WO2022088588A1 - 阶跃式惯性聚焦微流控芯片 - Google Patents

阶跃式惯性聚焦微流控芯片 Download PDF

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Publication number
WO2022088588A1
WO2022088588A1 PCT/CN2021/081624 CN2021081624W WO2022088588A1 WO 2022088588 A1 WO2022088588 A1 WO 2022088588A1 CN 2021081624 W CN2021081624 W CN 2021081624W WO 2022088588 A1 WO2022088588 A1 WO 2022088588A1
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channel
arc
sub
shaped flow
flow channel
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PCT/CN2021/081624
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English (en)
French (fr)
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关国峰
钞书哲
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深圳亘流科技有限公司
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Priority to JP2023539204A priority Critical patent/JP7470471B2/ja
Publication of WO2022088588A1 publication Critical patent/WO2022088588A1/zh
Priority to US18/138,026 priority patent/US20230256443A1/en

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502761—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip specially adapted for handling suspended solids or molecules independently from the bulk fluid flow, e.g. for trapping or sorting beads, for physically stretching molecules
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0647—Handling flowable solids, e.g. microscopic beads, cells, particles
    • B01L2200/0652—Sorting or classification of particles or molecules
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0832—Geometry, shape and general structure cylindrical, tube shaped
    • B01L2300/0838—Capillaries
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/088—Channel loops

Definitions

  • the present application relates to the technical field of biological particle microfluidics, in particular to a step-type inertial focusing microfluidic chip.
  • inertial focusing microfluidics has received extensive attention due to its superior properties such as purely physical methods utilizing hydrodynamics, ultra-high flow rates, and flow channel cross-sectional dimensions that avoid clogging.
  • the inertial focusing microfluidic technology still has a bottleneck in throughput.
  • a single channel inertial focusing microfluidic chip cannot achieve efficient sorting at a flux of 10 9 /s; multiple channels or multiple chips in parallel have problems such as complicated channel design, difficult processing and production.
  • the present application provides a step-type inertial focusing microfluidic chip, which can realize the concentration, liquid exchange, enrichment and sorting of ultra-high-throughput and multi-type microparticles.
  • the step-type inertial focusing microfluidic chip provided by the embodiment of the present application includes multi-stage arc-shaped flow channels connected in series in sequence, wherein at least one stage of the arc-shaped flow channels is divided into a radial direction of the arc-shaped flow channel A plurality of sub-flow channels distributed in sequence, one end of the multi-stage arc-shaped flow channel is provided with at least one fluid inlet and an inlet flow channel connecting one end of the arc-shaped flow channel and the fluid inlet, and the other end is provided with a plurality of fluid outlets and a plurality of outlet flow channels respectively connecting the other end of the arc-shaped flow channel and each of the fluid outlets; the curvature radius of the arc-shaped flow channel is 2-50 mm; the cross-section of the arc-shaped flow channel is along the The radial dimension of the arc-shaped flow channel is the section width, and the dimension along the normal direction of the arc-shaped flow channel is the section height, the section width is in the range of 50-5000 micron
  • the multi-stage arc-shaped flow channels form at least one spiral, and the arc-shaped flow channels belonging to the same spiral have the same bending direction.
  • the multi-stage arc-shaped flow channels form a plurality of spirals
  • adjacent spirals are connected by series-connected flow channels
  • the series-connected flow channels are straight flow channels or curved flow channels.
  • the cross-sectional shape of the sub-channel includes at least one of a rectangle, a right-angled trapezoid, and a right-angled triangle.
  • the two-stage arc-shaped runners connected to each other are directly connected or transitionally connected through a straight channel.
  • the number of stages of the multi-stage arc-shaped flow channel is not less than the number of the fluid outlets, and the number of sub-flow channels of the arc-shaped flow channel in at least one stage of the multi-stage arc-shaped flow channel with multiple sub-flow channels not less than the number of said fluid outlets.
  • the arc-shaped flow channels with a plurality of sub-flow channels are connected in series in sequence.
  • the last stage of the multi-stage arc-shaped flow channels has multiple sub-flow channels.
  • the plurality of fluid outlet flow channels are sequentially distributed at the output end of the last stage arc-shaped flow channel along the radial direction of the last-stage arc-shaped flow channel; One outlet drains the flow outwards.
  • one end of the multi-stage arc-shaped flow channel is provided with a plurality of fluid inlets and inlet flow channels, and the plurality of fluid inlet flow channels are sequentially distributed in the first stage along the radial direction of the first-stage arc-shaped flow channel.
  • the input end of the first-stage arc-shaped flow channel; among the plurality of fluid inlet flow channels, the innermost or outermost one along the radial direction of the first-stage arc-shaped flow channel is the buffer inlet flow channel; any one fluid inlet The flow channel drains inwardly through an inlet flow channel that communicates with it.
  • the sample is introduced into the multi-stage arc-shaped flow channel from the fluid inlet.
  • the micro-particles in the sample behave differently in the sub-channels of the arc-shaped flow channel according to their own size differences, and pass through the various stages.
  • the transition effect of the connecting part of the arc-shaped flow channel realizes the sorting of micro-particles in the same sub-channel and the convergence of micro-particles in different sub-channels, which meets the needs of high-throughput concentration, liquid exchange, enrichment and sorting operations.
  • the overall structure is simple and easy to process and produce.
  • FIG. 1 is a schematic structural diagram of a step-type inertial focusing microfluidic chip provided by an embodiment of the present application
  • FIG. 2a is a schematic diagram of a single helix structure of a step-type inertial focusing microfluidic chip provided by an embodiment of the present application (sub-channel distribution is not shown);
  • 2b is a schematic diagram of a multi-helix structure of a step-type inertial focusing microfluidic chip provided by an embodiment of the present application (sub-channel distribution is not shown);
  • 3a is a schematic diagram of a cross-sectional shape of a sub-channel of a step-type inertial focusing microfluidic chip provided by an embodiment of the present application;
  • 3b is a schematic diagram of another cross-sectional shape of a sub-channel of a step-type inertial focusing microfluidic chip provided by an embodiment of the present application;
  • FIG. 4 is a partial schematic diagram of a structure of a step-type inertial focusing microfluidic chip provided by an embodiment of the present application;
  • FIG. 5 is a partial schematic diagram of another structure of the step-type inertial focusing microfluidic chip provided by the embodiment of the present application;
  • 6a is a first partial schematic diagram of still another structure of the step-type inertial focusing microfluidic chip provided by the embodiment of the application;
  • 6b is a second partial schematic diagram of still another structure of the step-type inertial focusing microfluidic chip provided by the embodiment of the application;
  • 6c is a third partial schematic diagram of still another structure of the step-type inertial focusing microfluidic chip provided by the embodiment of the present application.
  • FIG. 7a is a first partial schematic diagram of still another structure of the step-type inertial focusing microfluidic chip provided by the embodiment of the application;
  • 7b is a second partial schematic diagram of still another structure of the step-type inertial focusing microfluidic chip provided by the embodiment of the application;
  • FIG. 7c is a third partial schematic diagram of still another structure of the step-type inertial focusing microfluidic chip provided by the embodiment of the present application.
  • FIG. 8 is a partial state schematic diagram of an application example of the step-type inertial focusing microfluidic chip provided by the embodiment of the present application;
  • FIG. 9 is a schematic view of a microscopic state of an application example of the step-type inertial focusing microfluidic chip provided by the embodiment of the present application;
  • FIG. 10 is a schematic structural diagram of still another structure of the step-type inertial focusing microfluidic chip provided by the embodiment of the application;
  • FIG. 11 is a schematic structural diagram of still another structure of the step-type inertial focusing microfluidic chip provided by the embodiment of the application;
  • FIG. 12 is a schematic structural diagram of still another structure of the step-type inertial focusing microfluidic chip provided by the embodiment of the present application (sub-channel distribution is not shown).
  • 11-arc runner 11A-multi-channel arc runner, 11B-single-channel arc runner, 111-sub runner, 112-sub runner partition wall, 12-joint, 13-fluid inlet, 14 -Fluid outlet, 15-flow channel, 16-inlet channel, 17-outlet channel, 1a-spiral.
  • this embodiment discloses a specific structure of a step-type inertial focusing microfluidic chip, including multi-stage arc-shaped flow channels 11 connected in series in sequence, wherein at least one stage of arc-shaped flow channels 11 is separated A multi-channel arc-shaped flow channel 11A is formed for a plurality of sub-flow channels 111 distributed in sequence along the radial direction of the arc-shaped flow channel 11 . Fluid outlet 14 .
  • the radius of curvature of the arc-shaped flow channel 11 of any level is 2 to 50 mm, such as 2 mm, 3 mm, 5 mm, 8 mm, 10 mm, 15 mm, 20 mm, 26 mm, 32 mm, 40 mm, 45 mm , 50 mm, etc.
  • the direction of the curvature radius of any point on the arc-shaped flow channel 11 is its radial direction at this point, perpendicular to its tangential direction at this point (that is, the main flow direction of the liquid in the flow channel) and the radial direction is its normal at that point.
  • the dimension of the cross section of the arc-shaped flow channel 11 along the radial direction of the arc-shaped flow channel is the section width, and the dimension along the normal direction of the arc-shaped flow channel is the section height (or referred to as the section depth).
  • the cross-sectional width ranges from 50 to 5000 microns, such as 50 microns, 80 microns, 100 microns, 200 microns, 500 microns, 800 microns, 1000 microns, 1200 microns, 1500 microns, 2000 microns, 3000 microns, 4000 microns, 5000 microns, etc. .
  • the cross-sectional height ranges from 20 to 2000 microns, such as 20 microns, 30 microns, 50 microns, 75 microns, 100 microns, 150 microns, 185 microns, 250 microns, 400 microns, 700 microns, 1200 microns, 1700 microns, 2000 microns, etc. .
  • the thickness of the sub-flow channel partition wall 112 of the arc-shaped flow channel 11A having a plurality of sub-flow channels 111 is 10-1000 microns, for example, 10 microns, 20 microns, 30 microns, 50 microns, 80 microns, 100 microns, 120 microns, 200 microns microns, 500 microns, 800 microns, 900 microns, 1000 microns, etc.
  • FIG. 1 shows an example with four-stage arc-shaped flow channels 11, and each stage of arc-shaped flow channels 11 has three sub-flow channels 111 (that is, with four-stage multi-channel arc-shaped flow channels 11A) , wherein, the fluid inlet 13 and the inlet flow channel 16 and the fluid outlet 14 and the outlet flow channel 17 are respectively two.
  • the sample fluid is introduced into the multi-stage arc-shaped flow channel 11 from the fluid inlet 13 .
  • the arc-shaped flow channel 11 is configured to realize the Dean vortex of the sample fluid, so that the sample fluid flows along the arc-shaped flow channel 11 to generate regular accompanying motion.
  • at least one microparticle in the sample fluid migrates perpendicular to the main flow direction in the cross-section of the flow channel to achieve inertial focusing.
  • the main flow direction is the flow direction of the sample fluid along the arc-shaped flow channel 11 , and the cross section of the flow channel is perpendicular to the main flow direction.
  • the arc-shaped flow channel 11 can be divided into a multi-channel arc-shaped flow channel 11A having at least two sub-flow channels 111 and a single-channel arc-shaped flow channel 11B without sub-flow channels. That is, the single-channel arc-shaped flow channel 11B has only one flow channel.
  • the multi-channel arc-shaped flow channel 11A may be only one stage, or, generally, may be multiple stages.
  • the multi-stage multi-channel arc-shaped flow channels 11A may be connected in series in sequence, or may not be directly connected to each other, or some of the stages are directly connected and the rest are not directly connected. articulate. It can be understood that the sub-flow channels 111 of the multi-channel arc-shaped flow channel 11A are also curved in an arc shape. In the aforementioned multi-stage arc-shaped flow channels, the number of single-channel arc-shaped flow channels 11B may be only one stage, or may be multiple stages, or may be zero.
  • the multi-stage arc-shaped flow channel 11 forms at least one helix 1a, which can be a single helix 1a (FIG. 2a) or a plurality of helixes 1a (FIG. 2b).
  • the arc-shaped runners 11 belonging to the same helix 1a have the same bending direction, forming a distribution of multiple turns of the helix 1a, which meets the layout requirements and the runner requirements of the Dean vortex.
  • the adjacent spirals 1a are connected by serial flow channels; wherein, the serial flow channels can be straight channels 15 or curved channels.
  • the two-stage arc-shaped flow channels 11 connected to each other are directly connected or transitionally connected through the straight channel 15 .
  • the two-stage arc-shaped flow channels 11 connected to each other are directly connected; for another example, the two-stage arc-shaped flow channels 11 belonging to different spirals 1a and connected to each other can be transitionally connected through the straight channel 15.
  • a plurality of outlet flow channels 17 are sequentially distributed at the output end of the last-stage arc-shaped flow channel 11 along the radial direction of the last-stage arc-shaped flow channel 11 to ensure that the The particles enter the corresponding outlet flow channels 17 exactly.
  • any one of the outlet flow channels 17 is drained to the outside through a fluid outlet 14 to further drain the flow to the outside.
  • one end of the multi-stage arc-shaped flow channel 11 is provided with a plurality of fluid inlets 13 and an inlet flow channel 16, and the plurality of inlet flow channels 16 are sequentially distributed in the first-stage arc along the radial direction of the first-stage arc-shaped flow channel 11.
  • the input end of the arc-shaped flow channel 11 ensures that various inlet solutions (such as sample fluid and buffer solution) are introduced into the multi-stage arc-shaped flow channel 11 without interfering with each other.
  • one of the plurality of inlet flow channels 16 located at the innermost or outermost position along the radial direction of the first-stage arc-shaped flow channel 11 is the buffer inlet, so as to ensure that the buffer solution is located at the innermost position of the arc-shaped flow channel 11 when the buffer is introduced.
  • the inner or outermost and the corresponding cushioning effect when the target particles that need to be enriched and obtained are larger particles in the sample fluid, the innermost one of the plurality of inlet channels 16 is used as the buffer inlet channel; when the target particles that need to be enriched and obtained are In the case of smaller particles in the sample fluid, the outermost one of the plurality of inlet channels 16 serves as the buffer inlet channel.
  • any one of the inlet flow channels 16 extends outward through a fluid inlet 13 to ensure a better introduction effect.
