CN103191791A - Integrated chip system for high-throughput sorting and counting detection of biological particles, and application - Google Patents
Integrated chip system for high-throughput sorting and counting detection of biological particles, and application Download PDFInfo
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- CN103191791A CN103191791A CN2013100666179A CN201310066617A CN103191791A CN 103191791 A CN103191791 A CN 103191791A CN 2013100666179 A CN2013100666179 A CN 2013100666179A CN 201310066617 A CN201310066617 A CN 201310066617A CN 103191791 A CN103191791 A CN 103191791A
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Abstract
The invention discloses an integrated chip system for high-throughput sorting and counting detection of biological particles, and an application. The chip system comprises a main microfluidic chip, a micropipe, a sample liquid micropump, an exchange liquid micropump, a first waste liquid collecting device, a second waste liquid collecting device, a third waste liquid collecting device, laser emitters, photoelectric conversion devices, optical fibers and a computer, wherein the main microfluidic chip comprises an asymmetric curved flow path, a first branch channel, a second branch channel, a third branch channel, a main flow path, a branch flow path, aligning marks, etc. The system utilizes the asymmetric curved flow path to realize pre-focusing and sorting for the particles, utilizes a liquid changing flow channel to realize change of a carrier liquid of to-be-tested particles and particle cleaning, and utilizes a viscoelastic effect and an inertial effect of a viscoelastic fluid to realize focus of single equilibrium position of section centers of the particles. The system does not need a sheath liquid, complex pre-cleaning of the particles, and optical alignment, has advantages of high speed, high precision, integration, miniaturization, automation, low cost, simple production process, easy batch production, etc.
Description
Technical field
The present invention relates to that miniflow is controlled and detection range, what be specifically related to is system-on-chip and the application of the sorting of biological particle high flux and count detection.This chip system mainly comprises the fluid operated module of multichannel, optical detection module, signal processing module etc.
Background technology
Microflow control technique is an integrated complicated Laboratory Function, by controlling the long-pending fluid of microbody, realizes the microchip technology of functions such as sample preparation, reaction, focusing, sorting and detection.And realize that based on microflow control technique the sorting of micron order biomone and counting are the important contents of area researches such as biomedicine, environmental monitoring, analytical chemistry.Particle prefocus efficiently and size purification technique are the prerequisites that realizes HIAC, and common focusing sorting technology mainly can be divided into based on the focusing sorting technology in outfields such as magnetic field, electric field, sound field and the focusing sorting technology etc. that utilizes sheath fluid folder stream.The former needs optional equipment that the outfield is provided, and exists power consumption big, is unfavorable for deficiencies such as integrated microization and easy damaged biological specimen.The latter needs the multiply sheath fluid, has problems such as control and complicated operation.Aspect the biology microparticle counting detection method, mainly contain traditional artificial counting at present, based on the electro-detection of Coulter principle, based on the detection of optical principle.Problems such as obviously traditional artificial technology can't satisfy the efficient sample treatment demand in modernized laboratory at aspects such as precision, intellectuality, microminiaturizations, and then there is easy damaged biomone activity in the Coulter technology, and accuracy of detection is not high.Based on the optical detective technology of two-dimension focusing, because there is certain overlapping possibility in particle on third dimension degree, cause count results to exist than mistake.In the recent period twice sheath fluid of existing research and utilization three-dimensional focal of realizing particle to be avoiding the overlapping of particle, but uses twice sheath fluid folder flow operation complicated.Simultaneously, (Reynolds number is generally 10 owing to most micro-fluidic chip flow velocitys are lower
-6～10
1) and be subjected to the restriction of count detection equipment, make existing biomone count detection flux based on microflow control technique all very low (being generally several to a hundreds of per second).In addition, before the biomone count detection, often need to sample filter, complicated pre-treatment operation such as centrifugal, cleaning, the equipment needed thereby complexity, volume is big and operation is comparatively loaded down with trivial details.
Therefore, the automation of the sorting of biomone quick high accuracy, cleaning, counting if can be proposed, integrated, miniaturized devices will overcome above-mentioned limitation to a certain extent.
Summary of the invention
Goal of the invention: the multichannel system-on-chip that the purpose of this invention is to provide the sorting of biological particle high flux and count detection.Realize the sorting of micron order biomone and focusing by the microfluid inertia effect in the curved runner on the single substrate, realize that by laminar flow effect and inertia lift particle cleans and the exchange of carrying liquid, single equilbrium position, the runner central area vernier focusing that utilizes elastic force in the viscoplasticity stream and inertia lift to realize biomone, based on optical detection and signal processing technology detected photosignal is identified at last, realized the HIAC of biomone and obtain the various features parameter of biomone.Simultaneously, realize the further lifting of flux by piling up of multi layer substrate.Above technological means has overcome present micro-fluidic sorting to a certain extent and count detection technology flux is low, precision is low, outfield power consumption, automatically and limitation such as integrated degree is low.
