Microfluidic liquid path structure, and device comprising same and operation method therefor

Abstract

A liquid path structure and an operation method therefor. The liquid path structure comprises: a first wall surface (1); a second wall surface (2), configured to be disposed close to the first wall surface (1) or to be disposed in at least partial contact with the first wall surface (1), wherein the space between the first wall surface (1) and the second wall surface (2), where the two face each other, forms a flow domain (3), and the flow domain (3) comprises a thin flow domain; an inlet structure, configured to comprise one or more inlets (4) which are communicated with the flow domain (3) during operation, allowing a fluid comprising at least a first fluid to be introduced into the flow domain (3); and an outlet structure, configured to comprise one or more outlets (5) which are communicated with the flow domain (3) during operation, allowing the fluid passing through the flow domain (3) to be discharged. The first fluid is configured to be capable of receiving applied energy.

Description

Microfluidic liquid path structure, device containing the liquid path and operation method thereof

[0001] This application claims priority to the application number 202311673673.9 filed with the Patent Office of China on December 7, 2023, entitled “A liquid circuit structure, a device comprising the liquid circuit and an operating method thereof”, the entire contents of which are incorporated by reference into this application. Technical Field

[0002] The present application relates to a liquid path structure for constructing a novel flow field and an operation method thereof, and particularly to the manipulation and replacement process of a tiny amount of liquid. Background Art

[0003] Traditional biochemical and electromechanical devices typically use macroscopic amounts of fluid when working with fluids. For example, medical equipment uses a whole tube of reagent to test a single sample, or the chip is directly rinsed with pure water connected to a pipe or immersed in a pool of chemical reagents for reaction and cleaning. This creates two problems:

[0004] 1. Expensive and requires a large amount of reagents;

[0005] 2. Performance may be poor because mass transfer in bulk liquids is always slow.

[0006] According to Whitesides' review paper, "Microfluidics is the science and technology of systems that process or manipulate small volumes (10^-9 to 10^-18 liters) of liquids using channels with dimensions ranging from tens to hundreds of microns. The first applications of microfluidics were in analysis, where it provided many useful features: the ability to separate and detect with high resolution and sensitivity using very small sample and reagent volumes; low cost; shorter analysis times; and a small footprint for analytical equipment. Microfluidics exploits its most obvious characteristic, its small size, as well as some less obvious properties of liquids in microchannels, such as laminar flow. It provides fundamentally new capabilities in controlling the concentrations of molecules in space and time."

[0007] As a technology, microfluidics is almost too good to be true: it offers so many advantages and, in its primary application (analysis), has few drawbacks. However, it has not yet become widely used. Some of the key reasons for this include:

[0008] 1. Developers and even users need certain background skills to develop and use (such as fluid-related skills);

[0009] 2. Microfluidic chips have many complex supporting components and require related accessories to work, such as pumps and valves;

[0010] 3. The number of manufacturing steps is large, resulting in higher costs and lower yields;

[0011] 4. The size of the pipeline is small, and the products produced require strict quality control, otherwise the coefficient of variation (CV value) will be too high and the results will be inaccurate.

[0012] Specifically, when the pipeline size is small, even a small size change will lead to a relatively large change in the microstructure size (for example, if the size of 50 microns changes by 50 microns during production, the change is 100%, while if the size of 1 mm changes by 50 microns during production, the change is 5%), resulting in an excessively high coefficient of variation (CV value) of the result, and large intra-batch and inter-batch differences.

[0013] Microfluidics confines reactions to a single chip. Although the channels are micrometer-scale, consuming little reagent, allowing for rapid mass transfer and rapid reactions, traditional microfluidics requires the construction of three-dimensional liquid channels to constrain liquid flow. The channels are microscopic in height and width, but macroscopic in the direction of flow. To provide energy to offset the friction of the liquid moving through the microchannels, the entire system typically needs to be encapsulated, and pump-type fluidic devices are used to continuously provide pressure to propel the fluid and prevent leaks. This results in a system with numerous components and difficult-to-clean tubing, leading to increased reagent consumption. Furthermore, if passive methods such as capillary force are used instead of pressure, the device becomes even more difficult to control and is typically used for simpler assays. While microfluidics saves reagents, the chip costs are high, and both R&D and production are challenging, so they have yet to gain widespread adoption. Furthermore, the tubing connecting the chip is macroscopic, resulting in high reagent consumption, partially negating the advantages of microfluidics.

[0014] The higher barrier to entry, coupled with performance improvements not exceeding orders of magnitude compared to existing solutions, has limited the number of microfluidic devices available on the market. The most common types are either simple and inexpensive, such as antigens or pregnancy test strips, or high-value-added, such as DNA sequencing chips.

[0015] For example: Illumina's flow cell system for gene sequencing, and Roche's Cobas Liat system for nucleic acid detection. Summary of the Invention

[0016] To address the aforementioned issues in microfluidics, this application provides a technology comprising a Couette-like flow field construction method, a construction device, and applications in the microfluidics field. Product considerations typically focus on several key aspects, including reliability, performance, and cost. The technology of this invention draws on the advantages of both traditional biochemical electromechanical devices and microfluidics, maintaining the reagent-saving and rapid reaction times of microfluidics while offering the stability, reliability, and ease of manufacturing of traditional devices, potentially replacing both.

[0017] In order to solve at least one of the above-mentioned problems and / or other potential problems of the prior art, it is necessary to invent a new fluid driving method and its hardware platform. Our technology is called the Couette-like flow field construction method, and the related hardware platform is called the shear-driven fluid platform. It mainly uses the shear force of the fluid to construct a flow field similar to the Couette flow field, to replace the traditional method - the Poisson flow field that uses pure pressure drive to overcome the friction between the fluid and the solid wall surface that constitutes the thin flow domain. The purpose of this design is first to be able to use a small amount of fluid to quickly clean the surface and replace the liquid originally existing in the flow domain, saving costs. Secondly, there are fewer parts involved, eliminating complex seals and pipe valves, and increasing reliability. Third, the quality control of the device becomes simpler because the number of parts is greatly reduced. Fourth, operation and development become simple and low-cost because there is no need for packaging and no fluid knowledge background.

[0018] The present application first provides a fluid circuit structure, comprising

[0019] The first wall,

[0020] The second wall is configured to be disposed close to or at least partially in contact with the first wall, and the space facing each other forms a flow basin, which includes a thin flow basin;

[0021] The inlet structure is configured to include one or more inlets, which are in communication with the flow basin when in operation so that a fluid including at least a first fluid can be introduced into the flow basin; the outlet structure is configured to include one or more outlets, which are in communication with the flow basin when in operation so that the fluid passing through the flow basin can be discharged;

[0022] wherein the first fluid comprises a liquid;

[0023] Among them, when working:

[0024] The fluid at at least one inlet location of the inlet structure can be directly exposed to the environment outside the flow basin without passing through a pipeline; and / or

[0025] The fluid at at least one outlet location of the outlet structure can be directly exposed to the environment outside the flow basin without passing through a pipeline, and / or

[0026] The fluid at at least one location in the basin is directly exposed to the environment outside the basin;

[0027] The first fluid is configured to be able to be applied with energy during operation, and the energy can be converted into fluid kinetic energy, thereby forming a shear flow of the first fluid in the flow domain. The thin flow domain can be emptied or filled with fluid during operation.

[0028] Optionally, during operation, the first wall surface is configured to be able to move relative to the second wall surface, thereby applying energy to the first fluid and driving the shear flow of the first fluid.

[0029] Optionally, the relative movement of the first wall includes translation in a direction substantially parallel to the second wall, translation in a direction approaching or moving away from the second wall, and rotation relative to the second wall.

[0030] Optionally, the first wall surface rotating relative to the second wall surface includes the first wall surface rotating and the second wall surface being stationary.

[0031] Optionally, the first wall and the second wall comprise a disc shape, the first wall is substantially planar, the second wall is substantially planar, and the first wall is substantially parallel to the second wall;

[0032] During operation, the first wall is configured to rotate, thereby applying energy to the first fluid and driving the first fluid to traverse the second wall.

[0033] Optionally, the first fluid is configured to be capable of shear flow when energy is applied thereto based on one of force, heat, light, and electrical effects.

[0034] Optionally, the inlet structure includes a first inlet and a second inlet;

[0035] In which, the first fluid flows into the flow basin from the first inlet and flows out from an outlet of the outlet structure, the second fluid flows into the flow basin from the second inlet and flows out from an outlet of the outlet structure, sharing an outlet with the first fluid, or flows out from another outlet of the outlet structure, using different outlets with the first fluid, wherein the second fluid and the first fluid are laminar flows in the thin flow basin, and the second fluid occupies a certain space in the thin flow basin, so that the required amount of the first fluid is further reduced.

[0036] Optionally, the second fluid contacts the first fluid in the thin flow region, and its flow area does not overlap with the first fluid.

[0037] Optionally, the movement of the second fluid can drive the first fluid to perform shear flow.

[0038] Optionally, the fluid can be introduced in a temporally or spatially discrete manner through the inlet structure, wherein:

[0039] The inlet structure includes an inlet, wherein the first fluids are introduced into the inlet at different times, or when the first fluids are introduced into the inlet at the same time, an incompatible fluid is used to separate the first fluids so that the first fluids do not mix with each other before entering the thin flow region; or

[0040] The inlet structure includes a plurality of inlets, and each first fluid is introduced through a different inlet, so that each first fluid will not mix with each other before entering the thin flow region.

[0041] Optionally, the inlet structure further includes a liquid storage structure for storing a predetermined amount of the first fluid to ensure that a sufficient amount of the first fluid fills the flow field through the inlet while preventing air from being brought into the flow field;

[0042] The predetermined amount is configured to be slightly larger than a required fluid capacity of the flow domain.

[0043] Optionally, the first wall and the second wall include curved surfaces to form a sleeve shape, wherein one of the first wall and the second wall forms an outer cylinder and the other forms an inner cylinder, and a flow domain is formed between the two. During operation, at least one of the outer cylinder and the inner cylinder can move, and the movement includes: rotation or axial linear motion or axial linear motion while rotating.

[0044] Optionally, the first wall forms an outer cylinder, and the second wall forms an inner cylinder. The inner cylinder moves, and the outer cylinder is stationary. The movement includes: rotation and / or axial movement.

[0045] Optionally, the height of the inner cylinder is lower than that of the outer cylinder.

[0046] Optionally, both the inner barrel and the outer barrel comprise cylinders; or

[0047] The inner cylinder comprises a multifaceted cylindrical cylinder, and the outer cylinder comprises a cylindrical cylinder; or

[0048] The outer cylinder comprises a multifaceted cylindrical cylinder, and the inner cylinder comprises a cylindrical cylinder.

[0049] Optionally, the outlet structure is configured to enable the fluid from the thin flow region to be discharged freely and unobstructed, so as to avoid blockage that affects the fluid introduction inlet.

[0050] Optionally, the materials of the first wall and the second wall are selected to have hydrophilicity and hydrophobicity such that the first fluid can be freely located between the first wall and the second wall without being expelled by surface tension. For example, the hydrophilic and hydrophobic material includes an HMDS coating.

[0051] Optionally, the material of the second wall is selected such that it has poor affinity with the first fluid in the flow domain, so that the first fluid flowing out of the flow domain by shear flow will be sucked back into the flow domain.

[0052] Optionally, the sum of cosine values ​​of contact angles of the first wall and the second wall with respect to the first fluid is greater than or equal to zero.

[0053] Optionally, the inlet includes a free surface, or the fluid connected to the inlet has at least one free surface; the outlet includes a free surface, or the fluid connected to the outlet has at least one free surface.

[0054] Optionally, the thick dimension of the thin flow domain is at least one order of magnitude smaller than the long and / or wide dimensions of the thin flow domain.

[0055] Optionally, the thin flow domain has a thickness of 2-100 microns.

[0056] Optionally, the first fluid between the first wall and the second wall has a velocity gradient, and the first fluid has a faster flow rate on the side affected by energy or with less resistance.

[0057] Optionally, the liquid path structure further includes a heater;

[0058] The heater is configured to be capable of heat transfer with the first wall surface and / or the second wall surface for heating the flow area.

[0059] Optionally, the flow domain includes a plurality of temperature zones, and the plurality of temperature zones are separated by at least one insulation block provided on the second wall surface, wherein the temperatures of the plurality of temperature zones are the same or different.

[0060] Optionally, the first wall and the second wall include a disc shape, and the second wall is configured to rotate during operation, thereby applying energy to the first fluid and driving the shear flow of the first fluid.

[0061] Optionally, the first wall is configured to be stationary, or to rotate, or to move linearly in a direction substantially parallel to the second wall, or to rotate and move linearly in a direction substantially parallel to the second wall.

[0062] Optionally, the inlet structure includes a channel provided at a predetermined position of the first wall and / or the second wall, for introducing fluid into the flow field.

[0063] Optionally, the channel includes a through hole provided on the first wall and / or the second wall near the center of the disk.

[0064] Optionally, the channel includes a liquid inlet pipe attached to the first wall and / or the second wall, so that the first fluid is sucked into the flow field.

[0065] Optionally, the outlet structure includes an area between the disc periphery of the first wall and the disc periphery of the second wall, enabling the first fluid to be discharged through the area.

[0066] Optionally, the liquid path structure is a microfluidic liquid path structure.

[0067] A second aspect of the present application provides a device comprising the fluid path structure according to the present application.

[0068] A third aspect of the present application provides an operating method of a fluid circuit structure, comprising:

[0069] providing a first wall surface,

[0070] Providing a second wall surface, configured to be disposed close to or at least partially in contact with the first wall surface, wherein the space facing the second wall surface forms a flow domain, and the flow domain includes a thin flow domain;

[0071] Providing an inlet structure configured to include one or more inlets in operative communication with the flow basin so that a fluid including at least a first fluid can be introduced into the flow basin;

[0072] Providing an outlet structure, which is configured to include one or more outlets and is in communication with the flow basin when in operation, so that the fluid passing through the flow basin is discharged;

[0073] wherein the first fluid comprises a liquid;

[0074] Among them, when working:

[0075] The fluid at at least one inlet location of the inlet structure can be directly exposed to the environment outside the flow basin without passing through a pipeline; and / or

[0076] The fluid at at least one outlet location of the outlet structure can be directly exposed to the environment outside the flow basin without passing through a pipeline, and / or

[0077] The fluid at at least one location in the basin is directly exposed to the environment outside the basin;

[0078] The first fluid is configured to be capable of being applied with energy, which can be converted into fluid kinetic energy, thereby forming a shear flow of the first fluid in the flow domain. The thin flow domain can be emptied or filled with fluid during operation.

[0079] Optionally, during operation, the first wall surface is configured to be able to move relative to the second wall surface, thereby applying energy to the first fluid and driving the shear flow of the first fluid.

[0080] Optionally, the relative movement of the first wall includes translation in a direction substantially parallel to the second wall, translation in a direction approaching or moving away from the second wall, and rotation relative to the second wall.

[0081] Optionally, the first wall surface rotating relative to the second wall surface includes the first wall surface rotating and the second wall surface being stationary.

[0082] Optionally, the first wall and the second wall comprise a disc shape, the first wall is substantially planar, the second wall is substantially planar, and the first wall is substantially parallel to the second wall;

[0083] During operation, the first wall is configured to rotate, thereby applying energy to the first fluid and driving the first fluid to traverse the second wall.

[0084] Optionally, the first fluid is configured to be capable of shear flow when energy is applied thereto based on one of force, heat, light, and electrical effects.

[0085] Optionally, the inlet structure includes a first inlet and a second inlet,

[0086] wherein the first fluid flows from the first inlet, passes through the flow field, and flows out from an outlet of the outlet structure;

[0087] The second fluid flows into the flow field from the second inlet and flows out from one outlet of the outlet structure, and the first fluid and the second fluid share the same outlet, or flows out from another outlet of the outlet structure, and the first fluid and the second fluid use different outlets respectively.

[0088] The second fluid and the first fluid are laminar flows in the thin flow region, and the second fluid occupies a certain space in the thin flow region, so that the required amount of the first fluid is further reduced.

[0089] Optionally, the second fluid contacts the first fluid in the thin flow region, and its flow area does not overlap with the first fluid.

[0090] Optionally, the movement of the second fluid can drive the first fluid to perform a shearing movement.

[0091] Optionally, the fluid is introduced in a temporally or spatially discrete manner through an inlet structure, wherein:

[0092] The inlet structure includes an inlet, wherein the first fluids are introduced into the inlet at different times, or when the first fluids are introduced into the inlet at the same time, an incompatible fluid is used to separate the first fluids so that the first fluids do not mix with each other before entering the thin flow region; or

[0093] The inlet structure includes a plurality of inlets, and each first fluid is introduced through a different inlet, so that each first fluid will not mix with each other before entering the thin flow region.

[0094] Optionally, the inlet structure further includes a liquid storage structure for storing a predetermined amount of the first fluid to ensure that a sufficient amount of the first fluid fills the flow basin through the inlet while preventing air from being brought in; wherein the predetermined amount is slightly larger than the fluid capacity required by the flow basin.

[0095] Optionally, the first wall and the second wall include curved surfaces to form a sleeve shape, wherein one of the first wall and the second wall forms an outer cylinder and the other forms an inner cylinder, and a flow domain is formed between the two. During operation, at least one of the outer cylinder and the inner cylinder can move, and the movement includes: rotation or axial linear motion or axial linear motion while rotating.

[0096] Optionally, the first wall forms an outer cylinder, and the second wall forms an inner cylinder. The inner cylinder moves, and the outer cylinder is stationary. The movement includes: rotation and / or axial movement.

[0097] Optionally, the inner cylinder is configured to be lower in height than the outer cylinder.

[0098] Optionally, both the inner and outer barrels comprise cylinders, or

[0099] The inner tube comprises a multi-faceted cylinder and the outer tube comprises a cylinder, or

[0100] The outer cylinder comprises a multifaceted cylindrical cylinder and the inner cylinder comprises a cylindrical cylinder.

[0101] Optionally, the inner cylinder comprises a multifaceted cylindrical cylinder and the outer cylinder comprises a cylindrical cylinder, further comprising the steps of:

[0102] S1. A chip is provided on the cylindrical surface of a multi-faceted cylinder, with the chip facing the outer cylinder and located in the flow field between the inner and outer cylinders;

[0103] S2. A first first fluid is provided through the inlet until the inner and outer cylinders are filled with the first first fluid, wherein the first first fluid is a liquid, preferably, pure water, or IPA, or Acetone;

[0104] S3. The outer cylinder starts to rotate and move axially back and forth, while the first fluid is continuously added and continuously flows out of the outlet.

[0105] S4. As the outer cylinder moves, the first fluid moves, and the first fluid approaches laminar flow where the inner wall of the inner cylinder and the outer cylinder are close to each other;

[0106] S5. Provide a second first fluid to the flow field through the inlet to clean the inner surface of the chip; the second first fluid includes a high-pressure gas and / or a surfactant;

[0107] S6. Lower the inner cylinder to expose the chip surface and dry it with high-pressure air.

[0108] S7. Take out the chip,

[0109] This completes the cleaning of the chip.

[0110] Optionally, the outlet structure is configured to enable the fluid from the thin flow region to be discharged freely and unobstructed, so as to avoid blockage that affects the fluid introduction inlet.

[0111] Optionally, the materials of the first wall and the second wall are selected such that their hydrophilicity and hydrophobicity enable the first fluid to be located between the first wall and the second wall in a free state without being expelled by surface tension. For example, the hydrophilic and hydrophobic material includes an HMDS coating.

[0112] Optionally, the material of the second wall is selected such that it has poor affinity with the first fluid in the flow domain, so that the first fluid flowing out of the flow domain by shear flow will be sucked back into the flow domain.

[0113] Optionally, the sum of cosine values ​​of contact angles of the first wall and the second wall with respect to the first fluid is greater than or equal to zero.

[0114] Optionally, the inlet includes a free surface, or the fluid connected to the inlet has at least one free surface; the outlet includes a free surface, or the fluid connected to the outlet has at least one free surface.

[0115] Optionally, the thick dimension of the thin flow domain is at least one order of magnitude smaller than the long and / or wide dimensions of the thin flow domain.

[0116] Optionally, the thin flow domain has a thickness of 2-100 microns.

[0117] Optionally, there is a velocity gradient for the first fluid between the first wall and the second wall, and the first fluid has a faster flow rate on the side affected by energy or with less resistance.

[0118] Optionally, the fluid path structure further includes a heater, and the heater is configured to perform heat transfer with the first wall surface and / or the second wall surface to heat the flow region.

[0119] Optionally, the flow domain includes a plurality of temperature zones, and the plurality of temperature zones are separated by at least one insulation block provided on the second wall surface, wherein the temperatures of the plurality of temperature zones are the same or different.

[0120] Optionally, the first wall and the second wall comprise a disc shape, the first wall is substantially planar, the second wall is substantially planar, and the first wall is substantially parallel to the second wall;

[0121] During operation, the second wall surface is configured to rotate relative to the first wall surface, thereby applying energy to the first fluid and driving the shear flow of the first fluid.

[0122] Optionally, the first wall is configured to be stationary, or to rotate, or to move linearly in a direction substantially parallel to the second wall, or to rotate and move linearly in a direction substantially parallel to the second wall.

[0123] Optionally, the second wall includes a chip, and the second wall is configured to have alternating hydrophilic regions and hydrophobic regions, wherein biomolecules are immobilized on the hydrophilic regions, the biomolecules including single-stranded DNA, and the hydrophobic regions are covered with a hydrophobic substance, and the area of ​​the first wall is greater than or equal to the area of ​​the second wall; the operating method further includes:

[0124] S1. providing a first first fluid through an inlet structure, the first first fluid comprising a reagent capable of disconnecting an azide group, to cause a first reaction between the first first fluid and the biomolecule;

[0125] S2 provides a second first fluid through the inlet structure, the second first fluid comprises a buffer reagent for cleaning the first first fluid and the product of the first reaction;

[0126] S3 provides a third first fluid through the inlet structure, the third first fluid includes a synthetic reagent containing four bases ACTG and corresponding dye groups, so that a second reaction occurs between the third first fluid and the biomolecule;

[0127] S4 provides a fourth first fluid through the inlet structure, the fourth first fluid comprises a buffer reagent for cleaning the third first fluid, wherein the fourth first fluid and the second first fluid are the same or different components of the buffer reagent;

[0128] S5. Recording and determining the base type of the product of the third reaction on the chip by sensing;

[0129] Repeat steps S1-S5 multiple times to obtain the base sequence of the DNA single strand based on the base types of the product of the third reaction.

[0130] Optionally, the following steps are further included between step S4 and step S5:

[0131] S4.1. A fifth first fluid is provided through the inlet structure, wherein the fifth first fluid comprises a synthetic reagent comprising four base groups of ACTG and corresponding dye groups, so that a third reaction of the fifth first fluid with the biomolecule occurs;

[0132] S4.2. Provide a sixth first fluid through the inlet structure, wherein the sixth first fluid includes a buffer reagent for cleaning the fifth first fluid, wherein the sixth first fluid is a buffer reagent with the same or different components as the second first fluid and the fourth first fluid.

