitatively develop the reaction of each link. Meanwhile, the microfluidic chip and the microfluidic method thereof can be suitable for detection experiments in various organisms or other fields, and are convenient and fast to operate, simple and easy to implement and wide in application range.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below, it is obvious that the drawings in the following description are only embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the provided drawings without creative efforts.
Fig. 1 is a schematic diagram of an internal structure of a microfluidic chip according to an embodiment of the present invention;
FIGS. 2a to 2f are schematic diagrams illustrating the flow directions of liquids in different stages of the operation of a microfluidic chip according to the first experimental example of the present invention;
fig. 3a to 3f are schematic diagrams of liquid flow directions in different stages of the operation of the microfluidic chip according to the second experimental example of the present invention;
fig. 4 is a schematic structural diagram of a check mechanism between the midstream reaction chambers of the microfluidic chip according to another embodiment of the present invention.
The labels in the figure are listed below: 100-a microfluidic chip, 101-a sample port and 102-a sample cell; 103 a-a first connecting pipeline, 103 b-a second connecting pipeline, 103 c-a third connecting pipeline, 103 d-a fourth transfer pipeline, 105 a-a first siphon pipeline, 105 b-a second siphon pipeline; 104 a-a transfer pool, 104 b-an air pool, 106 a-a mixing pool, 106 b-an aluminum foil liquid sac, 107-a distribution pipeline, 108-a reaction hole, 109-an air pipe and 110-a chip fixing groove.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Group 1 example, a microfluidic chip with self-driven units according to the invention
The group of embodiments provides a microfluidic chip with a self-driving unit. All embodiments of this group share the following common features: the microfluidic chip includes: the device comprises a reaction cavity, a self-driving unit and a fluid pipeline; according to the fluid flowing direction, a plurality of reaction cavities are arranged along the upstream, the midstream and the downstream; the self-driving unit can be communicated with the midstream reaction cavity through a fluid pipeline and is positioned at the upstream of the upstream reaction cavity; the upstream reaction cavity can be communicated with the midstream reaction cavity through a fluid pipeline; the middle-stream reaction cavity can be communicated with the downstream reaction cavity through a fluid pipeline; a quantitative flow distribution mechanism is arranged on the midstream reaction cavity; compressed air may be generated within the self-powered unit that provides a driving force for the fluid flow downstream.
In some specific embodiments, the quantitative distribution mechanism is a height-adjustable opening arranged on the wall of the midstream reaction chamber;
preferably, the height-adjustable opening is; the opening or closing door or the sliding door which can radially slide, is matched with the cavity wall corresponding to the periphery of the opening in shape and size and is in sealing contact with the cavity wall is arranged in the cavity wall at the bottom edge of the opening, and the height of the opening can be determined by the radial (up-down) moving position of the opening or the sliding door; the adjustment of the amount of liquid entering the downstream buffer cavity can be realized by adjusting the height of the opening on the cavity wall of the reaction cavity or the buffer cavity;
preferably, the height adjustable opening is in communication with a fluid line.
In a further embodiment, the microfluidic chip with the self-driving unit is characterized by further comprising: a ventilation unit; the ventilation unit comprises a ventilation pipe; the cavity wall of the reaction cavity far away from the downstream end of the chip is provided with an air vent communicated with an air pipe;
preferably, the vent pipe on the upstream reaction chamber, the vent pipe on the midstream reaction chamber and the vent pipe on the downstream reaction chamber are communicated with each other;
more preferably, the mutual intercommunication department of each breather pipe extends to the direction of keeping away from chip low reaches end and bends to increase actual air circulation space, effectively widen the air passage, make the fluid flow in the chip more unobstructed.
In other embodiments, the microfluidic chip with the self-driving unit further includes: a liquid storage unit; the liquid storage unit is positioned at the upstream of the upstream reaction cavity and is communicated with the midstream reaction cavity through a fluid pipeline;
at least 2 midstream reaction chambers are arranged; a check mechanism is arranged between the interconnected midstream reaction chambers, and can prevent the fluid from flowing back to the upstream reaction chamber as shown in FIG. 4;
preferably, anti-contact mechanisms are further arranged among the interconnected midstream reaction chambers and between the midstream reaction chamber and the downstream reaction chamber, so that fluid can not contact a siphon pipe in the next step in advance to avoid entering a cavity positioned at the downstream chamber too early;
preferably, the contact prevention mechanism is a bending structure, wherein the fluid pipeline extends towards the direction away from the downstream end and is higher than the top of the midstream reaction chamber;
preferably, the non-return mechanism means that the pipe diameter of the fluid pipeline between the midstream reaction chambers is larger than that between the midstream reaction chambers and the upstream reaction chambers.