Technical scheme: at present biomone sorting, not enough and the limitation that exists in the research of counting device and the application, the system-on-chip of biological particle high flux of the present invention sorting and count detection, comprise the main body micro-fluidic chip, microtubule, the sample liquid Micropump, exchange liquid Micropump, the first waste collection device, the second waste collection device, three wastes liquor collecting device, laser beam emitting device, photoelectric conversion device, computer and optical fiber are connected with microtubule on the main body micro-fluidic chip, the sample liquid Micropump, exchange liquid Micropump, the first waste collection device, the second waste collection device, three wastes liquor collecting device, laser beam emitting device, photoelectric conversion device, optical fiber;
Described main body micro-fluidic chip includes asymmetric curved runner, first branched bottom, second branched bottom, the 3rd branched bottom, sprue, bypass passage, gateway connecting hole, sample inlet, exchange liquid entrance, the outlet of pre-sorting interference particle, is replaced the outlet of carrying liquid, waste liquid outlet, exciting light optical fiber passage, forward angle light scatter optical-fibre channel, lateral angle scattering optical-fibre channel and fluorescence optical fiber passage and alignment mark;
Described main body micro-fluidic chip piles up bonding by a plurality of single substrate and forms;
Every layer of substrate layout is just the same, described sample inlet, exchange liquid entrance, the particle outlet is disturbed in pre-sorting, be replaced the outlet of carrying liquid, be equipped with the gateway connecting hole on the waste liquid outlet, described sample liquid Micropump is connected with microtubule one end, the microtubule other end links to each other with gateway connecting hole on the sample inlet, sample inlet is connected with asymmetric curved runner, asymmetric curved runner is told first branched bottom and second branched bottom, first branched bottom disturbs the particle outlet to be connected with pre-sorting, pre-sorting disturbs the gateway connecting hole in the particle outlet to be connected with the first waste collection device, second branched bottom and the 3rd branched bottom one end are intersected in sprue, described the 3rd branched bottom other end is connected with exchange liquid entrance, gateway connecting hole on the exchange liquid entrance is connected with exchange liquid Micropump, be provided with successively on the described sprue and change the liquid runner, kernel of section focus DC road, the optical detection zone, described sprue is terminal to be connected with waste liquid outlet, gateway connecting hole on the waste liquid outlet is connected with the second waste collection device, the described liquid runner that changes is told a bypass passage, described bypass passage be replaced carrying liquid outlet and be connected, the gateway connecting hole that is replaced in the outlet of carrying liquid is connected with three wastes liquor collecting device, described laser beam emitting device is connected with exciting light optical fiber passage by optical fiber, described photoelectric conversion device by optical fiber respectively with the forward angle light scatter optical-fibre channel, lateral angle scattering optical-fibre channel is connected with the fluorescence optical fiber passage, described photoelectric conversion device is connected with computer by optical fiber, described exciting light optical fiber passage and forward angle light scatter optical-fibre channel lay respectively at the sprue both sides, exciting light optical fiber channel vertical is in sprue, the angle of forward angle light scatter optical-fibre channel and exciting light optical fiber passage extended line is 0.5 °～6 °, described lateral angle scattering optical-fibre channel and fluorescence optical fiber passage lay respectively at the both sides of sprue, described lateral angle scattering optical-fibre channel becomes 95 °～120 ° with exciting light optical fiber passage, described fluorescence optical fiber passage becomes 60 °～85 ° angle respectively with exciting light optical fiber passage, described alignment mark has a plurality of, lays respectively at four angles of described single substrate.
The described liquid cross section of fluid channel that changes is rectangle.
The described exchanging liquid that changes in the liquid runner amasss flow greater than sample liquid volume flow, and kernel of section focus DC road width is greater than bypass passage, and the long-pending flow of exchanging liquid/sample liquid volume flow is greater than kernel of section focus DC road width/bypass passage.
Described main body micro-fluidic chip is that the on all four substrate stack bonding of multilayer forms.
The used material of described its substrate of main body micro-fluidic chip is a kind of in dimethyl silicone polymer, glass, epoxy resin, polymethyl methacrylate, the Merlon.
Be integrated with exciting light optical fiber passage, forward angle light scatter optical-fibre channel, lateral angle scattering optical-fibre channel, fluorescence optical fiber passage around the described optical detection zone, exciting light optical fiber and detection fiber are all inserted passage and fixedly are integrated on the chip, launch exciting light from the side and receive sensed light signal.
The height of described asymmetric curved runner, sprue, first branched bottom, second branched bottom, the 3rd branched bottom, bypass passage, exciting light optical fiber passage, forward angle light scatter optical-fibre channel, lateral angle scattering optical-fibre channel and fluorescence optical fiber passage equates.Described photoelectric conversion device is converted to data signal with detected optical signal and imports computer and utilize corresponding software to carry out the analyzing and processing of related data.Wherein, the operation principle of photoelectric conversion device is as follows: the optical filter that described photoelectric conversion device utilization is integrated in wherein detects optical signal, the optical signal that to consider is converted to the signal of telecommunication and the modulus in being integrated in photoelectric conversion device dress and changes simultaneously, and the signal of telecommunication is converted to data signal input computer.Described electrical switching device comprises filter, analog-digital converter and photodiode, photomultiplier etc.