[0133] Optionally, the operating method further includes: immediately before step S5, the step of providing a seventh first fluid through the inlet structure, wherein the seventh first fluid includes a protective reagent to prevent the recording process from causing adverse effects on the DNA.

[0134] Optionally, the first fluid comprises a triphenylphosphine solution.

[0135] Optionally, step S5 includes: recording by sensing means including: taking photos to record the fluorescence on the chip, and determining the type of base by a basecall algorithm.

[0136] Optionally, the outlet structure includes an area between the periphery of the disc on the first wall and the periphery of the disc on the second wall, enabling the first fluid to be discharged through the area, and the operating method further includes:

[0137] A waste liquid collecting structure is provided for collecting the discharged first fluid.

[0138] Optionally, in step S2, the reaction time of the first reaction is 1 minute.

[0139] Optionally, in step S2, the volume of the second first fluid is three times the volume of the flow basin.

[0140] Optionally, in step S3, the volume of the third first fluid is 1.5 times the volume of the flow basin.

[0141] Optionally, in step S3, the second reaction is carried out at a temperature of 55° C., and the reaction time of the second reaction is 1 minute.

[0142] Optionally, the inlet structure includes a channel provided at a predetermined position on the first wall and / or the second wall, for introducing fluid into the flow field.

[0143] Optionally, the channel includes a through hole provided on the first wall and / or the second wall near the center of the disk.

[0144] Optionally, the channel includes a liquid inlet pipe attached to the first wall and / or the second wall, so that the first fluid is sucked into the flow field.

[0145] Optionally, the outlet structure includes an area between the disc periphery of the first wall and the disc periphery of the second wall, enabling the first fluid to be discharged through the area.

[0146] A fourth aspect of the present application provides an operating method of a microfluidic circuit structure, comprising:

[0147] Providing a pipeline, the pipeline comprising an inlet structure and an outlet structure, the inlet structure comprising at least one inlet, and the outlet structure comprising at least one outlet;

[0148] During operation, a first fluid and a second fluid incompatible with the first fluid are introduced into the pipeline through different inlets of at least one inlet, wherein the first fluid and the second fluid are discharged through at least one outlet, forming a flow domain between the inlet structure and the outlet structure; wherein the second fluid occupies a certain volume of the flow domain to form a thin flow domain of the first fluid.

[0149] Optionally, the second fluid flows in the pipeline, driving the first fluid to shear flow in the pipeline.

[0150] Optionally, the second fluid is configured not to undergo macroscopic flow.

[0151] Optionally, the thin flow domain has a thickness of at least 2 microns.

[0152] Optionally, the inlet structure includes a solenoid valve configured to control the introduction of the first fluid and the second fluid into the pipeline.

[0153] The liquid path structure provided in the present application mainly utilizes the shear force of the fluid to construct a Couette-like flow field, replacing the Poisson leaf flow field constructed using pure pressure drive in the prior art.

[0154] The device provided by this application significantly reduces the number of fluid path components, which facilitates overall quality control. In addition, since the fluid path structure does not need to be encapsulated, the device operator does not need to have a fluid knowledge background, which facilitates operation and development while reducing costs.

[0155] The Couette-like flow field construction method provided in the present application injects the fluid into the inlet and starts the shear force driving device, so that the fluid is injected into at least a thin flow domain within the flow domain, so that interaction can occur. In the present application, since the pressure drive or surface tension drive of the traditional microfluidic platform is replaced by shear force drive, on the one hand, the improvement of energy input and performance optimization are more convenient, and there is no problem of pressure overlimit; in addition, the structure is simple, avoiding the learning and use obstacles caused by a large number of external equipment; thirdly, a large number of external pipelines are eliminated, saving cleaning time and cost. Fourth, sealing is not required, avoiding the cost and inconsistency of packaging.

[0156] Therefore, this application overcomes the problems of high cost, difficulty in getting started, and low performance of traditional microfluidic devices, making its market penetration prospects more prominent. BRIEF DESCRIPTION OF THE DRAWINGS

[0157] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for use in the embodiments of the present invention. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0158] Figure 1 is a schematic diagram comparing the structural principles of the Couette flow device in the present invention and the Poiseuille flow device in the prior art, wherein Figure 1(a) and Figure 1(b) respectively show the typical implementation form of the device of the present invention and two ways of generating shear force, and Figure 1(c) shows the Poiseuille flow device in the prior art, a typical structural cross-sectional view of the flow cell and schematic diagrams of different models of actual objects.

[0159] Figure 2 shows a comparison of the simulation of a traditional microfluidic device flow cell and a Shear-driven microfluidics device using fluid simulation software, where Figure 2(a) shows the effect of flow rate on the pressure difference between the inlet and outlet of the patented method and the traditional flow cell method when other parameters are constant; Figure 2(b) shows the effect of the wall gap on the pressure difference when other parameters are constant; Figure 2(c) shows the effect of the wall length on the pressure difference when other parameters are constant, where the wall gap is 20 microns, the chip length is 7 cm, and the average flow rate is 0.16 m / s.

[0160] Figure 3 is a schematic diagram comparing the reagent replacement speed and reagent consumption of a traditional microfluidic device flow cell and a Couette-like flow device simulated using fluid simulation software, wherein Figure 3(a) shows a 3D graph of the concentration change of the reagent replacement speed of the Couette-like flow device from 0.16 m / s to the average speed, Figure 3(b) shows a side view of the concentration change, Figure 3(c) shows the effect on the replacement ratio when the flow rate is used as a variable and other constants compared with the flow cell, the replacement ratio is defined as the ratio of the required reagent volume to the chamber volume, and Figure 3(d) shows the effect of the pipe / chamber volume ratio as a variable on the amount of dNTP used in each nanopore.

[0161] FIG4 is a schematic diagram of a device for applying a Couette-like flow to two planes approaching each other and moving relative to each other to save the amount of fluid consumed in the process.

[0162] FIG5 is a schematic diagram of an apparatus for applying a Couette-like flow to two adjacent planes to save fluid consumption in a gene sequencing process according to the embodiment of FIG4 .

[0163] Figure 6 is a schematic diagram of a device that applies Couette-like flow to two curved surfaces in relative motion and approaching each other to reduce reagent consumption during a process. Figure 6(a) shows a schematic diagram of the device in this embodiment, Figure 6(b) shows a schematic diagram of the operating principle of this embodiment, and Figure 6(c) shows a schematic diagram of the instrument of the prior art Roche Cobas Liat microfluidic system.

[0164] FIG. 7 is a schematic diagram showing changes in fluorescence intensity during the DNA amplification cycle according to the embodiment of FIG. 6 .

[0165] Figure 8 is a schematic diagram of a device for actively moving a Couette-like wall surface, wherein the wall surface is a moving liquid that flows in a stratified manner with the liquid to be conserved. Figure 8(a) shows a photograph and an enlarged microscopic photograph of a conventional flow cell; Figure 8(b) shows a 3D diagram of the flow process in two directions, including velocity slices (showing the velocity distribution, indicating shear flow of the liquid to be conserved) and the stratified flow interface between the two fluids; Figure 8(c) shows another equivalent design for the flow field.

[0166] Figure 9(a) shows an inlet design of a flow field according to the embodiment of Figure 8, and Figure 9(b) shows a system according to the embodiment of Figure 8, which shows a device that utilizes a macroscopically stationary liquid that is layered and in contact with the liquid to be saved.

[0167] Figure 10 is a schematic diagram of a device in which the type of stationary wall (second wall) of Couette-like flow is selected to have very low affinity for the fluid between the two walls, and when the first wall moves, the fluid flowing out of the flow area will retract and always follow the movement of the wall.

[0168] FIG. 11 is a top view of another structure of the device according to the embodiment of FIG. 10 , wherein the fluid can move into one or several areas in the checkerboard structure.

[0169] FIG12 is a schematic diagram of a device in which the wall type of active motion of Couette-like flow is selected as an unwinding and winding strip, and the liquid inlet is kept filled so that fluid can be directly added.

[0170] FIG. 13( a ) and FIG. 13 ( b ) show two implementations of bypass arrangement when the liquid inlet of the liquid path structure remains filled with excess fluid.

[0171] Figure 14(a) is a schematic diagram of a sampling method device through time discretization in this embodiment, Figure 14(b) is a schematic diagram of a sampling method device through space discretization in this embodiment, Figure 14(c) is a schematic diagram of a sampling method device through time and space discretization in this embodiment, and Figure 14(d) is a schematic diagram of a sampling method device through changing the shape of one of the walls to keep the inlet full in this embodiment.

[0172] Figure 15(a) is a schematic diagram of another sampling method device through time discreteness according to the embodiment of Figure 14(a), Figure 15(b) is a schematic diagram of another sampling method device through space discreteness according to the embodiment of Figure 14(b), and Figure 15(c) is a schematic diagram of another sampling method device through time and space discreteness according to the embodiment of Figure 14(c).

[0173] FIG16 is a schematic side and top view of a device for maintaining a Couette-like flow within a flow domain by providing a retaining force through a hydrophobic material at a curved liquid surface or an edge, without adding side walls on both sides of the flow direction.

[0174] Figures 17(a), 17(b), 17(c) and 17(d) are schematic diagrams of four devices in which the first wall and the second wall do not move, but there is a mechanism between the walls to push the liquid to form shear flow.

[0175] FIG18 is a schematic diagram of a device for selecting the direction of wall motion of the active motion of the Couette-like flow as up and down motion.

[0176] FIG19 is a schematic diagram of applying a Couette-like flow to a nucleic acid assay system according to the embodiment of FIG18 .

[0177] FIG20 is a schematic diagram of a device that applies a Couette-like flow to two surfaces approaching and moving relative to each other, one selected plane and one selected curved surface, to save the amount of reagents consumed in the process.

[0178] FIG21 is a schematic diagram of a device in which the second wall is set to be stationary and the first wall is set to rotate.

[0179] FIG22 is a schematic diagram of various possible forms of thin basins.

[0180] FIG23 is a flow chart for constructing a Couette-like flow field microfluidic device. DETAILED DESCRIPTION

[0181] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. All other embodiments obtained by ordinary technicians in this field based on the embodiments of the present invention without making any creative efforts shall fall within the scope of protection of the present invention.

[0182] In the description of this application, it should be understood that the terms "first" and "second" are used for descriptive purposes only and cannot be understood as indicating or implying the function, relative importance or implicitly indicating the number of the indicated technical features.

[0183] It should be noted that when a component is referred to as being "fixed to" or "mounted on" another component, it may be directly on the other component or there may be a central component. When a component is considered to be "disposed on" another component, it may be directly on the other component or there may be a central component at the same time. As used herein, the term "and / or" includes all and any combinations of one or more of the relevant listed items.

[0184] To help better understand the solutions provided by the embodiments of the present disclosure, before introducing the methods provided by the embodiments of the present disclosure, the following explanatory description is provided for the Couette-like flow field and the device constructed therefrom in the aforementioned embodiments:

[0185] A Couette flow is a typical shear-driven flow field in fluid mechanics. It describes the flow between two parallel walls of infinite length and width, where one wall is fixed and the other moves at a constant speed, thus generating a stable shear force. Therefore, a device for constructing a Couette flow field should have the following elements:

[0186] 1. Parallel walls: Couette flow occurs between two parallel walls, which can be flat plates, cylinders or other parallel geometric shapes.

[0187] 2. Relative motion: One of the two walls remains stationary while the other moves at a constant speed. This relative motion triggers the flow of the fluid.

[0188] 3. No pressure gradient: In an ideal Couette flow field, there is no pressure gradient along the flow direction (i.e., parallel to the moving wall). This means that the pressure can only change in the direction perpendicular to the flow direction.

[0189] 4. Viscous fluids: Couette flow usually involves viscous fluids, where viscosity plays a key role. The viscosity of the fluid leads to velocity gradients between fluid layers, creating shear forces.

[0190] 5. Shear flow: Due to the movement of one wall and the stationary state of the other wall, the velocity of the fluid decreases as the distance from the moving wall increases. Flow caused by this velocity gradient is called shear flow.

[0191] 6. Steady-state flow: Under constant conditions, Couette flow eventually reaches a steady state, that is, the flow state of the fluid no longer changes with time.

[0192] An ideal Couette flow field consists of two parallel walls of infinite length or width, with unpressurized fluid initially filling the space between the walls. However, in practical applications, equipment size is limited, and certain techniques are required to introduce the fluid into the flow field while minimizing the impact on the flow field characteristics.

[0193] In this regard, the present application provides a fluid device, the technical concept of which is:

[0194] First, parallel walls are a major factor. In order to simulate infinite walls within a limited area, the inventors considered the following three key points:

[0195] The first point is that the sidewalls perpendicular to the flow direction restrict the fluid from overflowing or can control the overflow without affecting the flow field;

[0196] The second point is to ensure that the supply volume is not less than or slightly exceeds the volume flowing through the basin in the import and export directions, and that the passage is unobstructed;

[0197] The third point is that the walls need to be close enough together (the scales involved in microfluidics are usually micrometers) to work well, ensuring that the walls can still be parallel at such a small distance.

[0198] Regarding the first key point, the inventor believes that there are at least the following practical methods:

[0199] 1. Within the range where two walls are opposite to each other, the inventors design the wall surface or its various related properties to match the flowing fluid, such as hydrophilic wall and aqueous fluid, or hydrophobic material and oily fluid, which can confine the liquid between the two adjacent walls.

[0200] 2. Design obstacles around the flow area that are difficult for the liquid to cross. For example, when the fluid is aqueous, designing a hydrophobic area on the wall will require a lot of energy for the liquid to flow through.

[0201] The result of both schemes is that the fluid at the boundary is in direct contact with the air, thus forming a slip interface, which theoretically can achieve the same effect as a wall of infinite width, thereby realizing the same characteristics as Couette flow.

[0202] 3. One wall is wider (perpendicular to the flow direction) than the other. This allows the liquid between the walls to be constrained using a principle similar to pinning lines, preventing it from significantly exceeding the narrow wall. In this case, the flow at the edge is more complex, but any overflowing fluid is eventually carried away by shear forces, as shown in Figure 13.

[0203] 4. Design a wall, such as a half-wall or liquid wall, as shown in Figure 8 or 9, to form a physical constraint. This will make the velocity of the fluid contacting the wall zero or slower than the fluid inside, and even cause overflow and capillary phenomena. However, if the flow domain area is large enough or the overflow is controllable, the fluid inside the thin film area can still be less affected, and the overall behavior is close to that of Couette flow.

[0204] Regarding the second key point, to prevent the inlet from drawing in unwanted fluids, such as air, sufficient fluid is required. Furthermore, the Couette field is a zero-pressure field, where the flux equals the cross-sectional area multiplied by the average velocity. Because reality deviates from the ideal, pressure may exist and sometimes fluctuate. This is difficult to measure due to the narrow gap. Therefore, to ensure safety, there must always be excess fluid at the inlet. In terms of operation, the amount of liquid should exceed the system's requirements, and the excess can be discharged from the system through a bypass, as shown in Figure 13.

[0205] There are many ways to allow fluid to enter the thin flow domain at the inlet. The preferred solution proposed in this disclosure is a discrete solution. Specific implementation methods include:

[0206] 1. Using a pipette, droplets are dripped onto the perforations at the bottom of the chip. Discrete droplets, entrained by air, enter the thin flow field directly. This eliminates the need for cleaning or for different reagents to pass through a common path. This is impossible with traditional pressure-driven microfluidics, which require sealed, pressurized equipment and piping.

[0207] 2. Different reagents enter the thin flow basin separately through physical isolation, and different reagents are also discrete in space. After entering the flow basin, they are still mainly driven by laminar flow and shear, which can achieve better cleaning.

[0208] In the embodiments of the present application, physical isolation between different reagents can be achieved by air or an inert reagent incompatible with other reagents, or by different pipeline structures and multiple different inlets, as shown in FIG14 .

[0209] 3. Allow the reagent to enter the thin flow area in the form of steam and solidify into liquid, or use gas to push the liquid into the thin flow area.

[0210] 4. The liquid first enters a liquid storage structure, such as a liquid storage pool formed on a single wall or multiple walls close to each other. This structure is also part of the flow basin, and finally enters the thin flow basin.

[0211] 5. The liquid first adheres to a certain wall surface, and then enters the thin flow basin due to the relative movement between the walls. For example, a lifting platform controls the two walls to approach each other, and liquid is pre-attached to one of the walls. There are many different printing schemes that can be used to attach liquids, such as lamination, transfer, coating (or spraying, printing), mutual exclusion, coating, inkjet, etc. In short, to avoid cross-contamination of liquids, either the common channel is removed or the common channel can be emptied with the assistance of gas / air pressure. The ultimate effect is to prevent the liquids from mixing with each other before entering the flow basin, or the amount of mixing is extremely low compared to the pressure-driven method through the pipeline.

[0212] Regarding the second key point, at the outlet, it is necessary to keep the flow unobstructed and the pressure stable (for example, stable at 0), otherwise the liquid at the inlet may not flow through the thin flow area but directly flow to the surrounding bypass. The key point here is the diversion function at the outlet, which can be achieved in the following ways:

[0213] 1. The outlet has a shape that allows fluid to escape easily, such as a slope, a pointed mouth, a comb-like structure, or one side is longer than the other;

[0214] 2. The outlet has some means of removing the accumulated liquid, such as contact with fiber-containing water-absorbing materials or blowing with air flow, and the waste liquid is collected by negative pressure;

[0215] 3. Set up a certain flow channel at the outlet to reduce the resistance of the fluid leaving the system;

[0216] 4. There is no physical obstruction at the outlet, and one sliding wall is longer than the other walls. The liquid directly follows the shear force of the sliding wall to leave the flow area;

[0217] 5. Contact with other fluids such as air and use gravity to separate;

[0218] 6. Pressure-assisted release.

[0219] Regarding the third key point, Couette flow requires parallel walls, which may not be perfectly parallel in reality, especially at a microscopic scale. The following methods can be used:

[0220] 1. Achieve generally parallelism, and a certain inclination is also acceptable. In this case, some backflow may occur, but the purpose of the fluid channel is also achieved;

[0221] 2. Let the two walls directly contact each other. The actual flow channel thickness is determined by the roughness. This is because only the highest points have atomic-level contact, and the fluid will flow through the microscopic gaps, regardless of whether the rough structure is artificial or natural.

[0222] 3. Precise control, such as lifting platform or mechanical locking;

[0223] 4. Using an object of a certain thickness as a spacer to create a space between walls without spacers. The disadvantage is that some of the spacer area will be lost. Generally speaking, in order for the shear force to play a major role, the walls need to be close enough to each other.

[0224] Through the above three key points, the simulation of the flow domain within a limited area can be basically achieved.

[0225] After the simulated flow domain is realized, how to generate shear force is also a major factor. See Figure 23. In order to generate shear force by moving part of the liquid in the flow domain, the following three methods are considered:

[0226] 1. The simplest one is that the walls that make up the basin move relative to each other;

[0227] 2. The wall can be a solid wall or a liquid wall;

[0228] 3. The wall does not move physically, but the liquid close to the wall moves through some force, heat, light, electricity or magnetism.

[0229] Among them, regarding the first method of generating shear force, the inventor believes that there are at least the following practical operation methods:

[0230] 1. The wall moves relative to the wall in a parallel direction. Due to the non-slip boundary condition, the fluid layer in contact with the wall moves at a constant speed. Different walls have different velocities, which generates a velocity gradient in the direction between the flow domains. For thin flow domains, a velocity gradient is generated in the height direction. Then, each particle in the viscous fluid in the height direction will be affected by this velocity gradient and start to move.

[0231] 2. The relative movement of the wall is in the vertical or rotational direction. In this case, to ensure the single direction of the liquid, auxiliary devices such as valves or gravity are required. However, its essence is still to obtain shear force by moving the wall and ultimately convert it into the power of fluid flow, as shown in Figure 1(b).

[0232] 3. The relative motion of the wall rotates around a certain point or line. In this case, the direction of the shear force is consistent with the direction of rotation, and a centripetal force is also generated. The difference between this and the existing microfluidic turntable is that the traditional turntable rotates with the upper and lower parts glued together, which only has centripetal force but no shear force, and the liquid flows from the center to the outside.

[0233] The traditional method uses various structures to form resistance. Since there is no surface tension of the valve without air, air is a necessary component.

[0234] In the embodiment of the present application, one wall is configured to move while the other wall may be stationary, and a shear force is applied to the upper and lower parts. This shear force forms the driving force for fluid movement, and the liquid can flow in a direction perpendicular to the diameter, as shown in Figure 6. Even if both walls move simultaneously, there is no air in the flow domain during the reaction.

[0235] Regarding the second method of generating shear force, the inventor believes that there are at least the following practical operating methods:

[0236] 1. Use a magnetic field and magnetic fluid to form a tube wall, and the liquid flows in the tube formed in the middle of the magnetic fluid. When the wall of the magnetic fluid moves due to the movement of the magnetic field, the liquid in contact with it also flows due to the shear force;

[0237] 2. In a thin flow domain, two or more immiscible and easily separable liquids are filled. During laminar flow, the two liquids may undergo stratification in various situations. Among them, the effective fluid at least partially contacts other auxiliary liquids that are immiscible with it. At this time, the auxiliary liquid becomes the liquid wall of the effective fluid. When the liquid wall flows, the effective liquid is also affected by the shear force and begins to flow at the same time, requiring less energy.

[0238] Among them, regarding the third method of generating shear force, the inventor believes that there are at least the following practical operation methods:

[0239] 1. In electrowetting, the surface tension of an interface is the Helmholtz free energy required to create a certain area of ​​the surface. It consists of both chemical and electrical components. By changing the electric field, the properties of the liquid itself or the hydrophilicity and hydrophobicity of the wall can be changed, causing the liquid close to the wall to move and form a velocity gradient with the liquid away from the wall.

[0240] 2. Light-induced liquid deformation causes part of the liquid to begin to flow, and shear force and continuous liquid feeding are used to make the entire system flow;

[0241] 3. By controlling the movement of the magnetic fluid, other liquids in contact with the magnetic fluid in the flow area will flow;

[0242] 4. Through vibration (e.g., Rayleigh waves) or resonance, some liquids gain energy and begin to flow, thereby affecting the flow of other liquids.

[0243] 5. Use the method of hot bubbles to make part of the liquid move first, thereby affecting the flow of other liquids.

[0244] In short, energy is obtained within the system and shear force is generated. Then, through continuous liquid supply, a relatively stable shear flow is generated in the thin flow area, thereby achieving rapid surface cleaning and liquid replacement.

