CN103323383A - Particle counting system of micro-fluidic chip based on electric resistance technology - Google Patents
Particle counting system of micro-fluidic chip based on electric resistance technology Download PDFInfo
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- CN103323383A CN103323383A CN2013102176884A CN201310217688A CN103323383A CN 103323383 A CN103323383 A CN 103323383A CN 2013102176884 A CN2013102176884 A CN 2013102176884A CN 201310217688 A CN201310217688 A CN 201310217688A CN 103323383 A CN103323383 A CN 103323383A
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Abstract
The invention discloses a particle counting system of a micro-fluidic chip based on an electric resistance technology. The system comprises a micro-fluidic chip and a signal detection circuit. The micro-fluidic chip comprises a glass substrate, a PDMS substrate and two pairs of metal needles used as electrodes. Normal conductive metal needles are utilized as the electrodes of the micro-fluidic chip to produce an electric field which is across a micro-channel, therefore the preparation process of the micro-fluidic chip is comparatively simple and the production cost is comparatively low. The signal detection circuit comprises two I/V conversion circuit, a differential circuit, an envelope detection circuit, a high-pass filter circuit, a low-pass filter circuit and an amplifying circuit. The resistance signals are detected in the signal detection circuit by utilizing signal differential detection method to ensure precision of signal detection.
Description
Technical field
Invention relates to a kind of counting micro particles system, is specifically related to a kind of micro-fluidic chip counting micro particles system based on electrical impedance technology, belongs to the electrical detection technical field.
Background technology
The electrical impedance counting technology is to be used for the earliest particulate/Cytometric automatic technology.Because particulate/cell can be used as insulating bodies to a certain extent, when particulate/cell passes through a certain fixed area electric field, can make the impedance in this stationary electric field zone become large; When particulate/cell left electric field region, it is normal that impedance recovers again; The size of impedance signal and the volume of particulate/cell are directly proportional.Therefore people utilize this characteristic particulate/cell is counted and to be classified.But present commercial electrical impedance counter is generally relatively large, can't satisfy portable requirement; And based on the counting technology of micro-fluidic chip technology, provide the possibility that solves for this requirement.
The micro-fluidic chip technology refers to integrated basic operation units such as sample preparation related in the fields such as biological and chemical, reaction, separation, detections or substantially is integrated on the chip of more than square centimeters (even less), form network by the microchannel, run through whole system with controlled fluid, in order to a kind of technology platform of the various functions that replace conventional biological or chemical laboratory.Obviously, the micro-fluidic chip technology has the series of features such as volume is little, portable high, application is convenient, so that on-the-spot instant detection of some pathology parameters become possibility, the application space is very extensive.Over past ten years, the micro-fluidic chip technical development is very rapid, especially in the research field for particulate/cell count and sorting.
But the micro-fluidic chip counting micro particles device of present stage all need to micro-fluidic chip electroplate or splash-proofing sputtering metal as electrode, and with electrode for generation of the electric field across the microchannel.This design is so that chip manufacturing process and cost relative complex, and cost compare is high.Simultaneously this design, the electrode each interval is very near, easily causes passage internal induction electric field intensity inhomogeneous.Even the particulate of same class size because the position of the microchannel of flowing through is different, also can cause signal intensity to differ; Have a strong impact on the concrete application of counting assembly.In order to solve this class problem, the researchist introduces various focus methods, and for example dielectrophoresis focuses on, and the methods such as ultrasound wave focusing focus on particulate/cell, although improved so to a certain extent signal stabilization, also improved simultaneously complexity and the cost of package unit.
Simultaneously, in the micro-fluidic chip counting micro particles device of present stage, because signal to noise ratio (S/N ratio) is lower, so detection system generally adopts the technology of more complicated, synchronous detection technology is for example perhaps used very expensive instrument, realizes detection to feeble signal such as lock-in amplifier etc.So that the cost burden of whole device is very large, special-purpose instrument also can't satisfy portability, cheaply requirement simultaneously.
Summary of the invention
In view of this, the invention provides a kind of micro-fluidic chip counting micro particles system based on electrical impedance technology, this system architecture is simple, easily manufactured, cost is low and be easy to carry.
This system comprises micro-fluidic chip and signal deteching circuit; Described micro-fluidic chip comprises: glass substrate, polydimethylsiloxane substrate and two pairs of metal needles as electrode; Described signal deteching circuit comprises: two I/V change-over circuits, difference channel, envelope detection circuit, high-pass filtering circuit, low-pass filter circuit and amplifying circuits.