In some embodiments, the fluid line is preferably a siphon tube, the siphon tube has hydrophilic characteristics, and fluid can flow into the interior of the siphon tube as soon as the fluid contacts one end of the siphon tube;
preferably, each reaction cavity is internally provided with a dry reaction reagent;
preferably, the reaction reagents comprise: nucleic acid extraction reagent, nucleic acid releaser, primer, enzyme required for nucleic acid amplification, amplification buffer solution and dNTP;
preferably, the microfluidic chip is selected from a disc-type structure or a fan-shaped structure.
In a further embodiment, the microfluidic chip with the self-driving unit further comprises a chip fixing mechanism for fixing the chip in the fluid flow driving device or connecting the chip with the fluid flow driving device; the chip fixing mechanism is a chip fixing groove; the fluid flow driving device provides driving force for fluid flow in the chip; the driving force is preferably centrifugal force, pressure and gravity; the fluid flow driving means is preferably a centrifugal device or a negative pressure device;
in some preferred embodiments, the microfluidic chip is a disc-shaped structure; the microfluidic chip includes: the device comprises a sample pool, a transfer pool, a mixing pool, an air pool, a distribution pipeline and a reaction hole;
a sample adding hole is formed in the wall of the sample cell serving as the upstream reaction cavity and used for adding samples;
the transfer pool and the mixing pool are used as a midstream reaction cavity and are communicated through a fluid pipeline; the transfer pool is positioned at the upstream of the blending pool according to the fluid flowing direction; the self-driving unit comprises an air pool and a gas pipeline, and the pool wall at the top of the transfer pool is communicated with the air pool through the gas pipeline; the air pool is located upstream of the sample pool; the fluid flowing direction is the direction from the circle center to the circumference of the disc;
the distribution pipeline and the reaction holes as the downstream reaction cavity are positioned on the inner side of the edge of the chip;
preferably, the liquid storage unit is communicated with a mixing pool of the midstream reaction cavity through a fluid pipeline; in some specific embodiments, the fluid pipelines among the distribution pipeline, the liquid storage unit and the mixing pool of the downstream reaction cavity do not adopt a siphon with hydrophilic property, and only need to adopt common pipelines;
preferably, a quantitative distribution mechanism A is arranged on the side wall of the side, close to the mixing pool, of the transfer pool of the midstream reaction cavity, and a quantitative distribution mechanism B is arranged on the side wall, far from the transfer pool, of the mixing pool of the midstream reaction cavity;
the fluid quantity q which can be divided by the quantitative flow dividing mechanism A1Satisfies the following relation: q. q.s1=Q1-s1h1，
The height of the opening B of the quantitative flow distribution mechanism B with adjustable height is h2Satisfies the following relation: (Q)2+q1)/s2＞h2＞q1/s2，
Wherein: q1For the total amount of fluid entering the interior of the transfer tank, Q2The amount of fluid in the reservoir unit, h1The height, s, of the opening a is adjustable for the height of the quantitative distribution mechanism A1To transfer the area of the pool bottom, s2The area of the bottom of the mixing pool;
in a specific embodiment, as shown in fig. 1 and 4, a fluid pipeline between the transfer cell 104a of the midstream reaction chamber and the sample cell 102 of the upstream reaction chamber is a first connecting pipeline 103a, a circumferential fluid pipeline between the transfer cell 104a of the midstream reaction chamber and the mixing cell 106a of the midstream reaction chamber is a third connecting pipeline 103c, and a radial fluid pipeline is a first siphon pipeline 105 a; the first connecting pipeline 103a is communicated with the third connecting pipeline 103c, the third connecting pipeline 103c is communicated with the first siphon pipeline 105a, and the inner diameters of the first siphon pipeline 105a are larger than the inner diameter of the first connecting pipeline 103a and the inner diameter of the second connecting pipeline 103b, so that a check mechanism is formed;
the check mechanism is preferably: the inner diameter of the first siphon pipe 105a is 2-3 times the inner diameter of the first connection pipe 103 a;
preferably, the reaction holes are multiple and are respectively communicated with the distribution pipeline; a fluid pipeline between the blending pool 106a of the middle-stream reaction cavity and the distribution pipeline 107 of the downstream reaction cavity is a second siphon pipeline 105 b;
preferably, the front projection character of the blending pool is L-like; the design is convenient for the first siphon pipe 105a to be connected with the blending pool at a higher position, and the fluid cannot enter the first siphon pipe 105a in advance in the process of entering the transfer pool from the sample pool;
preferably, the first siphon pipe 105a and the second siphon pipe 105b both extend out of a bending structure higher than the L-shaped top of the mixing pool 106a of the midstream reaction chamber in the central direction of the disc; the bending position of the first siphon pipe 105a is far higher than the blending pool 106a of the midstream reaction chamber, and in the process that the fluid enters the transfer pool 104a of the midstream reaction chamber from the sample pool 102 of the upstream reaction chamber, the fluid cannot contact the first siphon pipe 105a due to the fact that the bending position of the first siphon pipe 105a is too high and under the action of strong centrifugal force; the bending position of the second siphon pipe 105b is far higher than the blending pool 106a of the midstream reaction chamber, the fluid in the transfer pool 104a of the midstream reaction chamber is extruded to the blending pool 106a of the midstream reaction chamber by the compressed air in the air pool, the bending position of the second siphon pipe 105b is too high, and the fluid cannot contact the second siphon pipe 105b and then enters in advance by combining high-speed centrifugation.