The application of the system-on-chip of the sorting of described biological particle high flux and count detection in biomone sorting and count detection.
The main body micro-fluidic chip that proposes among the present invention is the integrated composite construction of multilayer, the used material of main body chip can be dimethyl silicone polymer (PDMS), PDMS has good optical property and mechanical performance, satisfy the optical detection requirement, biological specimen is not caused damage, and the cheap method of molding of maturation that cooperates is suitable for producing in batches.In addition, the main body micro-fluidic chip also can select for use glass, epoxy resin, polymethyl methacrylate (PMMA), Merlon materials such as (PC) to make.The processing technology of different materials correspondence may be different, can select the chip material according to processing conditions and application.The present invention adopts maskless photoetching technology to make required micro-structural formpiston and utilizes method of molding to copy the PDMS substrate of corresponding construction.Every layer of substrate has on all four size and structure, can utilize same formpiston to carry out batch duplicating.
The micro-structural alignment mark all is set on every layer of substrate, utilizes body formula mirror to carry out accurate stack operation, and utilize UV/ozone to handle or the oxygen plasma treatment technology realizes irreversible bonding between each layer substrate, and then finish the compound of sandwich construction.
Single substrate comprises two imports, wherein biomone suspension drives through Micropump and injects asymmetric curved runner by entrance, realize prefocus and the size separation of particle by the microfluid inertia effect (inertia migration and cross section secondary stream), particle to be measured continues to move in chip, disturbs the survey particle then to flow to the waste collection device from the chip outlet.Another entrance of chip feeds PVP, PEO, PSB etc. and has viscoelastic property and the good cleaning exchange liquid of optical property.
The long-pending flow of exchanging liquid needs obviously greater than sample liquid, and exchange liquid and particle suspension to be replaced are intersected in and change the liquid runner.Because two kinds of flow rate of liquid differences make exchange liquid a fluid stream width greater than particle suspension a fluid stream width to be replaced, particle migrates to and changes liquid runner center under the effect of inertia lift, is in the exchange liquid.After long enough distance, obtain the viscoplasticity particle suspension and do not contain the waste liquid of particle to be measured.After two kinds of fluids process fork structures, waste liquid flow to the waste collection device by the chip outlet, and the viscoplasticity particle suspension then continues to flow along straight channel.Utilization is originally changed the liquid runner and is realized that particle to be measured cleans automatically, has eliminated impurity in the particle suspension to be measured (for example hemoglobin, bib and other small size interference cells etc.).Realize that by the microfluid inertia effect and Viscoelastic effect particle to be measured focuses on cross section of fluid channel geometric center position and goes forward side by side into optics detection counting region.After optical detection, finally flow to the waste collection device from outlet.In the optical detection link four optical-fibre channels are arranged, the optical fiber level is inserted these passages, is used for emission laser and receiving optical signals.Wherein exciting light optical fiber channel vertical is in sprue, is the fluorescence optical fiber passage in the optical-fibre channel of exciting light optical fiber passage homonymy, and opposite side then is respectively forward angle light scatter optical-fibre channel and side scattered light optical-fibre channel.The optical signalling of injecting optical fiber is converted to data signal through photoelectric conversion device, and obtains number of particles to be measured and multinomial biomone detected parameters by corresponding recognizer.All substrates share identical gateway connecting hole, namely no matter the substrate number of plies what, chip gateway connecting hole quantity is constant.
The integrated design of multilayer, multichannel that the present invention proposes, biomone sorting, counting efficiency have significantly been improved, compare with traditional flow cytometry detection technique, multi layer substrate pile up and the pendular ring joint is cleaned and changed to asymmetric curved runner inertia prefocus link, viscoelastic fluid particle, viscoplasticity has realized high flux, high-precision biomone sorting and count detection well with the integrated application of the single equilbrium position focusing of inertia effect link, optical detection link.
Beneficial effect: integrated highly effective particle sorting counting, detection chip system that the present invention proposes, ingenious focusing and the sorting that utilizes the inertia effect realization particle of microfluid in the asymmetric curved runner on the single substrate, utilize in the straight channel inertia migration to realize that particle cleans and change liquid then, moreover utilizing viscoplasticity and the inertia effect to realize particle at single equilbrium position of runner central area vernier focusing, the integrated optical fiber passage is convenient to and optics encapsulation splicing simultaneously.Detect counting with other particle countings and compare, this chip system have cost low, simple to operate, need not sheath fluid, precision height and automation, integrated degree advantages of higher.In addition, the main body micro-fluidic chip adopts multi layer substrate to pile up among the present invention, realizes high flux, quick, the microminiaturized count detection of particle.Chip system and method that the present invention proposes can be widely used in fields such as biology, clinical diagnosis, environmental monitoring and biochemical analysis.
Description of drawings
System-on-chip schematic diagram in Fig. 1 embodiment of the invention 1.
Non-bottom substrate schematic diagram, i.e. A-A cross-sectional view in Fig. 2 embodiment of the invention 1.
Change liquid runner particle carrying liquid exchange principle figure in Fig. 3 embodiment of the invention 7.