In the described micro-fluidic chip, the PDMS substrate is bonded in the upper surface of glass substrate, is processed with respectively sample flow entrance, liquid flow export, sprue, sheath fluid inflow entrance and electrode mounting hole at the PDMS substrate upper surface; Be specially: in the center of PDMS substrate upper surface, process strip groove as sprue along its length direction.Symmetria bilateralis processing two arrays of electrodes mounting hole at sprue is embedded in a metal needle at each electrode mounting hole.Connect by rectangular recess between four electrode mounting holes and the sprue; At the sample flow entrance that the processing of an end end of sprue and sprue connect, the liquid flow export that end processing and the sprue of the other end connects.Symmetria bilateralis at described sample flow entrance is processed with the sheath fluid inflow entrance, and two sheath fluid inflow entrances and sprue connect.The degree of depth of above-mentioned sample flow entrance, liquid flow export, sheath fluid inflow entrance and electrode mounting hole all with the consistency of thickness of PDMS substrate.Be referred to as the microchannel with the sprue on the described micro-fluidic chip and with passage that sprue connects, the degree of depth of described microchannel is all consistent; In two pairs of metal needles on the described micro-fluidic chip, two metal needles that are positioned at sprue one side link to each other with outside sine wave AC driving source respectively, and each links to each other two metal needles of opposite side with an I/V change-over circuit.
In the described signal deteching circuit, the output terminal of two I/V change-over circuits links to each other with two input ends of difference channel respectively, the output terminal of difference channel links to each other with envelope detection circuit, envelope detection circuit links to each other with low-pass filter circuit by high-pass filtering circuit, the amplifying circuit of the output termination afterbody of low-pass filter circuit.Described I/V change-over circuit is used for the current signal that collects is converted to voltage signal, and the two-way voltage signal produces into differential signal by difference channel; Described envelope detection circuit is used for extracting the impedance signal of differential signal, and the impedance signal that extracts is carried out the amplification of the first order; After the flip-flop in the received impedance signal of high-pass filtering circuit filtering impedance signal is carried out the amplification of the second level; After the carrier signal in the impedance signal that the low-pass filter circuit filtering receives, impedance signal is carried out the amplification of afterbody by amplifying circuit, the number of last impedance signal according to exporting realizes the counting to particulate.
The degree of depth of described sprue and width are 1.5 times to 3 times of mean particle dia to be detected; The width of rectangular recess is 10 μ m to 50 μ m between through electrode mounting hole and the sprue; Described electrode mounting hole and and sprue between distance be 20 μ m; Distance H between two groups of metal needles
1Be 100 μ m to 200 μ m.
In the described signal deteching circuit, the version of two I/V change-over circuits is identical; The I/V change-over circuit comprises operational amplifier A and sampling resistor; The electrode input end ground connection of operational amplifier A wherein, negative input links to each other with metal needle as electrode, is connected sampling resistor R0 between its output terminal and negative input; Described difference channel comprises differential amplifier U1, operational amplifier C, resistance R 3 and resistance R 4; The output terminal of operational amplifier links to each other with two input ends of differential amplifier U1 respectively in two I/V change-over circuits, the output terminal of differential amplifier U1 links to each other with the electrode input end of operational amplifier C, the negative input of operational amplifier C passes through resistance R 3 ground connection, simultaneously contact resistance R4 between its negative input and output terminal; The output terminal of operational amplifier C links to each other with envelope detection circuit.
Described envelope detection circuit comprises diode D6, resistance R 2, capacitor C 1 and operational amplifier D; The output terminal of operational amplifier C links to each other with the negative electrode of diode D6, and the anode of diode D6 links to each other with the electrode input end of operational amplifier D; Be connected between the anode and ground of diode after resistance R 2 and capacitor C 1 parallel connection; The output terminal of described operational amplifier D links to each other with high-pass filtering circuit.
Described high-pass filtering circuit comprises operational amplifier E, resistance R 5, resistance R 6, capacitor C 2 and capacitor C 3; The output terminal of operational amplifier D links to each other with the electrode input end of operational amplifier E with resistance R 6 afterwards by resistance R 5 successively, the electrode input end of operational amplifier E is by capacitor C 3 ground connection simultaneously, one end of capacitor C 2 links to each other with the output terminal of operational amplifier E, and the other end is connected between resistance R 5 and the resistance R 6; Contact resistance R7 between the negative input of operational amplifier E and ground, connecting resistance R8 between its negative input and the output terminal; The output terminal of operational amplifier E links to each other with low-pass filter circuit.
Described low-pass filter circuit comprises resistance R 9, resistance R 12, capacitor C 4, capacitor C 5 and operational amplifier F; The output terminal of operational amplifier E links to each other with the electrode input end of capacitor C 5 with operational amplifier F by capacitor C 4, and the electrode input end of operational amplifier F is by resistance R 9 ground connection simultaneously; One end of resistance R 12 links to each other with the output terminal of operational amplifier F, and the other end is connected between capacitor C 4 and the capacitor C 5; Contact resistance R10 between operational amplifier F negative input and ground, connecting resistance R11 between operational amplifier F negative input and the output terminal; The output terminal of operational amplifier F links to each other with amplifying circuit.