The first connecting pipeline 103a, the second connecting pipeline 103b, the third connecting pipeline 103c, the fourth transfer pipeline 103d, the first siphon pipeline 105a and the second siphon pipeline 105b all belong to a fluid pipeline;
the distribution pipeline 107 and the reaction holes 108 both belong to a downstream reaction cavity;
the transfer pool 104a and the mixing pool 106a both belong to a midstream reaction cavity;
the air reservoir 104b belongs to the self-driven unit;
the aluminum foil liquid bag 106b belongs to a liquid storage unit;
the sample cell 102 belongs to an upstream reaction chamber.
Preferably, the plurality of reaction holes are uniformly distributed along the distribution pipeline and are all positioned at the downstream side of the distribution pipeline; reaction reagents are arranged in the reaction holes;
preferably, an aluminum foil liquid sac is arranged in the liquid storage unit and is communicated with the blending pool; the aluminum foil liquid bag is easy to crush, so that the fluid in the liquid bag flows into the blending pool through a fluid pipeline;
preferably, the chip fixing groove is provided at the center of the disk.
EXAMPLE 2 group 2 microfluidic method of the invention
The present disclosure provides a micro-fluidic method with a self-driving unit. All embodiments of this group share the following common features: injecting fluid into a microfluidic chip with a self-driven unit provided in any one of the embodiments in group 1 for fluid control.
In a specific embodiment, the microfluidic method with the self-driving unit comprises the following steps:
(1) a fluid sample enters a sample cell of an upstream reaction cavity through a sample adding hole of the microfluidic chip, the microfluidic chip is placed in the fluid flow driving device or is connected with the fluid flow driving device, and the driving force of the fluid flow driving device is adjusted to perform reaction;
(2) adjusting the driving force to enable the fluid sample in the sample cell to enter the transfer cell of the midstream reaction chamber through the fluid pipeline for reaction, and meanwhile, air in the transfer cell is forced to be compressed and enters the air cell through the gas pipeline of the self-driving unit;
(3) adjusting the driving force, expanding compressed air in the air pool to extrude the fluid in the transfer pool, enabling the fluid in the transfer pool to enter the blending pool through a fluid pipeline under the action of a check mechanism under the action of the quantitative flow dividing mechanism, breaking an aluminum foil liquid bag of the liquid storage unit through extrusion, adjusting the driving force, and enabling the fluid in the liquid storage unit to enter the blending pool through the fluid pipeline to react; this step can not only be used for quantitative distribution, but also for separation in special cases, for example, in case of example 2, the blood sample is separated into layers by high speed centrifugation in this step, and the upper serum layer enters the mixing pool.
(4) Adjusting the driving force, enabling the fluid in the mixing pool to enter a distribution pipeline of a downstream reaction cavity through a fluid pipeline, and adjusting the driving force to enable the fluid to enter each reaction hole respectively for reaction;
preferably, the fluid flow driving means is selected from: a centrifuge, a negative pressure pump;
preferably, the driving force is selected from: centrifugal force, pressure, gravity;
preferably, the adjusting of the driving force refers to reducing or increasing the rotation speed of the centrifugal machine, and reducing or increasing the pressure of the negative pressure pump;
preferably, the reaction is selected from: nucleic acid extraction reaction, nucleic acid release reaction, nucleic acid amplification reaction and cell culture reaction;
preferably, the fluid sample is selected from a reaction solution, or, a sample to be tested; the sample to be tested is selected from the group consisting of cell culture fluid, blood, swab rinsing fluid, cerebrospinal fluid, alveolar lavage fluid and urine; the reaction solution may be a reaction reagent in a liquid form.