Fig. 4 A embodiment of the invention 8 middle section centre focus straight channel particle list equilbrium position focusing principle side views.
Fig. 4 B is that the embodiment of the invention 8 middle section centre focus straight channel particle list equilbrium positions focus on runner B-B sectional view.
Fig. 4 C is that the embodiment of the invention 8 middle section centre focus straight channel particle list equilbrium positions focus on runner C-C sectional view.
Optical detection zone particle optics Characteristics Detection schematic diagram in Fig. 5 embodiment of the invention 8.
The specific embodiment
The biological particle high flux sorting that the present invention proposes and the system-on-chip of count detection, embodiment as shown in Figure 1.Non-bottom substrate schematic diagram, namely the A-A cross-sectional view as shown in Figure 2.The present invention the application of chip material, manufacture craft, the substrate number of plies, microstructure size, optical fiber specification, fluorescence detector, signal processing method and the chip system that can use be not limited to present embodiment.
Embodiment 1:
As depicted in figs. 1 and 2, the system-on-chip of the sorting of biological particle high flux and count detection, comprise main body micro-fluidic chip 10, microtubule 17, sample liquid Micropump 11, exchange liquid Micropump 18, the first waste collection device 12, the second waste collection device 19, three wastes liquor collecting device 20, laser beam emitting device 13, photoelectric conversion device 14, computer 15 and optical fiber 16 are connected with microtubule 17 on the main body micro-fluidic chip 10, sample liquid Micropump 11, exchange liquid Micropump 18, the first waste collection device 12, the second waste collection device 19, three wastes liquor collecting device 20, laser beam emitting device 13, photoelectric conversion device 14, optical fiber 16;
Described main body micro-fluidic chip 10 includes asymmetric curved runner 23, first branched bottom 285, second branched bottom 286, the 3rd branched bottom 287, sprue 288, bypass passage 289, gateway connecting hole 201, sample inlet 21, exchange liquid entrance 22, particle outlet 24 is disturbed in pre-sorting, be replaced carrying liquid outlet 26, waste liquid outlet 29, exciting light optical fiber passage 281, forward angle light scatter optical-fibre channel 282, lateral angle scattering optical-fibre channel 283 and fluorescence optical fiber passage 284 and alignment mark 202;
Described main body micro-fluidic chip 10 piles up bonding by a plurality of single substrate 101,102,103 and forms;
Every layer of single substrate 101,102,103 layouts are just the same, described sample inlet 21, exchange liquid entrance 22, particle outlet 24 is disturbed in pre-sorting, be replaced carrying liquid outlet 26, be equipped with gateway connecting hole 201 on the waste liquid outlet 29, described sample liquid Micropump 11 is connected with microtubule 17 1 ends, microtubule 17 other ends link to each other with gateway connecting hole 201 on the sample inlet 21, sample inlet 21 is connected with asymmetric curved runner 23, asymmetric curved runner 23 is told first branched bottom 285 and second branched bottom 286, first branched bottom 285 disturbs particle outlet 24 to be connected with pre-sorting, pre-sorting disturbs the gateway connecting hole 201 in the particle outlet 24 to be connected with the first waste collection device 12, second branched bottom 286 and the 3rd branched bottom 287 1 ends are intersected in sprue 288, described the 3rd branched bottom 287 other ends are connected with exchange liquid entrance 22, gateway connecting hole 201 on the exchange liquid entrance 22 is connected with exchange liquid Micropump 18, be provided with successively on the described sprue 288 and change liquid runner 25, kernel of section focus DC road 27, optical detection zone 28, described sprue 288 ends are connected with waste liquid outlet 29, gateway connecting hole 201 on the waste liquid outlet 29 is connected with the second waste collection device 19, the described liquid runner 25 that changes is told a bypass passage 289, described bypass passage 289 be replaced carrying liquid outlet 26 and be connected, the gateway connecting hole 201 that is replaced in the carrying liquid outlet 26 is connected with three wastes liquor collecting device 20, described laser beam emitting device 13 is connected with exciting light optical fiber passage 281 by optical fiber, described photoelectric conversion device 14 by optical fiber respectively with forward angle light scatter optical-fibre channel 282, lateral angle scattering optical-fibre channel 283 is connected with fluorescence optical fiber passage 284, described photoelectric conversion device 14 is connected with computer 15 by optical fiber 16, described exciting light optical fiber passage 281 and forward angle light scatter optical-fibre channel 282 lay respectively at sprue 288 both sides, exciting light optical fiber passage 281 is perpendicular to sprue 288, forward angle light scatter optical-fibre channel 282 is 0.5 ° with the angle of exciting light optical fiber passage 281 extended lines, described lateral angle scattering optical-fibre channel 283 and fluorescence optical fiber passage 284 lay respectively at the both sides of sprue 288, the angle of described lateral angle scattering optical- fibre channel 283 and 281 one-tenth 120 ° in exciting light optical fiber passage, described fluorescence optical fiber passage 284 respectively with the angle of 281 one-tenth 60 ° in exciting light optical fiber passage, described alignment mark 202 has a plurality of, lay respectively at described single substrate 101, four angles of 102,103.
