CN102650512B - Drop measuring method and drop controlling method - Google Patents
Drop measuring method and drop controlling method Download PDFInfo
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- CN102650512B CN102650512B CN201110046966.5A CN201110046966A CN102650512B CN 102650512 B CN102650512 B CN 102650512B CN 201110046966 A CN201110046966 A CN 201110046966A CN 102650512 B CN102650512 B CN 102650512B
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- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
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- B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
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Abstract
The invention provides a drop measuring method and drop controlling method for an electrowetting-based microflow device, wherein the drop measuring method includes steps as follows: the electrowetting-based microflow device and a capacitance measuring device connected with the microflow device are provided; the microflow device includes a substrate and a drive electrode array arranged on the substrate and including multiple drive electrodes; the capacitance measuring device is used for measuring the capacitance of one or multiple drive electrodes in the microflow device; and the overlapping condition of the drops in the microflow device and the drive electrodes is judged according to the capacitance measurement result obtained through the capacitance measuring device. Compared with the prior art, the drop measuring method and drop controlling method can precisely monitor the overlapping condition of the drops in the microflow device and the drive electrodes as position, size, volume, speed and the like, so as to precisely controls the drops to be produced, moved, separated, combined and the like according to the monitoring result, and accordingly improve the working efficiency.
Description
Technical field
The present invention relates to a kind of microfluidic control technology, particularly a kind of liquid drop measuring method and drop control method based on the wetting microfluidic device of electricity.
Background technology
In the past during the decade, microfluid system (Microfluidic System) has developed into a gordian technique in the fields such as life science gradually.Have a wide range of applications in the multiple fields including biotechnology, medical detection, environmental monitoring, food hygiene, chemical industry are processed.Under many circumstances, micro-fluidic system is all to utilize the technology of microelectromechanical systems (Micro ElectroMechanical Systems, MEMS) to make, such as at the various electrodes of various Growns, electronic circuit etc.What for example patent WO2009/003184 kind was described realizes polymerase chain reaction (Polymerase Chain Reaction, PCR) on micro-fluidic system.
How fast, accurately and efficiently the key that microfluid system performance is brought into play and basis are microfluidic control technology, namely handle micro fluid.There is many microfluidic control technology although current, for example, utilize mechanical pump and electrophoretic effect (Electrophoresis) and the electroosmotic effect (Electroosmosis) that the vacuum that produces or pressure, high voltage produce, centrifugal force, the piezoelectric effect etc. of rotating generation.But these technology are understood some weak point conventionally, comprise that element manufacturing costliness, complicated operation, energy consumption are high, poor durability etc., this also becomes restriction microfluid system more extensively and one of the technical bottleneck of successful Application.
In numerous microfluidic control technology, the micro-drop control technology operating based on dielectric material electricity wetting (Electro Wetting On Dielectrics the is called for short EWOD) liquid to released state (drop) of principle is a kind of emerging microfluidic control technology.Compare with other microfluidic control technology (as electroosmotic flow, micromechanics pump and valve, hot capillary pump etc.), the micro-drop control technology of EWOD have realize simple, low in energy consumption, without movable member thereby reliable, size is little, control the many and fast and flexible of function, without the overall merit such as dead volume, quantification.Electrowetting effect on dielectric material is a kind of by change the reversible of surface tension of liquid to applying electromotive force between solid electrode and liquid.
The fluid operated institute that microfluidic device based on electrowetting effect can be realized biochemical reaction in steps, generation, movement, fractionation, merging, the stirring of such as drop and mix, hatching (Incubation), collection etc., this,, to realizing biochemical point deserved micro-ization, robotization, digitizing etc., has profound significance.
Wherein, WO 2006/124458, US 2008/0038810 and US 6,911, the technology of the miniflow device of individual layer drive electrode has been described in 132 patent documentations such as grade, the patent documentation of WO 2008/101194A2 has been described a kind of structure of microfluidic control device of double-face electrode of two-layer drive electrode, compared with aforementioned each patent documentation, the microfluidic device structure of two-layer drive electrode has a lot of advantages, and for example design is more general, element manufacturing cost is lower, design corresponding control instrument is simpler.
Structure and the drop method of operating of the microfluidic control device proposing in patent WO 2008/101194A2 have suitable accuracy, but chip manufacturing and drop operation have stochastic error unavoidably, for example, in the situation that multiple drops occur along same column or row, in the time attempting mobile other drops, some drop may experience unintentionally or unpredictable movement, can not monitor exactly the situation of drop (position, size, volume, speed etc.), affect accuracy and the work efficiency of drop control.