  • Any one-level multi-channel arc-shaped flow channel 11A can realize the transition sorting of at least one kind of micro-particles, and realize the transition-sorting of target micro-particles through the transition focusing effect of the multi-stage multi-channel arc-shaped flow channel 11A, and there are at least one level
  • the multi-channel arc-shaped flow channel 11A has a sufficient number of sub-flow channels 111 to form classification liquids of corresponding types, and finally obtains classification liquids of multiple types of microparticles, which are output from different fluid outlets 14 to meet the sorting requirements.
  • each target liquid only contains or mostly one type of microparticles
  • the classification liquid only includes the aforementioned multi-channel targets liquid, but not waste liquid. If only one or several types of microparticles need to be sorted from the sample fluid, one target liquid and one waste liquid, or several completely independent target liquids and one waste liquid will be generated. At this time, the sorting liquid includes the target liquid and waste fluid.
  • the number of sub-flow channels 111 of the two-stage multi-channel arc-shaped flow channels 11A connected to each other is equal, which meets the transition requirements and keeps the structure neat and concise.
  • the number of the sub-flow channels 111 of the two-stage multi-channel arc-shaped flow channels 11A connected to each other can also vary.
  • the multi-channel arc-shaped flow channels 11A are successively connected in series to ensure continuous transition of micro-particles, achieve rapid and accurate sorting, and ensure ultra-high throughput performance, efficiency and good effects of microfluidics.
  • the multi-stage arc-shaped flow channel includes at least two-stage multi-channel arc-shaped flow channels 11A connected to each other, for example, there may be two-stage, three-stage or five-stage multi-channel arc-shaped flow channels 11A connected continuously.
  • the multi-stage arc-shaped runners there are three-stage arc-shaped runners (ie, the three-stage multi-channel arc-shaped runner 11A) that are continuously connected and have sub-runners respectively.
  • the first-stage multi-channel arc-shaped runner and the second-stage multi-channel arc-shaped runner are two-stage arc-shaped runners connected to each other, and the second-stage multi-channel arc-shaped runner and the third-stage multi-channel arc-shaped runner are also connected. It is a two-stage arc-shaped flow channel connected to each other.
  • the flow rate of the sub-flow channel 111 is related to various factors, such as the cross-sectional state of the sub-flow channel 111 , the length of the flow channel, the arrangement position, and the like.
  • Section state includes section shape and section size
  • section size includes section width and section height
  • the size of the cross section of the flow channel along the radial direction of the flow channel is the section width
  • the dimension along the normal direction of the flow channel is the section height.
  • the flow differences of the corresponding sub-channels 111 of the front and rear arc-shaped channels can be realized, which provides conditions for the transition of micro-particles.
  • the embodiment of the present application does not limit the flow design method of the sub-flow channel 111 , and it is limited to meet the aforementioned fluid layer flow requirements at the junction.
  • the cross-sectional state of the sub-channel 111 can be designed.
  • the cross-sectional shape of the sub-channel 111 includes at least one of a rectangle, a right-angled trapezoid, and a right-angled triangle.
  • the cross-sectional shape of a certain sub-channel 111 may be any one of a rectangle, a right-angled trapezoid, and a right-angled triangle. , it can also be a combination of any two of rectangle, right-angled trapezoid and right-angled triangle, or it can be a combination of three shapes of rectangle, right-angled trapezoid and right-angled triangle.
  • the cross-sectional shapes of the sub-flow channels 111 of the same-level arc-shaped flow channel 11 may be different, and the cross-sectional dimensions of the sub-flow channels 111 with the same cross-sectional shape may also be different.
  • the cross-sectional shape and cross-sectional size of each sub-flow channel 111 of the arc-shaped flow channel 11 of different stages may be different from each other.
  • FIGS. 3 a to 3 b show exemplary examples of several cross-sectional states of the sub-channels 111 .
  • the arc-shaped flow channel 11 has three sub-flow channels 111 , and the cross-sectional shape of each sub-flow channel 111 is a rectangle, but the cross-sectional size is different.
  • the larger micro-particles are focused near the inner boundary of the flow channel bending direction.
  • a focal line is formed near the boundary; the smaller particles move with the Dean vortex on the cross section of the flow channel at a relatively constant speed, and in the top view, the boundary periodically oscillates on both sides of the bending direction of the flow channel.
  • the multi-channel arc-shaped flow channel 11A has three sub-flow channels 111 , and the cross-sectional shapes of the two sub-flow channels 111 on one side are both based on the inner and outer sides of the bending direction, and the width direction is A high right-angled trapezoid, the cross-sectional shape of the other sub-channel 111 is a combination of a right-angled trapezoid and a right-angled triangle.
  • the sub-channel 111 having the combined cross-section of a right-angled trapezoid and a right-angled triangle is the innermost sub-channel 111 along the radial direction of the multi-channel arc-shaped channel 11A.
  • the characteristics of the two sub-channels 111 with right-angled trapezoidal cross-sections are that the inner sub-channel 111 has a smaller cross-sectional height near the inner side of the runner’s bending direction, and a larger cross-sectional height near the outer side of the runner’s bending direction.
  • the cross-sectional characteristics of shallow and deep outside, the cross-sectional height of the outer sub-channel 111 near the inner side of the runner bending direction is larger, and the cross-sectional height near the outer side of the runner bending direction is smaller, showing the cross-sectional characteristics of deep inside and shallow outside.
  • the number of stages of the arc-shaped flow channels 11 is not less than the number of the fluid outlets 14 .
  • the microfluidic chip has at least two stages of arc-shaped flow channels 11 .
  • the number of the sub-flow channels 111 of the at least one-stage arc-shaped flow channel 11A is not less than the number of the fluid outlets 14 .
  • the number of fluid outlets 14 is two, at least one level of arc-shaped flow channel 11 has at least two sub-flow channels 111 , and there may also be more than two levels of arc-shaped flow channel 11 with at least two sub-flow channels 111 . That is, there may be two or more arc-shaped flow channels 11 with sub-flow channels 111 not less than the number of fluid outlets 14 .
  • the sample fluid when in use, is introduced from the inlet channel 16 located outside the curved direction of the arc-shaped channel 11 and the fluid inlet 13 connected to it, and the buffer solution
  • the inlet channel 16 on the inner side of the channel 11 in the bending direction and the fluid inlet 13 communicated with it are introduced.
  • the microparticles in the sample After the transition of the first n-1 stage arc-shaped flow channel 11, the microparticles in the sample are located in the three sub-channels 111 outside the bending direction of the n-th stage arc-shaped flow channel 11, and the buffer solution fills the inner two sub-channels 111.
  • micro-particles with larger particle size and some micro-particles with smaller particle size are located in the middle sub-channel (the third sub-channel 111 counted from the outside to the inside, the lower one is closer to the inner side of the arc-shaped channel 11 in the bending direction). The same), and the remaining micro-particles with smaller particle size are located in the two outermost sub-channels 111 in the bending direction of the arc-shaped channel 11 after the previous n-1-level transition sorting.
  • the middle sub-channel due to the combined action of inertial focusing and Dean drag force, the larger micro-particles are all located inside the sub-channel 111 , and the smaller micro-particles are scattered around the sub-channel 111 .
  • the n-th stage arc-shaped flow channel 11 When all the liquid passes through the junction 12 of the n-th stage arc-shaped flow channel 11 and the n+1-th stage arc-shaped flow channel 11 to enter the n+1-th stage arc-shaped flow channel 11, the n-th stage arc-shaped flow channel 11
  • the liquid in the middle sub-channel is obviously divided: all the larger micro-particles in this sub-channel 111 all transition into the inner sub-channel 111 in the n+1-th arc-shaped channel 11 (from the outside to the inside).
  • the fourth sub-channel 111) of the number the smaller particles still enter the middle sub-channel of the n+1-th arc-shaped channel 11.
  • the larger microparticles will flow out with a small amount of smaller microparticles from the outlet channel 17 located on the inner side of the curved flow channel 11 and the fluid outlet 14 connected with it after multi-stage transition, and the number of the larger microparticles will be larger. Most of the smaller particles will flow out from the outlet flow channel 17 on the outer side of the curved flow channel 11 and the fluid outlet 14 connected with it to achieve sorting.
  • This application example is suitable for the type of demand where the target microparticles to be enriched are larger than other microparticles and the relative number is very small.
  • the sample fluid is introduced from the inlet channel 16 located on the inner side of the arc-shaped channel 11 in the bending direction and the fluid inlet 13 connected to it, and the buffer solution is introduced from the inlet channel 13 located in the arc-shaped channel 11
  • the inlet flow channel 16 on the outer side of the bending direction of the channel 11 and the fluid inlet 13 communicated with it are introduced.
  • the micro-particles in the sample are located in the three sub-channels 111 inside the bending direction of the n-th stage arc-shaped flow channel 11, and the buffer solution fills the two outer sub-channels 111.
  • the middle sub-channel the third sub-channel 111 from the inside to the outside, lower The same
  • the remaining micro-particles with larger particle size are located in the two innermost sub-channels 111 in the bending direction of the arc-shaped channel 11 after the previous n-1 level transition sorting.
  • the middle sub-channel due to the combined action of inertial focusing and Dean drag force, the larger micro-particles are all located inside the sub-channel 111 , and the smaller micro-particles migrate to the outside of the sub-channel 111 .
  • the n-th stage arc-shaped flow channel 11 When all the liquid passes through the junction 12 of the n-th stage arc-shaped flow channel 11 and the n+1-th stage arc-shaped flow channel 11 to enter the n+1-th stage arc-shaped flow channel 11, the n-th stage arc-shaped flow channel 11
  • the liquid in the middle sub-channel 111 has obvious shunting: all the smaller micro-particles in this sub-channel 111 all transition into the outer sub-channel 111 in the n+1-th arc-shaped channel 11 (from the inside to the outside).
  • the fourth sub-channel 111) of the number the larger micro-particles still enter the middle sub-channel of the n+1-th arc-shaped channel 11.
  • the smaller microparticles will flow out with a small amount of larger microparticles from the outlet channel 17 located outside the curved direction of the arc-shaped channel 11 and the fluid outlet 14 connected with it after the multi-stage transition, and the number is more Most of the larger particles will flow out from the outlet channel 17 on the inner side of the curved channel 11 in the bending direction and the fluid outlet 14 connected with it to achieve sorting.
  • This application example is suitable for the type of demand that the target microparticles to be enriched are smaller than other microparticles and the relative number is very small.
  • the sub-flow channel 111 (the first sub-flow channel 111 located at the outermost side in the bending direction of the arc-shaped flow channel 11 )
  • the cross-sectional shape of the channel 111) is a right-angled trapezoid that is shallow inside and deep outside, that is, in the same right-angled trapezoid, the cross-sectional height (forming a small bottom) close to the inner side of the arc-shaped runner 11 in the bending direction is smaller than that far from the outer side of the arc-shaped runner 11 in the bending direction.
  • the cross-sectional width of the first sub-flow channel 111 of the arc-shaped flow channel 11 of the same level gradually becomes wider from upstream to downstream;
  • the cross-sectional height of the first sub-flow channel 111 of the shaped flow channel 11 that is, the first sub-flow channel 111 gradually decreases from upstream to downstream.
  • the cross-sectional shapes of the remaining sub-channels 111 (the second sub-channel 111 , the third sub-channel 111 , the fourth sub-channel 111 , and the fifth sub-channel 111 ) in each stage of the arc-shaped channel 11 are all rectangular, wherein As the sub-channel 111 (fifth sub-channel 111) located at the innermost in the bending direction of the arc-shaped channel 11, the cross-sectional width of the fifth sub-channel 111 of the same-level arc-shaped channel 11 gradually narrows from upstream to downstream.
  • the cross-sectional width and cross-sectional height of the remaining sub-runners 111 (the second, third, and fourth sub-runners 111 ) of the upper-stage arc-shaped runner 11 are the same as those of the corresponding sub-runners 111 (the first
  • the cross-sectional width and cross-sectional height of the second, third, and fourth sub-channels 111) are respectively equal, that is, the cross-sectional dimensions of the second, third, and fourth sub-channels 111 remain unchanged from upstream to downstream.
  • the sample fluid When in use, the sample fluid is introduced from the inlet flow channel 16 located on the outside of the curved flow channel 11 and the fluid inlet 13 connected with it, and the buffer solution is introduced from the inlet flow channel 16 located on the inner side of the curved flow channel 11 in the bending direction and is connected with it.
  • the connected fluid inlet 13 is introduced.
  • the sample fluid contains four kinds of microparticles a, b, c, d from large to small.
  • the sample fluids carrying a, b, c, and d enter the first sub-channel 111 of the aforementioned first-stage arc-shaped channel 11 .
  • the microparticles a gather on the inner side of the first sub-channel 111 along the bending direction
  • the micro-particles b, c, and d gather on the inner side of the first sub-channel 111 along the bending direction under the action of the Dean circle.
  • the largest micro-particle b gathers on the inner side of the sub-channel 111 along the bending direction, and the remaining micro-particles c and d are in Under the action of Dean's circle, it gathers on the outer side of the sub-runner 111 along the bending direction; at the junction 12 of the second-stage arc-shaped flow channel 11 and the third-stage arc-shaped flow channel 11, due to the effect of the aforementioned structure, only the The enclosed micro-particles (c, d) can enter the first sub-channel 111 of the third-stage arc-shaped channel 11, and the micro-particle b transitions from the first sub-channel 111 of the second-level arc-shaped channel 11 into the first sub-channel 111.
  • the microparticles a further transition from the second sub-channel 111 of the second-level arc-shaped channel 11 into the third-level arc-shaped channel 11 . in the sub-runner 111 .
  • the microparticles d, c, b, and a respectively enter and remain in the first, second, third, and fourth sub-channels 111 of the fourth-stage arc-shaped channel 11, and each type of microparticle occupies one sub-channel 111 to realize sorting Purpose.
  • the four sub-flow channels 111 of the fourth-stage arc-shaped flow channel 11 can be respectively connected to the four fluid outlets 14 to output the four kinds of micro-particles to different containers respectively.
  • the cross-sectional shapes of the four sub-runners 111 of the arc-shaped runners 11 of each stage are all rectangular, and along the bending direction of the arc-shaped runners 11 from the inside to the outside,
  • the cross-sectional heights of the sub-channels 111 at the same level decrease, that is, the cross-sectional height of the inner sub-channels 111 is larger than that of the outer sub-channels 111 , forming a distribution structure with deep inside and shallow outside.
  • the cross-sectional width of the sub-channel 111 outside the i-th sub-channel 111 of the i-th arc-shaped channel 11 is smaller than the cross-sectional width of the i-th sub-channel 111 .