Described liquid runner 25 cross sections of changing are rectangle.
The described exchanging liquid that changes in the liquid runner 25 amasss flow greater than sample liquid volume flow, kernel of section focus DC road 27 width are greater than bypass passage 289, and the long-pending flow of exchanging liquid/sample liquid volume flow is greater than kernel of section focus DC road 27 width/bypass passage 289.
Described main body micro-fluidic chip 10 forms for the on all four substrate stack bonding of multilayer.
The used material of described main body micro-fluidic chip 10 its substrates is a kind of in dimethyl silicone polymer, glass, epoxy resin, polymethyl methacrylate, the Merlon.
Around optical detection zone 28, be integrated with exciting light optical fiber passage 281, forward angle light scatter optical-fibre channel 282, lateral angle scattering optical-fibre channel 283, fluorescence optical fiber passage 284, exciting light optical fiber and detection fiber are all inserted passage and fixedly are integrated on the chip, launch exciting light from the side and receive sensed light signal.
The height of described asymmetric curved runner 23, sprue 288, first branched bottom 285, second branched bottom 286, the 3rd branched bottom 287, bypass passage 289, exciting light optical fiber passage 281, forward angle light scatter optical-fibre channel 282, lateral angle scattering optical-fibre channel 283 and fluorescence optical fiber passage 284 equates.
Described photoelectric conversion device 14 is converted to data signal with detected optical signal and imports computer 15 and utilize corresponding software to carry out the analyzing and processing of related data.Wherein, described photoelectric conversion device 14 comprises filter, analog-digital converter and photodiode, photomultiplier etc.
Present embodiment with a kind of sandwich construction biological particle based on viscoplasticity and the inertia effect fast, high accuracy sorting and count detection chip be that example is set forth method, element manufacturing, system constructing and the count detection principle that proposes among the present invention.The material of the non-bottom substrate of main body micro-fluidic chip is selected dimethyl silicone polymer (PDMS) for use in the present embodiment.Certainly, also can select for use glass, epoxy resin, polymethyl methacrylate (PMMA), the good material of Merlon optical properties such as (PC) to make.Chip manufacture technology, the bonding techniques of different materials correspondence may there are differences, and can select respective material according to processing conditions and application demand.Utilize maskless lithography technology to make the SU-8 formpiston in the present embodiment, and adopt method of molding to make individual layer PDMS substrate.This manufacture craft has that cost is low, fabrication cycle is short, be suitable for advantage such as batch process.Certainly can consider also that in conjunction with practical application request and processing conditions employing has technology such as mask lithography, ultraprecise machined to make formpiston, even can directly finish substrate by other manufacturing process and make.
Embodiment 2:
The same substantially with embodiment 1, difference is, forward angle light scatter optical-fibre channel 282 is 6 ° with the angle of exciting light optical fiber passage 281 extended lines, described lateral angle scattering optical-fibre channel 283 and fluorescence optical fiber passage 284 lay respectively at the both sides of sprue 288, the angle of lateral angle scattering optical- fibre channel 283 and 281 one-tenth 110 ° in exciting light optical fiber passage, the angle of fluorescence optical fiber passage 284 and 281 one-tenth 70 ° in exciting light optical fiber passage, the used material of described main body micro-fluidic chip 10 its substrates is epoxy resin.
Embodiment 3:
The same substantially with embodiment 1, difference is, forward angle light scatter optical-fibre channel 282 is 3 ° with the angle of exciting light optical fiber passage 281 extended lines, described lateral angle scattering optical-fibre channel 283 and fluorescence optical fiber passage 284 lay respectively at the both sides of sprue 288, the angle of lateral angle scattering optical- fibre channel 283 and 281 one-tenth 100 ° in exciting light optical fiber passage, the angle of fluorescence optical fiber passage 284 and 281 one-tenth 80 ° in exciting light optical fiber passage, the used material of described main body micro-fluidic chip 10 its substrates is methyl methacrylate.
Embodiment 4:
The same substantially with embodiment 1, difference is, forward angle light scatter optical-fibre channel 282 is 3.5 ° with the angle of exciting light optical fiber passage 281 extended lines, described lateral angle scattering optical-fibre channel 283 and fluorescence optical fiber passage 284 lay respectively at the both sides of sprue 288, the angle of lateral angle scattering optical- fibre channel 283 and 281 one-tenth 105 ° in exciting light optical fiber passage, the angle of fluorescence optical fiber passage 284 and 281 one-tenth 75 ° in exciting light optical fiber passage, the used material of described main body micro-fluidic chip 10 its substrates is Merlon.
Embodiment 5:
The same substantially with embodiment 1, difference is, forward angle light scatter optical-fibre channel 282 is 4.5 ° with the angle of exciting light optical fiber passage 281 extended lines, described lateral angle scattering optical-fibre channel 283 and fluorescence optical fiber passage 284 lay respectively at the both sides of sprue 288, the angle of lateral angle scattering optical- fibre channel 283 and 281 one-tenth 95 ° in exciting light optical fiber passage, the angle of fluorescence optical fiber passage 284 and 281 one-tenth 85 ° in exciting light optical fiber passage, the used material of described main body micro-fluidic chip 10 its substrates is glass.