Described amplifying circuit comprises operational amplifier H, resistance R 13 and resistance R 14; The output terminal of described operational amplifier F links to each other with the electrode input end of operational amplifier H, and the negative input of operational amplifier H is by resistance R 13 ground connection, simultaneously contact resistance R14 between the output terminal of operational amplifier H and negative input.
Described sine wave AC driving source frequency is 500KHz～1.2MHz, and peak value is 3V～5V.
The resistance of sampling resistor is 30K Ω～300K Ω in the described I/V change-over circuit, and the enlargement factor of described differential amplifier U1 is less than or equal to 10 times, and described low-pass filter circuit cutoff frequency is 1/10th of sine-wave excitation frequency input signal.
Described metal needle as electrode is acupuncture needle or platinum pin.
Job operation based on micro-fluidic chip in the micro-fluidic chip counting micro particles system of electrical impedance technology is:
After the size of microchannel each several part, draw on computers the microchannel plane design drawing on step 1, the known micro-fluidic chip;
The developing solution dissolution of the negative photoresist coupling in step 5, utilization and the step 3 is fallen the negative photoresist that cross-linking reaction does not occur on the silicon chip; Then adopt the pure water rinsing silicon chip, dry up pure water on the silicon chip with nitrogen after cleaning; The remaining negative photoresist structure of silicon chip upper surface this moment is the formpiston part of micro-fluidic chip, and described formpiston partly refers to the spatial structure of microchannel, and its thickness is consistent with the degree of depth of microchannel;
In the described step 4, after exposure is finished, the silicon chip after the exposure was heated 1 minute under 100 ℃ constant temperature.
The PDMS substrate that will be bonded together in the described step 9 and glass substrate heated 4 hours under 100 ℃ constant temperature.
Beneficial effect:
This system directly is installed in the conducting metal pin on the micro-fluidic chip as electrode, thereby produces the electric field across the microchannel, so that chip manufacturing process is simple, cost is low; Simultaneously this kind design, electrode interval to each other is by the width decision of sprue, and two electrode symmetries are installed on the sprue both sides, make the induction field even intensity in the induction zone, guarantee the stability of impedance signal.
For guaranteeing the accuracy of input, at the symmetria bilateralis processing sheath fluid inflow entrance of sample flow entrance, utilize sheath fluid stream that particulate is one by one gathered relatively more fixing fluid position, thereby be convenient to the detection of signal in this system.
In this system, adopt simultaneously differential signal detection circuit to improve the degree of accuracy of detection, not only can improve the sensitivity of input, simultaneously so that the cost of whole system is little, can satisfy portability, cheaply requirement.
Description of drawings
Fig. 1 is the structural representation that is used for the micro-fluidic chip of counting micro particles;
Fig. 2 is the vertical view of PDMS substrate;
Fig. 3 is the enlarged drawing in induction of signal district;
Fig. 4 is the integrated connection figure of this system;
Fig. 5 is the circuit theory diagrams of I/V conversion, differential amplification and envelope detection part;
Fig. 6 is the circuit theory diagrams of high-pass filtering and low-pass filtering part;
Fig. 7 passes through the differential signal that the electro-induction district forms for the particulate that adopts system of the present invention to detect;
Fig. 8 is for adopting the testing result comparison diagram of the present invention and prior art.
Wherein, 1-glass substrate, 2-PDMS substrate, 3-sample flow entrance, 4-liquid flow export, 5-sprue, 6-sheath fluid inflow entrance, 7-electrode mounting hole, 8-respond to core space, 9-sense blind area, 10-metal needle, 11-induction of signal district
Embodiment
Below in conjunction with the accompanying drawing embodiment that develops simultaneously, describe the present invention.
The present embodiment provides a kind of micro-fluidic chip counting micro particles system based on electrical impedance technology, this system utilizes common conducting metal pin as the electrode of micro-fluidic chip, and the method for utilizing signal differential to detect detects its impedance signal, has simple, the with low cost and feature such as be easy to carry of chip manufacturing process.
This system comprises micro-fluidic chip and signal deteching circuit.Wherein micro-fluidic chip comprises: glass substrate, PDMS(dimethyl silicone polymer) substrate and two pairs of metal needles as electrode.Signal deteching circuit comprises: two I/V change-over circuits, difference channel, envelope detection circuit, high-pass filtering circuit, low-pass filter circuit and amplifying circuits.The integrated connection of this system closes: in two pairs of metal needles on the micro-fluidic chip, two metal needles that are positioned at sprue one side link to each other with outside sine wave AC driving source respectively, and each links to each other two metal needles of opposite side with an I/V change-over circuit.Described sine wave AC driving source frequency range is chosen as between 500KHz～1.2MHz, the peak value scope at 3V between the 5V.