  • the sub-flow channel 111 located at the innermost side in the bending direction of the arc-shaped flow channel 11 can ensure the flow rate of each sub-flow channel 111 and adjust the total flow rate of each arc-shaped flow channel 11 so that the two can be consistent.
  • the sample fluid When in use, the sample fluid is introduced from the inlet flow channel 16 located on the outside of the curved flow channel 11 and the fluid inlet 13 connected with it, and the buffer solution is introduced from the inlet flow channel 16 located on the inner side of the curved flow channel 11 in the bending direction and is connected with it.
  • the connected fluid inlet 13 is introduced.
  • the sample fluid contains four kinds of microparticles a, b, c, d from large to small.
  • the sample fluids carrying a, b, c, and d enter the first sub-flow channel 111 of the first-stage arc-shaped flow channel 11 .
  • the microparticles a, b, and c are gathered at the inner side of the first sub-channel 111 along the bending direction, and the micro-particle d is gathered at the outer side of the first sub-channel 111 along the bending direction under the action of the Dean vortex ;
  • the junction 12 of the first-stage arc-shaped flow channel 11 and the second-stage arc-shaped flow channel 11 due to the effect of the aforementioned structure, only the micro-particles d brought back to the outside by the Dean vortex can enter the second-stage arc shape
  • the first sub-flow channel 111 of the flow channel 11, and the remaining micro-particles b, c, d jump inward from the first sub-flow channel 111 of the first-stage arc-shaped flow
  • the micro-particles a and b are gathered in the inner side of the sub-channel 111 along the bending direction, and the smallest micro-particle c is in the Dean Under the action of the eddy current, it gathers on the outer side of the sub-flow channel 111 along the bending direction; at the junction 12 of the second-stage arc-shaped flow channel 11 and the third-stage arc-shaped flow channel 11, due to the effect of the aforementioned structure, it is only absorbed by a whole
  • the microparticles c brought back to the outside by the vortex flow can enter the second sub-channel 111 of the third-stage arc-shaped channel 11 , and the micro-particles a and b travel from the first sub-channel 111 of the second-level arc-shaped channel 11 to the second sub-channel 111 .
  • the internal transition enters the third sub-channel 111 of the third-stage arc-shaped channel 11, and the microparticle d directly connects from the first sub-channel 111 of the second-level arc-shaped channel 11 because the two-stage sub-channel 111 is directly connected. into the first sub-channel 111 of the third-stage arc-shaped channel 11 .
  • the microparticles d, c, b, and a respectively enter and remain in the first, second, third, and fourth sub-channels 111 of the fourth-stage arc-shaped channel 11, and each type of microparticle occupies one sub-channel 111 to realize sorting Purpose.
  • the four sub-flow channels 111 of the fourth-stage arc-shaped flow channel 11 can be respectively connected to the four outlet flow channels 17 and the fluid outlet 14 communicated therewith, and output the four kinds of microparticles to different containers respectively.
  • the number of the sub-flow channels 111 may be equal or different.
  • the two-stage arc-shaped flow channels 11 respectively have a plurality of sub-flow channels 111 and are connected to each other, and the number of sub-flow channels 111 is not equal to each other; wherein the first-stage arc-shaped flow channel with a smaller number of sub-flow channels 111
  • the cross-sectional width of the sub-flow channel 111 of the flow channel 11 has a gradient structure, which can effectively reduce the overall width of the arc-shaped flow channel 11 .
  • the features of the arc-shaped flow channel can be designed to achieve the purpose of the application.
  • the radius of curvature of the arc-shaped flow channel 11 is 2 ⁇ 50 mm.
  • the cross-sectional width of the arc-shaped flow channel 11 is in the range of 50-5000 microns, and the cross-sectional height is in the range of 20-2000 microns.
  • the last stage in the multi-stage arc-shaped flow channel 11 has a plurality of sub-flow channels 111, so as to directly output the classified liquid in each sub-flow channel 111 to the outlet flow channel 17 and the fluid outlet 14 connected with it,
  • the application effect is ideal.
  • the microfluidic chip in this example includes a four-stage arc-shaped flow channel 11, two inlet flow channels 16, a fluid inlet 13 and two outlet flow channels 17 communicated therewith With the fluid outlet 14 connected with it, the four-stage arc-shaped flow channel 11 forms two spirals 1a, and each spiral 1a contains two-stage arc-shaped flow channels 11, which are connected by a straight flow channel 15 as a whole.
  • Each stage of the arc-shaped flow channel 11 is 1.8 to 2.2 circles, and the four-stage arc-shaped flow channel 11 has a total of 7 to 9 circles.
  • the first-stage arc-shaped flow channel 11 has inner and outer sub-channels 111 .
  • the cross-sectional shape of the outer sub-channel is rectangular, the cross-sectional width is 800 microns, the depth is 160 microns, and the designed flow rate l 0 is 0.8-3.0 ml/min;
  • the flow rate of the sub-flow channel 111 is equal to 2.1 times the design flow rate l 0 of the outer sub-flow channel.
  • the second-stage arc-shaped flow channel 11 has three sub-flow channels 111 , which are inner, middle and outer.
  • the cross-sectional dimension of the middle sub-channel is the same as that of the outer sub-channel of the first-stage arc-shaped channel 11; Compared with the inner sub-flow channel of the first-stage arc-shaped flow channel 11, it is reduced by 0.7l 0 ; .
  • the third-stage arc-shaped flow channel 11 also has three sub-flow channels 111 , which are inner, middle and outer.
  • the cross-sectional dimension of the middle sub-flow channel is consistent with the outer sub-flow channel of the first-stage arc-shaped flow channel 11; Compared with the inner sub-channel of the second-stage arc-shaped channel 11, it is reduced by 0.7l 0 ;
  • the flow rate of the outer sub-flow channel of the arc-shaped flow channel 11 is twice.
  • the fourth-stage arc-shaped flow channel 11 has inner and outer sub-channels 111 .
  • the cross-sectional size and flow rate of the inner sub-channels are the same as those of the outer sub-channels of the first-stage arc-shaped channel 11 .
  • the flow rate of the outer sub-channel 111 is also the same as that of the inner sub-channels of the first-level arc-shaped channel 11 .
  • the same, that is, 2.1l 0 .
  • the cross-sectional widths of the sub-runners 111 inside the first-stage arc-shaped flow channels 11 and outside the fourth-stage arc-shaped flow channels 11 may have a gradual configuration to reduce the overall width of the arc-shaped flow channels 11 .
  • a specific application of the microfluidic chip may be to sort trace-level circulating tumor cells, fetal cells and other abnormal circulating cells that do not belong to blood cells from human peripheral blood whole blood for in vitro diagnosis.
  • the whole blood sample is introduced from the inlet flow channel 16 located on the outer side of the curved flow channel 11 and the fluid inlet 13 connected with it, and the flow rate is 0.5l0 (about 1.0ml/min);
  • the inlet flow channel 16 on the inner side of the curved flow channel 11 and the fluid inlet 13 connected with it are introduced, and the flow rate is 2.6l 0 .
  • the first-stage arc-shaped flow channel 11 all the whole blood samples enter the outer sub-channel and occupy the outer half of the outer sub-channel; the rest of the outer sub-channel and the entire inner sub-channel are defined by Buffer occupied.
  • the circulating abnormal cells with larger particle size appear in the inner 1/3 area of the outer sub-channel under the action of inertial focusing, while the blood cells are in the Dean flow channel.
  • the entire arc-shaped flow channel 11 is filled; when the fluid flows into the second-stage arc-shaped flow channel 11, the sample located in the inner 1/3 area of the outer sub-channel of the first-stage arc-shaped flow channel 11 jumps inward and enters The middle sub-channel of the second-stage arc-shaped flow channel 11 , and the rest of the samples enter the outer sub-channel of the second-stage arc-shaped flow channel 11 .
  • the motion states of the samples in the two are the same.
  • the number of blood cells in the intermediate sub-channel is reduced to 1/3 of the outer sub-channel of the first-stage arc-shaped channel 11, only part of the circulation abnormality will appear on the inner side of the end of the intermediate sub-channel under the action of Dean flow. cell space.
  • the circulating abnormal cells enrichment targets
  • the circulating abnormal cells continue to transition into the intermediate sub-channel of the third-level arc-shaped flow channel 11 , and more blood cells will be shunted. down into the outer sub-channel.
  • the abnormal circulating cells When entering the fourth-level arc-shaped flow channel 11, the abnormal circulating cells jump into the inner sub-channel of the fourth-level arc-shaped flow channel 11. At this time, only a small amount of blood cells follow the abnormal circulating cells into the inner sub-channel, and most of the blood cells enter the inner sub-channel. Part of the blood cells will be shunted to the outer sub-channels of the fourth-stage arc-shaped channel 11 . At the end of the fourth-stage arc-shaped flow channel 11, the abnormal circulating cells focus on the inner 1/3 area of the inner sub-channel of the fourth-stage arc-shaped flow channel 11, and the trace amount of blood cells contained in the sub-channel 111 will migrate to the The outer 2/3 area of the sub-channel 111 .
  • the cross-sectional dimension of the outlet flow channel 17 located inside the fourth-stage arc-shaped flow channel 11 and connected to the end of the fourth-stage arc-shaped flow channel 11 is configured so that the fluid outlet 14 connected with it can only receive the fourth-stage flow channel.
  • the fluid in the inner 1/3 area of the inner sub-channel of the arc-shaped flow channel 11, and the rest of the fluid in the inner sub-channel of the fourth-stage arc-shaped flow channel 11 is discharged into the outer side of the fourth-stage arc-shaped flow channel 11
  • the outlet channel 17 and the fluid outlet 14 communicated with it, so as to realize the enrichment of circulating abnormal cells.
  • Figure 9 shows the microfluidic chip of this application example under a microscope when it is actually used.
  • Figure 9a shows the flow of the blood sample at the junction 12 of the first-stage arc-shaped flow channel 11 and the second-stage arc-shaped flow channel 11. It can be seen that blood cells fill the end of the outer sub-channel of the first-stage arc-shaped flow channel 11, and When entering the second-stage arc-shaped flow channel 11 on the right, part enters the outer sub-channel of the second-stage arc-shaped flow channel 11 , and part enters the middle sub-channel of the second-stage arc-shaped flow channel 11 .
  • Figure 9b shows the flow of a typical cancer cell line A549 at the junction 12 of the first-stage arc-shaped flow channel 11 and the second-stage arc-shaped flow channel 11 under the same inlet flow configuration. It can be seen that in the first-stage arc-shaped flow channel The end of the outer sub-channel of 11 gathers, and cancer cell lines gather in the inner area of this sub-channel 111; when the cancer cell lines enter the second-level arc-shaped channel 11 located on the right side, all cancer cell lines enter the second sub-channel 11. The intermediate sub-flow channel of the stage arc-shaped flow channel 11.
  • Figure 9c shows the flow of the blood sample at the junction 12 of the third-stage arc-shaped flow channel 11 and the fourth-stage arc-shaped flow channel 11.
  • FIG. 9e shows the flow of the blood sample at the junction between the end of the fourth-stage arc-shaped flow channel 11 and the outlet flow channel 17. It can be seen that only a small amount of blood cells are located outside the end of the outer sub-channel of the fourth-stage arc-shaped flow channel 11 at this time.
  • FIG. 9f shows the flow of A549 at the junction of the end of the fourth-stage arc-shaped flow channel 11 and the outlet flow channel 17. It can be seen that at the end of the inner sub-channel of the fourth-stage arc-shaped flow channel 11, cancer cell lines still gather in The inner area of the sub-channel 111; when entering the outlet channel 17 on the right, the cancer cell lines all enter the target cell-enriched outlet channel 17 on the inner side of the curved direction.
  • the microfluidic chip in this example has a three-stage arc-shaped flow channel 11 , an inlet flow channel 16 , a fluid inlet 13 and two outlet flow channels 17 communicating with it. and the fluid outlet 14 in communication therewith.
  • each level of arc-shaped flow channel 11 is composed of two sub-flow channels 111 with rectangular cross-sections, and the cross-sectional height of each sub-flow channel 111 is 130 microns, respectively.
  • the first-level arc-shaped flow channel 11 and the third-level arc-shaped flow channel 111 The cross-sectional widths of the inner and outer sub-channels 111 of the channel 11 are 400 and 600 microns, respectively, and the widths of the inner and outer sub-channels 111 of the second-level arc-shaped channel 11 are 600 and 400 microns.
  • the curvature radius of the arc-shaped flow channel 11 located at the innermost side of the spiral 1a is 7.5 mm, and the curvature radius of the outermost arc-shaped flow channel 11 is 15 mm.
  • the sub-flow channels 111 are the same, and the cross-sectional width ratio of the outlet flow channels 17 located inside and outside the arc-shaped flow channel 11 in the bending direction is 1:8.
  • any sub-channel 111 in the three-stage arc-shaped channel 11 can focus cells with a diameter in the range of 9-15 microns to the sub-channel 111 inside.
  • a specific application of the microfluidic chip can be to separate cell metabolites such as peptides, proteins, biologically active enzymes, antibodies and the like in the bioreactor from the culture medium thereof.
  • cell metabolites such as peptides, proteins, biologically active enzymes, antibodies and the like
  • the culture solution containing cultured cells enters the first-stage arc-shaped flow channel 11 through the fluid inlet 13 and the inlet flow channel 16, it will be divided into two parts and flow into the two sub-channels of the first-stage arc-shaped flow channel 11 respectively.
  • 111 Under the action of inertial focusing, when cells flow to the end of the first-stage arc-shaped flow channel 11, they will focus on the inner area of each sub-channel 111 close to the bending direction.
  • the focused cells originally located in the outer sub-channels of the first-stage arc-shaped flow channel 11 will flow into the second-stage arc-shaped flow channel 11 . in the inner sub-channel.
  • all cells will focus on the inner area of the inner sub-channel of the second-stage arc-shaped flow channel 11 close to the bending direction.
  • the work in this application example can be performed continuously without harming cells, making it suitable for small and medium-sized bioreactors. When further concentration or flux is required, it may be considered to increase the number of sub-channels 111 and the number of series of arc-shaped channels 11, depending on the actual use requirements.
  • the microfluidic chip in this example has a two-stage arc-shaped flow channel 11 , an inlet flow channel 16 , a fluid inlet 13 and two outlet flow channels 17 communicating with it. and the fluid outlet 14 in communication therewith.