[0245] After the shear force is generated, zero pressure is also a major factor considered in this application. The ideal case of zero pressure gradient in the definition of Couette flow field is that pressure is almost inevitable in practice. In order to achieve a pressure drive that is several orders of magnitude smaller than the traditional microfluidic pressure-driven Poisson flow, the inventors mainly made the following considerations: the inlet or outlet of the traditional pressure-driven microfluidic device is directly connected to the pump, and there is a considerable pressure difference between the inlet and outlet. The pressure energy of the fluid is provided by the pump, which offsets the friction of the liquid in the microchannel and is eventually converted into heat energy. The low-pressure injection pump pressure is about 50kPa. The fluid device of this application is mainly affected by the velocity gradient generated by the shear force on the upper and lower sides of the thin flow basin, and the shear force has nothing to do with the pump. Even if a pump is involved, it is for the purpose of more convenient automated liquid feeding, etc. The pressure difference between the outlet and outlet of the flow basin is less than 20kpa and may even be 0, and at least half of the energy is provided by the shear force.

[0246] Specifically, conventional pressure-driven microfluidic devices have their inlet or outlet directly connected to a pump, resulting in a closed device with a small inlet and outlet, a thin laminar flow in between, and a large pressure differential required to propel the flow. In the microfluidic device of the present application, the liquid is driven by shear forces, and at least one of the inlet, outlet, or flow field is open to the environment, requiring a lower pressure.

[0247] Finally, regarding the viscosity of fluids, the inventors primarily considered the following: greater viscosity indicates a greater ability to resist external shear forces. If the viscosity of a fluid needs to be adjusted, this can be accomplished by mixing inert materials of varying viscosities. One approach involves adding glycerin to water to increase viscosity.

[0248] In summary, the present invention creates a thin flow domain, as shown in Figure 18, which shows the possible shape of the thin flow domain; by combining at least one of the key points mentioned above, a part of the liquid in the flow domain can be continuously moved due to the shear force, and other liquids are also driven to move together due to viscosity, thereby forming a continuous flow in the thin flow domain without the need for external pressure, forming a Couette-like flow field. As shown in the design mind map of this patent in Figure 23, this type of platform that realizes this flow field is called a shear-driven open microfluidic platform. It is different from the Poisson flow of the traditional pressure-driven microfluidic platform. The thin flow domain here is not necessarily a regular wall surface, but can also be various curved surfaces as shown in Figure 22. As long as the key points listed above are met, a Couette-like flow field can be formed.

[0249] Please refer to Figure 1(a), which illustrates the principle of a typical Couette-like flow field constructed using the shear-driven fluid platform of the present invention. A first fluid 6 is added directly into flow region 3 via inlet 4. Driven by the relative motion between first wall 1 and second wall 2, it passes through the gap between them and exits flow region 3 via outlet 5. While the sidewalls of flow region 3 are open, surface tension prevents the first fluid 6 from overflowing.

[0250] It should be noted that, when there is no relative movement between the first wall 1 and the second wall 2 , after the first fluid 6 is added to the flow basin 3 through the inlet 4 , the first fluid 6 can pass through the flow basin 3 by gravity or other forces after the flow basin 3 is filled.

[0251] In the flow field 3, the first fluid 6 forms a shear flow, see Couette flow. Furthermore, the first fluid 6 in a device can be a gas or a liquid, or multiple liquids or multiple gases. By utilizing the relative movement of the gaseous first fluid 6 and / or the first wall 1 and the second wall 2, the original liquid in the flow field 3 can be drained. By utilizing the relative movement of the liquid first fluid 6 and / or the first wall and the second wall, combined with a full inlet and an unobstructed outlet, the flow field can be filled with new liquid, quickly replacing the original liquid. In short, by controlling the type of the first fluid, the speed and method of the relative movement of the first wall and the second wall, and the gap, it is possible to:

[0252] 1. Drain the original liquid in the basin;

[0253] 2. Renew and / or replace the original liquid in the basin with another liquid;

[0254] 3. Fill the gas-filled flow area with a first fluid 6.

[0255] 4. Use another fluid to squeeze out the original fluid in the flow basin.

[0256] 5. Use surface tension to draw in fluid outside the flow area.

[0257] Unless otherwise specified, generally, the wall surface with the chip structure is used as the second wall surface, and the other wall surface is used as the first wall surface.

[0258] The ultimate goal of the above-mentioned operations is to rapidly manipulate fluids and save costs. These strategies achieve this goal because, first, conventional solutions apply pressure to the cross-section of the microfluidic channel. Because the cross-sectional area is typically very small, for example, tens of microns in length and width, the pressure must be relatively high to provide sufficient energy. This poses a significant challenge to seals such as valves and seals, making performance improvement relatively difficult. However, when the new solution uses shear force to actuate the flow, the entire flow basin area—typically a macroscopic area—is affected, and the required pressure is often reduced by an order of magnitude. Specifically, when a thin flow basin is preferred over a traditional microchannel, where only one dimension is microscopic, the actuation area can increase by two orders of magnitude, and the required pressure can decrease by more than one order of magnitude. As shown in the simulation in Figure 2, a microfluidic flow cell used for gene sequencing exhibits three orders of magnitude greater pressure at the same gap and flow rate compared to the solution of the present invention. This allows for a smaller gap, significantly reducing the amount of reagents, cleaning fluids, or precious samples used. This also allows for faster speeds. In addition, because only one dimension is microscopic, it is easier to manufacture.

[0259] Specifically, Figures 2(a), 2(b) and 2(c) respectively show the relationships between flow velocity-pressure, gap size-pressure and length-pressure within the flow area of ​​the flow cell and the technical solution of the present application.

[0260] In particular, when the shear motion is not sufficient to discharge the fluid between the two walls (for example, the shear speed is slow or the fluid has poor affinity with the larger surface), a "pinning line" phenomenon will be formed, that is, the liquid discharged from the shear flow field is sucked back into the flow field. This situation results in the fluid between the two walls following the movement of one of the moving walls, while no fluid remains on the other wall. Another situation is that the outlet is not smooth. In this case, the inlet liquid will be directly bypassed, and most of the liquid between the two walls will be retained. Although the flow field is still in a state of shear flow in these two cases, the effect is that "the fluid between the first wall 1 and the second wall 2 always follows the wall with strong affinity." Therefore, this function can be used when you do not want it to perform fluid replacement work. The equipment or use methods formed by these different phenomena of Couette-like flow fields will be introduced in the following embodiments and descriptions.

[0261] Therefore, in an optional embodiment, by controlling the type of the first fluid, the speed, mode and gap of the relative movement between the first wall and the second wall can also:

[0262] 6. Allow the fluid between the first wall 1 and the second wall 2 to continue following a certain wall.

[0263] When using the "renewing and / or replacing the existing liquid in the flow domain with another liquid" function, due to the lower gap, the diffusion of the liquid can reach equilibrium quickly, making the replacement particularly rapid. As shown in Figure 3, equilibrium is reached within 1 second, achieving 99.9% replacement, thereby further reducing the amount of liquid used. As shown in the comparative simulation of the flow cell of a traditional microfluidic device, the amount of liquid required is only a few times the volume of the area directly opposite the first wall 1 and the second wall 2. Traditional flow cells require about five times. Referring to Figure 3, combined with the lower gap and smaller replacement ratio, the amount of reagent required is generally 1 / 100 to 1 / 5 of that of traditional microfluidic solutions, depending on the size of the chip. In contrast, although traditional microfluidics diffuses quickly within the microfluidic device, it needs to be connected to the microfluidic device through a pipeline. The efficiency of the reagent in the pipeline is very low, thus greatly reducing the advantage of microfluidic devices in saving reagents. If the function "1. Drain the original liquid in the flow area" is used, first replacing it with gas and then filling it with liquid, the required amount may be lower, but the effect of the gas on the molecules on the chip needs to be considered.

[0264] In an optional embodiment, the first fluid includes one or more reagents with different components. The different reagents enter the flow field simultaneously or in a certain order. The first fluid is usually a relatively precious substance that is conserved through various special arrangements in the present invention.

[0265] In an optional embodiment, the flow domain includes more than one area with different reagents attached, wherein the different areas are spatially discrete, and different kinetic reagents can enter different flow domains separately or sequentially in a certain order as they dissolve.

[0266] In an optional embodiment, at least one wall is formed by other fluids that are incompatible with the effective fluid, and friction is reduced on these walls; at the same time, because the fluid wall occupies a certain volume, the consumption of the effective fluid is further reduced. Furthermore, by adjusting the volume occupied by the fluid wall, the fluid consumption of a very thin chamber can be achieved. Increasing the shear force to move a movable part of the system with greater power (such as using a more powerful motor) is much easier in terms of engineering design and implementation difficulty than increasing the pressure of the pump that can be used in traditional microfluidic systems and the sealing of the system. Since surface reactions or actions generally do not require a lot of liquid, for this embodiment, a layer of fluid on the surface is sheared with a large velocity gradient in a smaller space, which can achieve a cleaner and more thorough fluid replacement effect than flushing and replacing with a large amount of liquid.

[0267] In an optional embodiment, the liquid path structure also includes a heater, which can be arranged on the first wall and / or the second wall to heat the flow domain so that the temperature of the flow domain can change over time, thereby realizing temporal temperature change of the flow domain, which is conducive to the reaction of reagents under different environments.

[0268] In an optional embodiment, the liquid circuit structure further includes a cooler for accelerating cooling.

[0269] In an optional embodiment, the flow domain is heated by a heater arranged on the first wall and / or the second wall, so that more than one temperature zone is generated in the flow domain to achieve spatial temperature change of the flow domain, which is conducive to the simultaneous implementation of different reactions or multiple reactions.

[0270] Example 1

[0271] In one embodiment, a shear-driven fluid platform as shown in Figure 4 is constructed, wherein the first wall 1 and the second wall 2 are arranged parallel to each other, with a certain distance between them as a flow domain 3, wherein the movement of the first wall 1 includes: translation basically parallel to the second wall 2, translation in a direction approaching or away from the second wall 2, and rotation relative to the second wall 2.

[0272] The side view of the shear-driven fluid platform is similar to Figure 1(a), and the top view is disc-shaped, and the rotation ensures that every point can be traversed by the flow domain. The upward surface of the silicon wafer forms the second wall 102. The robot places the silicon wafer on the vacuum suction cup 114, and the suction cup drives the second wall 102 to start rotating at a speed of, for example, 1000 r / min. The first wall 101 is a glass grinding disc that is transported to a position parallel to the second wall 102, for example, 100 microns away.

[0273] First fluid 106 is added to the central channel of first wall 101 through inlet 104, forming flow domain 103 between the two walls. First wall 101 also begins to rotate, driving the fluid to form a shear motion on the surface of second wall 102. At this time, fluid continuously enters through inlet 104 and leaves flow domain 103 through the four outlets. It is blocked by waste liquid cover 128 and flows into the wastewater area.

[0274] In an optional embodiment, the first fluid is various reagents of the RCA cleaning method, which allows organic matter and metal ions to enter the flow domain by etching, dissolving, reacting with wafer surface contaminants, etc. without destroying the surface features of the wafer.

[0275] 1. APM, commonly known as SC1 cleaning solution, has a formula of NH4OH:H2O2:H2O=1:1:5 to 1:2:7, which uses oxidation and micro-etching to undercut and remove surface particles;

[0276] 2. HPM, commonly known as SC-2 cleaning fluid, has a formula of HCl: H2O2: H2O = 1:1:6 to 1:2:8. It can dissolve alkali metal ions and hydroxides of aluminum, iron, and magnesium. In addition, the chloride ions in hydrochloric acid react with residual metal ions to form complexes that are easily soluble in aqueous solution, which can remove metal pollutants from the bottom layer of silicon.

[0277] 3. SPM, commonly known as SC3 cleaning fluid, consists of a sulfuric acid to water ratio of 1:3 by volume and is typically used to remove organic contaminants. Sulfuric acid dehydrates organic matter and carbonizes it, while hydrogen peroxide oxidizes the carbonized product into carbon monoxide or carbon dioxide gas.

[0278] 4. Diluted hydrofluoric acid (HF:H2O=1:2:10) is mainly used to remove oxides from specific areas, etch silicon dioxide and silicon oxide, and reduce surface metal. It forms silicon-hydrogen bonds on the surface of silicon wafers, resulting in a hydrophobic surface.

[0279] 5.Ultrapure water, using ozonated water to dilute chemicals and rinse wafers after chemical cleaning.

[0280] The addition of megasonic energy to RCA cleaning can reduce the consumption of chemicals and DI water.

[0281] Specifically, a reagent is added, causing it to overflow channel 104 and spread onto the surface of first wall 101. Subsequently, the center point of first wall 101 moves from the edge to the center and then to the edge of the second wall, repeatedly and thoroughly cleaning second wall 102. Preferably, high-pressure gas can be used to physically impact second wall 102 while cleaning. Finally, a robotic arm removes second wall 102.

[0282] Without the first wall, the shape of the fluid on the second wall is entirely determined by the affinity between the two, causing the fluid to form a thicker layer on the second wall, similar to a dewdrop on a lotus leaf. Therefore, by adjusting the hydrophilicity and distance between the first wall 101 and the second wall 102, a thinner fluid layer can be maintained between the two walls, further guiding the fluid to form an even thinner flow domain.

[0283] In an optional embodiment, the rotation process of the first wall 101 and the movement process of the first wall 101 on the surface of the second wall 102 are conducive to the uniform distribution of the new fluid in the flow field 103, rather than causing more liquid to flow to places with less flow resistance due to some uneven manufacturing gaps.

[0284] The provision of first wall 101 also prevents fluid evaporation, thereby helping to prevent damage to DNA or circuits caused by fluid drying during heating. Furthermore, the provision of first wall 101 helps prevent waste during fluid addition. Without the first wall, the shear force generated by the rotation of second wall 102 causes the fluid to centrifugally move, leaving flow field 103.

[0285] In an optional embodiment, the second wall 102 remains stationary, and the first wall 101 rotates while moving from the edge to the center and then to the edge of the second wall 102, traversing the second wall 102 to fully clean the second wall 102. Because the chip structure is attached to the second wall 102, the fluid in the flow field 103 is driven to shear by the first wall 101. This allows the chip structure and the attached circuit structure to be cleaned and replaced while maintaining the chip structure and its attached circuit structure stationary, thereby reducing the impact of movement on the chip structure during cleaning and replacement.

[0286] In an alternative embodiment, the liquid inlet can be located at the edge of the first wall, very close to the flow domain. For example, the liquid inlet pipe can be placed against, rather than through, the first wall 101, allowing liquid to be drawn into the flow domain. Alternatively, the second wall 102 can be a surface other than a silicon wafer that requires liquid exchange, such as a glass chip or a biochip. For example, a gene sequencing chip. Furthermore, the first fluid 106 can be other fluids, such as dilute chemical formulations, IMEC cleaning formulations, or even dry gaseous formulations, such as thermal chemical gases or plasma reaction gases. Furthermore, particles such as alumina, silica, ceria, zirconia, and diamond particles can be mixed into the first fluid 106 to enhance cleaning effectiveness. The particle size of these particles can range from 1 to 50 microns. Furthermore, the first fluid can be a mixture of gas and liquid to enhance cleaning effectiveness. Furthermore, the polishing disc can be made of polyurethane, non-woven fabric, or other composite materials. While the distance in the aforementioned embodiment is 100 microns, the distance can be directly adjacent to the silicon wafer or at a certain angle to the wafer, allowing fluid to remain between two surfaces that are not absolutely smooth. In addition, the two planes can also be shapes other than disks. In addition, the function can also be for other fluid operation purposes besides liquid replacement, such as allowing reagents to react in a smaller shear flow domain, such as crystal growth. In addition, the first wall surface can be larger than, smaller than or equal to the second wall surface. The existing solution is to directly splash the chip surface through a water pipe, and the chip is in a rotating state. The amount of ultrapure water used in this solution is quite large, for example, 50mL per second. It is reported that TSMC's Hsinchu plant requires 150,000 tons of water every day. This solution uses 1% of the reagent usage of the current solution, which is 0.5mL per second or even less. At the same time, according to the fluorescence replacement experiment, it takes less time, but the effect is better.

[0287] In an optional embodiment, the inlet 104 is not in direct contact with the flow area 103. For example, the inlet 104 can be located near the flow area 103. After passing through the inlet 104, the first fluid 106 is adsorbed by the flow area 103 and then introduced into the flow area 103.

[0288] In an optional embodiment, the inlet 104 is configured to be attached to a side edge of the first wall 101 .

[0289] In an optional embodiment, as shown in FIG5 , the first wall 101 remains stationary, while the second wall 102 rotates under the drive of the vacuum chuck 114, so that every point on the second wall 102 and the first wall 101 can be located in the flow region 103. The first wall 101 and the second wall 102 are coaxially arranged, and the relative rotation of the first wall 101 and the second wall 102 allows the second wall 102 to be repeatedly and comprehensively cleaned.

[0290] In an optional embodiment, as shown in FIG5 , the second wall surface 102 remains stationary and the first wall surface 101 keeps rotating, so that the second wall surface 102 is fully cleaned.

[0291] As mentioned above, this embodiment can be used on any chip surface that requires fluid replacement. The following, in conjunction with Figure 5 , uses a second-generation sequencing solution using SBS (sequencing by synthesis) as an example to further describe the fluid path structure features provided by this embodiment. The technical solution of this embodiment can include the following steps:

[0292] 1. providing a first fluid through an inlet structure, wherein the first fluid includes a reagent capable of breaking an azide group to cause a first reaction between the first fluid and the biomolecule;

[0293] 2. providing a second first fluid through the inlet structure, wherein the second first fluid includes a buffer reagent for cleaning the first first fluid and the product of the first reaction;

[0294] 3. Providing a third first fluid through the inlet structure, wherein the third first fluid includes reagents of four bases, ACTG, to cause a second reaction between the third first fluid and the biomolecule;

[0295] 4. Providing a second first fluid through the inlet structure for cleaning the third first fluid;

[0296] 5. Record and determine the base type of the product of the third reaction on the chip;

[0297] Repeat steps 1 to 5 multiple times to obtain the base sequence of the DNA single strand based on the base types of the product of the third reaction.

[0298] In an optional embodiment, the outlet structure includes an area between the periphery of the disc on the first wall and the periphery of the disc on the second wall, enabling the first fluid to be discharged through the area. The operating method of the microfluidic path structure also includes providing a waste liquid collection structure 150 for collecting the discharged first fluid.

[0299] In an optional embodiment, the third first fluid further comprises dye groups corresponding to the bases.

[0300] In an optional embodiment, step 5 includes recording the fluorescence on the chip by sensing, and determining the base type by a basecall algorithm.

[0301] In an optional embodiment, the first wall surface and the second wall surface are coaxial disc structures in the vertical direction.

[0302] In an optional embodiment, the area of ​​the first wall is greater than or equal to that of the second wall.

[0303] In an optional embodiment, the reaction time of the first reaction is 1 minute.

[0304] In an optional embodiment, the volume of the second first fluid is three times the volume of the flow basin.

[0305] In an optional embodiment, the volume of the third first fluid is 1.5 times the volume of the flow basin.

[0306] In an optional embodiment, the second reaction is carried out at a temperature of 55° C., and the reaction time of the second reaction is 1 minute.

[0307] Specifically, the method includes the following steps:

[0308] 1. A patterned chip (glass or silicon wafer) with a certain depth (e.g., 50 microns) is provided as the second wall 102. The patterned portion of the second wall 102 has alternating hydrophilic and hydrophobic regions. Single-stranded DNA can be immobilized on the hydrophilic regions, where the DNA binds to bases with distinguishable signals. The hydrophobic regions are covered with a hydrophobic substance, such as HMDS. In this case, the first and second walls are coaxial disc structures in the vertical direction, and the area of ​​the first wall is greater than or equal to that of the second wall.

[0309] 2. A cleavage reagent 161, such as a triphenylphosphine solution, capable of cleaving azide groups, is added dropwise from inlet 104 in a volume equivalent to 1.5 times the volume of the flow basin to clean the single-stranded DNA. The cleavage reagent is directed from the inlet to the outlet via centrifugation, pressure differential (e.g., 50 kPa at the inlet and 0 kPa at the outlet, open to the atmosphere), or a combination of both. The outlet can be directly exposed to the environment without being connected to a pipeline, and any droplets dripping from the edge are collected by negative pressure.

[0310] 3. The excision reagent 161 occupies flow area 103, cleaning the chip and allowing it to react for 1 minute to prepare for the next synthesis step. Buffer 162 enters flow area 103 through inlet 104, with a volume equivalent to three times the volume of the flow area, to clean the excision reagent and reaction products. Because the area of ​​the first wall is greater than or equal to that of the second wall, excess reagent forms droplets at the junction of the two walls, dripping under gravity and being collected by the waste liquid collection structure below.

[0311] 4. A synthesis reagent 163 containing the four bases ACTG and corresponding dye groups is passed through the inlet 104 into the flow basin 103 (each base carries a distinguishable signal, such as a fluorescent group of a different wavelength, which is connected through an azide group. For example, A, C, T, and G are connected to the dyes ROX and CY5 from Thermo Fisher Scientific, Alexa Fluor 532 from Thermo Fisher Scientific, and iFluor 700 from AAT Bioquest, respectively. At the same time, the 5' end is also modified with an azide group, so that the single-stranded DNA that the synthetase can bind to stops after synthesizing one base and cannot bind to the next one).

[0312] 5. After the synthesis reagent 163, equivalent to 1.5 times the volume of the watershed, has traversed the chip, achieving 99.9% replacement, the pressurization device and / or the rotation are stopped. After heating to 55°C and dwelling for one minute, the synthesis reaction incorporates bases with distinguishable signals onto each DNA strand. Typically, a single strand will have multiple copies in a hydrophilic region, resulting in a strong fluorescent signal for a single base. For example, the replication time can be controlled to produce 200 copies.

[0313] 6. The buffer solution 162 is introduced into the flow basin 103 through the inlet 104 to clean the synthesis reagent and prevent the fluorescent signal inside from being confused with the signal synthesized on the DNA during sensing.

[0314] 7. Through sensing methods such as taking photos, the fluorescence emitted by each point on the chip is recorded, and the basecall algorithm determines the type of base just synthesized.

[0315] Repeat steps 2-7 35-300 times. After the excision reagent, the 5' end can bind to a new base. After recording the different base information, the base sequence at each point is finally obtained using a software algorithm, and these sequences are finally pieced together into the base sequence of the sample.

[0316] In some optional embodiments, a step may be added between steps 6 and 7: To prevent some copies of the same hydrophilic region from not participating in the reaction in step 4, a synthesis reagent 163 containing four bases, ACTG, and corresponding dye groups, is introduced through inlet 104 into flow basin 103 (each base carries no distinguishable signal, but the 5' end is also modified with an azide group, so that the DNA single strand that the synthesizer can bind to stops after synthesizing one base and cannot bind to the next). After the synthesis reagent 163, equivalent to 1.5 times the volume of the flow basin, has traversed the chip, 99.9% replacement is completed, and the pressurizing device and / or rotation are stopped. Buffer 162 is introduced into flow basin 103 through inlet 104 to clean the synthesis reagent.

[0317] In some optional embodiments, a step may be added between steps 6 and 7: In order to avoid adverse effects on DNA during the photography process, the protective reagent 164 is introduced into the flow basin 103 through the inlet 104, the original reagent is replaced, and then transferred to the optical machine to start photography.