The concrete structure of the micro-fluidic chip that is used for counting micro particles that the present embodiment provides as shown in Figure 1, wherein metal needle requires and can conduct electricity, and certain biocompatibility and stability are arranged, and adopts acupuncture needle in the present embodiment.The PDMS substrate is bonded in the upper surface of glass substrate, is processed with respectively sample flow entrance, liquid flow export, sprue, sheath fluid inflow entrance and electrode mounting hole on the PDMS substrate, as shown in Figure 2.Be specially: in the center of PDMS substrate upper surface, process strip groove as sprue along its length direction; Symmetria bilateralis at sprue is processed with two groups of (two every group) electrode mounting holes (two along the sprue symmetry is a group), is embedded in a metal needle at each electrode mounting hole.The consistency of thickness of the degree of depth of described electrode mounting hole and PDMS substrate; Connect by rectangular recess between four electrode mounting holes and the sprue.The circular hole that connects at the processing of an end end of sprue and sprue is used as the sample flow entrance, and the circular hole that end processing and the sprue of the other end connects is as the liquid flow export.Some particulate is easy to be sticked together such as cell etc., affects the detection of signal; For guaranteeing the accuracy of input, utilize sheath fluid stream that particulate is one by one gathered relatively more fixing fluid position in the present embodiment, symmetria bilateralis processing circular hole at the sample flow entrance is used as the sheath fluid inflow entrance for this reason, and described two sheath fluid inflow entrances connect by bar-shaped trough and the sprue that tilts.The degree of depth of above-mentioned sample flow entrance, liquid flow export and sheath fluid inflow entrance all with the consistency of thickness of PDMS substrate.
The below describes in detail on the size Selection that directly affects system sensitivity on the PDMS substrate.
On the PDMS substrate, be the induction of signal district along the zone between two metal needles of sprue symmetry, the enlarged drawing in induction of signal district is as shown in Figure 3.In impedance signal detected, the volume in induction of signal district and the volume ratio of particulate/cell to be detected were very important parameters.If this ratio is too large, can cause input sensitivity low.The induction of signal district comprises induction core space and sense blind area, and wherein the zone of sprue between symmetrical two metal needles is the induction core space; Coupling part between sprue and the electrode mounting hole is sense blind area.Wherein respond to the volume of core space and determined by the degree of depth, width and the electrode mounting hole of sprue and the width of the rectangular recess between the sprue, ideally, the volume of particulate/cell to be detected is more approaching better with the volume of induction core space; But in actual conditions, if too approaching, be easy to cause sprue to get clogged.Therefore, in the present embodiment the degree of depth of sprue and width all be taken as 1.5 times of mean particle dia to be detected, can when guaranteeing detection sensitivity, do not block sprue.The width of rectangular recess has then defined the coverage of electric field between electrode mounting hole and the sprue, if too little, is unfavorable for that processing realizes; If too large, then so that the volume ratio increase of volume and the particulate to be detected of induction core space, and then reduced the sensitivity of system; The width of this rectangular recess is set to 20 μ m in the present embodiment.The volume of sense blind area by the degree of depth, width and the electrode mounting hole of the rectangular recess between electrode mounting hole and the sprue and and sprue between distance determine.In theory, the distance between electrode mounting hole and the sprue is the smaller the better.Be confined to micro fabrication, if be worked into very littlely, can cause yield rate too low, therefore under the prerequisite that guarantees than high finished product rate, in the present embodiment electrode mounting hole and and sprue between distance be chosen as 20 μ m.。With the sprue on the described micro-fluidic chip and and the passage that connects of sprue (comprising the bar shaped between rectangular recess between electrode mounting hole and the sprue, two sheath fluid inflow entrances and the sprue) be referred to as the microchannel, the degree of depth of microchannel is consistent.
The degree of accuracy that detects for improving, this system carries out difference processing to two groups of impedance signals, and the distance H between two groups of metal needles directly affects the effect of input.Although the position of electric field is limited by the size of sprue, electric field outwards itself needs an attenuation process at the induction core space; If two pairs of electrode contacts are too near, the electric field that produces between the two pairs of electrodes easily interferes with each other, and is unfavorable for input; If but at a distance of too far away, the detection rates of reduction particulate that then can be serious.Distance H in the present embodiment between two groups of metal needles
1Be 100 μ m, under this distance, namely guaranteed the detection rates of particulate, the electric field that produces between while two pairs of electrodes can not interfere with each other yet.