  • the first-stage arc-shaped flow channel 11 is a single-channel arc-shaped flow channel 11B, with a cross-sectional height of 130 microns and a cross-sectional width of 800 microns;
  • the second-stage arc-shaped flow channel 11 is a multi-channel arc-shaped flow channel 11A.
  • the cross-sectional height and width of the inner and outer sub-channels 111 of the channel arc-shaped channel 11A are 130 micrometers and 300 micrometers, respectively.
  • the curvature radius of the arc-shaped flow channel 11 located at the innermost side of the spiral 1a is 7.5 mm, and the curvature radius of the outermost arc-shaped flow channel 11 is 15 mm.
  • the sub-flow channels 111 are the same, and the cross-sectional width ratio of the outlet flow channels 17 located inside and outside the arc-shaped flow channel 11 in the bending direction is 1:5.
  • any sub-channel 111 of the multi-channel arc-shaped flow channel 11A can focus cells with a diameter in the range of 12-15 microns to the sub-channel 111. inside.
  • a specific application of the microfluidic chip can be to separate cell metabolites such as peptides, proteins, biologically active enzymes, antibodies and the like in the bioreactor from the culture medium thereof.
  • cell metabolites such as peptides, proteins, biologically active enzymes, antibodies and the like
  • the cells will be focused on the surface near the bending direction when they flow to the end of the first-stage arc-shaped flow channel 11. medial area.
  • the focused cells originally located inside the first-stage arc-shaped flow channel 11 will flow into the inner sub-channels of the second-stage arc-shaped flow channel 11 .
  • the work in this application example can be performed continuously without harming cells, making it suitable for small and medium-sized bioreactors.
  • it may be considered to increase the number of sub-channels 111 and the series of arc-shaped channels 11, depending on the actual use requirements.
  • the microfluidic chip in this example includes a three-stage arc-shaped flow channel 11 , two inlet flow channels 16 , a fluid inlet 13 communicating therewith, and three outlet flow channels 17 and the fluid outlet 14 in communication therewith.
  • the three-stage arc-shaped flow channel 11 forms two spirals 1a, wherein one spiral 1a includes a first-stage arc-shaped flow channel 11, and the arc-shaped flow channel 11 of this stage is 4 turns; the other spiral 1a includes a two-stage arc-shaped flow channel 11, Each stage of the arc-shaped flow channel 11 is 1.8 to 2.2 turns; the three-stage arc-shaped flow channel 11 has a total of 7 to 9 turns, and the curvature radius of the arc-shaped flow channel 11 is 7.5 to 15 mm.
  • Channel 15 is connected in series.
  • the first-stage arc-shaped flow channel 11 includes two sub-flow channels 111 with a rectangular cross-section and a cross-sectional height of 80 ⁇ m.
  • the second-stage arc-shaped flow channel 11 includes two sub-flow channels 111 with a rectangular cross-section and a cross-sectional height of 120 ⁇ m.
  • the third-stage arc-shaped flow channel 11 includes three inner, middle and outer sub-channels 111.
  • the cross-sectional shapes of the outer sub-channel and the middle sub-channel are both rectangular, the cross-sectional depth is 120 microns, and the cross-sectional widths are 220 microns and 330 microns, respectively.
  • the outer sub-channel is directly connected with the outer sub-channel of the second-level arc-shaped channel 11;
  • the inner sub-channel of the third-level arc-shaped channel 11 has a right-angled trapezoidal section with shallow inner and outer deep, and the inner section height is 70 microns, the outer section height is 90 microns, and the section width is 500 microns.
  • a specific application of the microfluidic chip can be to separate white blood cells, red blood cells and platelets in a blood sample.
  • the blood sample can be diluted to 1/10 of the original concentration (that is, the volume is changed to 10 times the original volume), and then the flow rate of 0.2ml/min is obtained from the inlet channel 16 located on the outside and the fluid connected to it.
  • the inlet 13 flows in; at the same time, the buffer solution flows in from the inlet flow channel 16 located on the inner side and the fluid inlet 13 connected thereto at a flow rate of 3.2 ml/min.
  • the blood sample When entering the first-stage arc-shaped flow channel 11, the blood sample will occupy the outer 1/8 width area of the outer sub-channel of this stage; the buffer will be divided into two parts, and one part will flow in at a flow rate of about 1.4ml/min The outer sub-channel, and the rest flow into the inner sub-channel at a flow rate of about 1.8ml/min; at the end of the first-stage arc-shaped channel 11, the red blood cells and leukocytes in the blood sample will accumulate in the inner side of the outer sub-channel region (that is, the region where the outer sub-channel is close to the inner sub-channel), and the smaller platelets will return to the outer region of the outer sub-channel (that is, the outer sub-channel is far away from the outer sub-channel) after a whole Dean cycle with the Dean vortex.
  • the fluid located in the inner side of the outer sub-channels of the first-stage arc-shaped flow channel 11 about 40% will enter the second-stage arc-shaped flow channel
  • the inner sub-channel of the flow channel 11 occupies about 25% of the area outside the inner sub-channel (that is, the area where the inner sub-channel is close to the outer sub-channel); About 40% of the red blood cells and white blood cells in the inner side of the outer sub-channel will also transition to the inner sub-channel of the second-level arc-shaped channel 11 accordingly.
  • the fluid located in the inner sub-channel of the second-stage arc-shaped flow channel 11 will be divided into two parts, and the inner part will be divided into two parts with about 1.0ml
  • the flow rate of /min flows into the inner sub-flow channel of the third-stage arc-shaped flow channel 11, and the outer part flows into the middle sub-flow channel of the third-stage arc-shaped flow channel 11 at a flow rate of about 1.4 ml/min.
  • the red blood cells will not all flow into the middle sub-channel of the third-level arc-shaped channel 11 , a small amount of red blood cells will enter into the inner sub-flow channel of the third-level arc-shaped flow channel 11 along with all the focused white blood cells.
  • leukocytes will focus on the inner area of the sub-channel 111 (that is, the area where the inner sub-channel is far from the middle sub-channel), while the red blood cells will be in the Dean circle. Under the action of the confinement, it is confined to the outer deep area of the sub-channel 111 (that is, the area of the inner sub-channel close to the middle sub-channel). When the sample flows out of the fluid outlet 14, this part of the red blood cells will be mixed with the middle sub-channel. The red blood cells in the channel converge and flow through the outlet channel 17 and the fluid outlet 14 located in the middle.
  • the leukocytes focused by the inner sub-channel of the third-stage arc-shaped channel 11 will flow out from the inner outlet channel 17 and the fluid outlet 14 together with the inner buffer at a flow rate of about 0.25 ml/min; the outer sub-channel will It is directly connected to the outlet flow channel 17 located on the outside, and flows out with platelets carried at a flow rate of about 1 ml/min, and finally realizes the complete separation of the three blood components.
  • the microfluidic chip in this example includes a three-stage arc-shaped flow channel 11 , two inlet flow channels 16 , a fluid inlet 13 communicating therewith, and three outlet flow channels 17 and the fluid outlet 14 in communication therewith.
  • the three-stage arc-shaped flow channel 11 forms two spirals 1a, wherein one spiral 1a includes the whole of the first-stage arc-shaped flow channel 11 (3 turns in total) and a part of the second-stage arc-shaped flow channel 11 (1 turn), and the other spiral One spiral 1a includes the remaining part (1.5 turns) of the second-stage arc-shaped flow channel 11; the entire third-stage arc-shaped flow channel 11 (2.5 turns in total); the third-stage arc-shaped flow channel 11 has a total of 8 turns, and two spirals 1a They are connected in series by a straight flow channel 15 .
  • a specific application of the microfluidic chip can be, in a sample with a concentration of 100,000 particles/microliter, to sort the microsphere samples with diameters ranging from 10 to 13 microns into 10 to 11 microns, 11 to 12 microns , 12 to 13 microns class 3.
  • the first-stage arc-shaped runner 11 has two sub-runners 111 .
  • the cross-sectional shape of the outer sub-channel is a right-angled trapezoid, the inner section height is 80 microns, the outer section height is 120 microns, and the section width is 600 microns; The width is 300 microns; the flow ratio of the inner sub-channel to the outer sub-channel is 1.1:1.5.
  • the second-stage arc-shaped flow channel 11 has two sub-flow channels 111, and the cross-sectional shapes of the two sub-flow channels 111 are both right-angled trapezoids.
  • the cross-section width is 600 microns.
  • the straight channel 15 arranged between the two parts of the second-stage arc-shaped channel 11 also has two sub-channels 111; wherein, the cross-sectional shape of the inner sub-channel is rectangular, the cross-sectional height is 120 ⁇ m, and the cross-sectional width is 600 ⁇ m. microns; wherein, the cross-sectional shape of the outer sub-channel is rectangular, the cross-sectional height is 80 microns, and the cross-sectional width is 600 microns.
  • the flow ratio of the inner and outer sub-channels 111 of the second-stage arc-shaped channel 11 is 1.5:1.1.
  • the third-stage arc-shaped flow channel 11 has three sub-flow channels 111 , inner, middle and outer.
  • the cross-sectional shape of the inner sub-channel is rectangular, the cross-sectional height is 140 microns, and the cross-sectional width is 300 microns;
  • the cross-sectional shape of the middle sub-channel is a right-angled trapezoid, the inner cross-sectional height is 80 microns, and the outer cross-section height is 120 microns.
  • the cross-section width is 600 microns; the cross-sectional shape of the outer sub-channel is rectangular, the cross-section height is 130 microns, and the cross-section width is 300 microns; the flow ratio of the inner sub-channel, the middle sub-channel and the outer sub-channel is 0.8:1.1 : 0.7.
  • the sample is introduced from the inlet channel 16 located on the outside and the fluid inlet 13 connected to it at a flow rate of less than 1.5 ml/min, and the buffer is introduced from the inlet channel 16 located on the inner side and the fluid inlet 13 at a constant flow rate.
  • the connected fluid inlets 13 are introduced so that the total flow introduced into the arc-shaped flow channel 11 is 2.6 ml/min, and the sample will be completely introduced into the outer sub-channels of the first-stage arc-shaped flow channel 11 .
  • the microspheres with a diameter of 12-13 microns will be focused on the inner region of the outer sub-channel of the first-stage arc-shaped channel 11, and the microspheres with a diameter of 10-12 microns will be absorbed by the Dean vortex circle. confined in the outer region of the outer sub-channel.
  • the microspheres with a diameter of 12-13 microns focused on the inner side of the outer sub-channel of the first-stage arc-shaped flow channel 11 will Transition to the inner sub-channel of the second-stage arc-shaped channel 11 . Because the microspheres with a diameter of 10-12 microns are relatively close to those with a diameter of 12-13 microns, the microspheres with a diameter of 12-13 microns will be trapped when they are focused on the inner side of the outer sub-channel of the first-stage arc-shaped channel 11.
  • microspheres with a diameter of 11-12 microns and synchronously transition to the inner sub-channel of the second-stage arc-shaped flow channel 11;
  • the microspheres with a diameter of 10-12 microns will be confined in the outer area of the sub-channel 111 by the Dean vortex circle, and the microspheres focused on the shallower area inside the sub-channel 111 will be of higher purity diameter 12 ⁇ 13 micron microspheres.
  • the microspheres with a diameter of 10-12 microns that are branched to the outer sub-channels of the second-stage arc-shaped channel 11 have the same cross-sectional shape/dimension of the front and rear sub-channels 111, but the flow rate decreases.
  • Microspheres with micrometers will focus on the inner region of the sub-channel 111 , while microspheres with a relatively smaller diameter of 10-11 micrometers will be confined in the outer region of the sub-channel 111 by the Dean vortex circle.
  • the microspheres with a diameter of 10-11 microns in the outer sub-flow channel of the second-stage arc-shaped flow channel 11 will continue to remain in the In the outer sub-channel of the third-stage arc-shaped flow channel 11; and the microspheres with a diameter of 11-12 microns focused on the inner side of the outer sub-channel of the second-stage arc-shaped flow channel 11 will transition to the third-stage arc-shaped flow channel The outer region of the middle sub-channel of channel 11.
  • microspheres with a diameter of 10-11 microns will be entrained during the transition, and the entrainment will be broken during the transition.
  • the microspheres with a diameter of 12-13 microns focused in the inner sub-channel of the second-stage arc-shaped flow channel 11 will transition to the inner sub-channel of the third-stage arc-shaped flow channel 11;
  • a small amount of microspheres with a diameter of 11-12 ⁇ m in the outer region of the inner sub-channel of the channel 11 is shunted into the middle sub-channel of the third-stage arc-shaped channel 11 .
  • the microspheres with a diameter of 11-12 microns will focus on the third-stage arc-shaped flow channel.
  • the inner area of the middle sub-channel of the arc-shaped flow channel 11; and the microspheres with a diameter of 10-11 microns that are entrained into the middle sub-channel of the third-stage arc-shaped flow channel 11 will be enclosed in the sub-channel 111. the outer area.
  • the inner sub-channel is directly connected to the outlet channel 17 located on the inner side, and the microspheres with a diameter of 12-13 microns will be directly connected to the outlet channel 17 and it.
  • the fluid outlet 14 is led out and collected, and the outlet channel 17 in the middle only collects the microspheres with a diameter of 11-12 microns focused on the inner side of the middle sub-channel of the third-stage arc-shaped channel 11, and the remaining diameters of 10-11 ⁇ m
  • the micro-sized microspheres flow out from the outlet channel 17 located on the outside and the fluid outlet 14 communicated with it, so as to realize the sorting.
  • the microfluidic chip in this example has two-stage arc-shaped flow channels 11, two inlet flow channels 16 and fluid inlets 13 and two outlet flow channels communicated therewith 17 and the fluid outlet 14 in communication therewith.
  • Each stage of the arc-shaped flow channel 11 has 2 turns, and the two-stage arc-shaped flow channel 11 has a total of 4 turns.
  • the curvature radius of the arc-shaped flow channel 11 ranges from 7.5 mm to 15 mm.
  • Each stage of the arc-shaped flow channels 11 has two sub-flow channels 111 , and the cross-sectional shapes of all the sub-flow channels 111 are rectangular.
  • the cross-sectional widths of the inner and outer sub-channels 111 of the first-stage arc-shaped flow channel 11 are respectively 300 microns and 500 microns; the second-level arc-shaped flow channel 11 is the opposite, the inner and outer sub-channels 111
  • a specific use of the microfluidic chip may be, when a cell sample is contaminated with relatively small-sized bacteria, viruses, etc., or when the establishment of a laboratory-level cell and bacteria automatic culture system requires overall cleaning and liquid change, the sample Perform a complete fluid change, as shown in the example below.