Embodiment 6:
The concrete technological process that the PDMS substrate is made is as follows: at first, utilize CAD software drafting chip runner figure and it is imported maskless lithography equipment.The SU-8 photoresist of spin coating specific thicknesses on through pretreated silicon chips such as cleaning, dehydration, and the SU-8 silicon chip after the spin coating placed progressively to heat up to heat on the hot plate carry out preceding baking.Then, the SU-8 silicon chip that preceding baking is intact places maskless lithography equipment to carry out exposure-processed, and the substrate of finishing exposure also need expose to the sun again to afterwards drying by the fire to heat and just can develop.At last, the formpiston that development is obtained dries by the fire heating firmly to improve the mechanical strength that keeps micro-structural, has so just finished the making of SU-8 formpiston.Based on SU-8 formpiston and method of molding, through concrete processing step such as PDMS proportioning, stirring, reverse mould, vacuum outgas, PDMS curing, the demoulding, finally obtain required individual layer PDMS substrate.
Embodiment 7:
Change liquid runner particle carrying liquid exchange process and principle:
Entered asymmetric curved runner 23 through microtubule 17 from sample inlet 21 by the sample liquid of sample liquid Micropump 11 superchargings.Satisfy a
P〉=0.07D
h(a wherein
PBe particle diameter, D
hBe the runner hydraulic diameter) particle drag at the Dien that inertia lift (comprise shear-induced inertia lift and wall and induce inertia lift) and cross section secondary stream are induced and focus on equilbrium position and the more big focal position of particle diameter under the acting in conjunction of power the closer to internal face, and particle diameter is less than 0.07D
hParticle then can't focus on and particle diameter more little of outside wall surface.Particle to be measured is that particle diameter is greater than 0.07D in the present embodiment
hClose outside wall surface than small-particle, near the disturbing particle outlet 24 to be drawn by branch road by pre-sorting and import waste collection devices 12 through microtubule 17 than macroparticle of internal face, then continue in chip, to flow to flow to the exchange liquid 252 that enters chip by exchange liquid entrance 22 than small-particle near internal face and change liquid runner 25.Utilize sample liquid Micropump 11 and the volume flow of changing two kinds of liquid of liquid Micropump 18 controls to make exchange liquid 252 volume flows obviously greater than sample liquid.Certainly, can increase asymmetric curved runner 23 terminal fork branch road numbers realizes multiple sized particles sorting and liquid runner 25 is changed in particle 253 place branch roads introducings to be measured.Unsuitable excessive and both flow velocitys of the angle that particle suspension to be replaced 251 and exchange liquid 252 cross can not be too high, is laminar condition to guarantee two fluid streams.Fig. 3 is for changing liquid runner particle carrying liquid exchange principle figure in the embodiment of the invention.Enter change liquid runner 25 after, because runner broadens and causes that the shearing rate gradient reduces on the width, thereby the shear-induced inertia lift 255 that causes particle 253 to be measured to be subjected to reduces, and induces inertia lift 254 less than wall, causes that particle 253 to be measured moves to the runner center position.Simultaneously, exchange liquid 252 volume flows are greater than particle suspension 251 volume flows to be replaced, make the former laminar flow width greater than the latter, and particle is in when focusing on balance in exchange liquid 252 a fluid streams, forms new viscoplasticity particle suspension 257.Do not contained particle to be measured and be replaced in carrying liquid 256 a fluid streams, flow to waste collection device 12 by being replaced carrying liquid outlet 26, thereby realized the renewal exchange of particle carrying liquid, new particle suspension does not contain interference impurity, namely reaches the purpose that particle cleans automatically.