[0318] In some optional embodiments, the buffer 162 in different steps may be composed of different components.

[0319] If there are multiple samples, each one needs to be combined with a specific DNA fragment before entering the chip to facilitate subsequent splitting.

[0320] According to the above embodiment, the gap between the first wall 101 and the second wall 102 is 10 microns, the flow rate of the fluid in the flow field is 468 uL / min, and the maximum pressure when the inlet diameter is 0.8 mm is 58 kPa, which is less than the system pressure limit of 100 kPa.

[0321] In contrast, the traditional flow cell structure is shown in Figure 1(c), where the upper and lower surfaces are encapsulated into narrow sheets, and the inlet and outlet are connected by pipes. The gap between the surfaces is 20 microns, and the flow rate in the flow cell is 936uL / min. At this time, when the inlet diameter is also 0.8mm, the maximum pressure is as high as 316kpa, which is much greater than the maximum pressure limit of the system and is difficult to achieve. For example, the UV glue forming the flow channel may come apart, and the seals may also leak. Therefore, the traditional implementation method usually sets the gap at 50 microns. Compared with this embodiment, the flow field thickness is 5 times different, with high reagent consumption, which is not conducive to rapid liquid exchange. Therefore, when the liquid path structure according to this embodiment is applied to the SBS method, the fluid usage can be reduced by at least five times, which is conducive to reducing reagent consumption and achieving rapid liquid exchange.

[0322] The above two examples are given for cleaning during chip production and reagent replacement for SBS reaction. In fact, it is just a platform for operating fluids. Any fluid operation that needs to reduce fluid usage and pressure requirements for surface physical or chemical reactions can similarly adopt the liquid path structure in the above embodiment, without exceeding the scope of the technical solution of this application. The principle is that because the type of fluid used is consistent with the replaced method, it does not interfere with the original physical effect (such as washing silicon wafers) or chemical effect (such as SBS gene sequencing). It only allows the original reaction to be carried out at a lower pressure and less reagent volume. Further, since the effective substances that need to act on the surface (such as corundum in water or bases in reagents) are very limited, for example, in gene sequencing, the substances that need to react are only equivalent to the bases contained in 2 microns of reagents. Therefore, when the traditional technical solution adopts a flow cell with a thickness of 50 microns or more, the fluid with a thickness of at least 48 microns does not participate in the reaction and is wasted. The liquid path structure of this embodiment can make the liquid thickness extremely low while enabling the reagent to produce a more effective effect through the shear flow field.

[0323] Example 2

[0324] In one embodiment, a shear-driven fluid platform as shown in FIG6(a) is constructed, wherein the first wall 201 and the second wall 202 include curved surfaces to form a sleeve shape, wherein one of the first wall 201 and the second wall 202 forms an outer cylinder and the other forms an inner cylinder, and a flow domain is formed between the two.

[0325] The two surfaces in relative motion are changed from planes to curved surfaces, forming a sleeve shape, which is also traversed by rotation. The second wall 202 is the outer cylinder, and the first wall 201 is the inner cylinder. The height of the inner cylinder is lower than the outer cylinder. When liquid is added, it will be thrown onto the cylinder wall and flow down into the flow basin. The distance between the inner and outer cylinders is 2mm. The inner cylinder can be rotated by the control mechanism 212 and can be temperature-controlled by the heater 208. The magnetic stand 209, the fan 210 and the camera 211 are used to attract magnetic particles, ventilate and obtain visual information such as fluorescence intensity respectively. Traditional equipment requires a large amount of reagents and requires professional manual intervention and a special place, such as a wet laboratory. Although traditional microfluidic equipment uses less reagents, it is expensive and lacks flexibility. It can only be used for one reaction purpose, and its reliability is questionable. This embodiment can make the reagents react and replace quickly in the shear flow basin. Different reaction purposes can be achieved by replacing the reagents. The instrument has high stability and both are achieved.

[0326] Specifically, since there is only relative rotation between the two walls, there is no complex operation such as transfer, splitting, and merging in traditional microfluidic devices, which makes the instrument more stable.

[0327] In the device constructed in this embodiment, a curved ultrathin chip (less than 100 microns thick and flexible) can be placed on the second wall 202 to implement the silicon wafer washing and gene sequencing operations described in Example 1. Furthermore, the device constructed in this embodiment can also be used for other reaction processes.

[0328] The features of the fluid circuit structure provided in this embodiment will be further described below, using the example of using the device constructed in this embodiment to replace Roche's Cobas Liat system for nucleic acid assays. Specifically, the encapsulated reagents are controlled by a control mechanism 212 (a memory metal that gradually restores its original shape upon heating) to move the reagent bags from one direction to another, sequentially passing through a cutter 213. As the bags rupture, the various first fluids 206 encapsulated in the bags flow down along the cutter 213 and are flung into the shear flow region 203 between the two walls. First, the sample is added using a dropper containing approximately 20 microliters of oral epithelial cell buffer. The sample preparation process is omitted here. Next, the bag containing PBS buffer and proteinase K is ruptured by the cutter 213 and enters the flow region 203. The second wall 202 is heated to 40 degrees Celsius by a heater 208. The control mechanism 212 (a micromotor) controls the first wall 1 at a speed of 30 r / min to mix the two with the sample. The control mechanism 212 controls the splitting of the hydrolyzed liquid, incubates it at 50°C in the shear flow field for 5 minutes, and stops rotating. The motion control mechanism 212 controls the splitting of the isopropanol magnetic bead suspension, and the second wall 202 is kept at 50 degrees. The control mechanism 212 mixes at a speed of 30 r / min for 30 seconds and then stays for 5 minutes. The control mechanism 212 rotates the first wall 201 at a speed of 30 r / min and brings the magnet close, and the magnetic beads are attracted. After 1 minute, the control mechanism 212 opens the outlet 205 and keeps rotating, and the liquid flows out under gravity control. The outlet 205 is closed, and the magnetic beads are washed and eluted in the same way. The control mechanism 212 removes the magnetic rack 209.

[0329] During this process, nucleic acids are first released from cells, then adsorbed to magnetic beads. During elution, they are separated from the remaining liquid by attraction from the magnetic rack 209. After the remaining liquid is drained, the nucleic acid to be tested is obtained. The reaction can proceed normally when the volume of each reagent is at least twice the volume of the fluid reservoir. The total volume can be less than 1 mL.

[0330] The following is the amplification phase. UNG is mixed at 37°C for 5 minutes to digest PCR contaminants. The temperature is then raised to 95°C to inactivate the UNG enzyme and denature the DNA. Amplification is then performed at 60°C. This process is repeated, and after each cycle, a photograph is taken and the fluorescence intensity is determined by analyzing the average grayscale value. Three experiments were conducted using fresh human whole blood samples treated with EDTA. The results are shown in Figure 7.

[0331] It can be seen that after 25 cycles, the positive sample and control signals are significantly different.

[0332] In an optional embodiment, the temperature of the second wall 202 can be changed over time, or multiple temperature zones can be set on the first wall 201 or the second wall 202, and spatial temperature change can be achieved by rotating the reagent to different temperature zones, as shown in Figure 6(b).

[0333] In addition to nucleic acid assay reactions, other reactions requiring the addition of multiple reagents into the shear flow field are also possible.

[0334] In addition, in addition to using a knife to cut open the sealed reagent bags, some premixed liquids can also be set up.

[0335] In addition, you can use a water-soluble bag to package the oily reagent, and an oil-soluble bag to package the water-based reagent, and then use the corresponding liquid to dissolve them.

[0336] Alternatively, a mechanical structure such as a perforated plate may be used to sequentially squeeze the reagents in the bag into the flow field.

[0337] In addition, freeze-dried reagents can also be added to the shear flow area in sequence according to the reaction order to save reagents and facilitate transportation.

[0338] Furthermore, by providing a heater on the first wall 201 or the second wall 202, multiple temperature zones are generated in the flow basin 203. As shown in FIG6(b), different reagents are moved to different temperature zones in the flow basin by relative rotation between the inner and outer cylinders to achieve spatial or temporal circulation. In addition, the invention can also be used in other reaction or detection scenarios that meet the requirements of this patent and require reagent conservation or rapid reaction, such as the detection of a component in sewage.

[0339] Figure 6(c) is a schematic diagram of the prior art Roche Cobas Liat system. The Roche Diagnostics Cobas Liat system experienced false positives during testing of the Cobas SARS-CoV-2 and Influenza A / B nucleic acid tests for two reasons:

[0340] 1. Test tubes may occasionally leak and cause light path obstruction in the Cobas Liat analyzer, resulting in abnormal PCR growth curves. This may lead to invalid or false positive results, particularly for influenza B testing. The FDA added that if the test tube does leak, subsequent testing may increase the likelihood of false positive results for influenza B.

[0341] 2. Abnormal PCR cycles in the reaction tubes can produce abnormal PCR growth curves, leading to false positives. The FDA stated that this issue is sporadic and may be caused by hardware positioning, volume movement, and curve interpretation. This issue may cause false positives for all analytes in the run.

[0342] In contrast, the device constructed in this embodiment has higher reliability, because Cobas Liat needs to squeeze and grind the bags storing reagents, which not only takes a certain amount of time, but also brings reliability problems (the bags cannot be broken while grinding). Manufacturing reliability issues are a common problem of microfluidic devices. In the device constructed in this embodiment, only the bag is scratched, which reduces the probability of reliability problems and speeds up the mixing speed. In addition, in the prior art Cobas Liat, due to the inconsistent functions of the reagents in each area, there is a need for hardware positioning. In the device constructed in this embodiment, the reagents are uniformly introduced into the shear flow zone and the position is controlled by rotation, without the need for hardware positioning, which further reduces the possibility of reliability problems.

[0343] In summary, in the liquid path structure of this embodiment, mixing reactions are carried out between different flow domains through shear flow fields. At the same time, the flow domains are open systems with simple structure, high reliability and convenient manufacturing.

[0344] Example 3

[0345] Furthermore, the shear-driven fluid platform can be configured as shown in Figure 8, where one of the moving walls is liquid. Currently, some biological reactions, such as the prior art microfluidic device flow cell used for gene sequencing shown in Figure 8(a), have a minimum gap of only 50 microns. Since pressure and gap are inversely correlated quadratically, if the gap is further reduced, the fluid pressure will be excessive, forcing the use of an excessively low flow rate, which reduces the time required to complete the task. However, in reality, because it is a surface reaction (the reaction surface in the schematic diagram is the channel bottom), the chip does not require a 50-micron reagent layer. Theoretically, only 2 microns are required, so 48 microns are wasted. To further conserve reagents, the shear-driven fluid platform in Figure 8 introduces a second inlet 304 and a second fluid 307. The second fluid 307 forms a fluid wall, allowing the active reagent to form a shear flow within the thin flow domain formed by the second fluid 307 and the bottom surface. This ensures that only a portion of the 50-micron channel is filled with active reagent, and the flowing reagent can cover the channel bottom surface, thereby achieving both speed and effective reagent conservation. As shown in Figure 8(c), the separation interface 361 between the two fluids is drawn in both Figure 8(b) and Figure 8(c).

[0346] The second fluid flows into the flow domain from the second inlet and flows out from one outlet of the outlet structure, sharing the same outlet with the first fluid, or flows out from another outlet of the outlet structure, using different outlets with the first fluid, wherein the second fluid and the first fluid are laminar flows in the thin flow domain, and the second fluid occupies a certain space in the thin flow domain so that the required amount of the first fluid is further reduced.

[0347] In this embodiment, reactants are fixed on the bottom surface of the channel.

[0348] Furthermore, FIG8 shows the flow rate thermal diagram scales of FIG8(b) and FIG8(c), wherein the flow rate magnitudes of the respective sections in FIG8(b) and FIG8(c) are shown in different colors, wherein each section is an isosurface of the volume fraction of the first fluid 306.

[0349] Taking the use of this device as an example of replacing Illumina's flow cell system for DNA sequencing, the specific implementation scheme is as follows: In a 50-micron microchannel, the upper inlet 304 in the 3D diagram pumps 98-grade gasoline produced by Sinopec to form a second fluid 307, with a hydraulic environment that meets the Reynolds number requirement of less than 1000. The lower inlet introduces a first fluid 306 containing fluorescent dNTPs. This inlet is positioned below the second fluid 307 and close to the bottom of the channel, where the DNA is attached, to facilitate the reaction. Under the microfluidic scale and laminar flow conditions, the two fluids flow distinctly, with a clear interface between them. As shown in Figure 8(b), the separating interface 361 in the figure represents the interface between the first fluid 306 and the second fluid 307. By adjusting the flow rate of the second fluid 307 to, for example, nine times that of the first fluid 306, the flow drives the first fluid 306 in the thin flow region into shear motion, while providing much less frictional resistance than a solid wall, thereby reducing the energy required for the first fluid 306 to flow. The second fluid 307 occupies most of the volume, making the total amount required for the first fluid 306 smaller. However, because the thickness of the first fluid is greater than 2 microns, it does not affect the reaction. After two seconds of liquid feeding to complete 99.9% of the reagent replacement, the solenoid valve controls the liquid feeding of both to stop at the same time, and the first fluid 306 reacts with the bottom surface of the tube (biochip) for 1 minute. Both resume liquid feeding at the same time, the first fluid 306 flows into the waste liquid tank, and the second fluid 307 is recovered from another outlet because it is incompatible with the aqueous reagent. A cleaning buffer solution is introduced into the pipeline for cleaning. The second wall 302 (chip) is taken to a light machine for photography. The reagent is removed by another first fluid 306, and the next cycle is carried out to test the type of the next base. The amount of reagent used in this method is only 10% of the original amount, because the pumping volume ratio of the incompatible fluid to the first fluid is 9:1.

[0350] Since fluorescent dNTP reagents are the most valuable reagents to save during SBS sequencing, this example provides a detailed description using this as an example. Furthermore, the reagent types, conditions, and sequence of the reaction can all be referenced to the steps described in Example 1 above. The SBS reaction principle itself is beyond the scope of this patent and will not be further described.

[0351] From the perspective of the flow field space that constrains the first fluid, the second fluid can be regarded as a "wall" or a "fluid wall". The principle and advantage of this embodiment is that when at least one wall is formed by other fluids that are incompatible with the effective fluid (i.e., the first fluid), friction is reduced on these walls. At the same time, because the fluid wall occupies a certain volume, the consumption of the effective fluid is further reduced. According to the method of this embodiment, the chamber does not need to be made very thin. By adjusting the volume occupied by the fluid wall, the fluid consumption of a very thin chamber can be achieved. When the chamber can be very thin, the pressure increases exponentially, which brings more problems to the system that cannot be solved. Then, increasing the shear force requires greater power (such as using a more powerful motor), which is much easier and more reliable in terms of engineering design and implementation difficulty than increasing the sealing of the system that can be used for traditional microfluidic systems. Finally, this control method is more intuitive, lowers the threshold for research and development and use, and does not require major changes to the system. This works in principle because surface reactions or actions typically don't require a lot of liquid; only a thin layer of fluid is needed. Shearing with a large velocity gradient within a relatively small space is cleaner and more thorough than flushing and replacing large volumes of liquid. This improvement, according to this embodiment, allows for thinning the chamber, which requires high pressures exceeding the sealing requirements of the microfluidic system (e.g., 100 kPa for sequencing systems), by using a "fluid wall" to define a smaller flow domain. This reduces manufacturing costs, maximizes system performance, and makes microfluidic devices easier to manufacture and use.

[0352] In an alternative embodiment, the inlet structure, outlet structure, and flow field 303 (reaction chamber) may not be channels, but rather other equivalent flow fields, or structures or components with similar fluid behavior. For example, as shown in Figure 9(a), the portion connecting the two inlets 341 and 342 and the outlet 305 are both thin-film structures. Furthermore, the inert second fluid 307 may not undergo macroscopic flow, occupying only a certain volume of the flow field. This reduces the manufacturing process requirements and allows the formation of very fine fluid paths. However, the interface remains in a fluidic state, and the movement of the first fluid 306 remains shear motion. Alternatively, the outlet can be connected to the same container, with the reagent and second fluid later separated by density differences. Furthermore, each inlet or outlet of the device can be a separate microfluidic chip, or similar, with a baffle 319 positioned in the middle of the existing chip to achieve better hydraulic conditions and form a distinct laminar flow, as shown in Figure 9(b). Alternatively, the reaction may be other reactions that require reagent conservation and emphasize surface replacement effects. Alternatively, the second fluid 307 can be a relatively inexpensive liquid, such as other oils. Alternatively, the first fluid 306 may be a liquid miscible with the first fluid, such as pure water, to form a laminar flow. Alternatively, the second fluid 307 may be pumped at other speeds, thereby occupying different volume fractions in the pipeline or thin-sheet flow domain, thereby achieving varying degrees of reagent saving. Furthermore, to increase the speed, both the first fluid 306 and the second fluid 307 may be connected to a pump. Furthermore, there may be multiple inlets. If biomolecules are immobilized on both the upper and lower surfaces of the channel, three inlets may be used, with the upper and lower inlets being the reaction reagents, and the middle being the second fluid 307 occupying a certain volume.

[0353] Specifically, as shown in Figure 9(b), first fluid 306 enters the flow domain through first inlet 341 and flows out of first outlet 351. Second fluid 307 enters the flow domain through second inlet 342 and flows out of second outlet 352. Due to the density difference and the action of baffle 319, first fluid 306 and second fluid 307 form a phase-separated laminar flow. Second fluid 307 does not undergo macroscopic flow, and first fluid 306 undergoes shear motion driven by second fluid 307.

[0354] This example illustrates how to conserve a specific reagent. The specific reagent type, conditions, and sequence vary depending on the application. For example, this could be a synthetic reagent containing a fluorescent base in SBS. An open system simplifies these operations, conserving precious reagents and samples without requiring major system modifications or increasing the system's pressure limit.

[0355] The above technical solution of forming the fluid wall by the second fluid is suitable for both closed pipelines and open flow domains formed by the first wall and the second wall. For the latter, as long as the pressure of the introduced fluid is not greater than the surface tension.

[0356] Example 4

[0357] In one embodiment, a shear-driven fluid platform, as shown in FIG10 , was constructed, utilizing the Couette-like flow field characteristic of "the fluid between the first and second walls follows the moving wall." Similar to Example 2, the first fluid 406 reagent can be translated between different temperature zones by the translation of the first wall 401. Insulation blocks 418 (e.g., made of ceramic) are provided between the zones. Areas without insulation blocks 418 can be set to different temperatures using a heater below. Furthermore, at least a portion of the second wall 402 is hydrophobic (e.g., a silicon wafer treated with silane, first wall 401 made of PET, and an aqueous reagent within flow region 403). This creates a "pinning line" phenomenon, confining the liquid to a specific area near the first wall 401. Liquid pushed out of flow region 403 by the shear flow field is drawn back into flow region 403 by surface tension. The liquid moves completely with the movement of the first wall 401, without remaining on the surface. As shown in FIG11 , the fluid can move similarly to a chess piece moving along the lines of a chessboard. The first wall 401 and the second wall 402 may have a larger area, with more functional partitions, on which different freeze-dried reagents are fixed to achieve different reactions, or multiple reactions can be carried out simultaneously.

[0358] In an optional embodiment, as shown in FIG11 , the second wall surface 402 is divided into a plurality of functional zones, and the functional zones of the second wall surface 402 are distributed in two dimensions.

[0359] The difference between this embodiment and embodiment 2 is that the liquid in the flow domain 403 can not only move along with the movement of the first wall, but also form a phenomenon similar to a "pinning line", so that the liquid can be confined to a certain area near the first wall 401, and the liquid pushed out of the flow domain 403 by the shear flow field will be sucked back into the flow domain 403 or near 403 by the surface tension.

[0360] Specifically, different freeze-dried reagents are fixed on each different functional partition on the second wall 402, and different reactions can be achieved when the flow field 403 moves above different functional partitions. Alternatively, the flow field 403 is located above multiple different functional partitions at the same time, so that multiple reactions are carried out simultaneously. Taking the QPCR process as an example, the timing and dosage of the reagents are similar to those in Example 2. The difference is that in Example 2, the liquid reagent is added to the flow field and then the excess reagent is removed. In this case, the liquid is moved to the functional area to dissolve the freeze-dried reagent fixed on the functional area for reaction. A similar solution now is digital microfluidics. In comparison, the equipment of this solution is simpler, and can also achieve the purpose of speed and saving more reagents.

[0361] This embodiment differs from existing digital microfluidics in that it uses electrical energy instead of a moving chessboard. This approach is more expensive, results in larger droplets, and larger chip gaps. The current can also undesirably affect the reaction and has a limited lifespan.

[0362] Taking this device as an example for nucleic acid testing, replacing the Roche Cobas Liat system, the specific implementation scheme is as follows: the second wall 402 is constructed of a hydrophobic silane-treated silicon wafer, and the first wall 401 is constructed of a PET surface. The two are spaced 50 microns apart, with a 50-micron spacer on the first wall 401 elevating the PET surface to create a suspended state. The first wall 401 measures 1 cm x 1 cm, while the second wall 402 measures 5 cm x 5 cm. Each functional area measures 1 cm x 1 cm. All movements are controlled by a control mechanism 412. First, a drop of oral epithelial cell-containing buffer from a dropper is placed in the sample application area of ​​the second wall 402. The first wall 401 is then moved past the sample, drawing the sample into the flow channel. The sample preparation process is omitted here. Next, the first wall 401 is moved to the initialization area containing a premix of PBS buffer and proteinase K, and the liquid enters the flow channel. The first wall 401 is heated to 40°C by a heater 408 and held there for one minute. Next, move first wall 401 to the lysis zone, containing lyophilized lysate. Move first wall 401 clockwise within the four surrounding squares to mix thoroughly, then heat and incubate at 50°C for 5 minutes (the four surrounding squares are not divided into functional zones). Next, move first wall 401 to the synthesis zone, containing lyophilized isopropanol magnetic beads. Move first wall 401 clockwise within the four surrounding squares to mix thoroughly, then incubate for 5 minutes. Next, move first wall 401 to the magnetic zone, where the beads are attracted. After 1 minute, move first wall 401 to the waste liquid zone. Fibers in the waste liquid absorb the original reagent, while the magnetic beads remain in the magnetic zone. Move to the wash liquid zone and aspirate 50 μL of liquid (similar to the sample addition process). Repeat this process several times to wash the magnetic beads, then move to the elution zone to aspirate liquid. Return to the magnetic zone to wash and elute the beads. Move first wall 401 to the UNG zone and mix at 37°C for 5 minutes to eliminate PCR contamination. Move the first wall 401°C to the 95°C zone to inactivate the UNG enzyme and denature the DNA. Move the first wall 401°C to the 60°C zone for amplification. Repeat this process, taking a picture after each cycle or after multiple consecutive cycles and analyzing the average grayscale of the image to determine the fluorescence intensity.