Summary of the invention
The object of the present invention is to provide a kind of liquid drop measuring method and drop control method, for the overlapping situation of Measurement accuracy drop and drive electrode, and to drop for example produce, move, the corresponding actions such as separation, merging, increase work efficiency.
The present invention provides a kind of liquid drop measuring method on the one hand, comprise: the microfluidic device and the capacitance measuring device that with described microfluidic device be connected, driving electrode array that described microfluidic device comprise substrate and be positioned at described substrate on, comprise multiple drive electrodes wetting based on electricity is provided; Utilize described capacitance measuring device, the one or more drive electrodes in described microfluidic device are carried out to capacitance measurement; The capacitance measurements obtaining according to described capacitance measuring device, judges the overlapping situation of drop and described drive electrode in described microfluidic device.
Alternatively, the drive electrode in described driving electrode array is the operation for described drop being had to electric wetting effect.
Alternatively, the overlapping situation of described drop and described drive electrode comprises: whether drop exists on drive electrode or part exists, position, droplet profile, the size at drop place on drive electrode.
The method of carrying out capacitance measurement alternatively, comprises the capacitance measurement based on resonance method and the capacitance measurement based on capacitor charging/discharging method.
The present invention also provides a kind of drop control method on the other hand, comprise: the microfluidic device and the capacitance measuring device that with described microfluidic device be connected, driving electrode array that described microfluidic device comprise substrate and be positioned at described substrate on, comprise multiple drive electrodes wetting based on electricity is provided; Utilize described capacitance measuring device, the one or more drive electrodes in microfluidic device are carried out to capacitance measurement, obtain the overlapping situation of drop on drive electrode, determine the position of drop in described microfluidic device; According to default operation requirements, the one or more drive electrodes in driving electrode array are applied to voltage according to certain order, control drop and carry out corresponding actions, and discharge the voltage in respective drive electrode after control drop completes corresponding actions; Utilize described capacitance measuring device, the one or more drive electrodes in described microfluidic device are carried out to capacitance measurement, to guarantee that the position of described drop meets described default operation requirements.
Alternatively, described control drop carries out corresponding actions and comprises: one or more in the generation of drop, movement, fractionation, merging.
Alternatively, described drop control method also comprises: if by determining after capacitance measurement while obtaining on target location that described drop can not arrive described default operation requirements, judge that described drive electrode is as losing efficacy; Again drop is operated to walk around the drive electrode of described inefficacy.
Compared to prior art, liquid drop measuring method of the present invention and drop control method can be monitored exactly to the overlapping situation of drop and drive electrode (position, size, volume, speed etc.), so according to monitored results, can accurately control drop and carry out the corresponding actions such as generation, movement, separation, merging, increase work efficiency.
In addition, invent the technical characterstic that can monitor exactly the overlapping situation of drop and drive electrode (position, size, volume, speed etc.) according to this microfluidic device, liquid drop measuring method of the present invention can also be carried out Quality Identification to microfluidic device.Utilize known experiment condition (as controlled alive order and interval time etc. on voltage swing, electrode) to operate (as produced, mobile, separate, merge) to drop, and drop is carried out to capacitance measurement, if the measurement result obtaining and predicted value have deviation, show that microfluidic device may be defective in quality.
Have, liquid drop measuring method of the present invention can also be carried out electric capacity to the drop in a certain fixed position and measured over time, thereby can the physics carrying out in drop, chemistry and bioprocess be measured and be judged again.Variation, the Apoptosis (Apoptosis) etc. of for example, the growth of the generation of bubble, protein crystal in drop, cytoactive (Cell Viability), toxicity (Cytotoxicity).
Brief description of the drawings
Figure 1A and Figure 1B are the schematic cross-section that two of the microfluidic device wetting based on electricity are 90 degree mutually;
Fig. 2 is the plan view from above that is embedded in the double-deck driving electrode array on the substrate surface of microfluidic device in Fig. 1;
Fig. 3 is liquid drop measuring method of the present invention schematic flow sheet in one embodiment;
Fig. 4 A to 4D is the equivalent schematic of the effective capacitance between first drive electrode and ground-electrode in the first drive electrode layer;
Fig. 5 A to 5D is the equivalent schematic of the effective capacitance between second drive electrode and ground-electrode in the second drive electrode layer;
Fig. 6 A has shown a kind of circuit diagram of capacitance measurement of resonance method;
Fig. 6 B has shown a kind of circuit diagram of the capacitance measurement based on capacitor charging/discharging method;
Fig. 6 C has shown and utilizes capacitance type sensor chip to come the simultaneously-measured circuit diagram of multiple unknown capacitance;
Fig. 7 has shown the overlapping degree of drop and drive electrode and has measured the relation between the relative electric capacity of gained;
Fig. 8 is drop control method of the present invention schematic flow sheet in one embodiment;
Fig. 9 A to 9D has shown that utilization the present invention is based on the wetting microfluidic device of electricity and is applied to the schematic diagram that drop produces;
Figure 10 A to 10E has shown that utilization the present invention is based on the wetting microfluidic device of electricity and is applied to the schematic diagram that drop moves;
Figure 11 A to 11D has shown and has utilized the schematic diagram that the present invention is based on the wetting microfluidic device of electricity and be applied to drop separation;
Figure 12 A to 12D has shown and has utilized the schematic diagram that the present invention is based on the wetting microfluidic device of electricity and be applied to droplet coalescence.