Group 3 examples, microfluidic chips according to the invention and use of the microfluidic method
The present set of embodiments provides for the use of the microfluidic chip and microfluidic method of the present invention.
Specifically, the microfluidic chip with the self-driving unit according to any one of the embodiments in group 1 and/or the microfluidic control method with the self-driving unit according to any one of the embodiments in group 2 are applied to nucleic acid extraction, and/or nucleic acid release, and/or nucleic acid amplification detection, and/or environmental monitoring, and/or food detection, and/or forensic identification.
The chip of the invention can be used for customizing a special matched centrifugal device, and the centrifugal device is provided with a heater and a controller in addition to the conventional component structure of the conventional centrifugal machine; the controller accessible circuit links to each other with heater and centrifuge respectively, is equipped with the control program that triggers through duration in the controller, for example, presets: the duration and the heating temperature of the steps such as the high-speed centrifugation step, the low-speed or stop centrifugation step, the low-speed forward and reverse rotation step and the like are respectively preset, and the rotating speed of the centrifuge is also required to be respectively preset in the high-speed centrifugation step and the low-speed centrifugation step; after the centrifugal equipment is started, the controller starts to work, controls the heater to heat to a preset temperature, controls the centrifugal machine to centrifuge at a high speed, triggers the controller to control the centrifugal machine to rotate at a low speed or stop centrifuging or rotate in forward and reverse directions after the time of the high-speed centrifuging step is over, and controls the heater to adjust the heating temperature to the preset temperature of the corresponding step. The presetting of the above-mentioned procedures is a corresponding routine setting or adjustment that can be carried out by those skilled in the art according to the reaction steps and reaction procedures (e.g., PCR reaction procedure, LAMP reaction procedure, RPA reaction procedure, nucleic acid extraction reaction, nucleic acid release reaction) actually carried out by the chip in practice, and the heater and the controller are all conventional parts in the art and are commercially available. The centrifugal device specially matched with the chip can be customized and produced by entrusted manufacturers and can also be assembled and integrated by self, so that the centrifugal device matched with the chip can be completely realized and prepared based on conventional existing products in the field and by combining with the common knowledge in the field for the skilled person.
The most specific embodiment of the present invention provides a microfluidic chip 100, as shown in fig. 1, including a reaction chamber, a self-driving unit, a liquid storage unit, and a ventilation unit. Wherein, specifically include: a sample addition port 101 and a sample cell 102 belonging to an upstream reaction chamber; a transfer tank 104a belonging to the reaction chamber at the midstream, an air tank 104b belonging to the self-driving unit, and fluid lines (e.g., a first connecting pipe 103a, a second connecting pipe 103b, a third connecting pipe 103 c) connecting the upstream and downstream chambers; the liquid storage unit comprises an aluminum foil liquid bag 106b, the upstream reaction chamber comprises a mixing pool 106a and a fluid pipeline (for example, a first siphon pipe 105a, a fourth transfer pipe 103d and a second siphon pipe 105 b) connecting the upstream and downstream chambers; the downstream reaction chamber comprises not less than two reaction holes 108 and a distribution pipe 107 for distributing liquid to the reaction holes; the aeration unit is a pipe, i.e., an aeration pipe 109, connecting the distribution pipe 107, the sample cell 102, and the kneading cell 106 a. Specifically, the sample addition port 101 is directly connected to the sample cell 102, the sample cell 102 is connected to the transfer cell 104a through the first connecting tube 103a, the transfer cell 104a is connected to the air cell 104b through the second connecting tube 103b, the transfer cell 104a and the mixing cell 106a are connected to the first siphon tube 105a through the third connecting tube 103c, the aluminum foil liquid bag 106b is connected to the mixing cell 106a through the fourth connecting tube 103d, and the mixing cell 106a and each reaction well 108 are connected to each other through the second siphon tube 105b and the distribution tube 107. The distribution pipe 107 is connected to the specimen cell 102 and the kneading cell 106a via a vent pipe 109 of the vent unit.
