CN102671722B - Field-programmable lab-on-a-chip based on microelectrode array architecture - Google Patents
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- B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
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Abstract
The invention discloses a field-programmable lab-on-a-chip based on microelectrode array architecture, concretely a system related to filed-programmable lab-on-chip (FPLOC) microfluidic operations, fabrications, and programming based on microelectrode array architecture. The FPLOC device by employing a microelectrode array interface may include the following: (a) a bottom plate comprising an array of multiple microelectrodes disposed on a top surface of a substrate covered by a dielectric layer; wherein each of the microelectrode is coupled to at least one grounding elements of a grounding mechanism, wherein a hydrophobic layer is disposed on the top of the dielectric layer and the grounding elements to make hydrophobic surfaces with the droplets; (b) a field programmability mechanism for programming a group of configured-electrodes to generate microfluidic components and layouts with selected shapes and sizes; and, (c) a FPLOC functional block, comprising: I/O ports; a sample preparation unit; a droplet manipulation unit; a detection unit; and a system control unit.
Description
The cross reference of related application
The application by reference to mode be incorporated to the name submitted on February 17th, 2011 and be called the associating Co-pending U.S. patent application No. of " DropletManipulations on EWOD Microelectrode Array Architecture "
13,029,137, on February 17th, 2011 name submitted to be called the associating Co-pending U.S. patent application No. of " Field-ProgrammableLab-on-a-Chip and Droplet Manipulations Based on EWOD Micro-Electrode ArrayArchitecture "
13,029,138and the name of submission on February 17th, 2011 is called the associating Co-pending U.S. patent application No. of " Microelectrode Array Architecture "
13,029,140full content.
Technical field
The present invention relates to chip lab (lab-on-a-chip, LOC) microfluid system and method.More specifically, the present invention relates to field-programmable chip lab (FPLOC) system adopting Microelectrode array architecture.
FPLOC can be used for microfluidic applications by field programming, and these microfluidic applications include, but is not limited to based on the microfluidic procedures of drop, based on continuous print microfluidic procedures, based on the excitation (actuation) of electrowetting on dielectric (EWOD) or the excitation based on (dielectrophoresis) DEP.
The structure that FPLOC is similar to field programmable gate array (FPGA) by utilization is that LOC designer provides solution more easily.Compared with exclusive hardwired solution, field-programmable microfluidic platforms realizes LOC design by software programming under without the need to the hardware design of complexity and the condition of encapsulation technology, this provides the advantage being significantly better than other platform.FPLOC can with the mode of simple and flexible realize different application specific systems (mensuration) just as utilization clearly characterize, large-scale production is the same with the FPGA of encapsulation.As a result, can be implemented in advantage in Time To Market, large-scale production, fault-tolerance, low cost and a lot of other advantages at microfluidic field by utilizing semicon industry experience.
Background technology
In order to realize the possibility of some chemistry, physics or biotechnology treatment technology, micro-fluidic technologies shoots up in the past during the decade.Microfluid refers to usually in the manipulation of microlitre to the micro fluid within the scope of millilambda.Use for the areal, fluid device implementing low capacity chemistry is proposed first by AC, and in order to this concept, biochemist employs term " miniaturized total chemical analysis system " (μ TAS).The base fluids principle of μ TAS is adopted, as a kind of mode developing the recent studies on instrument of chemistry and biology application from the very multi-disciplinary increasing researcher beyond biochemistry.In order to reflect this scope extended, except μ TAS, often use more broadly term " microfluid " and " chip lab (LOC) " now.
First generation micro-fluidic technologies is based on the manipulation of continuous liquid stream of passage flowing through microfabrication.The excitation of liquid stream is by external pressure source, integrated mechanical micropump or realized by electric structure.Continuous-flow system can meet the needs of a lot of clearly defined simple biochemistry application, but they are unsuitable for the more complicated task needing the flexibility of high level or the fluid actuated of complexity.Microfluid based on drop is the alternative of continuous-flow system, and wherein liquid is divided into the controlled drop of discrete independence, and these drops can by manipulation for move in the channel or on substrate.By utilizing the drop of discrete unit volume, microfluid function can be reduced to one group of basic operation repeated, that is, move the fluid of a unit when unit.Propose a lot for handling the method for microfluid drop in the literature.These technology can be classified into chemistry, calorifics, acoustics and electrical method.In all methods, receive extensive concern in recent years in order to encourage the electrical method of drop.