[0363] In addition, other liquid manipulation methods that can be used in digital microfluidics, such as "mixing," "reaction," "detection," and "separation," can also be used in this technology. The methods are basically the same and will not be described in detail here. Alternatively, other surfaces that can achieve the same purpose can be used, such as hydrophobic-treated glass as the second wall 402, aluminum as the first wall, and the flow domain containing aqueous reagents. Furthermore, the suspension height can be other heights, and spacers can be omitted. A gap of approximately 50 microns can be achieved by utilizing the inherent force of the liquid, or other mechanical positioning structures can be used to achieve the gap.

[0364] This embodiment uses a PCR process to illustrate the features of the fluid circuit structure provided by this embodiment. The reaction process and reaction timing are unrelated to the fluid operation (for fluid operation, other reagents can be used instead without affecting the final operation effect). Other devices using digital microfluidics or microfluidics can also be used as substitutes if the process is compatible with the configuration of this embodiment, such as environmental monitoring or SBS gene sequencing.

[0365] The technical solution of this embodiment adopts an open system, which will not cause the liquid to be difficult to move due to excessive pressure caused by viscous liquid, which is conducive to simplifying the equipment and making the liquid layer thinner, achieving the purpose of speed and saving more reagents.

[0366] Example 5

[0367] In one embodiment, a shear-driven fluidic platform as shown in FIG12 is constructed.

[0368] Example 6

[0369] In one embodiment, a shear-driven fluid platform is constructed as shown in Figure 13. First, there must be sufficient fluid at the inlet, otherwise other unnecessary fluids, such as air, will be sucked in. The Couette field is a zero-pressure field, so the flux within it is equal to the cross-sectional area multiplied by the average velocity. In reality, there are deviations from the ideal situation, and pressure may exist and sometimes fluctuate. When the gap is too narrow, it is difficult to actually measure. Therefore, the way to ensure safety is to always have excess liquid at the inlet. In terms of operation, the amount of liquid must exceed the amount required by the system, and the excess liquid can be discharged from the system through a bypass. One bypass method is to connect the liquid at the inlet or outlet to a waste liquid bucket along the device or by suction, as shown in Figure 13(a). The second method is to make one wall wider than the other wall, so that the excess liquid can eventually leave the shear flow domain through the relative movement of the walls, as shown in Figure 13(b). The advantages of this solution are that it saves reagents, is fast, and the equipment is cheap and simple, without the need for expensive and complex piping designs.

[0370] Specifically, as shown in FIG. 13( a ), excess first fluid leaves the flow region 603 at the inlet 604 through the bypass device 617 and enters the waste liquid tank 615 .

[0371] Figure 13(b) shows a top view of a portion of the flow basin 603, wherein the widths of the first wall 601 and the second wall 602 are different, and the excess first fluid leaves the flow basin 603 through the bypass device 617 with the help of the relative movement between the first wall 601 and the second wall 602, flows to the outlet and enters the waste liquid barrel 615.

[0372] This embodiment can be used independently or as a supplement to the above embodiments. For the technical solutions of this application, embodiments 1, 2, 3, and 5 can be combined with embodiment 6 to drain excess reagents from the flow field. The open system simplifies reagent removal without requiring major system modifications. Furthermore, the increased number of drainage channels allows for lower system pressure at the same flow rate, eliminating the need to increase the system's upper pressure limit.

[0373] Example 7

[0374] In one embodiment, a shear-driven fluid platform as shown in FIG14 is constructed, and fluid is introduced in a temporally or spatially discrete manner through an inlet structure, including:

[0375] In an optional embodiment, the inlet structure includes an inlet, into which the first fluids are introduced at different times, such as 761, 762 and 763 in FIG14(a).

[0376] Alternatively, when the first fluids are introduced into the inlet at the same time, incompatible fluids are used to separate the first fluids so that the first fluids will not mix with each other before entering the flow domain, as shown in 764, 765 and 766 in Figure 14(b).

[0377] In an optional embodiment, the inlet structure includes more than one inlet, and each first fluid is introduced through a different inlet so that the first fluids do not mix with each other before entering the flow field, such as 741, 742 and 743 in Figure 14(b).

[0378] The shear-driven fluid platform device can be in the form of Figure 14. The fluid supply method is changed to a discrete method in space or time. Many medical devices require a long time (e.g., half an hour) and a large amount of reagents / buffers to clean the pipelines. This is because the velocity of the fluid layer in contact with the tube wall is zero. Therefore, to completely replace this layer of fluid, diffusion is the only way. Therefore, although the reagents required inside the microfluidic device are very small, the mixing of reagents in the microfluidic chip's pipelines makes the reagents entering the microfluidic device impure, requiring the pipeline to be cleaned first, which prevents the microfluidic chip from fully realizing the reagent-saving vision. In a shear-driven open microfluidic platform, we do not need a pump to directly provide pressure to the microfluidic chip, so a common pipeline connected to the flow domain is not necessary. Therefore, we designed a spatially discrete liquid supply method. Its purpose is to prevent different types of liquids from mixing in space before entering the microfluidic chip. This minimizes cross-contamination and cleaning of the system's common channels, resulting in better reagent economy. As shown in FIG14( a ), the injection method is time-discrete, FIG14( b ) the injection method is space-discrete, and FIG14( c ) the injection method is both time-discrete and space-discrete.

[0379] Specifically, as shown in FIG14( a ), reagent 761 , reagent 762 and reagent 763 are allowed to enter the flow basin 703 sequentially through the same inlet 704 .

[0380] As shown in FIG14( b ), reagent 764 , reagent 765 and reagent 766 are allowed to enter the flow region 703 simultaneously through the same inlet 704 , wherein reagent 764 , reagent 765 and reagent 766 are gases or immiscible liquids.

[0381] As shown in FIG. 14( c ), reagent 767 is allowed to enter the flow region 703 through the inlet 741 , reagent 768 is allowed to enter the flow region 703 through the inlet 742 , and reagent 769 is allowed to enter the flow region 703 through the inlet 743 .

[0382] According to this embodiment, the inlet liquid supply must be neither excessive nor insufficient, without pressure and sealing, to avoid accumulation. This can also cause the chip to dry out and air to enter, unless air is introduced for more thorough cleaning. Furthermore, the outlet must be unobstructed, otherwise the inlet liquid will not be able to enter the flow area. Generally, a slight excess of liquid is required at the inlet. This can be achieved by widening inlet 704, as shown in Figure 14(d).

[0383] In an optional embodiment, as shown in Figures 15(a), 15(b), and 15(c), the pipeline in the flow region is open at one end and closed at the other end. The closed-end pipeline is beneficial for increasing the pressure inside the pipeline and reducing the amount of reagent introduced at the inlet structure.

[0384] The present embodiment can be used alone, and can also be the supplementary means of the above embodiment. Embodiment 1, 2, 3, 5 can be combined with embodiment 7 application, and the introduction mode of reagent in the shear-driven fluid platform constructed in conjunction with embodiment 7 can make the liquid inlet in the river basin more efficient. The open system makes it simpler for reagent to enter the river basin, and there is no need to make a big change to the original system. For an open river basin, when the channel for fluid import increases, reagents can be added directly through different inlets, avoiding large-scale use and cleaning of common pipelines, consuming time and reagents. When not directly added dropwise but dedicated by a special pipe, the sample volume in the river basin can be pressurized at the inlet (for example, maintaining an air pressure of 50kpa), and a metering pump at the outlet can be used to control a certain amount of liquid. It is not necessary to set multiple pumps at the inlet, which is conducive to reagent usage and pressure reduction, and reduces the use of common pipelines.

[0385] Example 8

[0386] In one embodiment, a shear-driven fluid platform as shown in FIG16 is constructed, wherein the sum of the cosine values ​​of the contact angles of the first wall 801 and the second wall 802 with the first fluid 806 is greater than or equal to zero.

[0387] The shear-driven fluid platform device can be in the form of Figure 16, so the packaging of the system can be omitted, and different walls can be directly manipulated to approach or even contact each other, and the fluid can be constrained in the system through surface tension or other means. The advantage of this design is that it avoids the high cost of packaging, and the liquid channel is formed by the surface shape and properties of the approaching walls or by manipulating the gap between them. Because the movement of the liquid is controlled by shear force rather than the pressure or capillary force of traditional microfluidics, it is no longer necessary for the system to have dimensional stability under high pressure and very strict dimensional consistency of the passage to make the liquid reach the specified place at the specified time to ensure the consistency of the product results. Instead, it can be controlled by controlling the movement of the wall to control the start and stop of the shear force, thereby achieving higher fault tolerance. This improvement reduces the difficulty of manufacturing and quality control, which is a key obstacle to the popularization of microfluidic devices.

[0388] To achieve this, the first wall 801 and the second wall 802 must retain the reagent. If the liquid is a liquid, the sum of the cosines of the contact angles of the liquid on the two walls must be greater than 0, as shown in Figure 16. However, when the sum of the cosines of the contact angles of the liquid on the two walls is greater than 0, and the liquid has a poor affinity for one of the walls and / or the shear rate is not high, such as a hydrophobic surface and an aqueous reagent, the liquid squeezed out of the flow field by the shear force will be sucked back into the flow field.

[0389] Specifically, Figure 16(a) shows a side view of flow domain 803, where the contact angle between first fluid 806 and first wall 801 is α, and the contact angle between first fluid 806 and second wall 802 is β. The sum of the cosines of the contact angles of first fluid 806 with the two walls, cosα+cosβ≥0, is ≥0. Figure 16(b) shows a top view of flow domain 803, where the width of first wall 801 is greater than that of second wall 802. When cosα+cosβ≥0, the range of flow domain 803 is confined to the range of first wall 801.

[0390] This embodiment can be used alone or as a supplement to the above embodiments. Embodiments 1, 2, 3, and 5 can all be used in combination with Embodiment 8. The shear-driven fluid platform constructed based on Embodiment 8 makes device assembly cheaper and more fault-tolerant. Traditional microfluidic devices typically use capillary action to manipulate liquids, which requires micron-level precision and is difficult to operate. According to the technical solution of this embodiment, micron-level precision is not required, and fluid movement is achieved through a moving surface.

[0391] Example 9

[0392] In one embodiment, a shear-driven fluid platform as shown in FIG. 17 is constructed, wherein the first fluid 906 can be subjected to shear flow by energy applied based on force, heat, light, electrical effects, etc.

[0393] A shear-driven fluid platform device can be configured as shown in Figure 17 . In the above embodiments, the two walls are always in relative motion, but this is not a requirement. The walls can also be stationary, with shear forces acting on the liquid through mechanical, thermal, optical, or electrical mechanisms. These solutions can make the system smaller and more intelligent, eliminating the need for wall motion control devices, thereby achieving reagent savings and rapid reactions.

[0394] In the first method of driving flow, thermocouples are placed on the wall to rapidly generate thermal bubbles. These bubbles are generated and / or transported from one end to the other, pushing the liquid in the thin flow region in a shearing manner. The liquid passes through pipe A, which has a one-way valve, pushing the original liquid toward a waste tank. The liquid cools, the bubbles disappear, and the liquid flows back into the flow region through pipe B, which also has a one-way valve, achieving liquid replacement. Pipes A and B can be at opposite ends of the surface and contain different liquids. Bubbles can also be introduced externally, such as through an external air line.

[0395] Specifically, as shown in Figure 17(a), a thermocouple 921 is located on the first wall 901, rapidly generating thermal bubbles 922. These bubbles are generated and transported from one end to the other, shearing the liquid within the thin flow basin 903. This liquid is pushed away from the flow basin 903 through an outlet pipe 931 equipped with a one-way valve. Upon cooling, the bubbles 922 disappear, and the liquid flows back into the flow basin through an inlet pipe 932 equipped with a one-way valve, achieving liquid replacement.

[0396] Similarly, in the second flow-driven method, a magnetic field is generated on the wall. The movement of the magnetic field rapidly propels the magnetic fluid into an elliptical shape within the flow domain, which in turn propels the liquid, creating shear flow. The liquid passes through pipe A, which has a one-way valve, pushing the original liquid toward the waste pool. Simultaneously, new liquid flows into the flow domain through pipe B, which also has a one-way valve. The magnetic field disappears or changes, causing the magnetic fluid to flow back in a dispersed form, and the next cycle begins.

[0397] Specifically, as shown in Figure 17(b), a moving magnet 923 is mounted on the first wall 901. The movement of magnet 923 rapidly propels magnetic fluid 924 within flow region 903. Magnetic fluid 924 then propels the liquid, creating shear flow. An outlet pipe 931 with a one-way valve pushes the original first fluid 906 out of flow region 903. Simultaneously, new liquid flows into flow region 903 through an inlet pipe 932 with a one-way valve, replacing the original liquid.

[0398] Similarly, in the third flow-driven method, green light penetrates the pipe wall, solidifying the naphthalene and the coupled molecule triazoledione. This solidification process promotes shear flow within the flow domain. Liquid flows through pipe A, which has a one-way valve, pushing the original liquid toward the waste pool. Simultaneously, new liquid flows into the flow domain through pipe B, which also has a one-way valve. The green light disappears, and the naphthalene and coupled molecule triazoledione soften and liquefy, facilitating the next cycle.

[0399] Specifically, as shown in Figure 17(c), green light 925 penetrates the tube wall and solidifies naphthalene and the coupled molecule triazoledione 926. This solidification process drives shear flow within flow region 903. The liquid passes through outlet pipe 931, which has a one-way valve, pushing the original liquid out of flow region 903. Simultaneously, new liquid flows into flow region 903 through inlet pipe 932, which also has a one-way valve. When green light 925 disappears, naphthalene and the coupled molecule triazoledione 926 soften and liquefy again.

[0400] Similarly, in the fourth method of driving flow, immiscible liquids or miscible liquids separated by bubbles are transported within the flow domain through the principle of electrowetting. The movement of the liquids drives shear flow within the flow domain. Liquid passes through pipeline A, which has a one-way valve, pushing the original liquid toward the waste pool. Simultaneously, new liquid flows into the flow domain through pipeline B, which also has a one-way valve. When the voltage is removed, the dissimilar liquids flow back in a non-plunger manner, facilitating the next cycle. Gases can be released outside the flow domain, for example, through bypass and liquid logic control, and new separating bubbles can be introduced.

[0401] Specifically, as shown in Figure 17(d), electrowetting transports a dissimilar liquid or gas 927 within flow region 903. The movement of dissimilar liquid or gas 927 drives shear flow within flow region 903. The liquid passes through outlet pipe 931, which has a one-way valve, pushing the original liquid out of flow region 903. Simultaneously, new liquid flows into flow region 903 through inlet pipe 932, which also has a one-way valve.

[0402] Example 10

[0403] In one embodiment, a shear-driven fluid platform as shown in FIG. 18 is constructed, wherein the height of the first wall 1001 is higher than the second wall 1002 , and the first wall 1001 moves axially relative to the second wall 1002 .

[0404] The shear-driven fluid platform device can be configured as shown in Figure 18 . Here, the Couette-like shear flow direction is altered to shear by the up-and-down motion of the first wall 1001. Clearly, upward motion draws fluid from the reactor, while downward motion squeezes it out. Because both surfaces are not perfectly smooth, even if the conditions of Example 6 are met and the flow domain is not completely filled with liquid, liquid at the edge of the flow domain will be drawn in.

[0405] Taking this device as an example for nucleic acid testing, replacing Roche's Cobas Liat system, the specific implementation scheme is as follows: the second wall 1002 is flat and made of hydrophobic glass, while the first wall 1001 is cylindrical and made of aluminum. The aluminum cylinder is placed on the hydrophobic glass. All movements are controlled by a control mechanism 1012. First, the sample is added. A drop of buffer containing oral epithelial cells from a matching dropper is placed on the second wall 1002. The first wall 1001 is moved to contact the sample edge, and the sample is drawn into the flow channel. The sample preparation process is omitted here. Next, a similar initialization zone containing PBS buffer and proteinase K premix is ​​added, and the liquid is drawn into the flow channel. The first wall 1001 is then moved up and down several times to mix the sample. Due to the inherent force of the liquid, even without a spacer, the gap between the aluminum cylinder and the glass remains approximately 50 microns. At this point, the first wall 1001 is heated to 40°C by a heater and left there for one minute. Next, the lysis solution is added dropwise. The first wall 1001 is moved up and down several times, then heated and held at 50°C for 5 minutes. Next, an isopropanol magnetic bead suspension is added dropwise. The first wall 1001 is moved up and down several times, then held for 5 minutes. Control mechanism 1012 then controls the magnetic rack 1009 to approach, attracting the magnetic beads. One minute later, a large amount of cleaning solution is added. The first wall 1001 is moved up and down 20 times to wash the magnetic beads, bringing the first wall 1001 into close contact with the second wall 1002. The rack is tilted 45 degrees to allow excess cleaning solution to drain. 50 microliters of cleaning solution is added, and the first wall 1001 is moved up and down several times, allowing the eluate to enter the flow basin. After several up and down movements, control mechanism 1012 removes magnetic rack 1009. UNG enzyme is added. The first wall 1001 is moved up and down several times, then held at 37°C for 5 minutes to digest PCR contamination. The first wall 1001 is heated to 95°C to inactivate the UNG enzyme and denature the DNA. The first wall 1001 is cooled to 60° C. for amplification. This process is repeated, and after each cycle (or after multiple consecutive cycles), a picture is taken and the fluorescence intensity is determined by analyzing the average grayscale of the picture.

[0406] In an alternative embodiment, as shown in FIG19 , inlet 1004 comprises a channel provided on second wall 102 for introducing fluid into the flow domain. Different components of first fluid 1006 are contained in multiple containers, and rotary valve 1015 introduces the first fluid 1006 of different components into the space between first wall 1001 and second wall 1002 through inlet 1004 .

[0407] In addition, the device can be used for other biochemical reactions to achieve different purposes. In addition, the device can use common medical device automation solutions, such as stepper motors or pneumatic control of the movement of the first wall 1001. In addition, a limit device can be added to control the movement distance of the first wall 1001. In addition, a ventilation device can be added for drying. If the droplet device performs automated sampling. Compared with traditional microfluidic devices such as Cobas Liat, the stability of this case is greatly improved, reducing the problem of false positive results due to unreliable packaging of Cobas Liat. At the same time, it has a simple structure, low cost, fast reaction speed, and uses less reagents.

[0408] Example 11

[0409] In one embodiment, a shear-driven fluid platform, as shown in Figure 20 , was constructed. Couette-like flow was applied to two surfaces in proximity and relative motion, one flat and the other curved, to reduce reagent consumption during the process. The shear-driven fluid platform, as shown in Figure 20 , shows that one of its two sleeves, the inner sleeve, is a polygonal prism, such as a hexagonal prism. The application and timing are similar to those of the sleeve in Example 2, and can be used for PCR, DNA sequencing, chip cleaning, and other applications.

[0410] In an optional embodiment, the inner cylinder is in the form of a cylinder, and the outer cylinder is in the form of a polygonal column.

[0411] 20 , in which the first wall 1101 rotates and the second wall 1102 remains stationary, a first fluid 1106 enters the flow region between the first wall 1101 and the second wall 1102 from the inlet 1104 and leaves the flow region from the outlet 1105. Vice versa.

[0412] In an optional embodiment, the process of cleaning a chip using a shear-driven fluid platform includes the following steps:

[0413] 1. Insert six chips into the slot to form a second wall surface 1102 with a hexagonal cross section close to the first wall surface 1101.

[0414] 2. The first fluid 1106 is added to the opening of the first wall 1101 and fills the thin flow region 1103 until the space between the first wall 1101 and the second wall 1102 is filled with liquid. The first liquid 1106 can be pure water, IPA, or Acetone.

[0415] 3. The first wall 1101 begins to rotate and axially reciprocate, while the first fluid 1106 is continuously added, and the first fluid 1106 continuously flows out from the outlet 1105 of the second wall.

[0416] 4. As the first wall 1101 rotates, the first fluid 1106 moves. Where the first wall 1101 and the second wall 1102 are close, the liquid approaches laminar flow. As the cross section increases, the liquid transitions to turbulent flow and may form a vortex.

[0417] 5. Add high-pressure gas and / or surfactant to clean the second wall 1102 together.

[0418] 6. The first wall 1101 descends to expose the chip surface, and the surface is dried with high-pressure air.

[0419] 7. Remove the chip.

[0420] Example 12

[0421] In one embodiment, a shear driven fluid platform as shown in FIG21 is constructed.

[0422] Specifically, referring to Figure 21 , the first wall 1201 is connected to the rotating mechanism 1273 via a fixed position 1272. A rotating filling head 1271 is provided on a gantry 1274. The first fluid 1206 flows out of the rotating filling head 1271 and enters the flow region 1203 through the inlet 1204 on the first wall 1201. The second wall 1202 is fixed to the gantry 1274 and remains stationary. The first wall rotates under the drive of the rotating mechanism 1273, allowing the first fluid 1206 to traverse the entire second wall 1202.

[0423] The shear-driven fluid platform of this embodiment can reduce the thickness of the fluid in the fluid path structure while enabling the reagents to react more efficiently through the shear flow field.

[0424] Through the description of the above embodiments, it can be seen that those skilled in the art can clearly understand that all or part of the steps in the above-mentioned embodiment methods can be implemented by means of software plus the necessary general hardware platform. Based on this understanding, the technical solution of the present application, or the part that contributes to the prior art, can be embodied in the form of a software product, which can be stored in a storage medium such as ROM / RAM, a magnetic disk, an optical disk, etc., and includes a number of instructions for enabling a computer device (which can be a personal computer, a server, or a network communication device such as a media gateway, etc.) to execute the methods described in each embodiment of the present application or certain parts of the embodiments.

[0425] It should be noted that the various embodiments in this specification are described in a progressive manner, with each embodiment focusing on the differences from other embodiments. Reference can be made to the common and similar parts between the various embodiments. The methods disclosed in the embodiments are described briefly because they correspond to the systems disclosed in the embodiments. For relevant details, refer to the description of the systems.

[0426] It should also be noted that, in this document, the terms "comprises," "includes," or any other variations thereof are intended to encompass non-exclusive inclusion, such that a process, method, article, or apparatus that includes a list of elements includes not only those elements but also other elements not explicitly listed, or elements inherent to such process, method, article, or apparatus. In the absence of further limitations, an element defined by the phrase "comprising a..." does not preclude the presence of additional identical elements in the process, method, article, or apparatus that includes the element.

[0427] The above description of the disclosed embodiments will enable those skilled in the art to implement or use various modifications of these embodiments, and it will be apparent to those skilled in the art that the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present application. Therefore, the present application will not be limited to the embodiments shown herein, but will conform to the widest scope consistent with the principles and novel features disclosed herein.

[0428] This application further includes the following examples:

[0429] A method for designing a flow basin that contains multiple walls, inlets, outlets, and flow basin sides.

[0430] 1) Multiple walls are close to or in contact with each other, and the space facing each other forms a flow basin.

[0431] 2) The watershed contains at least one thin watershed.

[0432] 3) There is viscous fluid in the flow domain, which is driven by shear force.

[0433] 4) According to the direction of the average flow velocity, the fluid inlet and outlet are formed.

[0434] In some possible embodiments, the height of at least a portion of the thin flow basin is one order of magnitude smaller than the length or width, and the height is preferably sub-millimeter level.