In this application, the air reservoir 104b is connected to the transfer reservoir 104a via the second connecting pipe 103b, and the air reservoir 104b is closer to the center of the chip, so that when the liquid enters the transfer reservoir 104a under the action of centrifugal force, the air originally in the transfer reservoir 104a will be compressed in the air reservoir 104b for subsequent use as power for controlling the liquid in the transfer reservoir 104 a; the aluminum foil fluid bag 106b is used for storing the diluent, and when the diluent is released, the fluid bag is broken by mechanical pressing, and then the liquid is thrown into the blending pool 106a under the action of centrifugal force. In addition, the third connecting pipe 103c connected to the transfer tank 104a is spaced apart from the bottom of the transfer tank 104a, so that only a part of the liquid in the transfer tank 104a enters the first siphon pipe 105a through the third connecting pipe 103 c; the width and depth of the first siphon pipe 105a are larger than those of the first connecting pipe 103a, so that the liquid in the transfer pool 104a enters the mixing pool 106a preferentially through the first siphon pipe 105a and does not return to the sample pool 102 through the first connecting pipe 103 a.
In this application, a straight slot for fixing a chip is used as the chip fixing slot 110 of the microfluidic chip 100, and this is used as the centrifugal rotation center of the chip.
The above arrangement can realize the controlled liquid passing through the transfer pool 104a, the uniform mixing pool 106a and other chambers on each chip.
The core of the present application is further detailed by the following most specific 2 experimental examples:
specific experimental example one:
In the experimental example, the micro-fluidic chip is used for realizing the biological reaction of two-step isothermal amplification, and the specific process is as follows.
Before the experiment begins, the aluminum foil liquid bag 106b in the microfluidic chip is filled with diluent in advance and sealed by aluminum foil; the sample pool 102 is stored with a freeze-drying reagent for the first isothermal amplification; the freeze-drying reagent of the second step of amplification is stored in the mixing pool 106 a; the reaction wells 108 contain primers of different indices, as shown in FIG. 2 a. After the experiment is started, the sample is added into the sample cell 102 through the sample port 101, the freeze-dried reagent is dissolved by low-speed centrifugation and the sample is mixed uniformly, and simultaneously the first isothermal amplification step is carried out, as shown in fig. 2 b. After the first isothermal amplification step is finished, the chip is centrifuged at high speed to make the product of the first isothermal amplification step enter the transfer cell 104a from the sample cell 102 through the first connecting pipe 103a, and simultaneously the air in the transfer cell 104a is compressed, so that part of the air enters through the second connecting pipe 103b and is stored in the air cell 104b, as shown in fig. 2 c. When the centrifugal speed is reduced, the air in the air reservoir 104b expands to push out the liquid in the transfer reservoir 104 a. Because the third connecting pipeline 103c, the first connecting pipeline 103a and the first siphon pipeline 105a connected to the right side of the transfer pool 104a have different thicknesses, and the width and the depth of the first siphon pipeline 105a are both larger than those of the third connecting pipeline 103c and the first connecting pipeline 103a, the liquid in the transfer pool 104a can preferentially enter the blending pool 106a through the first siphon pipeline 105a after being squeezed out. Specifically, the ratio of the cross-sectional area of the first siphon pipe 105a to the cross-sectional area of the first connecting pipe 103a is not less than 4. Meanwhile, because the third connecting pipe 103c connected to the transfer pool 104a is at a certain distance from the bottom of the transfer pool 104a, only a part of the liquid in the transfer pool 104a can enter the mixing pool 106a through the first siphon 105a, thereby achieving the purpose of partially transferring the first-step amplification product, as shown in fig. 2 d. When the product of the first amplification step enters the mixing pool 106a, it is dissolved (or partially dissolved) with the second amplification step reagent stored therein, but because the starting point of the second siphon 105b at the right side of the mixing pool 106a is at a certain distance from the bottom of the mixing pool 106a, the liquid cannot contact the second siphon 105 b. At this time, the aluminum foil fluid sac 106b is pressed by mechanical pressure, so that the fluid sac is broken, and the diluent inside is thrown into the blending pool 106a through the fourth transfer pipeline 103d under the action of centrifugal force, and the reagent is diluted and redissolved in the blending pool 106 a. The liquid level can now touch the beginning of the second siphon 105b, as shown in fig. 2 e. Then, the liquid in the mixing pool 106a fills the second siphon pipe 105b and the distribution pipe 107 by low speed centrifugation or standing the chip, and finally the liquid is finally distributed into the reaction hole 108 by high speed centrifugation, and the second isothermal amplification is performed in the reaction hole 108, as shown in fig. 2 f. It should be noted that the number of the reaction wells 108 is at least 2, and primers with different indexes can be pre-stored in each well, and the specific number of the reaction wells 108 can be selected according to actual needs, which is not limited in this experimental example.