Embodiment 8:
Particle list equilbrium position, kernel of section focus DC road focuses on process and optical characteristics testing process:
New particle carrying liquid is viscoelastic solution, particle with this flow of solution focuses on the runner center under the acting in conjunction of the inertia effect and buoyancy effect, shown in Fig. 4 A, 4B, 4C, Fig. 4 A is the flow passage side view, and Fig. 4 B and Fig. 4 C are respectively runner B-B and C-C sectional view.B place particle focuses near the runner upper and lower surface center, and particle is subjected to pointing to the elastic force 271 of kernel of section under the Viscoelastic effect effect, and particle also is subjected to wall and induces inertia lift 254 and shear-induced inertia lift 255 under inertia effect effect simultaneously.Under the acting in conjunction of these power, particle finally focuses on the kernel of section position.The big young pathbreaker of the particle beams to be measured influences the count detection precision, and the present invention has utilized the inertia effect and Viscoelastic effect to make particle beams size very near particle to be measured simultaneously, effectively avoids tested particle 55 overlapping, has improved the precision of count detection greatly.Exciting light optical fiber passage 281 is perpendicular to sprue, the exciting light that excitation light emission device 13 sends is through inserting the tested particle 55 of optical fiber directive of exciting light optical fiber passage 281, tested particle 55 is stimulated, with the angular range of 51 one-tenth 0.5 °～6 ° of incident lights in produce forward angle light scatter light 52, desirable 0.5 °～6 ° of the angle of forward angle light scatter optical-fibre channel 282 and exciting light optical fiber passage 281 extended lines, but exciting light optical fiber passage 281 can not be on same straight line with forward angle light scatter optical-fibre channel 282, otherwise exciting light will be injected forward angle light scatter optical fiber with forward angle light scatter light, disturb forward angle light scatter light to detect.Described lateral angle scattering optical-fibre channel 283 and fluorescence optical fiber passage 284 lay respectively at the both sides of sprue 288, described lateral angle scattering optical- fibre channel 283 and 281 one-tenth 95 °～120 ° in exciting light optical fiber passage, described fluorescence optical fiber passage 284 respectively with the angle of 281 one-tenth 60 °～85 ° in exciting light optical fiber passage, optical fiber surveyed area principle is as shown in Figure 5.Optical-fibre channel height and optical fiber external diameter equal and opposite in direction, guarantee that fiber optic hub and cross section of fluid channel center are that tested particle 55 is on same straight line, emission light can be hit tested particle 55 accurately like this, and the scattered light that tested particle 55 sends and fluorescence can be injected signal detection optical fiber accurately.Forward angle light scatter light 52 signals reflection cell volume size, forward angle light scatter light the last 52, then cell volume is more big, on the contrary cell volume is little.Lateral angle scattered light 53 signals can provide the information of the interior fine structure of cell and particle properties.Fluorescence 54 intensity are directly proportional with cell interior DNA, RNA and protein content, (generation of fluorescence signal mainly contains two kinds can to judge these constituent contents, antigen and enzymatic activity in the cell by fluorescence 54 signal detection, a kind of fluorescent material that is marked on the cell is stimulated and produces, and another kind is that cell self is stimulated and produces).Directly flow to waste collection device 12 through waste liquid outlet 29 through optical detection zone 28 back viscoplasticity particle suspensions 257.Simultaneously, for increasing the chip flux to improve the system counts detection speed, present embodiment adopts a plurality of single substrate 101,102,103 to pile up, and all substrates share gateway connecting hole 201.Utilize the irreversible bonding between UV/ozone bonding techniques realization substrate to realize accurately piling up between substrate by on-chip "+" alignment mark 202 ligand visors or other calibration auxiliary equipment simultaneously.To finish a plurality of single substrate 101,102 gateways of bonding before the bonding bottom substrate 103 earlier and punch with perforating device, obtain gateway connecting hole 201, finish the bonding with the single substrate 103 of the bottom at last.Insert corresponding optical fiber 16 in the chip optical-fibre channel, optical fiber 16 external diameters are corresponding with the optical-fibre channel size, to guarantee that optical fiber 16 is fixed on the chip.In addition, for avoiding the phase mutual interference of optical signal between the different layers substrate, selected Optical Fiber Numerical Aperture can not be excessive, away from simultaneously optical-fibre channel can not be crossed from optical detection zone 28 and single substrate thickness can not too small (the too little flow passage structure that also can cause of single substrate thickness be yielding).The optical fiber 16 of chip adds up to 4 times of substrate quantity (substrate 103 that does not comprise the bottom that does not have runner.Forward angle light scatter light 52 signals are stronger, can utilize photodiode that this optical signal is converted to the signal of telecommunication, and fluorescence 54 signals a little less than, need to realize that by photomultiplier (PMP) photoelectricity transforms that lateral angle scattered light 53 is selective light electric diode or photomultiplier according to demand.The detection signal that imports computer 15 into obtains parameters such as number of particles, dna content and surface antigen through the related software analyzing and processing.