Embodiment
In view of existing microfluidic control technology can not be monitored exactly to the situation of drop (position, size, volume, speed etc.), thereby there is the accuracy of drop control and the problem of work efficiency of affecting.Therefore, the present inventor improves prior art, has proposed a kind of liquid drop measuring method and drop control method, so, can obtain the good feedback information relevant to drop, can be better, more accurately drop is controlled, increase work efficiency.
Below by by specific embodiment to proposed by the invention being elaborated for the liquid drop measuring method based on the wetting microfluidic device of electricity and drop control method.
Referring to Figure 1A and Figure 1B, is the schematic cross-section based on the wetting microfluidic device SMIS lamella of electricity, and wherein the visual angle of Figure 1A and Figure 1B differs 90 °.In conjunction with Figure 1A and Figure 1B, microfluidic device, can be to operating with the liquid of unpack format or drop state as the digitizing microfluidic device that carries out microfluidic control.Microfluidic device comprises two the first chip layer 10 that arrange in opposite directions, the second chip layer 20 and corresponding control circuit (not shown in graphic).Below the first chip layer 10 in above-mentioned microfluidic device and the second chip layer 20 are elaborated.
The first chip layer 10 comprises: the first substrate 101, the first substrates 101 for the drive electrode of growing have a phase back side and a forward surface; Be positioned at the first drive electrode layer 103 on the forward surface of the first substrate 101, drive electrode layer 103 comprises multiple the first drive electrodes that be arranged in parallel; Be positioned at the dielectric substrate 105 on the first drive electrode layer 103; The second drive electrode layer 107, the second drive electrode layer 107 that are positioned on dielectric substrate 105 comprise multiple the second drive electrodes that be arranged in parallel; And, be positioned at and detest water insulation course 109 on the second drive electrode layer 107.Especially, it should be noted that, in the present invention, multiple the second drive electrodes in multiple the first drive electrodes and the second drive electrode layer 107 in the first drive electrode layer 103 mutually (for example structure orthogonality relation in 90 °) arranged in a crossed manner be configured to double-deck driving electrode array or grid.Separately can consult Fig. 2, it is the floor map that microfluidic device SMIS lamella demonstrates above-mentioned double-deck driving electrode array in the situation of overlooking.As shown in Figure 2, here, what only show is the part in latticed driving electrode array, suppose: the first drive electrode layer 103 comprises 5 the first drive electrodes that indicate with E1, E2, E3, E4, E5 respectively, the second drive electrode layer 107 comprises 5 the second drive electrodes that indicate with E6, E7, E8, E9, E10 respectively, described multiple the first drive electrode and described multiple the second drive electrode are arranged in a crossed manner, form rectangular latticed driving electrode array.
Have again, between multiple drive electrodes in same drive electrode layer, conventionally in the time of growth dielectric substrate, added electrolyte, but not as limit, what material these spaces also can not let alone or be full of different gas as air, nitrogen, helium, argon gas etc.
Between the described drive electrode based on all in the wetting microfluidic device of electricity, no matter be between same drive electrode layer or between different driving electrode layer, all normally not conductings in electricity.
Please continue to refer to Figure 1A and Figure 1B, the second chip layer 20 comprises: have and deviate from phase back side of the first chip layer 10 and a forward surface towards the first chip layer 10 for the second substrate 201, the second substrates 201 of the ground-electrode of growing; Be positioned at the ground-electrode G on the forward surface of the second substrate 201; And, be positioned at and detest water insulation course 205 on ground-electrode G.
Unimportant for making the material of substrate, as long as be used for arranging that the surface of drive electrode is that (or being processed into) is non-conductive.Material also should be enough hard, so that the original shape of substrate can substantially keep making time.Substrate can be made up of (but being not limited to) quartz, glass or the polymkeric substance such as poly-carbonic acid vinegar (PC) and cycloolefin co-polymer (COC).
The quantity of drive electrode can change to 100,000 from 2; Usually, be from 2 to 10,000; More preferably, be from 2 to 200.In same layer, the interelectrode interval of the width of each drive electrode or adjacent driven can change at about 0.005mm between about 10mm, preferably, is to change between about 2mm at about 0.05mm.