Specific experimental example two:
in the experimental example, the multi-index biochemical reaction is realized by using the microfluidic chip, and the specific process is as follows.
Before the experiment begins, the aluminum foil liquid bag 106b in the microfluidic chip is filled with diluent in advance and sealed by aluminum foil; the reaction wells 108 hold substrates for different biochemical reactions, as shown in FIG. 3 a. After the experiment starts, blood is added to the sample cell 102 through the sample port 101, as shown in fig. 3 b. Thereafter, the chip is subjected to high-speed centrifugation to cause blood to enter the transfer reservoir 104a from the sample reservoir 102 through the first connecting tube 103a, at which time serum and blood cells are separated under the high-speed centrifugation, while air in the transfer reservoir 104a is compressed, so that a part of the air enters through the second connecting tube 103b and is stored in the air reservoir 104b, as shown in fig. 3 c. When the centrifuge speed is reduced, the air in the air reservoir 104b expands to push the upper serum layer out of the transfer reservoir 104 a. Because the third connecting pipe 103c, the first connecting pipe 103a and the first siphon pipe 105a connected to the right side of the transfer pool 104a have different thicknesses, and the width and the depth of the first siphon pipe 105a are both larger than those of the third connecting pipe 103c and the first connecting pipe 103a, the upper serum in the transfer pool 104a is extruded out and then preferentially enters the blending pool 106a through the first siphon pipe 105 a. Meanwhile, because the third connecting pipe 103c connected to the transfer pool 104a is at a certain distance from the bottom of the transfer pool 104a, only a part of the serum in the transfer pool 104a can enter the mixing pool 106a through the first siphon pipe 105a, so as to achieve the purpose of quantitatively transferring the serum, as shown in fig. 3 d. After the serum enters the mixing pool 106a, the aluminum foil liquid sac 106b is pressed by a machine to release the diluent therein, so that the serum in the mixing pool 106a is diluted and mixed uniformly. The liquid level can now also touch the beginning of the second siphon 105b, as shown in fig. 3 e. Then, the chip is centrifuged at low speed or left still, the second siphon 105b and the distribution 107 are filled with the liquid in the mixing pool 106a, and finally the liquid is finally distributed to the reaction holes 108 by high speed centrifugation, and biochemical reaction is performed in the reaction holes 108, so as to realize biochemical reaction with multiple indexes, as shown in fig. 3 f. It should be noted that the number of the reaction wells 108 is at least 2, and each well can be pre-stored with biochemical reaction substrates with different indexes, and the specific number of the reaction wells 108 can be selected according to actual needs, which is not limited in this experimental example.
Claims (32)
1. The chip structure is used for generating compressed air in a microfluidic chip and is characterized in that the chip structure is provided with an air pool positioned at the upstream of a sample pool, a transfer pool positioned at the downstream of the sample pool, a pool wall at the top of the transfer pool communicated with the air pool through an air pipeline, a uniformly mixing pool with a similar L-shaped front projection shape, a bent structure with a first siphon pipeline between the transfer pool and the uniformly mixing pool extending out towards the center direction of the chip and higher than the similar L-shaped top of the uniformly mixing pool, and the inner diameter of the first siphon pipeline in the radial direction between the transfer pool and the uniformly mixing pool is larger than the inner diameter of a first connecting pipeline in the radial direction between the transfer pool and the sample pool; a circumferential fluid pipeline is arranged between the transfer pool and the blending pool and is a third connecting pipeline; the first connecting pipeline is communicated with a third connecting pipeline, the third connecting pipeline is communicated with a first siphon pipeline, and the inner diameter of the first siphon pipeline is larger than that of the second connecting pipeline, so that a non-return mechanism is formed; a fluid pipeline between the blending pool and the distribution pipeline is a second siphon pipeline; the micro-fluidic chip is a micro-fluidic chip with a self-driving unit; the microfluidic chip with the self-driving unit comprises: the device comprises a reaction cavity, a self-driving unit and a fluid pipeline; according to the fluid flowing direction, a plurality of reaction cavities are arranged along the upstream, the midstream and the downstream;
the self-driving unit can be communicated with the midstream reaction cavity through a fluid pipeline and is positioned at the upstream of the upstream reaction cavity; the air pool and the gas pipeline form the self-driving unit;
the upstream reaction cavity can be communicated with the midstream reaction cavity through a fluid pipeline; the middle-stream reaction cavity can be communicated with the downstream reaction cavity through a fluid pipeline; a quantitative flow distribution mechanism is arranged on the midstream reaction cavity;
compressed air can be generated in the self-driving unit;
the micro-fluidic chip is of a disc-shaped structure; the microfluidic chip includes: the device comprises a sample pool, a transfer pool, a mixing pool, an air pool, a distribution pipeline and a reaction hole;
a sample adding port is arranged on the wall of the sample cell as the upstream reaction cavity;
the transfer pool and the mixing pool are used as a midstream reaction cavity and are communicated through a fluid pipeline; the transfer pool is positioned at the upstream of the blending pool according to the fluid flowing direction; the fluid flowing direction is the direction from the circle center to the circumference of the disc;
distribution pipes and reaction holes as downstream reaction chambers are positioned on the inner side of the edge of the chip,
the chip structure can realize multi-step progressive flow direction and flow control of the fluid in the chip by using a self-driving unit built in the chip under the driving force provided by the fluid flow driving device.