When the nonconductors such as particulate/cell pass through the induction of signal district, the anti-increase of the overall resistance in induction of signal district; In case particulate/cell leaves, it is normal that the electrical impedance in induction of signal district is recovered again; A projection on the time impedance signal has been reacted above-mentioned whole process.Because the electric field at induction zone is an AC field, and particulate/cell flow rate is corresponding very fast, so impedance signal is on feature, very near an amplitude-modulated signal.For this judgement, the present invention utilizes the principles of modulation and demodulation of envelope detection, designs the respective impedance signal deteching circuit.In order to improve accuracy of detection and sensitivity, utilize difference detecting method simultaneously, utilize two pairs of electrode needle to make up to realize differential signal.In signal deteching circuit, wherein the output terminal of two I/V change-over circuits links to each other with two input ends of difference channel respectively, the output terminal of difference channel links to each other with envelope detection circuit, after the output signal of envelope detection circuit is amplified through amplifying circuit, by high-pass filtering circuit and low-pass filter circuit signal is processed again the amplifying circuit of the output termination afterbody of low-pass filter circuit.
Described I/V change-over circuit is used for current signal is converted to voltage signal, and the two-way voltage signal produces into differential signal by difference channel, and envelope detection circuit is used for extracting the rough envelope of differential signal, and namely particulate/cell passes through the impedance signal of electric field; Then by high-pass filtering circuit filtering flip-flop, amplifying circuit subsequently amplifies signal, then sends to the further filtering carrier signal of low-pass filter circuit, utilizes at last amplifying circuit that signal is amplified, so that identification; Then just can or show signals collecting.The parameter of envelope detection circuit and filtering circuit depends on that particulate/cell to be measured passes the speed in electro-induction district.The selection of operational amplifier in the circuit must be satisfied higher gain bandwidth product and lower bias current input requirements simultaneously, and the noise inputs error is also as much as possible little.
The concrete structure of signal deteching circuit as shown in Figure 5 and Figure 6.Described I/V change-over circuit is realized by operational amplifier and sampling resistor.Selected the integrated operational amplifier U2 that contains four operational amplifiers (being respectively operational amplifier A, B, C, D) in the present embodiment.Wherein operational amplifier A and operational amplifier B are respectively applied to two I/V change-over circuits, two I/V change-over circuits identical version of sampling.Take operational amplifier A as example, the electrode input end ground connection of operational amplifier A, negative input links to each other with the metal needle that is used as electrode, between its output terminal and negative input, be connected sampling resistor R0, in order to reduce error, R0 selects high-accuracy resistance, and its resistance is directly proportional with the volume in induction of signal district, scope at 30K Ω between the 300K Ω.Described difference channel comprises differential amplifier U1 and operational amplifier C; The output terminal of operational amplifier A and operational amplifier B links to each other with two input ends of differential amplifier U1 respectively, and the enlargement factor of differential amplifier U1 can not arrange too large, and 10 times take interior as good.The output terminal of differential amplifier U1 links to each other with the electrode input end of operational amplifier C, the negative input of operational amplifier C is by resistance R 3 ground connection, contact resistance R4 between its negative input and output terminal utilizes operational amplifier C and resistance R 3, R4 that the output signal of differential amplifier U1 is further amplified 23 times in the present embodiment simultaneously.The output terminal of operational amplifier C links to each other with envelope detection circuit, and described envelope detection circuit comprises diode D6, resistance R 2, capacitor C 1 and operational amplifier D.The output terminal of operational amplifier C links to each other with the negative electrode of diode D6, and the anode of diode D6 links to each other with the electrode input end of operational amplifier D; Be connected between the anode and ground of diode D6 after resistance R 2 and capacitor C 1 parallel connection.In the envelope detection circuit of the present embodiment, diode opposite direction in the direction of diode D6 and the envelope detector commonly used; Because the signal of I/V change-over circuit collection is a current signal, when crossing the induction of signal district owing to particulate/stream of cells, this zone impedance increases, and current value reduces, and the signal that therefore collects is a signal that peak value is downward; Here utilize reverse diode to arrange signal is swung to processing, make the peak value of signal upwards.The value of resistance R 2 and capacitor C 1 has determined the detection scope of envelope detection, so the selection of its value should much smaller than the incoming frequency of sine-wave excitation, also be greater than particulate cutting induction zone electric field frequency simultaneously.Operational amplifier D is used for follower, plays the effect of impedance matching.
The output terminal of operational amplifier D links to each other with high-pass filtering circuit.The detailed structure of described high-pass filtering circuit and low-pass filter circuit as shown in Figure 6, this part has been selected the integrated operational amplifier U3 that contains four operational amplifiers, has only used wherein three in the present embodiment, is respectively operational amplifier E, F, H.Wherein operational amplifier E and resistance R 5, resistance R 6, capacitor C 2, capacitor C 3 form the Order RC high-pass filtering circuit, the output terminal of operational amplifier D links to each other with the electrode input end of operational amplifier E with resistance R 6 afterwards by resistance R 5 successively, the electrode input end of operational amplifier E is by capacitor C 3 ground connection simultaneously, one end of capacitor C 3 links to each other with the output terminal of operational amplifier E, and the other end is connected between resistance R 5 and the resistance R 6.The cutoff frequency of high-pass filtering circuit is about 10Hz, for the DC component after the filtering envelope detection in the present embodiment.Then utilize negative input and the resistance R between the ground 7 be connected on operational amplifier E, and the resistance R between negative input and the output terminal 8 is put to its output signal and is twice.