  • the sample with cells and the fresh cleaning solution flowed from the inlet channel 16 on the outside and the fluid inlet 13 connected therewith and the inlet channel 16 on the inside and with it at constant flow rates of about 0.5ml/min and 3.5ml/min, respectively.
  • the sample and the new solution enter the first-stage arc-shaped flow channel 11
  • the sample will occupy about 1/5 of the width of the outer sub-channel
  • the new solution introduced from the inner side will occupy the inner sub-channel.
  • the cells in the sample will be focused in the inner 1/3 space of the outer sub-channel, and the old solution in the sample will complete a Dean vortex with the Dean flow Then return to the outer area of the sub-channel 111; although the space occupied by the old solution components has exceeded 1/5 of the width of the outer sub-channel under the effect of diffusion, it will still be controlled at the outer side of the sub-channel 111 1/3 area.
  • the cells will be washed again as in the first-stage arc-shaped channel 11, further removing the residual old solution therein, and finally at 0.8-1 ml per minute
  • the flow rate of the sample is led out from the outlet channel 17 on the inside and the fluid outlet 14 connected with it to the new collection container, while the solution mixed with the old sample is drawn from the outlet channel 17 on the outside and the fluid outlet connected with it. 14 to the waste pool.

Abstract

本申请提供一种阶跃式惯性聚焦微流控芯片，实现超高通量及多类微颗粒的浓缩、换液、富集、分选，包括依次串行衔接的多级弧形流道，至少一级弧形流道被分隔为沿弧形流道的径向依次分布的多个子流道，多级弧形流道一端设有至少一个流体入口及入口流道、另一端设有多个流体出口及多个出口流道；所述弧形流道的曲率半径为2～50毫米；所述弧形流道的横截面沿所述弧形流道的径向之尺寸为截面宽度、沿所述弧形流道的径向之垂向的尺寸为截面高度，所述截面宽度的范围为50～5000微米，所述截面高度的范围为20～2000微米；具有多个子流道的弧形流道的子流道隔离壁的厚度为10～1000微米。

Description

阶跃式惯性聚焦微流控芯片 技术领域
本申请涉及生物粒子微流控技术领域，特别涉及一种阶跃式惯性聚焦微流控芯片。
背景技术
在基于物理特征的分选方法中，惯性聚焦微流控技术以利用流体力学的纯物理方法、超高的流量以及避免堵塞的流道截面尺寸等优越的特性而受到广泛的关注。然而当样品量超过一定数值后，惯性聚焦微流控技术依然存在通量的瓶颈。单一流道惯性聚焦微流控芯片在10 9/秒的通量条件下即无法做到高效的分选；多流道或多芯片并联则存在流路设计复杂，加工、生产困难等问题。
发明内容
为了克服现有技术的不足，本申请提供一种阶跃式惯性聚焦微流控芯片，可实现超高通量及多类微颗粒的浓缩、换液、富集、分选。
本申请实施例提供的阶跃式惯性聚焦微流控芯片，包括依次串行衔接的多级弧形流道，其中至少一级弧形流道被分隔为沿所述弧形流道的径向依次分布的多个子流道，所述多级弧形流道一端设有至少一个流体入口及连接所述弧形流道一端和所述流体入口的入口流道、另一端设有多个流体出口及分别连接所述弧形流道另一端和每个所述流体出口的多个出口流道；所述弧形流道的曲率半径为2～50毫米；所述弧形流道的横截面沿所述弧形流道的径向之尺寸为截面宽度、沿所述弧形流道的法向之尺寸为截面高度，所述截面宽度的范围为50～5000微米，所述截面高度的范围为20～2000微米；具有多个子流道的弧形流道的子流道隔离壁的厚度为 10～1000微米。
可选的，所述多级弧形流道形成至少一个螺旋，属于同一螺旋的弧形流道弯曲方向相同。
可选的，当所述多级弧形流道形成多个螺旋时，邻接的螺旋之间通过串接流道衔接，所述串接流道为直流道或弯曲流道。
可选的，所述子流道的截面形状包括矩形、直角梯形和直角三角形中的至少一种。
可选的，相互衔接的两级弧形流道直接衔接或通过直流道过渡衔接。
可选的，所述多级弧形流道的级数不小于所述流体出口的数量，所述多级弧形流道中至少一级具有多个子流道的弧形流道之子流道的数量不小于所述流体出口的数量。
可选的，所述具有多个子流道的弧形流道依次连续串行衔接。
可选的，所述多级弧形流道中的最后一级具有多个子流道。
可选的，所述多个流体出口流道沿最后一级弧形流道的径向依次分布于所述最后一级弧形流道的输出末端；任意一个流体出口流道通过与其相连通的一个出口向外引流。
可选的，所述多级弧形流道一端设有多个流体入口及入口流道，所述多个流体入口流道沿第一级弧形流道的径向依次分布于所述第一级弧形流道的输入端；所述多个流体入口流道中沿所述第一级弧形流道的径向位于最内侧或最外侧的一者为缓冲液入口流道；任意一个流体入口流道通过与其相连通的一个入口流道向内引流。
本申请实施例中提供的一个或多个技术方案，至少具有如下技术效果或优点：
样品自流体入口引入多级弧形流道中，在惯性聚焦引起的迁移行为过程中，样品中的微颗粒根据自身的尺寸差别在弧形流道的子流道中发生差异表现，并通过在各级弧形流道的衔接部位的跃迁作用，实现同一子流道 内的微颗粒分选和不同子流道的微颗粒汇合，满足高通量的浓缩、换液、富集、分选操作的需要，整体结构简单、易于加工生产。
附图说明
为了更清楚地说明本申请实施例的技术方案，下面将对实施例中所需要使用的附图作简单地介绍，应当理解，以下附图仅示出了本申请的某些实施例，因此不应被看作是对范围的限定，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他相关的设计。
图1为本申请实施例提供的阶跃式惯性聚焦微流控芯片的结构示意图；
图2a为本申请实施例提供的阶跃式惯性聚焦微流控芯片的单螺旋结构示意图(未示出子流道分布)；
图2b为本申请实施例提供的阶跃式惯性聚焦微流控芯片的多螺旋结构示意图(未示出子流道分布)；
图3a为本申请实施例提供的阶跃式惯性聚焦微流控芯片的子流道的一种截面形状的示意图；
图3b为本申请实施例提供的阶跃式惯性聚焦微流控芯片的子流道的另一种截面形状的示意图；
图4为本申请实施例提供的阶跃式惯性聚焦微流控芯片的一种构造的局部示意图；
图5为本申请实施例提供的阶跃式惯性聚焦微流控芯片的又一种构造的局部示意图；
图6a为本申请实施例提供的阶跃式惯性聚焦微流控芯片的再一种构造的第一局部示意图；
图6b为本申请实施例提供的阶跃式惯性聚焦微流控芯片的再一种构造的第二局部示意图；
图6c为本申请实施例提供的阶跃式惯性聚焦微流控芯片的再一种构造的第三局部示意图；
图7a为本申请实施例提供的阶跃式惯性聚焦微流控芯片的再一种构造的第一局部示意图；
图7b为本申请实施例提供的阶跃式惯性聚焦微流控芯片的再一种构造的第二局部示意图；
图7c为本申请实施例提供的阶跃式惯性聚焦微流控芯片的再一种构造的第三局部示意图；
图8为本申请实施例提供的阶跃式惯性聚焦微流控芯片的一种应用示例的局部状态示意图；
图9为本申请实施例提供的阶跃式惯性聚焦微流控芯片的一种应用示例的显微状态示意图；
图10为本申请实施例提供的阶跃式惯性聚焦微流控芯片的再一种构造的结构示意图；
图11为本申请实施例提供的阶跃式惯性聚焦微流控芯片的再一种构造的结构示意图；
图12为本申请实施例提供的阶跃式惯性聚焦微流控芯片的再一种构造的结构示意图(未示出子流道分布)。
主要元件符号说明：
11-弧形流道，11A-多通道弧形流道，11B-单通道弧形流道，111-子流道，112-子流道隔离壁，12-衔接处，13-流体入口，14-流体出口，15-直流道，16-入口流道，17-出口流道，1a-螺旋。
具体实施方式
需要说明的是，当元件被称为“固定于”另一个元件，它可以直接在 另一个元件上或者也可以存在居中的元件。当一个元件被认为是“连接”另一个元件，它可以是直接连接到另一个元件或者可能同时存在居中元件。相反，当元件被称作“直接在”另一元件“上”时，不存在中间元件。本文所使用的术语“垂直的”、“水平的”、“左”、“右”以及类似的表述只是为了说明的目的。
除非另有定义，本文所使用的所有的技术和科学术语与属于本申请的技术领域的技术人员通常理解的含义相同。本文所使用的术语只是为了描述具体的实施例的目的，不是旨在限制本申请。本文所使用的术语“和/或”包括一个或多个相关的所列项目的任意的和所有的组合。
请参阅图1，本实施例公开了阶跃式惯性聚焦微流控芯片的一种具体构造，包括依次串行衔接的多级弧形流道11，其中至少一级弧形流道11被分隔为沿弧形流道11的径向依次分布的多个子流道111而形成多通道弧形流道11A，多级弧形流道11一端设有至少一个流体入口13、另一端设有多个流体出口14。任意一级弧形流道11的曲率半径为2～50毫米，例如2毫米、3毫米、5毫米、8毫米、10毫米、15毫米、20毫米、26毫米、32毫米、40毫米、45毫米、50毫米等。弧形流道11上任意一点沿其在该点的曲率半径的方向为其在该点的径向，垂直于其在该点的切向(即流道内液体的主流方向)与径向的方向为其在该点的法向。弧形流道11的横截面沿弧形流道的径向之尺寸为截面宽度、沿弧形流道的法向之尺寸为截面高度(或称之为截面深度)。截面宽度的范围为50～5000微米，例如50微米、80微米、100微米、200微米、500微米、800微米、1000微米、1200微米、1500微米、2000微米、3000微米、4000微米、5000微米等。截面高度的范围为20～2000微米，例如20微米、30微米、50微米、75微米、100微米、150微米、185微米、250微米、400微米、700微米、1200微米、1700微米、2000微米等。具有多个子流道111的弧形流道11A的子流道隔离壁112的厚度为10～1000微米，例如10微米、20微米、30微米、50微米、80微米、100微米、120微米、200微米、500微米、800微米、900微米、1000微米等。
在该限定尺寸条件下，经多级弧形流道11分选后的不同微颗粒成分，自不同的流体出口14输出，实现富集、分选目的。可以理解，如经多级弧形流道11分选后残留废液，则废液自一流体出口14排出。示范性地，图1示出了一种具有四级弧形流道11、每级弧形流道11具有三个子流道111的示范例(亦即具有四级多通道弧形流道11A)，其中，流体入口13及入口流道16与流体出口14及出口流道17分别为两个。
样品流体自流体入口13引入该多级弧形流道11，弧形流道11被配置为实现样品流体的迪恩涡流，使样品流体沿弧形流道11流动时产生有规律的伴随运动。在迪恩涡流和流体惯性力的作用下，样品流体中的至少一种微颗粒在流道的横截面内发生垂直于主流动方向的迁移行为，实现惯性聚焦。其中，主流动方向为样品流体沿弧形流道11的流动方向，流道的横截面与主流动方向垂直。
请参阅图11，需要说明的是，弧形流道11可区分为具有至少两个子流道111的多通道弧形流道11A和不具有子流道的单通道弧形流道11B，具体来说，单通道弧形流道11B仅具有一个流道。在前述的多级弧形流道中，多通道弧形流道11A可仅为一级，或者，通常地可为多级。当多通道弧形流道11A的数量为复数时，该复数级多通道弧形流道11A可依次连续串行衔接，或者可互不直接衔接，或者其中数级直接衔接、余下者则不直接衔接。可以理解，多通道弧形流道11A的子流道111同样弧形弯曲。在前述的多级弧形流道中，单通道弧形流道11B的数量可仅为一级，或者可为多级，或者可为零。
示范性地，多级弧形流道11形成至少一个螺旋1a，可为单一螺旋1a(图2a)，亦可为多个螺旋1a(图2b)。属于同一螺旋1a的弧形流道11弯曲方向相同，形成多圈螺旋1a分布，满足布局要求与迪恩涡流的流道要求。请参阅图2b，当多级弧形流道11形成多个螺旋1a时，邻接的螺旋1a之间通过串接流道衔接；其中，串接流道可为直流道15或弯曲流道。多个螺旋1a分布下，单个螺旋1a的流道长度得以控制在较佳范围内，显著降低微流控装置上游所需的驱动压力。