Drive electrode can be made up of any conductive material, and such as copper, chromium and indium tin oxide (ITO) etc. are made.For convenient, the shape of the drive electrode shown in accompanying drawing is shown as rectangle, but not as limit, drive electrode can adopt a lot of other shapes to have substantially similar electrowetting effect.Every limit of drive electrode can be straight (as shown in FIG.), bending or zigzag etc.Although the accurate shape of each electrode is not strict, the electrode shape at same layer place should be substantially similar, and each other should be substantially parallel.
For dielectric substrate 105 and the material of detesting water insulation course 109,205 can be (but being not limited to) teflon, polychlorostyrene for P-xylene and silicon dioxide etc., preferably, the surface of detesting water insulation course 109,205 is hydrophobes.This can be coated in the thin layer of teflon or other hydrophobe materials to detest on water insulation course 109,205 by (but being not limited to) and realize.Detest that water insulation course 109,205 can also use configuration of surface technology, to utilize net grain surface to make hydrophobe or super hydrophobe.
Space between the first chip layer 10 and the second chip layer 20 as drop (using alphabetical D as mark) running space (as shown in Figure 1A, 1B, 2).Here, drop D refers to based on being filling liquid or air is included or part comprises the liquid that has certain volume in the wetting microfluidic device of electricity.Drop D can have various shapes, for example, for example, wide variety of shapes in the middle of spherical, disc, cylindricality, bar shaped, spherical, the oval shape blocking, avette and drop operation (separate or merge).In addition, the drop of mentioning in the present invention normally conducts electricity, carry out the associative operation of drop by controlling the first electrode in the second chip layer 20 and/or the second electrode, described drop operation specifically comprises: liquid is put into microfluidic device, produce drop from the fluid storage of microfluidic device, drop is moved to another place from one, a drop is divided into two or more, by synthetic one of two or more drops, drop is stirred, by drop deformation, hatching drop, heating drop, drop is shifted out from microfluidic device, and the combination of any these operations.
Utilize above-mentionedly based on the wetting microfluidic device of electricity, by applying selectively voltage to one or more drive electrode, excite them, realize operation to drop.Wherein, in the operation of drop, need to monitor exactly the situation of drop, therefore, the present invention provides liquid drop measuring method especially.As shown in Figure 3, described liquid drop measuring method comprises: S10, the microfluidic device and the capacitance measuring device that with described microfluidic device be connected, driving electrode array that described microfluidic device comprise substrate and be positioned at described substrate on, comprise multiple drive electrodes wetting based on electricity is provided; S12, utilizes described capacitance measuring device, and the one or more drive electrodes in described microfluidic device are carried out to capacitance measurement; S14, the capacitance measurements obtaining according to described capacitance measuring device, judges the overlapping situation of drop and described drive electrode in described microfluidic device.
Below described liquid drop measuring method is described in detail.
In the microfluidic device wetting based on electricity, one of them drive electrode and ground-electrode just form a capacitor.
Fig. 4 A to 4D has shown the equivalent schematic of the effective capacitance between first drive electrode and the ground-electrode in the first drive electrode layer 103.
Fig. 4 A is the exploded view of the electric capacity contribution of different ingredients between a drive electrode (being assumed to be E3) of the first drive electrode layer 103 and ground-electrode G.In the present invention, a capacitor (or equivalent condenser) can be regarded as a parallel plate capacitor, and for this capacitor, its capacitance can calculate (having ignored edge effect here) with formula once.
C＝ε
rε
0A/d；
Wherein C is capacitance, ε
rrelative dielectric constant, ε
0be absolute dielectric constant, A is platen area, and d is the distance between flat board.
As Fig. 4 A and 4B, C
t1and C
t2the equivalent capacity of detesting water insulation course 109 in the second chip layer 20, C
b1and C
b2the equivalent capacity of detesting water insulation course 109 in the first chip layer 10, C
d1and C
d2the equivalent capacity of the dielectric substrate 105 between two drive electrode layer 103,107, C
gthe equivalent capacity of the dielectric substrate between multiple the second drive electrodes in the second drive electrode layer 107, C
m1and C
m2the equivalent capacity in the space (the operated place of drop) between device the first chip layer 10 and the second chip layer 20, C
m3and C
m4it is the equivalent capacity at drop edge place between device the first chip layer 10 and the second chip layer 20.Compare with the space between device the first chip layer 10 and the second chip layer 20, detest water insulation course 109 and dielectric substrate 105 (being conventionally less than 1 micron) and want Bao get Duo, thereby in the time there is no drop in the space between the first chip layer 10 and the second chip layer 20, its capacitance is more much smaller than the capacitance of detesting water insulation course 106 and dielectric substrate 105.