2. The use according to claim 1, wherein the quantitative distribution mechanism is a height-adjustable opening provided on a wall of the midstream reaction chamber.
3. Use according to claim 2, wherein the height-adjustable opening is: the opening bottom is provided with an opening and closing door or a sliding door which can slide radially and is matched with the cavity wall corresponding to the periphery of the opening in shape and size and in sealing contact with the cavity wall.
4. Use according to claim 2, wherein the height-adjustable opening communicates with a fluid line.
5. Use according to claim 1 or 2, further comprising: a ventilation unit; the ventilation unit comprises a ventilation pipe; and the wall of the reaction cavity far away from the downstream end of the chip is provided with an air vent communicated with the vent pipe.
6. Use according to claim 5, wherein the vent pipe on the upstream reaction chamber, the vent pipe on the midstream reaction chamber and the vent pipe on the downstream reaction chamber are in communication with each other.
7. Use according to claim 5, wherein the interconnecting portions of the air ducts extend in a bent manner away from the downstream end of the chip.
8. Use according to claim 6, wherein the interconnecting portions of the air ducts extend in a bent manner away from the downstream end of the chip.
9. Use according to claim 1 or 6, further comprising: a liquid storage unit; the liquid storage unit is positioned at the upstream of the upstream reaction cavity and is communicated with the midstream reaction cavity through a fluid pipeline;
at least 2 midstream reaction chambers are arranged; and a check mechanism is arranged between the middle-stream reaction cavities which are communicated with each other, so that the fluid can be prevented from flowing back to the upstream reaction cavity.
10. The use according to claim 1 or 6, wherein anti-contact mechanisms are further arranged between the interconnected midstream reaction chambers and between the midstream reaction chamber and the downstream reaction chamber; the anti-contact mechanism is a bending structure which extends from the fluid pipeline towards the direction far away from the downstream end and is higher than the top of the midstream reaction cavity.
11. Use according to claim 9, wherein the non-return means that the pipe diameter of the fluid line between the midstream reaction chambers is larger than the pipe diameter of the fluid line between the midstream reaction chambers and the upstream reaction chambers.
12. Use according to any one of claims 1, 4 and 11, wherein the fluid line is a siphon.
13. Use according to any one of claims 1, 6 and 11, wherein dry reagents are provided in each reaction chamber.
14. Use according to claim 13, wherein the reactive agent comprises: nucleic acid extraction reagent, nucleic acid releaser, primer, enzyme required for nucleic acid amplification, amplification buffer solution and dNTP.
15. Use according to any of claims 1-4, 6-8, 11, 14, wherein the microfluidic chip is selected from a disc-type structure or a fan-shaped structure.
16. The use according to any one of claims 1 to 4, 6 to 8, 11 and 14, further comprising a chip fixing mechanism for fixing the microfluidic chip in or in connection with the fluid flow driving device; the chip fixing mechanism is a chip fixing groove.
17. The use according to claim 1, wherein the liquid storage unit is communicated with the blending pool of the midstream reaction chamber through a fluid pipeline.