示范性地，相互衔接的两级弧形流道11直接衔接或通过直流道15过渡衔接。例如，在同一螺旋1a中，相互衔接的两级弧形流道11直接衔接；又如，分属不同螺旋1a且相互衔接的两级弧形流道11，可通过直流道15过渡衔接。
示范性地，多个出口流道17沿最后一级弧形流道11的径向依次分布于最后一级弧形流道11的输出末端，保证经过惯性聚焦富集分选后的各类微颗粒准确地进入对应的出口流道17。其中，任意一个出口流道17通过一流体出口14向外引流，以进一步对外引流输出。
示范性地，多级弧形流道11一端设有多个流体入口13及入口流道16，多个入口流道16沿第一级弧形流道11的径向依次分布于第一级弧形流道11的输入端，保证各类入口溶液(如样品流体和缓冲液)互不干扰地引入多级弧形流道11中。示范性地，多个入口流道16中沿第一级弧形流道11的径向位于最内侧或最外侧的一者为缓冲液入口，保证缓冲液引入时处于弧形流道11的最内侧或最外侧及相应的缓冲作用。一般地，当需要富集获取的目标颗粒为样品流体中的较大颗粒时，多个入口流道16中位于最内侧的一者作为缓冲液入口流道；当需要富集获取的目标颗粒为样品流体中的较小颗粒时，多个入口流道16中位于最外侧的一者作为缓冲液入口流道。其中，任意一个入口流道16通过一流体入口13向外延伸，保证较佳的引入作用。
任意一级多通道弧形流道11A至少可实现一种微颗粒的跃迁分选，通过多级多通道弧形流道11A的跃迁聚焦作用实现目标微颗粒的跃迁分选，且至少存在一级多通道弧形流道11A具有足够数量的子流道111以形成对应类数的分类液，最终获得多类微颗粒的分类液，并自不同的流体出口14输出，满足分选要求。若样品流体中的每一类微颗粒均被分选出来，则形成多路完全独立的目标液，每一路目标液仅含或大部分为一类微颗粒，分类液仅包括前述的多路目标液、而不包括废液。若仅需从样品流体中分选出一类或某几类微颗粒，则会产生一路目标液和一路废液、或几路完全独立的目标液和一路废液，此时分类液包括目标液和废液。
示范性地，相互衔接的两级多通道弧形流道11A的子流道111数量相等，满足跃迁要求同时保持结构规整简洁。当然，相互衔接的两级多通道弧形流道11A之子流道111数量亦可不等。
示范性地，多通道弧形流道11A依次连续串行衔接，保证微颗粒连续发生跃迁、实现快速准确分选，保证微流控的超高通量性能、效率与良好效果。
在一些实施例中，多级弧形流道中包括相互衔接的至少两级多通道弧形流道11A，例如可以存在连续衔接的两级、三级或五级多通道弧形流道11A。
以多级弧形流道中存在连续衔接且分别具有子流道的三级弧形流道(即三级多通道弧形流道11A)为例，该三级多通道弧形流道11A中的第一级多通道弧形流道与第二级多通道弧形流道为相互衔接的两级弧形流道，第二级多通道弧形流道与第三级多通道弧形流道也为相互衔接的两级弧形流道。
其中，前后两级多通道弧形流道的子流道111的流量配置，对跃迁现象有较大影响。子流道111的流量与多种因素有关，例如是子流道111的截面状态、流道长度、布置位置等。截面状态包括截面形状与截面尺寸，截面尺寸包括截面宽度与截面高度，流道的横截面沿流道的径向之尺寸为截面宽度、沿流道的法向之尺寸为截面高度。通过对子流道111的上述特征进行设计，即可实现前后两级弧形流道的对应的子流道111的流量差异化，为微颗粒跃迁提供条件。本申请实施例对子流道111的流量设计方式不做限制，以能满足前述的衔接处的流体层流动要求为限。
在一些实施例中，可对子流道111的截面状态进行设计。示范性地，子流道111的截面形状包括矩形、直角梯形和直角三角形中的至少一种，例如，某一个子流道111的截面形状可以是矩形、直角梯形和直角三角形中的任意一种，也可以是矩形、直角梯形和直角三角形中任意两种的组合，还可以是矩形、直角梯形和直角三角形这三种形状的组合。示范性地，同 一级弧形流道11的各个子流道111的截面形状可各不相同，截面形状相同的各个子流道111的截面尺寸亦可各不相同。示范性地，不同级的弧形流道11的各个子流道111的截面形状与截面尺寸可各不相同。示范性地，图3a～3b示出了几种子流道111的截面状态的示范例。
请参阅图3a，在本示例中，弧形流道11具有三个子流道111，每个子流道111的截面形状均为矩形，但截面尺寸各不相同。
申请人发现，在上述的矩形截面流道中，在某一流量范围内，较大的微颗粒聚焦在流道弯曲方向的内侧边界附近，表现在俯视图上则为，在靠近流道弯曲方向的内侧边界附近形成一条聚焦线；较小的微颗粒则会以相对恒定的速度在流道截面上随迪恩涡旋运动，表现在俯视图上则为，在流道弯曲方向的两侧边界周期摆动。
请参阅图3b，在本示例中，多通道弧形流道11A具有三个子流道111，其中一侧的两个子流道111的截面形状均为以弯曲方向内侧和外侧为底，宽度方向为高的直角梯形，另一个子流道111的截面形状为直角梯形与直角三角形的组合。示范性地，具有直角梯形与直角三角形组合截面的子流道111为沿多通道弧形流道11A的径向位于最内侧的子流道111。其中，两个具有直角梯形截面的子流道111的特征为，内侧的子流道111靠近流道弯曲方向内侧的截面高度较小、靠近流道弯曲方向外侧的截面高度较大，呈现出内浅外深的截面特性，外侧的子流道111靠近流道弯曲方向内侧的截面高度较大、靠近流道弯曲方向外侧的截面高度较小，呈现出内深外浅的截面特性。
申请人发现，在内浅外深截面流道中，在某一流量范围内，较大的微颗粒聚焦在流道弯曲方向的内侧边界附近，表现在俯视图上则为，在靠近弧形流道11弯曲方向的内侧边界附近形成一条聚焦线；外侧较深区域的迪恩涡旋更为显著，受之影响，较小的微颗粒则会在流道弯曲方向的外侧边界附近锁定，表现在俯视图上则为，在靠近弧形流道11弯曲方向的外侧边界附近形成一条聚焦线。在内深外浅截面流道中，在多数流量范围内，所 有微颗粒都会在惯性聚焦和迪恩流圈囿的共同作用下保持在流道弯曲方向的内侧边界附近，表现在俯视图上则为，在靠近流道弯曲方向的内侧边界附近形成一条聚焦线。
示范性地，弧形流道11之级数不小于流体出口14的数量。例如，在流体出口14的数量为二时，微流控芯片具有至少两级弧形流道11。示范性地，至少一级弧形流道11A之子流道111的数量不小于流体出口14的数量。例如，在流体出口14的数量为二时，至少一级弧形流道11具有至少两个子流道111，也可以有两级以上弧形流道11具有至少两个子流道111。亦即，也可以有两级以上的弧形流道11具有不少于流体出口14的数量的子流道111。
作为图4示出结构的一种应用示例，使用时，样品流体自位于弧形流道11弯曲方向外侧的入口流道16及与之相连通的流体入口13引入，缓冲液自位于弧形流道11弯曲方向内侧的入口流道16及与之相连通的流体入口13引入。经过前n-1级弧形流道11的跃迁作用后，样品中的微颗粒处于第n级弧形流道11弯曲方向外侧的三个子流道111中，缓冲液充满内侧的两个子流道111中。其中，所有粒径较大的微颗粒和部分粒径较小的微颗粒处于较靠近弧形流道11弯曲方向内侧的中间子流道(自外而内数的第三个子流道111，下同)，而剩下的粒径较小的微颗粒则经之前n-1级跃迁分选后处于弧形流道11弯曲方向最外侧的两个子流道111中。在中间子流道中，由于惯性聚焦和迪恩曳力的共同作用，较大的微颗粒全部处于该子流道111的内侧，较小的微颗粒则分散在该子流道111各处。当所有液体经过第n级弧形流道11和第n+1级弧形流道11的衔接处12、以进入第n+1级弧形流道11时，第n级弧形流道11的中间子流道内的液体出现明显的分流：该子流道111中所有较大的微颗粒全部跃迁进入第n+1级弧形流道11中更内侧的子流道111(自外而内数的第四个子流道111)中，较小的微颗粒则仍然进入第n+1级弧形流道11的中间子流道中。如此重复，较大的微颗粒经多级跃迁后将与少量的较小微颗粒从位于弧形流道11弯曲方向内侧的出口流道17及与之相连通的流体出口14流出，而数量更多 的绝大部分较小微颗粒则将从弧形流道11弯曲方向外侧的出口流道17及与之相连通的流体出口14流出，实现分选。该应用示例适于需富集的目标微颗粒较其它微颗粒大且相对数量极少的需求类型。
作为图5示出结构的一种应用示例，使用时，样品流体自位于弧形流道11弯曲方向内侧的入口流道16及与之相连通的流体入口13引入，缓冲液自位于弧形流道11弯曲方向外侧的入口流道16及与之相连通的流体入口13引入。经过前n-1级弧形流道11的跃迁作用后，样品中的微颗粒处于第n级弧形流道11弯曲方向内侧的三个子流道111中，缓冲液充满外侧的两个子流道111中。其中，所有粒径较小的微颗粒和部分粒径较大的微颗粒处于较靠近弧形流道11弯曲方向内侧的中间子流道(自内而外数的第三个子流道111，下同)，而剩下的粒径较大的微颗粒则经之前n-1级跃迁分选后处于弧形流道11弯曲方向最内侧的两个子流道111中。在中间子流道中，由于惯性聚焦和迪恩曳力的共同作用，较大的微颗粒全部处于该子流道111的内侧，较小的微颗粒则迁移到该子流道111外侧。当所有液体经过第n级弧形流道11和第n+1级弧形流道11的衔接处12、以进入第n+1级弧形流道11时，第n级弧形流道11的中间子流道内的液体出现明显的分流：该子流道111中所有较小的微颗粒全部跃迁进入第n+1级弧形流道11中更外侧的子流道111(自内而外数的第四个子流道111)中，较大的微颗粒则仍然进入第n+1级弧形流道11的中间子流道中。如此重复，较小的微颗粒经多级跃迁后将与少量的较大微颗粒从位于弧形流道11弯曲方向外侧的出口流道17及与之相连通的流体出口14流出，而数量更多的绝大部分较大微颗粒则将从弧形流道11弯曲方向内侧的出口流道17及与之相连通的流体出口14流出，实现分选。该应用示例适于需富集的目标微颗粒较其它微颗粒小且相对数量极少的需求类型。
作为图6a～6c示出结构的一种应用示例，每一级弧形流道11的五个子流道111中，位于弧形流道11弯曲方向最外侧的子流道111(第一子流道111)的截面形状为内浅外深的直角梯形，亦即在同一直角梯形中、靠近弧形流道11弯曲方向内侧的截面高度(形成小底)小于远离弧形流道11弯 曲方向外侧的截面高度(形成大底)。同时，同级弧形流道11的第一子流道111的截面宽度自上游至下游逐渐变宽；下一级弧形流道11的第一子流道111的截面高度小于上一级弧形流道11的第一子流道111的截面高度，即第一子流道111自上游至下游逐级变矮。每一级弧形流道11的其余子流道111(第二子流道111、第三子流道111、第四子流道111、第五子流道)的截面形状均为矩形，其中作为位于弧形流道11弯曲方向最内侧的子流道111(第五子流道111)，同级弧形流道11的第五子流道111的截面宽度自上游至下游逐渐变窄。上一级弧形流道11的其余子流道111(第二、三、四子流道111)的截面宽度、截面高度，与下一级弧形流道11的对应子流道111(第二、三、四子流道111)的截面宽度、截面高度分别相等，即第二、三、四子流道111自上游至下游保持截面尺寸不变。
使用时，样品流体自位于弧形流道11弯曲方向外侧的入口流道16及与之相连通的流体入口13引入，缓冲液自位于弧形流道11弯曲方向内侧的入口流道16及与之相连通的流体入口13引入。其中，样品流体包含粒径从大到小的a、b、c、d四种微颗粒。
请参阅图6a，在缓冲液的排挤下，携带a、b、c、d的样品流体进入前述的第一级弧形流道11的第一子流道111中。在给定流量下，微颗粒a聚集于第一子流道111沿弯曲方向的内侧，微颗粒b、c、d则在迪恩圈囿作用下聚集于第一子流道111沿弯曲方向的外侧；在第一级弧形流道11与第二级弧形流道11的衔接处12，由于前述构造的作用，只有被圈囿的微颗粒(b、c、d)才能进入第二级弧形流道11的第一子流道111，最大的微颗粒a则自第一级弧形流道11的第一子流道111跃迁进入第二级弧形流道11的第二子流道111。
请参阅图6b，在第二级弧形流道11的第一子流道111中，其中最大的微颗粒b聚集于该子流道111沿弯曲方向的内侧，其余微颗粒c、d则在迪恩圈囿作用下聚集于该子流道111沿弯曲方向的外侧；在第二级弧形流道11与第三级弧形流道11的衔接处12，由于前述构造的作用，只有被圈囿的微颗粒(c、d)能进入第三级弧形流道11的第一子流道111，微颗粒 b自第二级弧形流道11的第一子流道111跃迁进入第三级弧形流道11的第二子流道111中，微颗粒a则进一步自第二级弧形流道11的第二子流道111跃迁进入第三级弧形流道11的第三子流道111中。
请参阅图6c，类似地，经过第三级弧形流道11的聚集/圈囿、第三级弧形流道11与第四级弧形流道11的衔接处12之跃迁作用，微颗粒d、c、b、a分别进入并保持于第四级弧形流道11的第一、二、三、四子流道111中，每种微颗粒分别占据一个子流道111，实现分选目的。最终，第四级弧形流道11的四个子流道111可分别连接于四个流体出口14，将四种微颗粒分别输出至不同的容器。
作为图7a～7c示出结构的一种应用示例，每一级弧形流道11的四个子流道111的截面形状均为矩形，且沿弧形流道11的弯曲方向自内而外，同一级的子流道111的截面高度递减，亦即位于内侧的子流道111的截面高度较之外侧的子流道111的截面高度更大、形成内深外浅的分布构造。其中，第i级弧形流道11的第i个子流道111外侧的子流道111(例如为第i-1个子流道111)的截面宽度小于第i个子流道111的截面宽度。示范性地，位于弧形流道11弯曲方向最内侧的子流道111能够保证各子流道111的流量及调节每段弧形流道11的总流量，使二者得以保持一致。
使用时，样品流体自位于弧形流道11弯曲方向外侧的入口流道16及与之相连通的流体入口13引入，缓冲液自位于弧形流道11弯曲方向内侧的入口流道16及与之相连通的流体入口13引入。其中，样品流体包含粒径从大到小的a、b、c、d四种微颗粒。
请参阅图7a，在缓冲液的排挤下，携带a、b、c、d的样品流体进入前述的第一级弧形流道11的第一子流道111中。在给定流量下，微颗粒a、b、c聚集于第一子流道111沿弯曲方向的内侧，微颗粒d则在迪恩涡流作用下聚集于第一子流道111沿弯曲方向的外侧；在第一级弧形流道11与第二级弧形流道11的衔接处12，由于前述构造的作用，只有被迪恩涡流带回至外侧的微颗粒d才能进入第二级弧形流道11的第一子流道111，其余 的微颗粒b、c、d则自第一级弧形流道11的第一子流道111向内跃迁进入第二级弧形流道11的第二子流道111。