Fig. 4 B is the wiring diagram expression way of Fig. 4 A, and Fig. 4 C is and the circuit of Fig. 4 B equivalence, wherein
1/C
1＝1/C
T1+1/C
M1+1/C
B1+1/C
D1；
1/C
2＝1/C
T2+1/C
M2+1/C
B2+1/C
D2+1/C
G；
1/C
L1＝1/C
T2+1/C
M3+1/C
B2+1/C
D2+1/C
G；
1/C
L2＝1/C
T1+1/C
B1+1/C
D1；
1/C
L3＝1/C
T2+1/C
M4+1/C
B2+1/C
D2+1/C
G；
The angle of expressing from electric capacity, Fig. 4 D is and the circuit of Fig. 4 C equivalence, wherein
C
Eff1＝C
1+C
2+C
1+CL
1+CL
2+CL
3+C
1+C
2+C
1。
Simpler a little to Fig. 4 D than Fig. 4 A, Fig. 5 A to Fig. 5 D is the exploded view of the electric capacity contribution of different ingredients between a drive electrode (being assumed to be E8) of the second drive electrode layer 107 and ground-electrode.In Fig. 5 A and 5B, C
t3, C
t4and C
tLthe equivalent capacity of detesting water insulation course 205 in the second chip layer 20, C
b3, C
b4, and C
bLthe equivalent capacity of detesting water insulation course 109 in the first chip layer 10, C
m3and C
m4it is the equivalent capacity in the space (the operated place of drop) between device the first chip layer 10 and the second chip layer 20.Compare with the space between device the first chip layer 10 and the second chip layer 20, detest water insulation course 109 and dielectric substrate 105 (being conventionally less than 1 micron) and want Bao get Duo, thereby in the time there is no drop in the space between the first chip layer 10 and the second chip layer 20, its capacitance is more much smaller than the capacitance of detesting water insulation course 109 and dielectric substrate 105.
Fig. 5 B is the wiring diagram expression way of Fig. 5 A, and Fig. 5 C is the circuit of Fig. 5 B equivalence, wherein
1/C
3＝1/C
T3+1/C
M3+1/C
B1；
1/C
4＝1/C
T4+1/C
M4+1/C
B4；
1/C
L＝1/C
TL+1/C
BL。
The angle of expressing from electric capacity, Fig. 5 D is the circuit of Fig. 5 C equivalence, wherein
C
Eff2＝C
3+C
4+C
L。
By the one or more drive electrodes in described microfluidic device are carried out to capacitance measurement, according to obtained capacitance measurements, can judge the situation (position of such as drop, shape, size etc.) of drop in control device.
The method of measuring electric capacity has a lot, and Fig. 6 A has shown a kind of circuit diagram of capacitance measurement of resonance method.As shown in Figure 6A, in resonance method, electric capacity to be measured is used to set the frequency of oscillator, and when electric capacity to be measured changes, the frequency of corresponding oscillator also changes thereupon.In Fig. 6 A, testing capacitance C
effsize can judge by the measurement of the frequency of the cyclical signal Vp to oscillator output.The measuring method of cyclical signal frequency has a lot, has now a lot of microprocessors, as digitizing microprocessor TMS320F28335 of Texas Instruments (Texas Instruments) etc., just can directly do the frequency measurement of signal.
Fig. 6 B has shown a kind of circuit diagram of the capacitance measurement based on capacitor charging/discharging method.As shown in Figure 6B, it is to utilize the maintenance of capacitor and the ability of transfer charge that mise-a-la-masse method is measured electric capacity, is added in the quantity of electric charge that the voltage of a capacitor and its capacitor hold and is directly proportional:
V＝Q/C
Wherein V is the voltage of capacitor, and Q is the quantity of electric charge that capacitor is held, and C is the electric capacity of capacitor.
What in Fig. 6 B, show is a kind of mode that charges and discharge electrical survey electric capacity, first, and by known capacitance C
refbe charged to a known magnitude of voltage V
ref, then by switching over parallel testing capacitance C with it
effon.For an ideal system, the total electric weight in front and back that switch turns is a constant, by measuring the voltage V after switching over
out, testing capacitance C
effjust can calculate:
C
Eff＝(V
Ref/V
Out-1)C
Ref。
Traditional high-accuracy capacitor is measured the complex combination that all needs a series of separating electronic components, and the connection of these electronic components and assembling also need suitable skill.Choosing of these electronic components is not only very consuming time, and after choosing, also needs a large amount of time and efforts to carry out qualitative assessment and optimization to design.Due to the development of semiconductor science and technology recently, the function of many capacitance measurements has all successfully been integrated on single semi-conductor chip, these make drop control and measurement become more accurate, economical and efficient for the existence of the semi-conductor chip of capacitance measurement.For example, the single electrode capacitance type sensor chip AD7147 that the Analog Devices of u s company design is produced has 13 input channels, can be for 13 electric capacity to be measured simultaneously, and this makes capacitance measurement easy a lot.Fig. 6 C utilizes capacitance type sensor chip to come the simultaneously-measured example of multiple unknown capacitance exactly, and capacitance type sensor chip is transferred to microprocessor by the capacitance measuring in digitized mode.This method has a lot of advantages, as the impact, the hyperchannel that have reduced neighbourhood noise are measured simultaneously, in chip with calibration logic etc.