The output terminal of operational amplifier E links to each other with low-pass filter circuit.The Order RC low-pass filter of described low-pass filter circuit for being consisted of by the operational amplifier F among resistance R 9, resistance R 12, capacitor C 4, capacitor C 5 and the operational amplifier U3.The output terminal of operational amplifier E links to each other with the electrode input end of capacitor C 5 with operational amplifier F by capacitor C 4, and the electrode input end of operational amplifier F is by resistance R 9 ground connection simultaneously.One end of resistance R 12 links to each other with the output terminal of operational amplifier F, and the other end is connected between capacitor C 4 and the capacitor C 5.Low-pass filter circuit is used for the sine wave exciting signal component of further filtered signal, and its cutoff frequency is relevant with the input sine wave excitation components, elects 1/10th of sine-wave excitation frequency input signal in the present embodiment as.Then utilize the resistance R 10 between operational amplifier F negative input and the ground, and the resistance R 11 between operational amplifier F negative input and the output terminal is put to its output signal and is twice.
The output terminal of operational amplifier F links to each other with the electrode input end of operational amplifier H, the negative input of operational amplifier F is by resistance R 13 ground connection, contact resistance R14 between the output terminal of operational amplifier H and negative input simultaneously, 14 pairs of signals of operational amplifier H and resistance R 13 and resistance R consist of the amplification of final step, and the output terminal of operational amplifier G outputs to final signal on display device or the collecting device.
The processing technology of described micro-fluidic chip is:
After the size of microchannel each several part, draw on computers microchannel plane design drawing as shown in Figure 7 on step 1, the known micro-fluidic chip;
The principle of work of this counting micro particles system is:
Before measuring process begins, in the microchannel, be full of first conducting solution, two electrodes of sprue one end connect sine wave AC excitation (frequency range is chosen as between 500KHz～1.2MHz, peak value scope at 3V between the 5V), and two electrodes of the other end connect the impedance signal testing circuit.Like this, just formed an electric field between the electrode of per two symmetries, this electric field and microchannel intersection form the induction of signal district.
When particulate/stream of cells during through the electric field of first pair of create electrode, there is this moment impedance signal to produce, and in the electric field of second pair of create electrode subsequently, owing to there not being particulate/stream of cells mistake, occurs so have any signal.Signal deteching circuit utilizes the difference of this two paths of signals that the particulate/cell in the induction of signal district that flows through is counted, and can effectively increase system sensitivity.
Fig. 7 is when adopting native system, 10 μ m particulates are by the testing result behind the electric field region, and this curve has represented that a particulate passes through the electro-induction district and the differential signal that forms.
Fig. 8 further tests comparing result with native system and existing flow cytometer, adopt hybrid fine particles sample (5 μ m, 10 μ m and 15 μ m), then sample is divided into two parts, a part utilizes flow cytometer to test, and a part utilizes system of the present invention to test in addition.Fig. 8 (a) is the Output rusults of flow cytometer, and horizontal ordinate is forward scattering light, and ordinate is side scattered light; Clearly demonstrate three sample collection districts among the figure, it represents respectively 5 μ m(A), 10 μ m(B) and 15 μ m(C) particulate samples, its ratio is respectively 54.3%(9), 28.5%(10) and 12.6%(11).Measurement result is turned to histogram based on forward scattering light, shown in Fig. 8 (b).Adopt the measurement result of system of the present invention shown in Fig. 8 (c), very obvious three piecemeals are arranged, every ratio that accounts for whole quantity is respectively 49.7%, 32.4%, 14,1%, and consistance is very good with Fig. 8 (a) with (b).
Micro-fluidic chip counting micro particles device of the present invention, simplicity of design, easily manufactured, with low cost can satisfy people to the instant needs that detect in scene, at aspects such as environment measuring, biological study and medical diagnosiss wide using value is arranged.