请参阅图7b，在第二级弧形流道11的第二子流道111中，微颗粒a、b聚集于该子流道111沿弯曲方向的内侧，最小的微颗粒c则在迪恩涡流作用下聚集于该子流道111沿弯曲方向的外侧；在第二级弧形流道11与第三级弧形流道11的衔接处12，由于前述构造的作用，只有被一整个迪恩涡流带回至外侧的微颗粒c能进入第三级弧形流道11的第二子流道111，微颗粒a、b自第二级弧形流道11的第一子流道111向内跃迁进入第三级弧形流道11的第三子流道111中，微颗粒d由于两级子流道111直连而自第二级弧形流道11的第一子流道111直接进入第三级弧形流道11的第一子流道111中。
请参阅图7c，类似地，经过第三级弧形流道11的迪恩涡流作用、第三级弧形流道11与第四级弧形流道11的衔接处12之跃迁作用，微颗粒d、c、b、a分别进入并保持于第四级弧形流道11的第一、二、三、四子流道111中，每种微颗粒分别占据一个子流道111，实现分选目的。最终，第四级弧形流道11的四个子流道111可分别连接于四个出口流道17及与之相连通的流体出口14，将四种微颗粒分别输出至不同的容器。
示范性地，分别具有多个子流道111且相互衔接的两级弧形流道11，其子流道111数量可相等或不等。在一些可选的实施例中，分别具有多个子流道111且相互衔接的两级弧形流道11，子流道111数量互不相等；其中子流道111数量较少的一级弧形流道11，其子流道111的截面宽度具有渐变构造，可以有效地降低弧形流道11的整体宽度。
在一些实施例中，可对弧形流道的特征进行设计，实现申请目的。示范性地，弧形流道11的曲率半径为2～50毫米。示范性地，弧形流道11之截面宽度的范围为50～5000微米，截面高度的范围为20～2000微米。
示范性地，多级弧形流道11中的最后一级具有多个子流道111，从而直接向出口流道17及与之相连通的流体出口14输出各个子流道111中的 分类液，应用效果较为理想。
以下简要介绍几种种典型的应用示例。
请参阅图2b，作为一种应用示例，本示例中的微流控芯片包括四级弧形流道11、两个入口流道16及与之相连通的流体入口13及两个出口流道17及与之相连通的流体出口14，四级弧形流道11形成两个螺旋1a，每个螺旋1a包含两级弧形流道11，并由一直流道15衔接为一体。每级弧形流道11为1.8～2.2圈，四级弧形流道11共7～9圈。
其中，第一级弧形流道11具有内、外两个子流道111。外侧子流道的截面形状为矩形，截面宽度为800微米、深度为160微米，设计流量l 0为0.8～3.0ml/min；内侧子流道的截面形状亦为矩形，其截面尺寸配置为使该子流道111的流量等于外侧子流道设计流量l 0的2.1倍。
其中，第二级弧形流道11具有内、中、外三个子流道111。中间子流道的截面尺寸与第一级弧形流道11的外侧子流道一致；第二级弧形流道11的内侧子流道的截面尺寸配置为，使该子流道111的流量较第一级弧形流道11的内侧子流道减少0.7l 0；第二级弧形流道11的外侧子流道的截面尺寸配置为，使该子流道111的流量等于0.7l 0。
其中，第三级弧形流道11也具有内、中、外三个子流道111。中间子流道的截面尺寸与第一级弧形流道11的外侧子流道一致；第三级弧形流道11的内侧子流道的截面尺寸配置为，使该子流道111的流量较第二级弧形流道11的内侧子流道减少0.7l 0；第三级弧形流道11的外侧子流道的截面尺寸配置为，使该子流道111的流量等于第二级弧形流道11的外侧子流道的流量的二倍。
其中，第四级弧形流道11具有内、外两个子流道111。内侧子流道的截面尺寸及流量与第一级弧形流道11的外侧子流道相同，相应地，外侧子流道111的流量亦与第一级弧形流道11的内侧子流道相同，即为2.1l 0。示范性地，第一级弧形流道11内侧、第四级弧形流道11外侧的子流道111的截面宽度可具有渐变构造，以降低弧形流道11的整体宽度。
该微流控芯片的一种具体用途可以是，从人体外周血全血中分选痕量级的循环肿瘤细胞、胎儿细胞等不属于血细胞的循环异常细胞，以进行体外诊断。例如，全血样本自位于弧形流道11弯曲方向外侧的入口流道16及与之相连通的流体入口13引入，流量为0.5l 0(约1.0ml/min)；PBS缓冲液自位于弧形流道11弯曲方向内侧的入口流道16及与之相连通的流体入口13引入，流量为2.6l 0。在第一级弧形流道11，全血样本全部进入外侧子流道，并占据外侧子流道中的外侧1/2区域；外侧子流道的其余区域及内侧子流道的全部区域则由缓冲液占据。
当全血样本流动至第一级弧形流道11的末端时，粒径较大的循环异常细胞在惯性聚焦作用下出现在外侧子流道的内侧1/3区域，而血细胞在迪恩流作用下充满整个弧形流道11；当流体流入第二级弧形流道11时，位于第一级弧形流道11的外侧子流道中的内侧1/3区域的样本，向内跃迁进入第二级弧形流道11的中间子流道，其余样本则进入第二级弧形流道11的外侧子流道。
由于第二级弧形流道11的中间子流道与第一级弧形流道11的外侧子流道一致，二者中的样本的运动状态相同。但由于该中间子流道的血细胞数量下降为第一级弧形流道11的外侧子流道的1/3，在中间子流道末端的内侧在迪恩流作用下会出现部分只有循环异常细胞的空隙。请参阅图8，在进入第三级弧形流道11时，循环异常细胞(富集目标)继续跃迁进入第三级弧形流道11的中间子流道，而更多血细胞会在分流作用下进入外侧子流道。在进入第四级弧形流道11时，循环异常细胞跃迁进入第四级弧形流道11的内侧子流道，此时仅有微量血细胞跟随循环异常细胞进入该内侧子流道，绝大部分血细胞将分流至第四级弧形流道11的外侧子流道。在第四级弧形流道11的末端，循环异常细胞聚焦于第四级弧形流道11的内侧子流道的内侧1/3区域，该子流道111中含有的微量血细胞会迁移至该子流道111的外侧2/3区域。对位于第四级弧形流道11内侧、且与第四级弧形流道11末端衔接的出口流道17的截面尺寸进行配置，使与之相连通的流体出口14仅能接收第四级弧形流道11的内侧子流道的内侧1/3区域的流 体，并将第四级弧形流道11的内侧子流道的其余流体全部排入位于第四级弧形流道11外侧的出口流道17及与之相连通的流体出口14，从而实现循环异常细胞的富集。
图9揭示了本应用示例的微流控芯片实际使用时的显微镜下状态。图9a为血液样本在第一级弧形流道11和第二级弧形流道11衔接处12的流动情况，可见血细胞充满第一级弧形流道11的外侧子流道的末端，并在进入位于右侧的第二级弧形流道11时，部分进入第二级弧形流道11的外侧子流道，部分进入第二级弧形流道11的中间子流道。图9b为一个典型的癌细胞系A549在相同入口流量配置下的第一级弧形流道11和第二级弧形流道11衔接处12的流动情况，可见在第一级弧形流道11的外侧子流道的末端聚集，癌细胞系聚集在该子流道111的内侧区域；当癌细胞系进入位于右侧的第二级弧形流道11时，全部癌细胞系进入第二级弧形流道11的中间子流道。图9c为血液样本在第三级弧形流道11和第四级弧形流道11衔接处12的流动情况，可见此时大量血细胞充满第三级弧形流道11的外侧子流道，少量血细胞聚集第三级弧形流道11的中间子流道末端的外侧，中间子流道的内侧存在明显的无细胞区域；在进入位于右侧的第四级弧形流道11时，绝大部分血细胞都进入第四级弧形流道112.0的外侧子流道，仅有少量血细胞进入内侧子流道。图9d为A549在第三级弧形流道11和第四级弧形流道11衔接处12的流动情况，在第三级弧形流道11的中间子流道的末端，癌细胞系依然聚集在该子流道111的内侧区域；在进入位于右侧的第四级弧形流道11时，癌细胞系全部跃迁进入第四级弧形流道11的内侧子流道。图9e为血液样本在第四级弧形流道11末端和出口流道17的衔接处流动情况，可见此时仅有少量血细胞位于第四级弧形流道11的外侧子流道末端的外侧，该子流道111的内侧存在很宽的无细胞区域，并在经过衔接区域后与第四级弧形流道11的内侧子流道内的血细胞一同进入位于右上方的废液废液出口流道17。图9f为A549在第四级弧形流道11末端和出口流道17的衔接处的流动情况，可见在第四级弧形流道11的内侧子流道的末端，癌细胞系依然聚集在该子流道111的内侧区域；在进入 右方的出口流道17时，癌细胞系全部进入其弯曲方向内侧的目标细胞富集出口流道17。综合图9中血细胞与较大的癌细胞在各个位置的表现，当血细胞中混有痕量(1～100个)癌细胞时，经过本应用示例的微流控芯片后，癌细胞将经由该芯片的内侧出口流道17流出，而其它血细胞将经由外侧出口流道17流出，总而达到循环异常细胞富集的目的。实践表明，本应用示例通过一个微流控芯片，即可实现1ml/min的超高通量全血循环异常细胞富集，将每个样本处理时间大幅压缩至10分钟以内，具有显著的应用优势。
请参阅图10，作为又一种应用示例，本示例中的微流控芯片具有三级弧形流道11、一入口流道16及与之相连通的流体入口13、两个出口流道17及与之相连通的流体出口14。其中，每级弧形流道11由两个具有矩形截面的子流道111构成，每个子流道111的截面高度分别为130微米，第一级弧形流道11和第三级弧形流道11的内、外两个子流道111的截面宽度分别为400和600微米，第二级弧形流道11的内、外两个子流道111的宽度为600和400微米。位于螺旋1a最内侧的弧形流道11的曲率半径为7.5毫米，最外侧的弧形流道11的曲率半径为15毫米，入口流道16、出口流道17的截面深度分别与对应衔接的子流道111一致，位于弧形流道11弯曲方向内、外侧的出口流道17的截面宽度比为1：8。在总流量为1.8～2.4ml/min的流量范围内，三级弧形流道11中的任意一个子流道111都可以将直径在9～15微米范围内的细胞聚焦到该子流道111的内侧。
该微流控芯片的一种具体用途可以是，对生物反应器中的肽、蛋白、生物活性酶、抗体等细胞代谢产物从其培养液中分离出来。例如，含有培养细胞的培养液由流体入口13及入口流道16进入第一级弧形流道11后，将被分为两部分而分别流入第一级弧形流道11的两个子流道111；在惯性聚焦作用下，细胞在流至第一级弧形流道11末端时将聚焦在各子流道111靠近弯曲方向的内侧区域。液体由第一级弧形流道11流入第二级弧形流道11时，原本处于第一级弧形流道11的外侧子流道内的聚焦细胞将流入第二级弧形流道11的内侧子流道中。在第二级弧形流道11的末端，所有细胞都将聚焦在第二级弧形流道11的内侧子流道靠近弯曲方向的内侧区域。 液体进入第三级弧形流道11后，所有细胞仍然处于第三级弧形流道11的内侧子流道中，但因该子流道111变窄、流量降低，其中的细胞在惯性聚焦作用下将进一步靠近该子流道111的内侧，并经位于弯曲方向内侧的出口流道17流出，最终从之相连通的流体出口14流回生物反应器中，而剩余的约90％的无细胞溶液则经由位于弯曲方向外侧的出口流道17流出，由与之相连通的流体出口14收集后浓缩回收。
本应用示例中的作业可连续进行，且对细胞无伤害，适用于中小型生物反应器。当需要进一步浓缩或增加通量时，可考虑增加子流道111的数目和弧形流道11的级数，具体情况视实际使用需求而定。
请参阅图11，作为再一种应用示例，本示例中的微流控芯片具有两级弧形流道11、一入口流道16及与之相连通的流体入口13、两个出口流道17及与之相连通的流体出口14。其中，第一级弧形流道11为单通道弧形流道11B，截面高度为130微米，截面宽度为800微米；第二级弧形流道11为多通道弧形流道11A，该多通道弧形流道11A的内、外两个子流道111的截面高度和宽度分别为130微米和300微米。位于螺旋1a最内侧的弧形流道11的曲率半径为7.5毫米，最外侧的弧形流道11的曲率半径为15毫米，入口流道16、出口流道17的截面深度分别与对应衔接的子流道111一致，位于弧形流道11弯曲方向内、外侧的出口流道17的截面宽度比为1：5。在总流量为1.0～1.6ml/min的流量范围内，多通道弧形流道11A的任意一个子流道111都可以将直径在12～15微米范围内的细胞聚焦到该子流道111的内侧。
该微流控芯片的一种具体用途可以是，对生物反应器中的肽、蛋白、生物活性酶、抗体等细胞代谢产物从其培养液中分离出来。例如，含有培养细胞的培养液由流体入口13进入第一级弧形流道11后，在惯性聚焦作用下，细胞在流至第一级弧形流道11末端时将聚焦在靠近弯曲方向的内侧区域。液体由第一级弧形流道11流入第二级弧形流道11时，原本处于第一级弧形流道11内侧的聚焦细胞将流入第二级弧形流道11的内侧子流道中。在第二级弧形流道11的末端，所有细胞都将聚焦在第二级弧形流道 11的内侧子流道靠近弯曲方向的内侧区域，并经位于弯曲方向内侧的出口流道17流出，最终从与之相连通的流体出口14流回生物反应器中，而剩余的约90％的无细胞溶液则由位于弯曲方向外侧的出口流道17流出，由之相连通的流体出口14收集后浓缩回收。
本应用示例中的作业可连续进行，且对细胞无伤害，适用于中小型生物反应器。当需要进一步浓缩或增加通量时，可考虑增加子流道111的数目和弧形流道11的级数，具体视实际使用需求而定。
请参阅图12，作为再一种应用示例，本示例中的微流控芯片包括三级弧形流道11、两个入口流道16及与之相连通的流体入口13、三个出口流道17及与之相连通的流体出口14。三级弧形流道11形成两个螺旋1a，其中一个螺旋1a包含一级弧形流道11，该级弧形流道11为4圈；另一个螺旋1a包含两级弧形流道11，每级弧形流道11为1.8～2.2圈；三级弧形流道11共7～9圈，弧形流道11的曲率半径范围为7.5～15毫米，两个螺旋1a之间由一直流道15串接衔接。