Fig. 7 has shown the overlapping degree of drop and drive electrode and has measured the relation between the relative electric capacity of gained, as shown in Figure 7, Yi Zhi, drop and drive electrode overlapping degree larger (volume that is drop D is larger), measured relative electric capacity is just larger.Therefore can judge by the relative electric capacity recording the overlapping degree of drop and drive electrode.
Hence one can see that, liquid drop measuring method of the present invention, can be to accurately measuring the overlapping situation (position, size, volume, speed etc.) of drop and drive electrode, thereby obtain the feedback information relevant to drop, be beneficial to follow-up, drop be moved (generation, movement, separation, merging etc.) accordingly, improve accuracy and the work efficiency of drop control.
In addition, invent the technical characterstic that can monitor exactly the overlapping situation of drop and drive electrode (position, size, volume, speed etc.) according to this microfluidic device, liquid drop measuring method of the present invention can also be carried out Quality Identification to microfluidic device.Utilize known experiment condition (as controlled alive order and interval time etc. on voltage swing, electrode) to operate (as produced, move, separate, merging) to drop, and drop is carried out to capacitance measurement, if the measurement result obtaining and predicted value have deviation, show that microfluidic device may be defective in quality.
Have, liquid drop measuring method of the present invention can also be carried out electric capacity to the drop in a certain fixed position and measured over time, thereby can the physics carrying out in drop, chemistry and bioprocess be measured and be judged again.For example, the growth of the generation of bubble, protein crystal in drop, cytoactive (Cell Viability), the variation of toxicity (Cytotoxicity), Apoptosis (Apoptosis), etc.
As mentioned above, because liquid drop measuring method provided by the invention can be monitored the situation of drop (position, size, volume, speed etc.), for follow-up to drop move accordingly (generation, movement, separation, merging etc.) feedback information is accurately provided, therefore, the present invention also provides a kind of drop control method, as shown in Figure 8, described drop control method comprises: S20, provides the microfluidic device and the capacitance measuring device that with described microfluidic device be connected wetting based on electricity; S22, utilizes described capacitance measuring device, and the one or more drive electrodes in microfluidic device are carried out to capacitance measurement, obtains the overlapping situation of drop on drive electrode, determines the position of drop in described microfluidic device; S24, according to default operation requirements, applies voltage to the one or more drive electrodes in driving electrode array according to certain order, controls drop and carries out corresponding actions, and discharge the voltage in respective drive electrode after control drop completes corresponding actions; S26, utilizes described capacitance measuring device, and the one or more drive electrodes in described microfluidic device are carried out to capacitance measurement, judges whether the position of described drop meets described default operation requirements; If judge, the position of described drop meets described default operation requirements, completes this part operation; If judge, the position of described drop does not meet described default operation requirements, continues execution step S24, until guarantee that the position of described drop meets described default operation requirements.
Alternatively, in above-mentioned steps, described control drop carries out corresponding actions and comprises: one or more in the generation of drop, movement, fractionation, merging.
Alternatively, described drop control method also comprises: if by determining after capacitance measurement while obtaining on target location that described drop can not arrive described default operation requirements, judge that described drive electrode is as losing efficacy; Again drop is operated to walk around the drive electrode of described inefficacy.