In sum, above is preferred embodiment of the present invention only, is not for limiting protection scope of the present invention.Within the spirit and principles in the present invention all, any modification of doing, be equal to replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (9)
1. the micro-fluidic chip counting micro particles system based on electrical impedance technology is characterized in that, comprises micro-fluidic chip and signal deteching circuit; Described micro-fluidic chip comprises: glass substrate, polydimethylsiloxane substrate and two pairs of metal needles as electrode; Described signal deteching circuit comprises: two I/V change-over circuits, difference channel, envelope detection circuit, high-pass filtering circuit, low-pass filter circuit and amplifying circuits;
In the described micro-fluidic chip, the PDMS substrate is bonded in the upper surface of glass substrate, is processed with respectively sample flow entrance, liquid flow export, sprue, sheath fluid inflow entrance and electrode mounting hole at the PDMS substrate upper surface; Be specially: in the center of PDMS substrate upper surface, process strip groove as sprue along its length direction; Symmetria bilateralis processing two arrays of electrodes mounting hole at sprue is embedded in a metal needle at each electrode mounting hole; Connect by rectangular recess between four electrode mounting holes and the sprue; At the sample flow entrance that the processing of an end end of sprue and sprue connect, the liquid flow export that end processing and the sprue of the other end connects; Symmetria bilateralis at described sample flow entrance is processed with the sheath fluid inflow entrance, and two sheath fluid inflow entrances and sprue connect; The degree of depth of above-mentioned sample flow entrance, liquid flow export, sheath fluid inflow entrance and electrode mounting hole all with the consistency of thickness of PDMS substrate; Be referred to as the microchannel with the sprue on the described micro-fluidic chip and with passage that sprue connects, the degree of depth of described microchannel is all consistent; In two pairs of metal needles on the described micro-fluidic chip, two metal needles that are positioned at sprue one side link to each other with outside sine wave AC driving source respectively, and each links to each other two metal needles of opposite side with an I/V change-over circuit;
In the described signal deteching circuit, the output terminal of two I/V change-over circuits links to each other with two input ends of difference channel respectively, the output terminal of difference channel links to each other with envelope detection circuit, envelope detection circuit links to each other with low-pass filter circuit by high-pass filtering circuit, the amplifying circuit of the output termination afterbody of low-pass filter circuit; Described I/V change-over circuit is used for the current signal that collects is converted to voltage signal, and the two-way voltage signal produces into differential signal by difference channel; Described envelope detection circuit is used for extracting the impedance signal of differential signal, and the impedance signal that extracts is carried out the amplification of the first order; After the flip-flop in the received impedance signal of high-pass filtering circuit filtering impedance signal is carried out the amplification of the second level; After the carrier signal in the impedance signal that the low-pass filter circuit filtering receives, impedance signal is carried out the amplification of afterbody by amplifying circuit, the number of last impedance signal according to exporting realizes the counting to particulate.
2. a kind of micro-fluidic chip counting micro particles system based on electrical impedance technology according to claim 1, it is characterized in that: the degree of depth of described sprue and width are 1.5 times to 3 times of mean particle dia to be detected; The width of rectangular recess is 10 μ m to 50 μ m between through electrode mounting hole and the sprue; Described electrode mounting hole and and sprue between distance be 20 μ m; Distance H between two groups of metal needles
1Be 100 μ m to 200 μ m.
3. a kind of micro-fluidic chip counting micro particles system based on electrical impedance technology according to claim 1, it is characterized in that: in the described signal deteching circuit, the version of two I/V change-over circuits is identical; The I/V change-over circuit comprises operational amplifier A and sampling resistor; The electrode input end ground connection of operational amplifier A wherein, negative input links to each other with metal needle as electrode, is connected sampling resistor R0 between its output terminal and negative input; Described difference channel comprises differential amplifier U1, operational amplifier C, resistance R 3 and resistance R 4; The output terminal of operational amplifier links to each other with two input ends of differential amplifier U1 respectively in two I/V change-over circuits, the output terminal of differential amplifier U1 links to each other with the electrode input end of operational amplifier C, the negative input of operational amplifier C passes through resistance R 3 ground connection, simultaneously contact resistance R4 between its negative input and output terminal; The output terminal of operational amplifier C links to each other with envelope detection circuit;
Described envelope detection circuit comprises diode D6, resistance R 2, capacitor C 1 and operational amplifier D; The output terminal of operational amplifier C links to each other with the negative electrode of diode D6, and the anode of diode D6 links to each other with the electrode input end of operational amplifier D; Be connected between the anode and ground of diode after resistance R 2 and capacitor C 1 parallel connection; The output terminal of described operational amplifier D links to each other with high-pass filtering circuit;
Described high-pass filtering circuit comprises operational amplifier E, resistance R 5, resistance R 6, capacitor C 2 and capacitor C 3; The output terminal of operational amplifier D links to each other with the electrode input end of operational amplifier E with resistance R 6 afterwards by resistance R 5 successively, the electrode input end of operational amplifier E is by capacitor C 3 ground connection simultaneously, one end of capacitor C 2 links to each other with the output terminal of operational amplifier E, and the other end is connected between resistance R 5 and the resistance R 6; Contact resistance R7 between the negative input of operational amplifier E and ground, connecting resistance R8 between its negative input and the output terminal; The output terminal of operational amplifier E links to each other with low-pass filter circuit;
Described low-pass filter circuit comprises resistance R 9, resistance R 12, capacitor C 4, capacitor C 5 and operational amplifier F; The output terminal of operational amplifier E links to each other with the electrode input end of capacitor C 5 with operational amplifier F by capacitor C 4, and the electrode input end of operational amplifier F is by resistance R 9 ground connection simultaneously; One end of resistance R 12 links to each other with the output terminal of operational amplifier F, and the other end is connected between capacitor C 4 and the capacitor C 5; Contact resistance R10 between operational amplifier F negative input and ground, connecting resistance R11 between operational amplifier F negative input and the output terminal; The output terminal of operational amplifier F links to each other with amplifying circuit;
Described amplifying circuit comprises operational amplifier H, resistance R 13 and resistance R 14; The output terminal of described operational amplifier F links to each other with the electrode input end of operational amplifier H, and the negative input of operational amplifier H is by resistance R 13 ground connection, simultaneously contact resistance R14 between the output terminal of operational amplifier H and negative input.