The above only is preferred embodiment of the present invention; be noted that for those skilled in the art; under the prerequisite that does not break away from the principle of the invention, can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (9)
1. the system-on-chip of the sorting of biological particle high flux and count detection, it is characterized in that: comprise main body micro-fluidic chip (10), microtubule (17), sample liquid Micropump (11), exchange liquid Micropump (18), the first waste collection device (12), the second waste collection device (19), three wastes liquor collecting device (20), laser beam emitting device (13), photoelectric conversion device (14), computer (15) and optical fiber (16) are connected with microtubule (17) on the main body micro-fluidic chip (10), sample liquid Micropump (11), exchange liquid Micropump (18), the first waste collection device (12), the second waste collection device (19), three wastes liquor collecting device (20), laser beam emitting device (13), photoelectric conversion device (14), optical fiber (16);
Described main body micro-fluidic chip (10) includes asymmetric curved runner (23), first branched bottom (285), second branched bottom (286), the 3rd branched bottom (287), sprue (288), bypass passage (289), gateway connecting hole (201), sample inlet (21), exchange liquid entrance (22), particle outlet (24) is disturbed in pre-sorting, be replaced carrying liquid outlet (26), waste liquid outlet (29), exciting light optical fiber passage (281), forward angle light scatter optical-fibre channel (282), lateral angle scattering optical-fibre channel (283) and fluorescence optical fiber passage (284) and alignment mark (202);
Described main body micro-fluidic chip (10) piles up bonding by a plurality of single substrate (101,102,103) and forms;
Every layer of single substrate (101,102,103) layout is just the same, described sample inlet (21), exchange liquid entrance (22), particle outlet (24) is disturbed in pre-sorting, be replaced carrying liquid outlet (26), be equipped with gateway connecting hole (201) on the waste liquid outlet (29), described sample liquid Micropump (11) is connected with microtubule (17) one ends, microtubule (17) other end links to each other with gateway connecting hole (201) on the sample inlet (21), sample inlet (21) is connected with asymmetric curved runner (23), asymmetric curved runner (23) is told first branched bottom (285) and second branched bottom (286), first branched bottom (285) disturbs particle outlet (24) to be connected with pre-sorting, pre-sorting disturbs the gateway connecting hole (201) in the particle outlet (24) to be connected with the first waste collection device (12), second branched bottom (286) and the 3rd branched bottom (287) one ends are intersected in sprue (288), described the 3rd branched bottom (287) other end is connected with exchange liquid entrance (22), gateway connecting hole (201) on the exchange liquid entrance (22) is connected with exchange liquid Micropump (18), be provided with successively on the described sprue (288) and change liquid runner (25), kernel of section focus DC road (27), optical detection zone (28), described sprue (288) is terminal to be connected with waste liquid outlet (29), gateway connecting hole (201) on the waste liquid outlet (29) is connected with the second waste collection device (19), the described liquid runner (25) that changes is told a bypass passage (289), described bypass passage (289) be replaced carrying liquid outlet (26) and be connected, the gateway connecting hole (201) that is replaced in the carrying liquid outlet (26) is connected with three wastes liquor collecting device (20), described laser beam emitting device (13) is connected with exciting light optical fiber passage (281) by optical fiber, described photoelectric conversion device (14) by optical fiber respectively with forward angle light scatter optical-fibre channel (282), lateral angle scattering optical-fibre channel (283) is connected with fluorescence optical fiber passage (284), described photoelectric conversion device (14) is connected with computer (15) by optical fiber (16), described exciting light optical fiber passage (281) and forward angle light scatter optical-fibre channel (282) lay respectively at sprue (288) both sides, exciting light optical fiber passage (281) is perpendicular to sprue (288), forward angle light scatter optical-fibre channel (282) is 0.5 °～6 ° with the angle of exciting light optical fiber passage (281) extended line, described lateral angle scattering optical-fibre channel (283) and fluorescence optical fiber passage (284) lay respectively at the both sides of sprue (288), described lateral angle scattering optical-fibre channel (283) becomes 95 °～120 ° with exciting light optical fiber passage (281), described fluorescence optical fiber passage (284) becomes 60 °～85 ° angle respectively with exciting light optical fiber passage (281), described alignment mark (202) has a plurality of, lay respectively at described single substrate (101,102,103) four angles.
2. the system-on-chip of biological particle high flux as claimed in claim 1 sorting and count detection is characterized in that: described to change liquid runner (25) cross section be rectangle.
3. the system-on-chip of biological particle high flux as claimed in claim 1 sorting and count detection, it is characterized in that: the described exchanging liquid that changes in the liquid runner (25) amasss flow greater than sample liquid volume flow, kernel of section focus DC road (27) width is greater than bypass passage (289), and the long-pending flow of exchanging liquid/sample liquid volume flow is greater than kernel of section focus DC road (27) width/bypass passage (289).
4. the system-on-chip of biological particle high flux as claimed in claim 1 sorting and count detection, it is characterized in that: described main body micro-fluidic chip (10) forms for the on all four substrate stack bonding of multilayer.
5. the system-on-chip of biological particle high flux as claimed in claim 1 sorting and count detection is characterized in that: the used material of its substrate of described main body micro-fluidic chip (10) is a kind of in dimethyl silicone polymer, glass, epoxy resin, polymethyl methacrylate, the Merlon.
6. the system-on-chip of biological particle high flux as claimed in claim 1 sorting and count detection, it is characterized in that: be integrated with exciting light optical fiber passage (281), forward angle light scatter optical-fibre channel (282), lateral angle scattering optical-fibre channel (283), fluorescence optical fiber passage (284) all around in optical detection zone (28), exciting light optical fiber and detection fiber are all inserted passage and fixedly are integrated on the chip, launch exciting light from the side and receive sensed light signal.
7. the system-on-chip of biological particle high flux as claimed in claim 1 sorting and count detection is characterized in that: the height of described asymmetric curved runner (23), sprue (288), first branched bottom (285), second branched bottom (286), the 3rd branched bottom (287), bypass passage (289), exciting light optical fiber passage (281), forward angle light scatter optical-fibre channel (282), lateral angle scattering optical-fibre channel (283) and fluorescence optical fiber passage (284) equates.
8. the system-on-chip of biological particle high flux as claimed in claim 1 sorting and count detection, it is characterized in that: described photoelectric conversion device (14) is converted to data signal with detected optical signal and imports computer (15) and utilize corresponding software to carry out the analyzing and processing of related data.
9. the application of system-on-chip in biomone sorting and count detection of each described biological particle high flux sorting of claim 1-8 and count detection.
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