Below, by example, the application to capacitance measurement in drop control is elaborated:
Fig. 9 A to 9D has shown the schematic diagram that is applied to drop generation.As shown in Figure 9 A, liquid in the LQ of liquid storage room is located immediately on a part of drive electrode E8, initial, the equal ground connection of all drive electrodes (using alphabetical G as mark), here, " ground connection " represents that corresponding drive electrode is configured to 0V or enough approaches with 0V.As shown in Figure 9 B, on drive electrode E8, add certain voltage (using V1 as mark, its amplitude is less than 100 volts conventionally, but should be greatly to observing obvious electrowetting effect or can be used for the capacitance measurement between electrode in microfluidic device), liquid in the LQ of liquid storage room starts to flow along drive electrode E8, by drive electrode E8 is carried out to capacitance measurement, liquid and the amount (the namely space overlap of liquid and drive electrode E8) flowing out from apotheca LQ just can be known, the volume of the drop that can produce as required with this decides the voltage when disconnecting on drive electrode E8.Fig. 9 C shown according to the volume of the drop of required generation and disconnected the upper voltage of drive electrode E8, after the liquid that makes to flow out in apotheca LQ separates with apotheca LQ, forms drop; Meanwhile, separately on drive electrode E1, adding the rear drop that separates rear formation of certain voltage (V2) starts extending on drive electrode E1.As shown in Fig. 9 D, when after the voltage disconnecting on E1, liquid is got back to natural circle, and so, the drop of a known dimensions has just been generated.
Certainly, for example to form the drop that volume is larger, also can: first on drive electrode E8, apply voltage, make the liquid in apotheca LQ flow along drive electrode E8, continue for some time, in the time that liquid extends abundantly on drive electrode E8, disconnect the voltage on drive electrode E8, then apply voltage and disconnect again on the relative for example drive electrode E3 away from apotheca LQ or E4, so, can obtain volume larger drop relatively.
Figure 10 A to 10E has shown and has been applied to the schematic diagram that drop moves.As shown in Figure 10 A, the initial position of drop D is the intersection point place of drive electrode E3, E7.At first, close on the whole ground connection of drive electrode (G) of this drop D, thereby now drop D is static and balance.As shown in Figure 10 B, when apply certain voltage (V on drive electrode E3
3) time, drop D just can extend on drive electrode E3, and its extensibility can be by judging the capacitance measurement of electrode E3.As shown in Figure 10 C and Figure 10 D, in due course, disconnect the voltage on drive electrode E3, and on drive electrode E8, apply certain voltage (V4), make drop D shift to drive electrode E8 and extend along drive electrode E8, described extensibility can be by judging the capacitance measurement of drive electrode E8.As shown in Figure 10 E, disconnect after the voltage on drive electrode E8, drop D becomes the circle naturally at the intersection point place that is positioned at two drive electrode E3, E8, and move the position that completes drop D.
Figure 11 A to 11D has shown the schematic diagram that is applied to drop separation.As shown in Figure 11 A, the initial position of drop D is the intersection point place of two drive electrode E3, E8.At first, close on the whole ground connection of drive electrode (G) of this drop D, now drop D is static and balance.As shown in Figure 11 B, when apply certain voltage (being respectively V5, V6, V7) on drive electrode E8, E2, E4 time, drop just can extend on drive electrode E8, E2 and E4, and its extensibility can be by concluding the capacitance measurement of drive electrode E8, E2 and E4.As shown in Figure 11 C, in due course, first disconnect the voltage on drive electrode E8, drop D is separated into the two parts that extend on drive electrode E2, E4 respectively.As shown in Figure 11 D, disconnect the voltage on drive electrode E2, E4, form the drop D1 at the intersection point place that lays respectively at drive electrode E2, E8 and be positioned at the drop D2 at the intersection point place of drive electrode E4, E8, realize the fractionation of drop D.
Figure 12 A to 12D has shown the schematic diagram that is applied to droplet coalescence.As shown in Figure 12 A, the initial position of drop D3 is the intersection point place of drive electrode E2 and E8, and the initial position of drop D4 is the intersection point place of drive electrode E4 and E8.At first, close on the whole ground connection of drive electrode (G) of these two drop D3, D4, now drop D1, D2 are static and balance.As shown in Figure 12 B, 12C, when apply certain voltage (being respectively V8, V9) on drive electrode E3, E8 time, first these two drop D1, D2 just can extend and jointly move towards drive electrode E3 on drive electrode E8, until two drop D1, D2 extend after converging on drive electrode E8, E3, its extensibility can be by concluding the capacitance measurement of drive electrode E3, E8.As shown in Figure 12 D, in due course, first disconnect the voltage on drive electrode E8, and then disconnect the voltage on drive electrode E3, the drop liquid being merged by two drop D1, D2 becomes the drop D that the intersection point place that is positioned at two drive electrode E3 and E8 is nature circle.
Above-described embodiment just lists expressivity principle of the present invention and effect is described, but not for limiting the present invention.Any person skilled in the art person all can without departing from the spirit and scope of the present invention, modify to above-described embodiment.Therefore, the scope of the present invention, should be as listed in claims.