4. a kind of micro-fluidic chip counting micro particles system based on electrical impedance technology according to claim 1, it is characterized in that: described sine wave AC driving source frequency is 500KHz～1.2MHz, and peak value is 3V～5V.
5. a kind of micro-fluidic chip counting micro particles system based on electrical impedance technology according to claim 1, it is characterized in that: the resistance of sampling resistor is 30K Ω～300K Ω in the described I/V change-over circuit, the enlargement factor of described differential amplifier U1 is less than or equal to 10 times, and described low-pass filter circuit cutoff frequency is 1/10th of sine-wave excitation frequency input signal.
6. a kind of micro-fluidic chip counting micro particles system based on electrical impedance technology according to claim 1 is characterized in that: described metal needle as electrode is acupuncture needle or platinum pin.
7. based on the job operation of micro-fluidic chip in the micro-fluidic chip counting micro particles system of electrical impedance technology, it is characterized in that,
After the size of microchannel each several part, draw on computers the microchannel plane design drawing on step 1, the known micro-fluidic chip;
Step 2, the microchannel plane design drawing that designs is worked on the mask, the mask after the processing is only at the microchannel partially transparent;
Step 3, negative photoresist evenly is applied to the silicon chip upper surface, the thickness of negative photoresist is consistent with the depth value of microchannel; Then silicon chip was heated 1 minute under 100 ℃ constant temperature, the negative photoresist of its upper surface is solidified;
Step 4, with the mask in the step 2 as light shield, see through light shield silicon chip is carried out 10 seconds of uv-exposure, this moment ultraviolet ray sees through the negative photoresist on the transparent part irradiation silicon chip on the mask, receives the negative photoresist generation cross-linking reaction of ultraviolet irradiation and polymerization;
The developing solution dissolution of the negative photoresist coupling in step 5, utilization and the step 3 is fallen the negative photoresist that cross-linking reaction does not occur on the silicon chip; Then adopt the pure water rinsing silicon chip, dry up pure water on the silicon chip with nitrogen after cleaning; The remaining negative photoresist structure of silicon chip upper surface this moment is the formpiston part of micro-fluidic chip, and described formpiston partly refers to the spatial structure of microchannel, and its thickness is consistent with the degree of depth of microchannel;
Step 6, the silicon chip that step 5 is obtained carry out the alkanisation processing;
Step 7, PDMS and rigidizer are mixed with the ratio of mass ratio 10:1 and stir, remove its air entrapment, then with the formpiston part of mixed liquid pouring on silicon chip, and cover the formpiston part fully; Silicon chip heated under 100 ℃ constant temperature it is solidified, then take the PDMS layer of silicon chip upper surface off, obtain thus having the PDMS substrate of microchannel;
Step 8, utilize card punch to have the position of sample flow entrance, liquid flow export, sheath fluid inflow entrance and electrode mounting hole to stamp through hole at the upper surface of PDMS substrate mark;
Step 9, PDMS substrate and glass substrate are carried out the oxygen plasma surface treatment, then the surface of accepting plasma treatment in two substrates is fitted tightly, so that the chemical bond on both surface of contact is bonded together mutually; At last four conducting metal pins are embedded respectively in four electrode mounting holes, form thus micro-fluidic chip.
8. the job operation based on micro-fluidic chip in the micro-fluidic chip counting micro particles system of electrical impedance technology as claimed in claim 7 is characterized in that, in the described step 4, after exposure is finished, the silicon chip after the exposure is heated 1 minute under 100 ℃ constant temperature.
9. the job operation based on micro-fluidic chip in the micro-fluidic chip counting micro particles system of electrical impedance technology as claimed in claim 7, it is characterized in that, the PDMS substrate that will be bonded together in the described step 9 and glass substrate heated 4 hours under 100 ℃ constant temperature.
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