[0435] In some possible embodiments, the inlet is a free surface, or the fluid connected to the inlet has at least one free surface. The outlet is a free surface, or the fluid connected to the outlet has at least one free surface.

[0436] In some possible embodiments, the sides of the flow region are not sealed between the walls, and the fluid overflows.

[0437] In some possible embodiments, the static pressure of the fluid connected to the inlet and outlet is equivalent to that of the external environment, or the pressure is no more than 1 / 5 of the pressure required for pure pressure drive under the same flow conditions (speed, spacing, length, liquid type, etc.), or / and has a constant speed.

[0438] In some possible embodiments, at the inlet, different types of fluids are not mixed before reaching the vicinity of the inlet area.

[0439] In some possible embodiments, at the inlet, there is an excess of fluid connected to the flow field.

[0440] In some possible embodiments, in the flow domain, the energy provided by the fluid pressure difference between the inlet and outlet of the flow domain is less than half of the energy consumed by the fluid flowing in the flow domain.

[0441] In some possible embodiments, the flow rate of the fluid entering the flow basin from the inlet is greater than or equal to the product of the smallest cross-sectional area in the direction of the average flow velocity in the flow basin and the average flow velocity at the inlet. The flow rate out of the outlet is less than or equal to the product of the largest cross-sectional area in the flow basin and the average flow velocity at the outlet.

[0442] In some possible embodiments, the shape of the flow domain includes at least one thin-sheet flow domain.

[0443] In some possible embodiments, the thin flow area is in a laminar flow state except for the edge of the flow area and discontinuous places (such as places where the height is 0).

[0444] In some possible embodiments, the thin-sheet flow basin has unique upper and lower walls that are parallel to each other, or the formed inclination angle is no greater than 30 degrees.

[0445] In some possible embodiments, the upper and lower walls of the thin flow basin are curved, and the tangent lines or tangent planes at two opposite points are parallel, or the angle formed is no greater than 30 degrees. In special cases, the thin flow basin is formed by two concentric cylinders.

[0446] In some possible embodiments, the direction of motion of each point on the wall of the flow domain is the direction of the tangent line at that point on the wall. Therefore, when the wall moves, it coincides with its shape at the previous moment. In special cases, the wall is a plane (translation), a cylinder, or a disk (rotation).

[0447] In some possible embodiments, the direction of movement of each point on the wall of the flow domain constituting the thin channel is consistent with the direction of movement of the liquid in the fluid channel. When the wall moves, it is parallel to its shape at the previous moment.

[0448] In some possible embodiments, the design of at least a portion of the upper and lower walls of the flow domain is tailored to the properties or flow of the liquid, enabling the liquid to be confined within the thin flow domain even without side walls. Preferably, the sum of the cosine values ​​of the contact angles of the upper wall and the opposing lower wall with the fluid over at least a portion of the flow domain area is greater than or equal to zero.

[0449] In some possible embodiments, at least a portion of the area is mismatched with the liquid's properties or flow process, making it difficult for the liquid to overflow across this portion of the area. Preferably, for at least a portion of the flow basin area, the sum of the cosine values ​​of the contact angles of the upper wall and the opposing lower wall with the fluid is less than or equal to zero.

[0450] In some possible embodiments, in actual operation, the liquid in the flow region may exceed the designed flow region of the thin sheet and overflow. In this case, the overflowing liquid can be carried away by shear force.

[0451] In some possible embodiments, the wall of the moving sheet channel, at least in part, is a flexible but non-stretchable membrane.

[0452] In some possible embodiments, the flow field wall is a liquid wall or a gas wall formed by immiscible liquids or gases.

[0453] In some possible embodiments, the flow field and shear force are generated by a portion of the liquid in the sheet being driven by physical methods such as force, heat, light, electricity, or magnetism, such as electrowetting, acoustic energy drive, bubble drive, photodeformation, and magnetic fluid.

[0454] In some possible embodiments, in the flow field, the distance between the upper and lower surfaces of the thin-sheet channel at least partially is 0. In this case, the liquid flows through the gaps between natural microscopic non-smooth surfaces or the gaps between artificially prepared non-smooth surfaces.

[0455] In some possible embodiments, the flow field can form a stable or substantially stable flow field within one minute.

[0456] In some possible embodiments, in the viscous flow field, a substance for adjusting viscosity, preferably glycerol, and / or a surfactant, preferably Tween, is added to the fluid.

[0457] Based on the above-mentioned method for constructing a Couette-like flow field, the present application also provides a method for using a hardware platform related to the construction method, the method comprising:

[0458] The fluid is filled into the inlet of the flow field, and the fluid is connected to the flow domain and fills at least the thin flow domain.

[0459] If necessary, fill the flow field with auxiliary fluid.

[0460] If necessary, open the auxiliary outflow mechanism and / or fluid outlet device of the outlet.

[0461] Apply shear forces to the system.

[0462] The hardware platform for constructing a Couette-like flow field, named a shear-driven fluid platform, includes:

[0463] The solid wall contacts the fluid and acts to constrain the fluid, wherein the fluid contains the fluid wall. The space between the walls is the flow domain.

[0464] The inlet can be the entrance to the flow basin, where the free surface of the fluid is visible; it can also be a liquid-retaining structure connected to the fluid within the flow basin, such as a pipe or funnel. The surface properties of the device prevent liquid adhesion. Before reaching the inlet area, the different fluids are physically isolated from each other. Once in the inlet area, the fluids are subjected to shear forces.

[0465] The driving device includes at least one energy conversion method that can generate shear force on the liquid in the flow area, so that the fluid speed near a certain wall is faster than the fluid speed near other walls. The driving device includes an energy supply device, which can be human power or power supply.

[0466] The flow domain contains substances that interact with the substances in the fluid. This can be the solid wall itself or substances fixed to the solid wall. It can be stored in a reservoir that the liquid will contact, or it can be added through an inlet.

[0467] When applying shear force, at least fill the thin areas in the basin.

[0468] In some possible embodiments, the driving device and the wall include:

[0469] The moving, tensioned membrane serves as the moving wall. The energy supply is an electrical system, including a reducer, motor, and power supply.

[0470] In some possible embodiments, a bypass device is further included;

[0471] The bypass device is used to discharge excess liquid from the basin to prevent the entire mechanism from being contaminated or liquid from accumulating.

[0472] In some possible embodiments, the positioning device includes a mechanical device that fixes the relative position of the moving wall to other walls but loosely constrains the moving direction. In particular, if the moving wall is a liquid, the device can be a solid container.

[0473] In some possible embodiments, the fluid system, the positioning device further includes a gap locking mechanism;

[0474] The gap locking mechanism includes a gap enlarging mechanism and a gap reducing mechanism. The gap locking mechanism is connected to different walls. The gap reducing mechanism controls the distance between different walls to prevent them from moving further away, while the gap enlarging mechanism adjusts the distance between the walls to prevent them from moving closer.

[0475] In some possible embodiments, a fluid introduction device is further included;

[0476] The fluid introduction device is used to add fluid to the inlet of the flow field. The fluid introduction device may have certain anti-pollution functions or be disposable. The fluid introduction device may be other microfluidic chips or microfluidic structures.

[0477] In some possible embodiments, the fluid introduction device includes at least one of coating, transferring, coating (or spraying, printing), mutual exclusion, coating, inkjet, pipette, hollow fiber catheter or guide wire.

[0478] In some possible embodiments, a temperature control device is further included;

[0479] The temperature control device is used to control the temperature of the reaction.

[0480] Furthermore, more than one temperature control device is included to control the temperature of different areas of the basin respectively.

[0481] Further, the inlet adds fluid to more than one temperature zone in the flow domain, respectively.

[0482] In some possible embodiments, a detection device is further included;

[0483] The detection device is used to detect post-reaction indicators, such as fluorescence, color development, gas production, luminescence, changes in the concentration of at least one product, and / or the absence of a reaction.

[0484] In some possible embodiments, a control unit is further included;

[0485] The control unit is respectively connected to the signals of the electrical components in the hardware platform to control the electrical components and / or read or transmit relevant signals / instructions.

[0486] The present application also provides a method for using a shear-driven fluid platform, the method comprising:

[0487] Add fluid to the inlet of the hardware platform;

[0488] When the drive is turned on, shear forces cause the fluid near one wall to flow faster than the fluid near the other walls.

[0489] The fluid fills at least the thin flow area within the flow domain.

[0490] When needed, different types of fluids are added to the inlet, and the different types of fluids do not mix before reaching the inlet area.

[0491] When necessary, stop adding fluid to the inlet and pause the drive unit.

[0492] The present application also provides a microfluidic chip system, comprising any one of the flow field construction methods described above or any one of the hardware platforms described above.

[0493] Currently, a wide range of microfluidic chips, such as blood gas flow cells, sequencing flow cells, and in vitro diagnostic biomarker detection chips (such as myocardial markers), introduce fluids into relatively thin tubes or thin flow channels. Fluids then react within the chip, performing various tasks such as assay detection, chemical synthesis, gene detection, PCR, separation, mixing, droplet formation, and active substance culture. During this process, reactants can reside within the chip, such as lyophilized powder being carried away by the fluid or immobilized elsewhere on the chip. However, the current mainstream pressure-driven fluid-driven approach is more advantageous in laboratory settings, but the requirement for all test personnel to use pumps to manipulate the chip increases user demands. Furthermore, the need for continuous sample injection and the considerable size of external equipment complicate microfluidic system deployment and reagent efficiency. Reagents often represent the largest cost, particularly in applications involving enzymes, bases, precious samples, or fluids. The small size of microfluidic chips combined with the bulky associated equipment negates the overall system's portability.

[0494] In order to solve the above technical problems, the present application provides a pressure-independent Couette-like flow field construction method and a shear fluid hardware platform. Specifically, the liquid path includes a first surface and a second surface.

[0495] The first surface at least includes the exposed chip surface. Specifically, the exposed chip surface refers to the surface of the chip to be sequenced that is loaded with the DNB (DNA nanoball) library and is used for reaction.

[0496] It should be noted that the exposed chip surface may also be the surface of a chip to be sequenced that is loaded with other substances.

[0497] It should also be noted that the first surface may be a completely exposed chip surface, or may include, in addition to the exposed chip surface, a circumferential protective surface for protecting the chip surface disposed at a position not participating in the reaction.

[0498] A reagent liquid is provided at a preset position of the second surface, and the reagent liquid can move along with the movement of the second surface.

[0499] The second surface can move in a predetermined direction and drive a reagent solution at a predetermined position to at least be injected into the gap between the chip surface and the second surface. In the present application, by injecting the reagent solution into at least the gap between the chip surface and the second surface, the reagent solution can flow through at least the chip surface to complete sequencing.

[0500] It should be noted that the reagent liquid at the preset position of the second surface can be applied to the preset position by a liquid application device. The types of the reagent liquids applied are sequentially loaded to the preset positions according to the reaction order. As the second surface moves, each type of reagent liquid can be cleaned and replaced by the next reagent liquid entering the liquid path.

[0501] Please note that the first surface can be located above or below the second surface. The figures provided in the embodiments of this application and any descriptions of the first and second surfaces are merely exemplary positions and are not intended to be limiting in this embodiment of the application. The reagent solution in the gap between the first and second surfaces is used to detect gene sequences. Specifically, the reagent solution reacts with the exposed chip surface to identify the base sequence in the gene.

[0502] During gene sequencing, the reagent solution reacts at different positions on the chip surface as the second surface moves. As an example, the sequencing process may require replacing multiple reagent solutions in the gap to achieve up to 200 "reaction-photographing" cycles. In the embodiment of the present application, a reagent solution is applied to a preset position on the second surface, and then the second surface moves in a preset direction V, so that the reagent solution at the preset position is injected into the gap between the first surface and the second surface, i.e., the gap. At the same time, the second surface originally located above the first surface moves out of the top of the first surface, so that the reagent solution in the gap attached to the second surface is extracted from the gap as the second surface moves. As the new reagent solution at the preset position is continuously injected and the original reagent solution in the gap is continuously extracted, the reagent solution in the gap is gradually replaced by the new reagent solution to complete the cleaning and filling of the liquid path, thereby achieving the displacement of the reagent solution contacted by the sequencing chip. For ease of expression, the original reagent solution is named the first reagent solution and the new reagent solution is named the second reagent solution.

[0503] In the present embodiment, when the first reagent liquid in the gap between the first and second surfaces is completely displaced by the second reagent liquid, the first reagent liquid has reacted, and the reaction results have been photographed and recorded. At this point, other reagent liquids can be provided, and the second surface continues to move. The second reagent liquid will replace the first reagent liquid in the gap between the first and second surfaces, thus achieving multiple "reaction-photographing" cycles and obtaining multiple gene sequencing results.

[0504] In order to ensure that the gap between the first surface and the second surface is filled with reagent liquid, the gap height between the first surface and the second surface is less than or equal to twice the thickness of the reagent liquid at the preset position. It should be noted that, during the movement of the second surface, the flow rate entering the gap is the moving speed of the second surface multiplied by the liquid thickness and liquid width at the preset position on the first surface. Since the first surface is stationary, the average flow rate of the reagent liquid in the gap is half the moving speed of the second surface, therefore, the flow rate of the reagent liquid in the gap is the moving speed of the second surface multiplied by the gap height and the reagent liquid width. Therefore, in order to make the flow rate of the reagent liquid 05 in the gap less than or equal to the liquid inlet flow rate, that is, the gap between the first surface and the second surface is filled with reagent liquid, the gap height between the first surface and the second surface is less than or equal to twice the thickness of the reagent liquid at the preset position.

[0505] In an embodiment of the present application, the hydrophilicity of the first surface and the second surface meet the requirements of the reagent liquid entering the gap, the cosine value of the contact angle between the first surface and the reagent liquid is greater than 0, and the cosine value of the contact angle between the second surface and the reagent liquid is greater than 0.

[0506] Through the description of the above embodiments, it can be seen that those skilled in the art can clearly understand that all or part of the steps in the above-mentioned embodiment methods can be implemented by means of software plus the necessary general hardware platform. Based on this understanding, the technical solution of the present application, or the part that contributes to the prior art, can be embodied in the form of a software product, which can be stored in a storage medium such as ROM / RAM, a magnetic disk, an optical disk, etc., and includes a number of instructions for enabling a computer device (which can be a personal computer, a server, or a network communication device such as a media gateway, etc.) to execute the methods described in each embodiment of the present application or certain parts of the embodiments.

[0507] The present invention also discloses the following technical solutions:

[0508] To address the aforementioned issues with microfluidics, this application provides a technology comprising a Couette-like flow field construction method, a construction device, and applications in the microfluidics field. A product is typically considered in terms of reliability, performance, and cost. Traditional biochemical, electromechanical, and mechanical devices typically utilize macroscopic amounts of fluid when working with fluids. For example, medical devices use a full tube of reagent to test a single sample, or chips are directly piped with pure water to rinse the surface and then immersed in a pool of chemical reagents for reaction and cleaning. This creates two problems: 1. High cost and the need for large amounts of reagents; 2. Potentially poor performance due to the slow mass transfer in large volumes of liquid. Microfluidics confines reactions to a single chip because channels are micrometer-scale, resulting in low reagent consumption, rapid mass transfer, and rapid reactions. However, traditional microfluidics requires the construction of three-dimensional liquid channels to constrain liquid flow. The channels are microscopic in height and width, and macroscopic in the direction of flow. To provide energy to offset the friction of the liquid moving through the microchannels, the entire system is typically encapsulated, and pump-type fluidic devices are used to continuously provide pressure to propel the fluid and prevent leakage. This results in a system with numerous components and difficult-to-clean tubing, leading to increased reagent consumption. Passive methods such as capillary force are also available, but these are more difficult to control and are generally used for simpler assays. Therefore, microfluidic devices: 1. Save reagents, but the chip costs are high; 2. R&D and production are challenging, and they have yet to achieve widespread adoption; 3. The tubing connecting the chip is macroscopic, resulting in high reagent consumption. Currently, there is a technique called "open microfluidics," but this primarily removes the cover from the microchannels and treats them with hydrophilic and hydrophobic modifications, allowing liquid to flow through the uncovered microchannels. While this approach simplifies manufacturing, it still cannot completely eliminate the aforementioned problems of traditional microfluidic devices, and active control is difficult, making it generally limited to simple use cases. The technology of the present invention draws on the advantages of both traditional biochemical electromechanical devices and microfluidic devices, achieving reagent savings, rapid response, and stable reliability while eliminating the shortcomings of both, thus potentially replacing them.

[0509] Couette-like flow field construction method

[0510] In order to solve at least one of the above-mentioned problems and / or other potential problems of the prior art, it is necessary to invent a new fluid driving method and its hardware platform. Our technology is called the Couette-like flow field construction method, and the related hardware platform is called the shear-driven fluid platform. It mainly uses the shear force of the fluid to construct a flow field similar to the Couette flow field, to replace the traditional method - the Poisson flow field that uses pure pressure drive to overcome the friction between the fluid and the solid wall surface that constitutes the thin flow domain. The purpose of this design is first to be able to use a small amount of fluid to quickly clean the surface and replace the liquid originally existing in the flow domain, saving costs. Secondly, there are fewer parts involved, eliminating complex seals and pipe valves, and increasing reliability. Third, the quality control of the device becomes simpler because the number of parts is greatly reduced. Fourth, operation and development become simple and low-cost because there is no need for packaging and no fluid knowledge background.

[0511] To construct a Couette-like flow field, the present application first provides a liquid path structure, including

[0512] The first wall,

[0513] The second wall is configured to be disposed close to or at least partially in contact with the first wall, and the space facing each other forms a flow basin, which includes a thin flow basin;

[0514] an inlet structure configured to include one or more inlets, in operative communication with the flow basin, such that a fluid including at least a first fluid can be introduced into the flow basin; wherein the fluid including the first fluid can be introduced directly into the flow basin without passing through a common pipeline;

[0515] An outlet structure is configured to include one or more outlets and is in communication with the flow basin when in operation, so that the fluid passing through the flow basin is discharged;

[0516] Wherein, during operation, the first fluid is configured to be able to be applied with energy, and the energy can be converted into fluid kinetic energy, thereby forming a shear flow of the first fluid in the flow domain.

[0517] Optionally, during operation, the first wall surface is configured to be able to move relative to the second wall surface, thereby applying energy to the first fluid and driving the shear flow of the first fluid.

[0518] Optionally, the first wall and the second wall comprise substantially parallel planes, preferably with an angle of no more than 30 degrees;

[0519] Optionally, the movement of the first wall includes translation substantially parallel to the second wall, translation in a direction approaching or moving away from the second wall, and rotation relative to the second wall.

[0520] Optionally, the first wall comprises a flexible membrane material.

[0521] Optionally, the first fluid is configured to be capable of shear flow when energy is applied thereto based on one of force, heat, light, and electrical effects.

[0522] Optionally, the inlet structure includes a first inlet and a second inlet,

[0523] wherein the first fluid flows from the first inlet, passes through the flow field, and flows out from an outlet of the outlet structure;

[0524] The second fluid flows into the flow domain from the second inlet and flows out from one outlet of the outlet structure, sharing the same outlet with the first fluid, or flows out from another outlet of the outlet structure, using different outlets with the first fluid. The second fluid and the first fluid are laminar flows in the thin flow domain, and the second fluid occupies a certain space in the thin flow domain, so that the required amount of the first fluid is further reduced.

[0525] Optionally, the second fluid contacts the first fluid in the thin region, and its flow region does not overlap with the first fluid.

[0526] Optionally, the fluid is introduced in a temporally or spatially discrete manner through an inlet structure, including:

[0527] The inlet structure includes an inlet, wherein the first fluids are introduced into the inlet at different times, or when the first fluids are introduced into the inlet at the same time, an incompatible fluid is used to separate the first fluids so that the first fluids do not mix with each other before entering the thin flow area; or

[0528] The inlet structure includes a plurality of inlets, and each first fluid is introduced through a different inlet, so that each first fluid will not mix with each other before entering the thin flow area.

[0529] Optionally, the inlet structure further includes a liquid storage structure for storing a predetermined amount of the first fluid to ensure that a sufficient amount of the first fluid fills the flow basin through the inlet and prevents air from being brought in; wherein the predetermined amount is slightly larger than the fluid capacity required by the flow basin.

[0530] Optionally, the first wall and the second wall include curved surfaces to form a sleeve shape, wherein one of the first wall and the second wall forms an outer cylinder, and the other forms an inner cylinder, and a flow domain is formed between the two.

[0531] Optionally, the outlet structure is configured to enable the fluid from the thin flow area to be discharged freely and unobstructed to avoid blockage that affects the fluid introduction inlet.

[0532] Optionally, the materials of the first wall and the second wall are selected such that their hydrophilicity and hydrophobicity enable the first fluid to be located between the first wall and the second wall in a free state without being expelled by surface tension.

[0533] Optionally, the material of the second wall is selected such that it has poor affinity with the first fluid in the flow domain, so that the first fluid flowing out of the flow domain by shear motion will be sucked back into the flow domain.

[0534] Optionally, the sum of cosine values ​​of contact angles of the first wall and the second wall with the first fluid is greater than or equal to 0.

[0535] Optionally, the inlet includes a free surface, or the fluid connected to the inlet has at least one free surface; the outlet includes a free surface, or the fluid connected to the outlet has at least one free surface.

[0536] Optionally, the thick dimension of the thin watershed is an order of magnitude smaller than the long and / or wide dimensions of the thin watershed.

[0537] Optionally, there is a velocity gradient for the first fluid between the first wall and the second wall, and the first fluid has a faster flow rate on the side affected by energy or with less resistance.

[0538] Optionally, the first fluid includes a liquid, specifically a medicine.

[0539] Optionally, the thickness is sub-millimeter.

[0540] The operating method of the aforementioned liquid circuit structure includes:

[0541] providing a first wall surface,

[0542] Providing a second wall surface, configured to be disposed close to or at least partially in contact with the first wall surface, wherein the space facing the second wall surface forms a flow domain, and the flow domain includes a thin flow domain;

[0543] Providing an inlet structure configured to include one or more inlets, in operative communication with the flow basin, such that a fluid including at least a first fluid can be introduced into the flow basin; wherein the fluid including the first fluid can be introduced directly into the flow basin without passing through a common pipeline;

[0544] Providing an outlet structure, which is configured to include one or more outlets and is in communication with the flow basin when in operation, so that the fluid passing through the flow basin is discharged;

[0545] Wherein, during operation, the first fluid is configured to be able to be applied with energy, and the energy can be converted into fluid kinetic energy, thereby forming a shear flow of the first fluid in the flow domain.

[0546] Optionally, during operation, the first wall surface is configured to be able to move relative to the second wall surface, thereby applying energy to the first fluid and driving the shear flow of the first fluid.

[0547] Optionally, the first wall and the second wall comprise substantially parallel planes, preferably with an angle of no more than 30 degrees;

[0548] Optionally, the movement of the first wall includes translation substantially parallel to the second wall, translation in a direction approaching or moving away from the second wall, and rotation relative to the second wall.

[0549] Optionally, the first wall comprises a flexible membrane material.