Claims (7)
1. a liquid drop measuring method, is characterized in that, described measuring method comprises:
The microfluidic device and the capacitance measuring device that with described microfluidic device be connected wetting based on electricity is provided, the double-deck driving electrode array that described microfluidic device comprises substrate and is positioned on described substrate, comprises multiple drive electrodes, wherein, described microfluidic device comprises two the first chip layer, the second chip layer that arrange in opposite directions; The first chip layer comprises: for the first substrate of the drive electrode of growing, the first substrate has a phase back side and a forward surface; Be positioned at the first drive electrode layer on the forward surface of the first substrate, the first drive electrode layer comprises multiple the first drive electrodes that be arranged in parallel; Be positioned at the dielectric substrate on the first drive electrode layer; Be positioned at the second drive electrode layer on dielectric substrate, the second drive electrode layer comprises multiple the second drive electrodes that be arranged in parallel; And, be positioned at and detest water insulation course on the second drive electrode layer, multiple the second drive electrodes in multiple the first drive electrodes and the second drive electrode layer in the first drive electrode layer are double-deck driving electrode array or the grid of being configured to arranged in a crossed manner mutually, the second chip layer comprises: for the second substrate of the ground-electrode of growing, the second substrate has and deviates from phase back side of the first chip layer and a forward surface towards the first chip layer; Be positioned at the ground-electrode on the forward surface of the second substrate; And, be positioned at and detest water insulation course on ground-electrode; Space between the first chip layer and the second chip layer is as the running space of drop; Described the first drive electrode and/or the second drive electrode carry out the associative operation of drop;
Utilize described capacitance measuring device, the one or more drive electrodes in described microfluidic device are carried out to capacitance measurement;
The capacitance measurements obtaining according to described capacitance measuring device, judges the overlapping situation of drop and described drive electrode in described microfluidic device.
2. liquid drop measuring method according to claim 1, is characterized in that, the drive electrode in described driving electrode array is the operation for described drop being had to electric wetting effect.
3. liquid drop measuring method according to claim 1, it is characterized in that, the overlapping situation of described drop and described drive electrode comprises: whether drop exists on drive electrode or part exists, position, droplet profile, the size at drop place on drive electrode.
4. liquid drop measuring method according to claim 1, is characterized in that, described in carry out capacitance measurement method comprise the capacitance measurement based on resonance method and the capacitance measurement based on capacitor charging/discharging method.
5. a drop control method, is characterized in that, comprising:
The microfluidic device and the capacitance measuring device that with described microfluidic device be connected wetting based on electricity is provided, the double-deck driving electrode array that described microfluidic device comprises substrate and is positioned on described substrate, comprises multiple drive electrodes, wherein, described microfluidic device comprises two the first chip layer, the second chip layer that arrange in opposite directions; The first chip layer comprises: for the first substrate of the drive electrode of growing, the first substrate has a phase back side and a forward surface; Be positioned at the first drive electrode layer on the forward surface of the first substrate, the first drive electrode layer comprises multiple the first drive electrodes that be arranged in parallel; Be positioned at the dielectric substrate on the first drive electrode layer; Be positioned at the second drive electrode layer on dielectric substrate, the second drive electrode layer comprises multiple the second drive electrodes that be arranged in parallel; And, be positioned at and detest water insulation course on the second drive electrode layer, multiple the second drive electrodes in multiple the first drive electrodes and the second drive electrode layer in the first drive electrode layer are double-deck driving electrode array or the grid of being configured to arranged in a crossed manner mutually, the second chip layer comprises: for the second substrate of the ground-electrode of growing, the second substrate has and deviates from phase back side of the first chip layer and a forward surface towards the first chip layer; Be positioned at the ground-electrode on the forward surface of the second substrate; And, be positioned at and detest water insulation course on ground-electrode; Space between the first chip layer and the second chip layer is as the running space of drop; Described the first drive electrode and/or the second drive electrode carry out the associative operation of drop;
Utilize described capacitance measuring device, the one or more drive electrodes in microfluidic device are carried out to capacitance measurement, obtain the overlapping situation of drop on drive electrode, determine the position of drop in described microfluidic device;
According to default operation requirements, the one or more drive electrodes in driving electrode array are applied to voltage according to certain order, control drop and carry out corresponding actions, and discharge the voltage in respective drive electrode after control drop completes corresponding actions;
Utilize described capacitance measuring device, the one or more drive electrodes in described microfluidic device are carried out to capacitance measurement, to guarantee that the position of described drop meets described default operation requirements.
6. drop control method according to claim 5, is characterized in that, described control drop carries out corresponding actions and comprises: one or more in the generation of drop, movement, fractionation, merging.
7. drop control method according to claim 5, is characterized in that, also comprises: if by determining after capacitance measurement while obtaining on target location that described drop can not arrive described default operation requirements, judge that described drive electrode is as losing efficacy; Again drop is operated to walk around the drive electrode of described inefficacy.
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