18. The use according to claim 1, wherein a quantitative flow distribution mechanism A is arranged on the side wall of the side, close to the mixing pool, of the transfer pool of the midstream reaction chamber, and a quantitative flow distribution mechanism B is arranged on the side wall, far from the transfer pool, of the mixing pool of the midstream reaction chamber;
the fluid quantity q which can be divided by the quantitative flow dividing mechanism A1Satisfies the following relation: q. q.s1=Q1-s1h1，
The height of the opening B of the quantitative flow distribution mechanism B with adjustable height is h2Satisfies the following relation: (Q)2+q1)/s2＞h2＞q1/s2，
Wherein: q. q.s1For the total amount of fluid entering the interior of the transfer tank, Q2The amount of fluid in the reservoir unit, h1The height, s, of the opening a is adjustable for the height of the quantitative distribution mechanism A1To transfer the area of the pool bottom, s2The area of the bottom of the mixing pool is obtained.
19. Use according to claim 1, wherein the non-return mechanism is: the inner diameter of the first siphon pipe is 2-3 times of the inner diameter of the first connection pipe.
20. Use according to claim 1, wherein the reaction well is in plurality and is respectively in communication with a distribution conduit.
21. The use of claim 1, wherein the second siphon pipe extends out of a bending structure higher than the L-shaped top of the blending pool towards the center of the disc to form an anti-contact mechanism.
22. Use according to claim 20, wherein the plurality of reaction holes are evenly distributed along the distribution pipe and are all located on the downstream side of the distribution pipe; reaction reagents are arranged in the reaction holes.
23. The use of claim 17 or 18, wherein the liquid storage unit is internally provided with an aluminum foil liquid sac and communicated with the blending pool; the aluminum foil liquid bag is easy to break, so that the fluid in the liquid bag flows into the blending pool through the fluid pipeline.
24. Use according to claim 1 or 21, wherein the chip fixation groove is provided in the center of the disc.
25. A microfluidic method with a self-driven unit, characterized in that the use of any of claims 1 to 24 is used to generate compressed air in a microfluidic chip for controlling the flow in the microfluidic chip.
26. A microfluidic method with self-driven element according to claim 25, comprising:
(1) a fluid sample enters a sample cell of an upstream reaction cavity through a sample adding hole of the microfluidic chip, the microfluidic chip is placed in the fluid flow driving device or is connected with the fluid flow driving device, and the driving force of the fluid flow driving device is adjusted to perform reaction;
(2) adjusting the driving force to enable the fluid sample in the sample cell to enter the transfer cell of the midstream reaction chamber through the fluid pipeline for reaction, and meanwhile, air in the transfer cell is forced to be compressed and enters the air cell through the gas pipeline of the self-driving unit;
(3) adjusting the driving force, expanding compressed air in the air pool to extrude the fluid in the transfer pool, enabling the fluid in the transfer pool to enter the blending pool through a fluid pipeline under the action of a check mechanism under the action of the quantitative flow dividing mechanism, breaking an aluminum foil liquid bag of the liquid storage unit through extrusion, adjusting the driving force, and enabling the fluid in the liquid storage unit to enter the blending pool through the fluid pipeline to react;
(4) and adjusting the driving force, enabling the fluid in the mixing pool to enter a distribution pipeline of a downstream reaction cavity through a fluid pipeline, and adjusting the driving force to enable the fluid to enter each reaction hole respectively for reaction.
27. The microfluidic method according to claim 26, wherein the fluid flow driving device is selected from the group consisting of: centrifuge, negative pressure pump.
28. A microfluidic method according to claim 26, wherein the driving force is selected from the group consisting of: centrifugal force, pressure, gravity.
29. The microfluidic method with self-driven unit according to claim 26, wherein adjusting the driving force is decreasing or increasing the rotation speed of the centrifuge, decreasing or increasing the pressure of the negative pressure pump.
30. A microfluidic method according to claim 26, wherein the reaction is selected from the group consisting of: nucleic acid extraction reaction, nucleic acid release reaction, nucleic acid amplification reaction and cell culture reaction.
31. The microfluidic method with self-driven unit according to claim 26, wherein the fluid sample is selected from a reaction solution, or a sample to be tested; the sample to be tested is selected from the group consisting of cell culture fluid, blood, swab rinse, cerebrospinal fluid, alveolar lavage fluid, and urine.
32. Use of a microfluidic method according to any one of claims 25 to 31 with a self-driven element for nucleic acid extraction, and/or nucleic acid release, and/or nucleic acid amplification detection, and/or environmental monitoring, and/or food detection, and/or forensic identification.
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