[0550] Optionally, the first fluid is configured to be capable of shear flow when energy is applied thereto based on one of force, heat, light, and electrical effects.

[0551] Optionally, the inlet structure includes a first inlet and a second inlet,

[0552] wherein the first fluid flows from the first inlet, passes through the flow field, and flows out from an outlet of the outlet structure;

[0553] The second fluid flows into the flow field from the second inlet and flows out from one outlet of the outlet structure, and the first fluid and the second fluid share the same outlet, or flows out from another outlet of the outlet structure, and the first fluid and the second fluid use different outlets respectively.

[0554] The second fluid and the first fluid are laminar flows in the thin flow region, and the second fluid occupies a certain space in the thin flow region, so that the required amount of the first fluid is further reduced.

[0555] Optionally, the second fluid contacts the first fluid in the thin region, and its flow region does not overlap with the first fluid.

[0556] Optionally, the fluid is introduced in a temporally or spatially discrete manner through an inlet structure, including:

[0557] The inlet structure includes an inlet, wherein the first fluids are introduced into the inlet at different times, or when the first fluids are introduced into the inlet at the same time, an incompatible fluid is used to separate the first fluids so that the first fluids do not mix with each other before entering the thin flow area; or

[0558] The inlet structure includes a plurality of inlets, and each first fluid is introduced through a different inlet, so that each first fluid will not mix with each other before entering the thin flow area.

[0559] Optionally, the inlet structure further includes a liquid storage structure for storing a predetermined amount of the first fluid to ensure that a sufficient amount of the first fluid fills the flow basin through the inlet and prevents air from being brought in; wherein the predetermined amount is slightly larger than the fluid capacity required by the flow basin.

[0560] Optionally, the first wall and the second wall include curved surfaces to form a sleeve shape, wherein one of the first wall and the second wall forms an outer cylinder, and the other forms an inner cylinder, and a flow domain is formed between the two.

[0561] Optionally, the outlet structure is configured to enable the fluid from the thin flow area to be discharged freely and unobstructed to avoid blockage that affects the fluid introduction inlet.

[0562] Optionally, the materials of the first wall and the second wall are selected such that their hydrophilicity and hydrophobicity enable the first fluid to be located between the first wall and the second wall in a free state without being expelled by surface tension.

[0563] Optionally, the material of the second wall is selected such that it has poor affinity with the first fluid in the flow domain, so that the first fluid flowing out of the flow domain by shear motion will be sucked back into the flow domain.

[0564] Optionally, the sum of cosine values ​​of contact angles of the first wall and the second wall with the first fluid is greater than or equal to 0.

[0565] Optionally, the inlet includes a free surface, or the fluid connected to the inlet has at least one free surface; the outlet includes a free surface, or the fluid connected to the outlet has at least one free surface.

[0566] Optionally, the thick dimension of the thin watershed is an order of magnitude smaller than the long and / or wide dimensions of the thin watershed.

[0567] Optionally, there is a velocity gradient for the first fluid between the first wall and the second wall, and the first fluid has a faster flow rate on the side affected by energy or with less resistance.

[0568] Optionally, the first fluid includes a liquid, specifically a medicine.

[0569] Optionally, the thickness is sub-millimeter.

[0570] The Couette-like flow field construction method provided in the present application injects the fluid into the inlet and starts the shear force driving device, so that the fluid is injected into at least the thin area within the flow domain, so that interaction can occur. In the present application, since the pressure drive or surface tension drive of the traditional microfluidic platform is replaced by shear force drive, on the one hand, the improvement of energy input and performance optimization are more convenient, and there is no problem of pressure overlimit; in addition, the structure is simple, avoiding the learning and use obstacles caused by a large number of external equipment; thirdly, a large number of external pipelines are eliminated, saving cleaning time and cost. Fourth, sealing is not required, avoiding the cost and inconsistency of packaging.

[0571] Therefore, this application overcomes the problems of high cost, difficulty in getting started, and low performance of traditional microfluidic devices, making its market penetration prospects more prominent.

[0572] In addition, this application also includes a note recording the following technical solutions:

[0573] 1. A method for designing a watershed, characterized by comprising a plurality of walls, an inlet, an outlet, and watershed sides.

[0574] The multiple walls are close to or in contact with each other, and the space facing each other forms a flow domain, and the flow domain includes at least one thin flow domain.

[0575] There is a viscous fluid in the thin flow domain, which moves under the drive of shear force. The fluid in contact with at least one wall moves faster than the fluid in contact with other walls.

[0576] The fluid inlet and outlet are formed according to the direction of the average flow velocity. The energy provided by the pressure difference between the inlet and outlet is less than the energy required for the fluid to flow through a channel composed of solid walls under the same conditions.

[0577] 2. The thin basin is characterized in that the height of at least part of the basin area is one order of magnitude smaller than the length or width, preferably in the sub-millimeter range.

[0578] 3. The inlet is characterized in that the inlet is a free surface or a fluid connected to the inlet has at least one free surface. The outlet is a free surface or a fluid connected to the outlet has at least one free surface.

[0579] 4. The inlet and outlet are characterized in that the static pressure of the fluid connected thereto is equal to or close to that of the external environment.

[0580] 5. The inlet and outlet are characterized in that the fluid connected thereto has a constant pressure or velocity.

[0581] 6. The side of the flow basin is characterized in that there is no sealing between the walls, and the fluid overflows.

[0582] 7. The inlet is characterized in that an excess of fluid is visible in connection with the flow basin.

[0583] 8. The watershed described above is characterized in that the energy provided by the fluid pressure difference between the inlet and outlet of the watershed is less than 2 / 3 of the energy consumed by the fluid flowing in a watershed of the same size under the same conditions and without the existence of shear force.

[0584] 9. The flow basin is characterized in that the flow rate of fluid entering the flow basin from the inlet is greater than or equal to the product of the smallest cross-sectional area in the direction of the average flow velocity within the flow basin and the average flow velocity at the inlet. The flow rate out of the outlet is less than or equal to the product of the largest cross-sectional area within the flow basin and the average flow velocity at the outlet.

[0585] 10. The watershed is characterized in that its shape comprises at least one thin-sheet watershed.

[0586] 11. The thin flow basin is characterized in that, except for the edge of the flow basin and discontinuous places (such as places where the height is 0), the interior of the thin flow basin is in a laminar state.

[0587] 12. The thin-sheet flow basin is characterized in that the upper and lower walls of the flow basin are unique and parallel to each other, or the inclination angle formed is no more than 30 degrees.

[0588] 13. The thin-sheet flow basin is characterized in that the upper and lower walls of the flow basin are curved, and the tangent lines or tangent planes at two directly opposite points are parallel, or the angle formed is no more than 30 degrees. In special cases, the walls are two concentric cylinders.

[0589] 14. The flow domain described above is characterized in that the direction of motion of each point on the wall forming the thin flow domain is the direction of the tangent line at that point on the wall. Therefore, when the wall moves, its shape coincides with its shape at the previous moment. In special cases, the wall is a plane (translation), a cylinder, or a disk (rotation).

[0590] 15. The flow field is characterized in that the direction of movement of each point on the wall forming the thin channel is consistent with the direction of liquid movement in the fluid channel. When the wall moves, it is parallel to its shape at the previous moment.

[0591] 16. The flow basin is characterized in that the design of at least a portion of the upper and lower walls is adapted to the liquid's properties or flow process, enabling the liquid to be confined within the thin flow basin even without side walls. Preferably, for at least a portion of the flow basin area, the sum of the cosine values ​​of the contact angles of the upper wall and the opposing lower wall with the fluid is greater than or equal to zero.

[0592] 17. The flow basin is characterized in that at least a portion of the area is mismatched with the liquid's properties or flow process, making it difficult for the liquid to overflow across this portion. Preferably, for at least a portion of the flow basin area, the sum of the cosine values ​​of the contact angles of the upper wall and the opposing lower wall with the fluid is less than or equal to zero.

[0593] 18. The flow basin is characterized in that, in actual operation, liquid may exceed the designed thin flow basin and overflow, and the overflowed liquid can be carried away by shear force.

[0594] 19. The flow field, characterized in that the shear force is generated due to the relative movement of the walls forming the flow domain.

[0595] 20. The movement described above is characterized in that at least part of the wall forming the lamella channel is a flexible but non-stretchable membrane.

[0596] 21. The flow field, characterized in that the wall is a liquid wall or a gas wall formed by immiscible liquid or gas.

[0597] 22. The flow field is characterized in that the shear force is generated by a portion of the liquid in the thin film being driven by physical methods such as force, heat, light, electricity, or magnetism, such as electrowetting, acoustic energy drive, bubble drive, photodeformation, and magnetic fluid.

[0598] 23. The flow field, characterized in that the distance between at least some points of the upper and lower surfaces of the thin-sheet channel is zero. In this case, the liquid flows through the gaps between natural microscopically non-smooth surfaces or the gaps between artificially prepared non-smooth surfaces.

[0599] 24. The flow field can form a stable or substantially stable flow field within one minute.

[0600] 25. The viscous flow field, characterized in that a substance for adjusting viscosity, preferably glycerol, and / or a surfactant, preferably Tween, is added to the fluid.

[0601] 26. Different types of fluids are not mixed before they reach the vicinity of the inlet area.

[0602] 27. A method for using a Couette-like flow field, wherein the method for using the flow field is characterized by the fluid circuit described in any one of the preceding items, the method comprising:

[0603] Fill the inlet of the flow field with fluid.

[0604] Apply shear forces to the system.

[0605] The fluid remains connected to the fluid outside the flow domain and fills at least the thin flow domain

[0606] If necessary, fill the flow field with auxiliary fluid.

[0607] If necessary, open the auxiliary inlet / outlet devices at the inlet and outlet.

[0608] 28. A hardware platform for constructing a Couette-like flow field, named a shear-driven fluid platform, characterized by comprising:

[0609] The solid wall contacts the fluid and acts to constrain the fluid, wherein the fluid contains the fluid wall. The space between the walls is the flow domain.

[0610] The inlet can be the entrance to the flow basin, where the free surface of the fluid is visible; it can also be a liquid-retaining structure connected to the fluid within the flow basin, such as a pipe or funnel. The surface properties of the device prevent liquid adhesion. Before reaching the inlet area, the different fluids are physically isolated from each other. Once in the inlet area, the fluids are subjected to shear forces.

[0611] The driving device includes at least one energy conversion method that can generate shear force on the liquid in the flow area, so that the fluid speed near a certain wall is faster than the fluid speed near other walls. The driving device includes an energy supply device, which can be human power or power supply.

[0612] The flow domain contains substances that interact with the substances in the fluid. This can be the solid wall itself or substances fixed to the solid wall. It can be stored in a reservoir that the liquid will contact, or it can be added through an inlet.

[0613] When applying shear force, at least fill the thin areas in the basin.

[0614] 29. The hardware platform, wherein the driving device and the wall comprise:

[0615] The moving, tensioned membrane serves as the moving wall. The energy supply is an electrical system, including a reducer, motor, and power supply.

[0616] 30. The hardware platform further comprises a bypass device;

[0617] The bypass device is used to discharge excess liquid from the basin to prevent the entire mechanism from being contaminated or liquid from accumulating.

[0618] 31. The hardware platform, characterized in that the positioning device comprises a mechanical device that fixes the relative position of the moving wall to other walls but loosely constrains the direction of motion. Specifically, if the moving wall is a liquid, the device can be a solid container and certain auxiliary fluid conditions (speed, liquid properties, etc.).

[0619] 32. The fluid circuit system, characterized in that the positioning device further comprises a gap locking mechanism;

[0620] The gap locking mechanism includes a gap enlarging mechanism and a gap reducing mechanism. The gap locking mechanism is connected to different walls. The gap reducing mechanism controls the distance between different walls to prevent them from moving further away, while the gap enlarging mechanism adjusts the distance between the walls to prevent them from moving closer.

[0621] 33. The platform is characterized in that it further comprises a fluid introduction device;

[0622] The fluid introduction device is used to add fluid to the inlet of the flow field. The fluid introduction device may have certain anti-pollution functions or be disposable. The fluid introduction device may be other microfluidic chips or microfluidic structures.

[0623] 34. The platform described above is characterized in that the fluid introduction device includes at least one of a coating, a transfer, a coating (or a spray, a print), a mutual exclusion, a coating, an inkjet, a pipette, a hollow fiber catheter or a guide wire.

[0624] 35. The platform is characterized in that it also includes a temperature control device;

[0625] The temperature control device is used to control the temperature of the reaction.

[0626] 36. The platform is characterized in that it also includes a detection device;

[0627] The detection device is used to detect post-reaction indicators, such as fluorescence, color development, gas production, luminescence, changes in the concentration of at least one product, and / or the absence of a reaction.

[0628] 37. The fluid circuit system further comprises a control unit;

[0629] The control unit is respectively connected to the signals of the electrical components in the hardware platform to control the electrical components and / or read or transmit relevant signals / instructions.

[0630] 38. A method for using a Couette-like flow field, comprising the hardware platform of any one of the foregoing items, the method comprising:

[0631] Add fluid to the inlet of the hardware platform;

[0632] When the drive is turned on, shear forces cause the fluid near one wall to flow faster than the fluid near the other walls.

[0633] The fluid fills at least the thin flow area within the flow domain.

[0634] When needed, different types of fluids are added to the inlet, and the different types of fluids do not mix before reaching the inlet area.

[0635] When necessary, stop adding fluid to the inlet and pause the drive unit.

[0636] 39. A microfluidic chip platform, characterized in that it comprises any one of the flow fields described above or any one of the hardware platforms described above.

[0637] The present invention also discloses the following supplementary note 1, including:

[0638] Item 1. A liquid path structure, characterized in that it includes

[0639] The first wall,

[0640] The second wall surface is configured to be disposed close to or at least partially in contact with the first wall surface, and the space facing each other forms a flow domain, wherein the flow domain includes a thin flow domain;

[0641] an inlet structure configured to include one or more inlets, in operative communication with the flow basin, such that a fluid including at least a first fluid can be introduced into the flow basin; wherein the fluid including at least a first fluid can be introduced directly into the flow basin without passing through a common pipeline;

[0642] an outlet structure, configured to include one or more outlets, which is in communication with the flow area during operation so that the fluid passing through the flow area is discharged;

[0643] Wherein, during operation, the first fluid is configured to be able to be applied with energy, and the energy can be converted into fluid kinetic energy, thereby forming a shear flow of the first fluid in the flow domain.

[0644] Item 2. The fluid path structure according to Item 1 is characterized in that, during operation, the first wall surface is configured to be able to move relative to the second wall surface, thereby applying energy to the first fluid and driving the shear flow of the first fluid.

[0645] Clause 3. The fluid path structure according to clause 2, wherein the first wall surface and the second wall surface comprise substantially parallel planes, preferably with an angle of no more than 30 degrees;

[0646] Item 4. The liquid path structure according to Item 2 is characterized in that the movement of the first wall surface includes a translation substantially parallel to the second wall surface, a translation in a direction approaching or away from the second wall surface, and a rotation relative to the second wall surface.

[0647] Item 5. The liquid path structure according to Item 3, wherein the first wall surface comprises a flexible film material.

[0648] Item 6. The fluid path structure according to Item 1, characterized in that the first fluid is configured to be capable of shear flow when energy is applied based on one of force, heat, light, and electrical effects.

[0649] Clause 7. The fluid path structure according to clause 1 or 2, wherein the inlet structure comprises a first inlet and a second inlet,

[0650] wherein the first fluid flows from the first inlet, passes through the flow region, and flows out from an outlet of the outlet structure;

[0651] The second fluid flows into the flow domain from the second inlet and flows out from one outlet of the outlet structure, sharing an outlet with the first fluid, or flows out from another outlet of the outlet structure, using different outlets with the first fluid, wherein the second fluid and the first fluid are laminar flows in the thin flow domain, and the second fluid occupies a certain space in the thin flow domain, so that the required amount of the first fluid is further reduced.

[0652] Item 8. The fluid path structure according to Item 7, wherein the second fluid contacts the first fluid in the thin region, and its flow region does not overlap with the first fluid.

[0653] Clause 9. The fluid circuit structure according to clause 1, wherein the fluid is introduced through the inlet structure in a temporally or spatially discrete manner, comprising:

[0654] The inlet structure includes an inlet, into which the first fluids are introduced at different times, or when the first fluids are introduced at the same time, an incompatible fluid is used to separate the first fluids, so that the first fluids do not mix with each other before entering the thin flow area; or

[0655] The inlet structure includes a plurality of inlets, and each first fluid is introduced through a different inlet, so that each first fluid will not mix with each other before entering the thin flow area.

[0656] Item 10. The liquid path structure according to Item 1 is characterized in that the inlet structure further includes a liquid storage structure for storing a predetermined amount of the first fluid to ensure that a sufficient amount of the first fluid fills the flow domain through the inlet and prevents air from being brought into it; wherein the predetermined amount is slightly larger than the fluid capacity required by the flow domain.

[0657] Item 11. The liquid path structure according to Item 2 is characterized in that the first wall and the second wall include curved surfaces to form a sleeve shape, wherein one of the first wall and the second wall forms an outer tube and the other forms an inner tube, and a flow domain is formed between the two.

[0658] Item 12. The fluid path structure according to Item 1, characterized in that the outlet structure is configured to enable the fluid from the thin flow area to be discharged freely and unobstructed to avoid blockage that affects the introduction of the fluid into the inlet.

[0659] Item 13. The liquid path structure according to Item 1 is characterized in that the materials of the first wall and the second wall are selected so that their hydrophilicity and hydrophobicity enable the first fluid to be located between the first wall and the second wall in a free state without being expelled by surface tension.

[0660] Item 14. The fluid path structure according to Item 1 is characterized in that the material of the second wall is selected so that it has poor affinity with the first fluid in the flow domain, so that the first fluid flowing out of the flow domain through shear motion will be sucked back into the flow domain.

[0661] Item 15. The fluid path structure according to Item 13, wherein the sum of the cosine values ​​of the contact angles of the first wall surface and the second wall surface with the first fluid is greater than or equal to zero.

[0662] Item 16. The fluid path structure according to Item 1 is characterized in that the inlet includes a free surface, or the fluid connected to the inlet has at least one free surface; the outlet includes a free surface, or the fluid connected to the outlet has at least one free surface.

[0663] Item 17. The fluid path structure according to Item 1, characterized in that the thickness dimension of the thin flow domain is one order of magnitude smaller than the length and / or width dimension of the thin flow domain.

[0664] Item 18. The liquid path structure according to Item 1 is characterized in that the first fluid has a velocity gradient between the first wall and the second wall, and the first fluid has a faster flow rate on the side affected by energy or with less resistance.

[0665] Item 19. The fluid path structure according to Item 1, characterized in that the first fluid comprises a liquid, specifically a reagent.

[0666] Item 20. The liquid path structure according to Item 17, characterized in that the thickness dimension is sub-millimeter.

[0667] Item 21. A device comprising the fluid path structure of any one of claims 1 to 19.

[0668] Clause 22. A method for operating a fluid circuit structure, comprising:

[0669] providing a first wall surface,

[0670] Providing a second wall surface, configured to be disposed close to or at least partially in contact with the first wall surface, with the facing space between the second wall surface forming a flow domain, wherein the flow domain includes a thin flow domain;

[0671] Providing an inlet structure configured to include one or more inlets, which are in operative communication with the flow basin, so that a fluid including at least a first fluid can be introduced into the flow basin; wherein the fluid of the first fluid can be introduced directly into the flow basin without passing through a common pipeline;

[0672] providing an outlet structure configured to include one or more outlets, which is in communication with the flow area during operation so that the fluid passing through the flow area is discharged;

[0673] Wherein, during operation, the first fluid is configured to be able to be applied with energy, and the energy can be converted into fluid kinetic energy, thereby forming a shear flow of the first fluid in the flow domain.

[0674] Item 23. The method for operating the fluid path structure according to Item 21, characterized in that during operation, the first wall surface is configured to be able to move relative to the second wall surface, thereby applying energy to the first fluid and driving the shear flow of the first fluid.

[0675] Clause 24. The method for operating the fluid path structure according to clause 22, wherein the first wall surface and the second wall surface comprise substantially parallel planes, preferably with an angle of no more than 30 degrees;

[0676] Item 25. The method for operating the liquid path structure according to Item 23 is characterized in that the movement of the first wall surface includes a translation substantially parallel to the second wall surface, a translation in a direction approaching or away from the second wall surface, and a rotation relative to the second wall surface.

[0677] Item 26. The method for operating a liquid path structure according to Item 23, wherein the first wall surface comprises a flexible membrane material.

[0678] Item 27. The method for operating a fluid circuit structure according to Item 21, wherein the first fluid is configured to be capable of shear flow when energy is applied based on one of force, heat, light, and electrical effects.

[0679] Clause 28. The method for operating the fluid circuit structure according to clause 21 or 22, wherein the inlet structure comprises a first inlet and a second inlet,

[0680] wherein the first fluid flows from the first inlet, passes through the flow region, and flows out from an outlet of the outlet structure;

[0681] wherein the second fluid flows into the flow field from the second inlet and flows out from the one outlet of the outlet structure, the first fluid and the second fluid share the same outlet, or flows out from another outlet of the outlet structure, the first fluid and the second fluid use different outlets respectively.

[0682] The second fluid and the first fluid are laminar flows in the thin flow region, and the second fluid occupies a certain space in the thin flow region, so that the required amount of the first fluid is further reduced.

[0683] Item 29. The method for operating a fluid path structure according to Item 27, wherein the second fluid contacts the first fluid in the thin region, and its flow region does not overlap with the first fluid.

[0684] Clause 30. The method for operating the fluid circuit structure according to Clause 21, wherein the fluid is introduced through the inlet structure in a temporally or spatially discrete manner, comprising:

[0685] The inlet structure includes an inlet, into which the first fluids are introduced at different times, or when the first fluids are introduced at the same time, an incompatible fluid is used to separate the first fluids, so that the first fluids do not mix with each other before entering the thin flow area; or

[0686] The inlet structure includes a plurality of inlets, and each first fluid is introduced through a different inlet, so that each first fluid will not mix with each other before entering the thin flow area.

[0687] Item 31. The operating method of the liquid path structure according to Item 21 is characterized in that the inlet structure further includes a liquid storage structure for storing a predetermined amount of the first fluid to ensure that a sufficient amount of the first fluid fills the flow domain through the inlet and prevents air from being brought into it; wherein the predetermined amount is slightly larger than the fluid capacity required by the flow domain.

[0688] Item 32. The operating method of the liquid path structure according to Item 22 is characterized in that the first wall and the second wall include curved surfaces to form a sleeve shape, wherein one of the first wall and the second wall forms an outer cylinder and the other forms an inner cylinder, and a flow domain is formed between the two.

[0689] Item 33. The method for operating the fluid path structure according to Item 21, wherein the outlet structure is configured to enable the fluid from the thin flow area to be discharged freely and unobstructed to avoid blockage that affects the introduction of the fluid into the inlet.