第一级弧形流道11包括具有矩形截面、且截面高度为80微米的两个子流道111，内外两个子流道111的截面宽度分别为450微米和400微米。第二级弧形流道11包括具有矩形截面、且截面高度为120微米的两个子流道111，内外两个子流道111的截面宽度分别为500微米和220微米。第三级弧形流道11包括内中外三个子流道111，外侧子流道和中间子流道的截面形状均为矩形、截面深度均为120微米，截面宽度分别为220微米和330微米，且外侧子流道与第二级弧形流道11的外侧子流道直接相连；第三级弧形流道11的内侧子流道具有内浅外深的直角梯形截面，内侧的截面高度为70微米、外侧的截面高度为90微米，截面宽度为500微米。
该微流控芯片的一种具体用途可以是，对血液样本中的白细胞、红细胞和血小板进行分离。例如，可先将血液样本稀释至原浓度的1/10(即体积变为原体积的10倍)，随后以0.2ml/min的流量自位于外侧的入口流道 16及与之相连通的流体入口13流入；同时，缓冲液以3.2ml/min的流量自位于内侧的入口流道16及与之相连通的流体入口13流入。
在进入第一级弧形流道11时，血液样本将占据该级的外侧子流道的外侧1/8宽度区域；缓冲液则将被分成两部分，一部分以约1.4ml/min的流量流入外侧子流道，其余部分则以约1.8ml/min的流量流入内侧子流道；在第一级弧形流道11的末端，血液样本中的红细胞和白细胞将聚集在外侧子流道的内侧区域(即外侧子流道靠近内侧子流道的区域)，而更小的血小板将随迪恩涡旋经一整个迪恩循环后返回到外侧子流道的外侧区域(即外侧子流道远离内侧子流道的区域)。在从第一级弧形流道11进入第二级弧形流道11时，位于第一级弧形流道11的外侧子流道的内侧约40％区域的流体将进入第二级弧形流道11的内侧子流道，占据该内侧子流道的外侧约25％区域(即内侧子流道靠近外侧子流道的区域)；相应地，聚焦在第一级弧形流道11的外侧子流道的内侧约40％区域的红细胞和白细胞也将随之跃迁到第二级弧形流道11的内侧子流道。
在第二级弧形流道11的末端，由于内侧子流道的截面高度增加，只有白细胞可以聚焦在该子流道111的内侧区域(即内侧子流道远离外侧子流道的区域)，而红细胞将随迪恩涡旋返回该子流道111的外侧区域。在从第二级弧形流道11进入第三级弧形流道11时，位于第二级弧形流道11的内侧子流道的流体将被分为两部分，内侧部分以约1.0ml/min的流量流入第三级弧形流道11的内侧子流道，外侧部分则以约1.4ml/min的流量流入第三级弧形流道11的中间子流道。因样本进入第二级弧形流道11内侧子流道时占据的空间较大以及细胞在流动过程中的扩散运动，红细胞不会全部分流到第三级弧形流道11的中间子流道中，少量的红细胞会随聚焦的全部白细胞进入第三级弧形流道11的内侧子流道中。
在第三级弧形流道11的内侧子流道中，白细胞会聚焦到该子流道111的内侧区域(即内侧子流道远离中间子流道的区域)，而红细胞则将在迪恩圈囿的作用下被限制在该子流道111的外侧较深区域(即内侧子流道靠近中间子流道的区域)，当样本自流体出口14流出时，这部分红细胞将会 与中间子流道中的红细胞汇合，流经位于中间的出口流道17及流体出口14。第三级弧形流道11的内侧子流道聚焦的白细胞将与内侧的缓冲液一起以约0.25ml/min的流量从位于内侧的出口流道17及流体出口14流出；外侧子流道将直接与位于外侧的出口流道17相接，以约1ml/min的流量携带血小板流出，最终实现三种血液成份的完全分离。
请参阅图12，作为再一种应用示例，本示例中的微流控芯片包括三级弧形流道11、两个入口流道16及与之相连通的流体入口13、三个出口流道17及与之相连通的流体出口14。三级弧形流道11形成两个螺旋1a，其中一个螺旋1a包含第一级弧形流道11的全体(共3圈)和第二级弧形流道11的一部分(1圈)，另一个螺旋1a包含第二级弧形流道11的剩余部分(1.5圈)第三级弧形流道11的全体(共2.5圈)；三级弧形流道11共8圈，两个螺旋1a之间由一直流道15串接衔接。
该微流控芯片的一种具体用途可以是，在浓度为10万颗粒/微升的样品中，将直径范围在10～13微米的微球样品分选为10～11微米、11～12微米、12～13微米3类。
第一级弧形流道11具有两个子流道111。外侧子流道的截面形状为直角梯形，内侧的截面高度为80微米，外侧的截面高度为120微米，截面宽度为600微米；内侧子流道的截面形状为矩形，截面高度为140微米、截面宽度为300微米；内侧子流道与外侧子流道的流量比为1.1:1.5。
第二级弧形流道11具有两个子流道111，两个子流道111的截面形状均为直角梯形，任意一个子流道111内侧的截面高度为80微米、外侧的截面高度为120微米，截面宽度为600微米。设置于第二级弧形流道11的两部分之间的直流道15，也具有两个子流道111；其中，内侧子流道的截面形状为矩形，截面高度为120微米、截面宽度为600微米；其中，外侧子流道的截面形状为矩形，截面高度为80微米、截面宽度为600微米。在此一直线道的阻抗差异影响下，第二级弧形流道11的内外子流道111的流量比为1.5:1.1。
第三级弧形流道11具有内中外三个子流道111。其中，内侧子流道的截面形状为矩形，截面高度为140微米、截面宽度为300微米；中间子流道的截面形状为直角梯形，内侧的截面高度为80微米，外侧的截面高度为120微米，截面宽度为600微米；外侧子流道的截面形状为矩形，截面高度为130微米、截面宽度为300微米；内侧子流道、中间子流道、外侧子流道的流量比为0.8:1.1:0.7。
在分选时，样品以低于1.5ml/min的流量从位于外侧的入口流道16及与之相连通的流体入口13引入，缓冲液以恒定流量从位于内侧的入口流道16及与之相连通的流体入口13引入，使得引入弧形流道11的总流量为2.6ml/min，样品将被全部导入第一级弧形流道11的外侧子流道中。在此流量配置下，直径为12～13微米的微球将聚焦在第一级弧形流道11的外侧子流道的内侧区域，直径为10～12微米的微球则被迪恩涡流圈囿在该外侧子流道的外侧区域。
在进入第二级弧形流道11时，因内外子流道111的流量比发生改变，聚焦在第一级弧形流道11的外侧子流道内侧的直径12～13微米的微球将跃迁到第二级弧形流道11的内侧子流道中。因直径10～12微米的微球与直径12～13微米的微球较为接近，直径12～13微米的微球在第一级弧形流道11的外侧子流道的内侧聚焦时，会裹挟微量的直径11～12微米的微球，并同步跃迁到第二级弧形流道11内侧子流道；在跃迁过程中，裹挟作用被打破，在第二级弧形流道11的内侧子流道内，其中直径10～12微米的微球将被迪恩涡流圈囿在该子流道111的外侧区域，聚焦在子流道111内侧较浅区域的微球则为纯度更高的直径12～13微米的微球。分流到第二级弧形流道11的外侧子流道的直径10～12微米的微球，因前后两级子流道111的截面形状/尺寸相同、但流量下降，其中的直径11～12微米的微球将聚焦在该子流道111的内侧区域，而相对更小的直径10～11微米微球将被迪恩涡流圈囿在该子流道111的外侧区域。
在进入第三级弧形流道11时，根据各子流道111流量比例的变化，第二级弧形流道11的外侧子流道内的直径10～11微米的微球，将继续保留 在第三级弧形流道11的外侧子流道内；而聚焦在第二级弧形流道11的外侧子流道内侧的直径11～12微米的微球，将跃迁到第三级弧形流道11的中间子流道的外侧区域。与第一次跃迁时的情形类似，跃迁过程中将有微量的直径10～11微米微球被裹挟，并在跃迁过程中打破裹挟作用。第二级弧形流道11的内侧子流道中聚焦的直径12～13微米的微球，将跃迁到第三级弧形流道11的内侧子流道；圈囿在第二级弧形流道11的内侧子流道的外侧区域的微量直径11～12微米的微球，则被分流到第三级弧形流道11的中间子流道中。在第三级弧形流道11的中间子流道中，因其流量与第二级弧形流道11的外侧子流道流量一致，直径11～12微米的微球将聚焦在第三级弧形流道11的中间子流道的内侧区域；而被裹挟进入第三级弧形流道11的中间子流道的直径10～11微米的微球，将被圈囿在该子流道111的外侧区域。
在第三级弧形流道11的末端，内侧子流道与位于内侧的出口流道17直接相连，其中的直径12～13微米的微球将直接由该出口流道17及与之相连通的流体出口14引出并收集，位于中间的出口流道17则只收集第三级弧形流道11的中间子流道的内侧聚焦的直径11～12微米的微球，剩余的直径10～11微米的微球则由位于外侧的出口流道17及与之相连通的流体出口14流出，从而实现分选。
本领域技术人员可通过微调微流控芯片的流量及各子流道111的尺寸等参数，实现精度更高或更低的不同尺寸范围的分选，也可通过重复分选等方法实现更高质量的分选。
请参阅图2a，作为又一种应用示例，本示例中的微流控芯片具有两级弧形流道11、两个入口流道16及与之相连通的流体入口13、两个出口流道17及与之相连通的流体出口14。每级弧形流道11各为2圈，两级弧形流道11共4圈，弧形流道11的曲率半径范围为7.5～15毫米。
每级弧形流道11具有两个子流道111，所有子流道111的截面形状均为矩形。第一级弧形流道11的内、外两子流道111的截面宽度分别为300 微米和500微米；第二级弧形流道11则相反，内、外两子流道111的截面宽度分别为500微米和300微米。
该微流控芯片的一种具体用途可以是，当有细胞样本被尺寸相对较小的细菌、病毒等污染，或建立实验室级细胞、细菌自动培养系统需要整体清洗、换液时，对样本进行彻底换液，具体过程示例如下。
带有细胞的样本和新清洗液分别以约0.5ml/min和3.5ml/min的恒定流量从位于外侧的入口流道16及与之相连通的流体入口13和内侧的入口流道16及与之相连通的流体入口13引入，当样本和新溶液进入第一级弧形流道11后，样本将占据外侧子流道的约1/5宽度，由内侧引入的新溶液则会占据内侧子流道和外侧子流道剩余空间。在第一级弧形流道11的末端，样本中的细胞将聚焦在外侧子流道的内侧1/3空间范围内，而样本中的旧溶液则会随迪恩流完成一个迪恩涡旋后回到该子流道111的外侧区域；虽然在扩散等效应下，旧溶液成份所占空间已经超过外侧子流道的1/5宽度，但依然会被控制在该子流道111的外侧1/3区域。
液体从第一级弧形流道11进入第二级弧形流道11时，第一级弧形流道11的外侧子流道内侧约40％的流体将被分流进入第二级弧形流道11的内侧子流道；因所有的细胞聚集在第一级弧形流道11的该区域，所有的细胞随之跃迁到第二级弧形流道11的内侧子流道并占据该子流道111外侧约40％的空间，此时除微量的旧溶液在细胞的裹挟下同样进入第二级弧形流道11的内侧子流道外，其余的旧溶液分流进入第二级弧形流道11的外侧子流道。
在第二级弧形流道11的内侧子流道中，细胞将如在第一级弧形流道11中一样再次被清洗，进一步去除其中残余的旧溶液，并最终以0.8～1毫升每分钟的流量从位于内侧的出口流道17及与之相连通的流体出口14引出到新收集容器中，而混有旧样本的溶液则由位于外侧的出口流道17及与之相连通的流体出口14排出到废液池中。
最后所应说明的是，以上具体实施方式仅用以说明本申请的技术方案 而非限制，尽管参照实例对本申请进行了详细说明，本领域的普通技术人员应当理解，可以对本申请的技术方案进行修改或者等同替换，而不脱离本申请技术方案的精神和范围，其均应涵盖在本申请的权利要求范围当中。

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  1. 阶跃式惯性聚焦微流控芯片，其特征在于，包括依次串行衔接的多级弧形流道，其中至少一级弧形流道被分隔为沿所述弧形流道的径向依次分布的多个子流道，所述多级弧形流道一端设有至少一个流体入口及连接所述弧形流道一端和所述流体入口的入口流道、另一端设有多个流体出口及分别连接所述弧形流道另一端和每个所述流体出口的多个出口流道；所述弧形流道的曲率半径为2～50毫米；所述弧形流道的横截面沿所述弧形流道的径向之尺寸为截面宽度、沿所述弧形流道的法向之尺寸为截面高度，所述截面宽度的范围为50～5000微米，所述截面高度的范围为20～2000微米；具有多个子流道的弧形流道的子流道隔离壁的厚度为10～1000微米。
  2. 根据权利要求1所述的阶跃式惯性聚焦微流控芯片，其特征在于，所述多级弧形流道形成至少一个螺旋，属于同一螺旋的弧形流道弯曲方向相同。
  3. 根据权利要求1所述的阶跃式惯性聚焦微流控芯片，其特征在于，当所述多级弧形流道形成多个螺旋时，邻接的螺旋之间通过串接流道衔接，所述串接流道为直流道或弯曲流道。
  4. 根据权利要求1所述的阶跃式惯性聚焦微流控芯片，其特征在于，所述子流道的截面形状包括矩形、直角梯形和直角三角形中的至少一种。
  5. 根据权利要求1所述的阶跃式惯性聚焦微流控芯片，其特征在于，所述多级弧形流道的级数不小于所述流体出口的数量，所述多级弧形流道中至少一级具有多个子流道的弧形流道之子流道的数量不小于所述流体出口的数量；所述具有多个子流道的弧形流道依次连续串行衔接。
  6. 根据权利要求1所述的阶跃式惯性聚焦微流控芯片，其特征在于，相互衔接的两级弧形流道直接衔接或通过直流道、弯曲流道过渡衔接。
  7. 根据权利要求1所述的阶跃式惯性聚焦微流控芯片，其特征在于，所述多级弧形流道中的最后一级具有多个子流道。
  8. 根据权利要求1所述的阶跃式惯性聚焦微流控芯片，其特征在于，所述多个流体出口流道沿最后一级弧形流道的径向依次分布于所述最后一 级弧形流道的输出末端；任意一个流体出口流道通过与其相连通的一个出口向外引流。
  9. 根据权利要求1所述的阶跃式惯性聚焦微流控芯片，其特征在于，所述多级弧形流道一端设有多个流体入口及入口流道，所述多个流体入口流道沿第一级弧形流道的径向依次分布于所述第一级弧形流道的输入端；所述多个流体入口流道中沿所述第一级弧形流道的径向位于最内侧或最外侧的一者为缓冲液入口流道；任意一个流体入口流道通过与其相连通的一个入口向内引流。
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