[0690] Item 34. The operating method of the liquid path structure according to Item 21 is characterized in that the materials of the first wall and the second wall are selected so that their hydrophilicity and hydrophobicity enable the first fluid to be located between the first wall and the second wall in a free state and will not be expelled by surface tension.

[0691] Item 35. The fluid path structure according to Item 21 is characterized in that the material of the second wall is selected so that it has poor affinity with the first fluid in the flow domain, so that the first fluid flowing out of the flow domain through shear motion will be sucked back into the flow domain.

[0692] Item 36. The method for operating a fluid path structure according to Item 33, wherein the sum of the cosine values ​​of the contact angles of the first wall surface and the second wall surface with the first fluid is greater than or equal to 0.

[0693] Item 37. The method for operating the fluid path structure according to Item 21, characterized in that the inlet includes a free surface, or the fluid connected to the inlet has at least one free surface; the outlet includes a free surface, or the fluid connected to the outlet has at least one free surface.

[0694] Clause 38. The method for operating the fluid path structure according to Clause 21, wherein the thickness dimension of the thin flow domain is one order of magnitude smaller than the length and / or width dimension of the thin flow domain.

[0695] Item 39. The operating method of the liquid path structure according to Item 21 is characterized in that the first fluid has a velocity gradient between the first wall and the second wall, and the first fluid has a faster flow rate on the side affected by energy or with less resistance.

[0696] Item 40. The method for operating the fluid path structure according to Item 21, wherein the first fluid comprises a liquid, specifically a medicine.

[0697] Item 41. The liquid path structure according to Item 37, characterized in that the thickness dimension is sub-millimeter.

[0698] It should be noted that the various embodiments in this specification are described in a progressive manner, with each embodiment focusing on the differences from other embodiments. Reference can be made to the common and similar parts between the various embodiments. The methods disclosed in the embodiments are described briefly because they correspond to the systems disclosed in the embodiments. For relevant details, refer to the description of the systems.

Claims

1. A liquid path structure, characterized in that: include The first wall, The second wall surface is configured to be disposed close to or at least partially in contact with the first wall surface, and the space facing each other forms a flow domain, wherein the flow domain includes a thin flow domain; an inlet structure configured to include one or more inlets, in operative communication with the flow field, so that a fluid including at least a first fluid can be introduced into the flow field; An outlet structure, configured to include one or more outlets, which is in communication with the flow field during operation so that the fluid passing through the flow field is discharged; wherein the first fluid comprises a liquid; Among them, when working: The fluid at at least one inlet position of the inlet structure can be directly exposed to the environment outside the flow field without passing through a pipeline; and / or The fluid at at least one outlet position of the outlet structure can be directly exposed to the environment outside the flow field without passing through a pipeline, and / or The fluid at at least one location in the flow basin can be directly exposed to the environment outside the flow basin; The first fluid is configured to be able to be applied with energy during operation, and the energy can be converted into fluid kinetic energy, thereby forming a shear flow of the first fluid in the flow domain, and the thin flow domain can be emptied or filled with the fluid during operation.

2. The liquid path structure according to claim 1, wherein: During operation, the first wall surface is configured to be able to move relative to the second wall surface, thereby applying energy to the first fluid and driving the shear flow of the first fluid.

3. The liquid path structure according to claim 2, wherein: The relative movement of the first wall surface includes a translation in a direction substantially parallel to the second wall surface, a translation in a direction approaching or moving away from the second wall surface, and a rotation relative to the second wall surface.

4. The liquid path structure according to claim 3, wherein: The first wall surface rotating relative to the second wall surface includes the first wall surface rotating and the second wall surface being stationary.

5. The liquid path structure according to claim 4, wherein: The first wall and the second wall comprise a disc shape, the first wall is substantially planar, the second wall is substantially planar, and the first wall is substantially parallel to the second wall; During operation, the first wall surface is configured to rotate so as to apply energy to the first fluid and drive the first fluid to traverse the second wall surface.

6. The liquid path structure according to claim 1, wherein: The first fluid is configured to be capable of shear flow when energy is applied thereto based on one of force, heat, light, and electrical effects.

7. The liquid path structure according to claim 1, wherein: The inlet structure comprises a first inlet and a second inlet, The first fluid flows into the flow basin from the first inlet, passes through the flow basin, and flows out from an outlet of the outlet structure, and the second fluid flows into the flow basin from the second inlet, passes through the flow basin, flows out from the one outlet of the outlet structure, and shares an outlet with the first fluid, or flows out from another outlet of the outlet structure, and uses different outlets with the first fluid, wherein the second fluid and the first fluid are laminar flows in the thin flow basin, and the second fluid occupies a certain space in the thin flow basin so that the required amount of the first fluid is further reduced.

8. The liquid path structure according to claim 7, wherein: The second fluid contacts the first fluid in the thin flow region, and its flow area does not overlap with the first fluid.

9. The fluid path structure according to claim 7, wherein the movement of the second fluid can drive the first fluid to perform shear flow.

10. The liquid path structure according to claim 1, wherein: The fluid can be introduced in a temporally or spatially discrete manner via the inlet structure, wherein: The inlet structure includes an inlet, into which the first fluids are introduced at different times, or when the first fluids are introduced at the same time, an incompatible fluid is used to separate the first fluids, so that the first fluids will not mix with each other before entering the thin flow area; or The inlet structure includes a plurality of inlets, and each first fluid is introduced through a different inlet, so that each first fluid will not mix with each other before entering the thin flow domain.

11. The liquid path structure according to claim 1, wherein: The inlet structure further includes a liquid storage structure for storing a predetermined amount of the first fluid to ensure that a sufficient amount of the first fluid fills the flow area through the inlet and prevents air from being brought into the flow area; Wherein, the predetermined amount is configured to be slightly larger than the fluid capacity required by the flow domain.

12. The liquid path structure according to claim 1, wherein: The first wall surface and the second wall surface include curved surfaces to form a sleeve shape, wherein one of the first wall surface and the second wall surface forms an outer cylinder, and the other forms an inner cylinder, and a flow domain is formed between the two. During operation, at least one of the outer cylinder and the inner cylinder can move, and the movement includes: rotation or axial linear motion or axial linear motion while rotating.

13. The liquid path structure according to claim 12, wherein: The first wall surface forms an outer cylinder, the second wall surface forms an inner cylinder, the inner cylinder moves, and the outer cylinder is stationary, including: rotating and / or axially moving.

14. The liquid path structure according to claim 13, wherein: The height of the inner cylinder is lower than that of the outer cylinder.

15. The liquid path structure according to claim 12 or 14, wherein The inner cylinder and the outer cylinder both comprise cylinders; or The inner cylinder comprises a multi-faceted cylindrical cylinder, and the outer cylinder comprises a cylindrical cylinder; or The outer cylinder comprises a multi-faceted cylindrical cylinder, and the inner cylinder comprises a cylindrical cylinder.

16. The liquid path structure according to claim 1, wherein: The outlet structure is configured to enable the fluid from the thin flow area to be discharged freely and unobstructed to avoid blockage that affects the introduction of the fluid into the inlet.

17. The liquid path structure according to claim 1, wherein: The materials of the first wall and the second wall are selected to have hydrophilicity and hydrophobicity such that the first fluid can be located between the first wall and the second wall in a free state without being expelled by surface tension. For example, the hydrophilic and hydrophobic material includes an HMDS coating.

18. The liquid path structure according to claim 1, wherein: The material of the second wall is selected such that it has a poor affinity with the first fluid in the flow domain, so that the first fluid flowing out of the flow domain by shear flow will be sucked back into the flow domain.

19. The liquid path structure according to claim 17, wherein: A sum of cosine values ​​of contact angles of the first wall surface and the second wall surface with respect to the first fluid is greater than or equal to zero.

20. The liquid path structure according to claim 1, wherein: The inlet includes a free surface, or the fluid connected to the inlet has at least one free surface; the outlet includes a free surface, or the fluid connected to the outlet has at least one free surface.

21. The liquid path structure according to claim 1, wherein: The thick dimension of the thin flow domain is at least one order of magnitude smaller than the long and / or wide dimensions of the thin flow domain.

22. The liquid path structure according to claim 21, wherein: The thickness of the thin flow domain is 2-100 microns.

23. The liquid path structure according to claim 1, wherein: The first fluid between the first wall and the second wall has a velocity gradient, and the first fluid has a faster flow velocity on the side affected by energy or with less resistance.

24. The liquid path structure according to claim 1, wherein: The liquid circuit structure further includes a heater; The heater is configured to perform heat transfer with the first wall surface and / or the second wall surface for heating the flow area.

25. The liquid path structure according to claim 24, wherein: The flow domain includes a plurality of temperature zones, and the plurality of temperature zones are respectively separated by at least one insulation block arranged on the second wall surface, wherein the temperatures of the plurality of temperature zones are the same or different.

26. The liquid path structure according to claim 1, wherein: The first wall and the second wall include a disc shape, and the second wall is configured to rotate during operation, thereby applying energy to the first fluid to drive the shear flow of the first fluid.

27. The liquid path structure according to claim 26, wherein: The first wall surface is configured to be stationary, or to rotate, or to perform linear motion in a direction substantially parallel to the second wall surface, or to rotate and perform linear motion in a direction substantially parallel to the second wall surface.

28. The liquid path structure according to claim 26, wherein: The inlet structure includes a channel provided at a predetermined position of the first wall surface and / or the second wall surface, for introducing the fluid into the flow field.

29. The liquid path structure according to claim 28, wherein: The channel includes a through hole arranged on the first wall surface and / or the second wall surface at a position close to the center of the disk.

30. The fluid path structure according to claim 28, wherein the channel comprises a liquid inlet pipe attached to the first wall surface and / or the second wall surface, so that the first fluid is sucked into the flow area.

31. The liquid path structure according to claim 26, wherein: The outlet structure includes an area between the disk periphery of the first wall and the disk periphery of the second wall, and the first fluid can be discharged through the area.

32. A device comprising the fluid path structure according to any one of claims 1 to 31.

33. A method for operating a fluid path structure, wherein: include: providing a first wall surface, Providing a second wall surface, which is configured to be disposed close to or at least partially in contact with the first wall surface, and the space facing the second wall surface forms a flow domain, wherein the flow domain includes a thin flow domain; Providing an inlet structure, configured to include one or more inlets, in operative communication with the flow field, so that a fluid including at least a first fluid can be introduced into the flow field; Providing an outlet structure, which is configured to include one or more outlets and is in communication with the flow area during operation so that the fluid passing through the flow area is discharged; wherein the first fluid comprises a liquid; Among them, when working: The fluid at at least one inlet position of the inlet structure can be directly exposed to the environment outside the flow field without passing through a pipeline; and / or The fluid at at least one outlet position of the outlet structure can be directly exposed to the environment outside the flow field without passing through a pipeline, and / or The fluid at at least one location in the flow basin can be directly exposed to the environment outside the flow basin; The first fluid is configured to be able to be applied with energy, and the energy can be converted into fluid kinetic energy, thereby forming a shear flow of the first fluid in the flow domain, and the thin flow domain can be emptied or filled with the fluid during operation.

34. The operating method according to claim 33, wherein: During operation, the first wall surface is configured to be able to move relative to the second wall surface, thereby applying energy to the first fluid and driving the shear flow of the first fluid.

35. The operating method according to claim 34, wherein: The relative movement of the first wall surface includes a translation in a direction substantially parallel to the second wall surface, a translation in a direction approaching or moving away from the second wall surface, and a rotation relative to the second wall surface.

36. The operating method according to claim 35, wherein: The first wall surface rotating relative to the second wall surface includes the first wall surface rotating and the second wall surface being stationary.

37. The operating method according to claim 36, wherein: The first wall and the second wall comprise a disc shape, the first wall is substantially planar, the second wall is substantially planar, and the first wall is substantially parallel to the second wall; During operation, the first wall surface is configured to rotate so as to apply energy to the first fluid and drive the first fluid to traverse the second wall surface.

38. The operating method according to claim 33, wherein: The first fluid is configured to be capable of shear flow when energy is applied thereto based on one of force, heat, light, and electrical effects.

39. The operating method according to claim 33, wherein: The inlet structure comprises a first inlet and a second inlet, wherein the first fluid flows from the first inlet through the flow field and flows out from an outlet of the outlet structure, The second fluid flows into the flow field from the second inlet and flows out from the one outlet of the outlet structure, and the first fluid and the second fluid share one outlet, or flows out from another outlet of the outlet structure, and the first fluid and the second fluid use different outlets respectively. The second fluid and the first fluid are laminar flows in the thin flow area, and the second fluid occupies a certain space in the thin flow area so that the required amount of the first fluid is further reduced.

40. The operating method according to claim 39, wherein: The second fluid contacts the first fluid in the thin flow region, and its flow area does not overlap with the first fluid.

41. The operating method according to claim 39, wherein the movement of the second fluid can drive the first fluid to perform shearing movement.

42. The operating method according to claim 33, wherein: The fluid is introduced through the inlet structure in a time- or space-discrete manner, wherein: The inlet structure includes an inlet, into which the first fluids are introduced at different times, or when the first fluids are introduced at the same time, an incompatible fluid is used to separate the first fluids, so that the first fluids will not mix with each other before entering the thin flow area; or The inlet structure includes a plurality of inlets, and each first fluid is introduced through a different inlet, so that each first fluid will not mix with each other before entering the thin flow domain.

43. The operating method according to claim 33, wherein: The inlet structure further includes a liquid storage structure for storing a predetermined amount of the first fluid to ensure that a sufficient amount of the first fluid fills the flow domain through the inlet and prevents air from being brought in; wherein the predetermined amount is slightly larger than the fluid capacity required by the flow domain.

44. The operating method according to claim 33, wherein: The first wall surface and the second wall surface include curved surfaces to form a sleeve shape, wherein one of the first wall surface and the second wall surface forms an outer cylinder, and the other forms an inner cylinder, and a flow domain is formed between the two. During operation, at least one of the outer cylinder and the inner cylinder can move, and the movement includes: rotation or axial linear motion or axial linear motion while rotating.

45. The operating method according to claim 44, wherein: The first wall surface forms an outer cylinder, and the second wall surface forms an inner cylinder. The inner cylinder moves, and the outer cylinder is stationary. The movement includes: rotation and / or axial movement.

46. ​​The operating method according to claim 45, wherein: The inner cylinder is configured to be lower in height than the outer cylinder.

47. The operating method according to claim 45 or 46, wherein: The inner cylinder and the outer cylinder both comprise cylinders, or The inner cylinder comprises a multi-faceted cylinder and the outer cylinder comprises a cylinder, or The outer cylinder comprises a multi-faceted cylinder and the inner cylinder comprises a cylindrical cylinder.

48. The operating method according to claim 47, wherein: The inner cylinder comprises a multi-faceted cylindrical cylinder and the outer cylinder comprises a cylindrical cylinder, further comprising the steps of: S1. A chip is disposed on the cylindrical surface of the multifaceted cylinder, the chip facing the outer cylinder and being located in the flow field between the inner cylinder and the outer cylinder; S2. providing a first first fluid through the inlet until the space between the inner cylinder and the outer cylinder is filled with the first first fluid, wherein the first first fluid is a liquid, preferably, pure water, or IPA, or Acetone; S3. The outer cylinder starts to rotate and axially reciprocate, while the first first fluid is continuously added, and the first first fluid continuously flows out from the outlet. S4. As the outer cylinder moves, the first first fluid moves, and the first first fluid approaches laminar flow where the inner wall of the inner cylinder and the outer cylinder are close to each other; S5. Provide a second first fluid into the flow field through the inlet to clean the chip on the surface of the inner cylinder; the second first fluid includes a high-pressure gas and / or a surfactant; S6. Lower the inner cylinder to expose the chip surface, and dry the surface with high-pressure air. S7. Take out the chip, This completes the cleaning of the chip.

49. The operating method according to claim 33, wherein: The outlet structure is configured to enable the fluid from the thin flow region to be discharged freely and unobstructed to avoid blockage that affects the introduction of the fluid into the inlet.

50. The operating method according to claim 33, wherein: The materials of the first wall and the second wall are selected to have hydrophilicity and hydrophobicity such that the first fluid can be located between the first wall and the second wall in a free state without being expelled by surface tension. For example, the hydrophilic and hydrophobic material includes an HMDS coating.

51. The operating method according to claim 33, wherein: The material of the second wall is selected such that it has poor affinity with the first fluid in the flow domain, so that the first fluid flowing out of the flow domain by shear flow will be sucked back into the flow domain.

52. The operating method according to claim 50, wherein: A sum of cosine values ​​of contact angles of the first wall surface and the second wall surface with respect to the first fluid is greater than or equal to zero.

53. The operating method according to claim 33, wherein: The inlet includes a free surface, or the fluid connected to the inlet has at least one free surface; the outlet includes a free surface, or the fluid connected to the outlet has at least one free surface.

54. The operating method according to claim 33, wherein: The thick dimension of the thin flow domain is at least one order of magnitude smaller than the long and / or wide dimensions of the thin flow domain.

55. The operating method according to claim 54, wherein: The thickness of the thin flow domain is 2-100 microns.

56. The operating method according to claim 33, wherein: The first fluid has a velocity gradient between the first wall and the second wall, and the first fluid has a faster flow rate on the side that is affected by energy or has less resistance.

57. The operating method according to claim 33, wherein: The fluid path structure further includes a heater, and the heater is configured to perform heat transfer with the first wall surface and / or the second wall surface to heat the flow region.

58. The operating method according to claim 33, wherein: The flow domain includes a plurality of temperature zones, and the plurality of temperature zones are respectively separated by at least one insulation block arranged on the second wall surface, wherein the temperatures of the plurality of temperature zones are the same or different.

59. The operating method according to claim 33, wherein: The first wall and the second wall comprise a disc shape, the first wall is substantially planar, the second wall is substantially planar, and the first wall is substantially parallel to the second wall; During operation, the second wall surface is configured to be able to rotate relative to the first wall surface, thereby applying energy to the first fluid and driving the shear flow of the first fluid.

60. The operating method according to claim 58, wherein: The first wall surface is configured to be stationary, or to rotate, or to perform linear motion in a direction substantially parallel to the second wall surface, or to rotate and perform linear motion in a direction substantially parallel to the second wall surface.

61. The operation method according to claim 59, wherein the second wall comprises a chip, the second wall is configured to have hydrophilic regions and hydrophobic regions arranged alternately, wherein biomolecules are fixed on the hydrophilic regions, the biomolecules comprising single-stranded DNA, the hydrophobic regions are covered with hydrophobic substances, and the area of ​​the first wall is greater than or equal to the area of ​​the second wall; The operation method further comprises: S1. providing a first first fluid through the inlet structure, wherein the first first fluid comprises a reagent capable of disconnecting an azide group, so that a first reaction between the first first fluid and the biomolecule occurs; S2. providing a second first fluid through the inlet structure, wherein the second first fluid comprises a buffer reagent for cleaning the first first fluid and the product of the first reaction; S3. providing a third first fluid through the inlet structure, wherein the third first fluid comprises a synthetic reagent containing four bases ACTG and corresponding dye groups, so as to cause a second reaction between the third first fluid and the biomolecule; S4. Providing the fourth first fluid through the inlet structure, the fourth first fluid comprising a buffer reagent for cleaning the third first fluid, wherein the fourth first fluid and the second first fluid are buffer reagents of the same or different components; S5. recording and determining the base type of the product of the third reaction on the chip by sensing; Repeat steps S1-S5 multiple times to obtain the base sequence of the DNA single strand based on the base types of the product of the third reaction.

62. The operating method according to claim 61, wherein: The method further includes the following steps between step S4 and step S5: S4.

1. providing a fifth first fluid through the inlet structure, wherein the fifth first fluid comprises a synthetic reagent containing four bases ACTG and corresponding dye groups, so that a fourth reaction of the fifth first fluid with the biomolecule occurs; S4.

2. The sixth first fluid is provided through the inlet structure, wherein the sixth first fluid includes a buffer reagent for cleaning the fifth first fluid, wherein the sixth first fluid and the second first fluid and the fourth first fluid are buffer reagents of the same or different components.

63. The operating method according to claim 61 or 62, wherein the operating method further comprises: Immediately before step S5, the method further includes the step of providing a seventh first fluid through the inlet structure, wherein the seventh first fluid includes a protective reagent to prevent the recording process from causing adverse effects on the DNA.

64. An operating method according to claim 61, wherein the first first fluid comprises a triphenylphosphine solution.

65. The operating method according to claim 64, wherein the recording by sensing in step S5 comprises: The fluorescence on the chip is recorded by taking a photo, and the type of the base is determined by a basecall algorithm.

66. The operating method according to claim 65, wherein the outlet structure comprises an area between the disc periphery of the first wall and the disc periphery of the second wall, enabling the first fluid to be discharged through the area, and the operating method further comprises: A waste liquid collecting structure is provided for collecting the discharged first fluid.

67. The operating method according to claim 61, wherein in step S2, the reaction time of the first reaction is 1 minute.

68. The operating method according to claim 61, wherein in step S2, the volume of the second first fluid is three times the volume of the flow basin.

69. The operating method according to claim 61, wherein in step S3, the volume of the third first fluid is 1.5 times the volume of the flow basin, 70. The operating method according to claim 61, wherein in the step S3, the second reaction is carried out at a temperature of 55°C, and the reaction time of the second reaction is 1 minute.

71. The operating method according to claim 59, wherein: The inlet structure includes a channel disposed at a predetermined position of the first wall surface and / or the second wall surface, and is used to introduce the fluid into the flow field.

72. The operating method according to claim 71, wherein: The channel includes a through hole arranged on the first wall surface and / or the second wall surface at a position close to the center of the disk.

73. The operating method according to claim 71, wherein the channel comprises a liquid inlet pipe attached to the first wall and / or the second wall, so that the first fluid is sucked into the flow area.

74. The operating method according to claim 71, wherein: The outlet structure includes an area between the disk periphery of the first wall and the disk periphery of the second wall, and the first fluid can be discharged through the area.

75. A method for operating a fluid path structure, wherein: include: Providing a conduit, the conduit comprising an inlet structure and an outlet structure, the inlet structure comprising at least one inlet, the outlet structure comprising at least one outlet; In operation, a first fluid and a second fluid incompatible with the first fluid are introduced into the pipeline through different inlets of the at least one inlet, respectively, wherein the first fluid and the second fluid are discharged through the at least one outlet, and a flow domain is formed between the inlet structure and the outlet structure; The second fluid occupies a certain volume of the flow domain to form a thin flow domain of the first fluid.

76. The operating method according to claim 75, wherein the second fluid flows in the pipeline, driving the first fluid to shear flow in the pipeline.

77. The operating method according to claim 75, wherein the second fluid is configured so as not to undergo macroscopic flow.

78. The operating method according to claim 75, wherein: The thin flow domain has a thickness of at least 2 microns.

79. The operating method according to claim 75, wherein: The inlet structure includes a solenoid valve configured to control the introduction of the first fluid and the second fluid into the pipeline.

80. The liquid path structure according to any one of claims 1-31, wherein the liquid path structure is a microfluidic liquid path structure.

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