Based in the microfluidic device of drop, liquid folder between two parallel plates and carry with the form of drop.Microfluid system based on drop provides lot of advantages: they have low power consumption and do not need the mechanical component of such as pump or valve and so on.In recent years, the microfluid system based on drop has been widely used in such as hybrid analysis thing and reactant, analysing biomolecules and has handled in the multiple application of particle and so on.In digital micro-fluid system, electrowetting on dielectric (EWOD) and liquid dielectric electrophoresis (LDEP) are two kinds of main mechanisms for distributing and handle drop.EWOD and LDEP adopts electro mechanical force to control drop.EWOD micro-system is generally used for generation, conveying, cutting and merges drop.In such systems, drop presss from both sides between two parallel plates and is energized under the effect being energized the wetability difference between unexcited electrode.In LDEP micro-system, drop is placed on coplanar electrodes.Upon application of a voltage, liquid becomes polarizable, and towards the region flowing of more highfield intensity.Difference between LDEP and EWOD incentive mechanism is driving voltage and frequency.In EWOD excitation, apply the DC or the low frequency AC voltage that are usually less than 100V, and LDEP needs higher driving voltage (200-300Vrms) and higher frequency (50-200kHz).
Electrowetting on dielectric (EWOD) is one of modal electrical method.Such as the digital micro-fluid of chip lab (LOC) and so on typically refers to the droplet manipulation utilizing EWOD technology.Traditional LOC device based on EWOD generally includes two parallel plates.Base plate comprises the patterned array of independent controllable electrodes, and top board is coated with continuous print ground electrode.Material preferably by similar tin indium oxide (ITO) forms electrode, makes it in thin layer, have the assemblage characteristic of electric conductivity and light transmission.The dielectric insulator being coated with hydrophobic membrane is added on plate, to reduce wettability of the surface and to be increased in the electric capacity between drop and control electrode.In between the plates, drop is mobile in filling medium inside simultaneously for drop containing biochemical samples and filling media clip.In order to mobile drop, apply control voltage to the electrode being adjacent to drop, the electrode simultaneously immediately below drop is removed excitation.
In recent years, LDEP has also attracted to pay close attention to widely, because it is easy to implement and can distribute and handle the minimum drop being raised to picoliter scope from millimicro.Liquid D EP excitation is defined as polarizable liquid heap (liquid mass) of region attraction towards higher electric-field intensity.The basic structure of liquid D EP drop dispenser comprises two coplanar electrodes, and these two coplanar electrodes are coated with dielectric layer to protect them not by electrolysis.Ahmed and Jones optimizes liquid D EP liquid droplet distribution, and on coplanar electrodes, create picoliter drop.Effect and the key factor relevant with the reliable excitation of the liquid D EP using coplanar electrodes of surface coating are reported.The people such as Fan change coplanar LDEP electrode into two parallel LDEP electrodes.The LDEP device of parallel construction is adopted by micro-mixer, and is integrated with EWOD micro-system.Conveying, division and merge dielectric drop and realized by the DEP in parallel-plate (biplane) device, the fluid of digital micro-fluid expands to from the only scope of conduction and water-based by it contains non-conductive scope.The biplane DEP of dielectric drop encourages by applying voltage to realize between parallel pole, will have the liquid dielectric drop pump of relatively high-k to the region with relatively low dielectric constant (such as air) by DEP.
Disadvantageously, the conventional LOC system of set up so far employing EWOD technology is still highly exclusively used in specific application.Current LOC system used leaves much room depends on manual control and optimize and do biologicall test.In addition, the current application in LOC system and function are consuming time, and need expensive hardware design, test and maintenance program.Disadvantage about these systems is " hardwired " electrode." hardwired " refers to that the shape of electrode, size, position and the electrical wiring track about electrode controller are physically limited to the structure of permanent etch.Once electrode manufactured go out, no matter what their function is, their shape, size, position and track just can not change.Therefore, this means relative to the high disposable engineering cost of LOC design and after shipment the ability of limited more New function or the local LOC of configuration section again.
This area exists for reducing the needs with the system and method for utilize droplet manipulation to produce manpower that microfluid system is associated and cost.This area expects that LOC is designed rises to application layer, is manually optimizing the burden in biologicall test, hardware design consuming time, expensive test and maintenance program to alleviate LOC designer.
This area exists for reducing the needs with the system and method for utilize droplet manipulation to produce manpower that microfluid system is associated and cost.Microelectrode array architecture technology can provide field programmability, and wherein the electrode of LOC and integral layout can be software programmables.If microfluidic device or its (being stored in the nonvolatile memory of such as ROM and so on) firmware of embedded system can " in field " be modified, and without the need to disassembling apparatus or device to be returned its manufacturer, then can be described as field-programmable or existing field-programmable.This feature expected very much often because this can reduce for replace problematic or degenerate firmware needed for expense and the turnaround time.After shipment more New function ability, local again configuration section design and relative to LOC design lower disposable engineering cost will for much application advantage will be provided.
In addition, based on the Microelectrode array architecture of novelty, the technology of the manipulation drop in LOC system can significantly be improved.In the droplet manipulation based on the advanced person in the generation of EWOD Microelectrode array architecture, conveying, mixing and cutting process, the invention provides various embodiment.
Can believe, adopt the field-programmable chip lab (FPLOC) of Microelectrode array architecture owing to having the ability of the new LOC system that should be used for dynamically programming based on field, therefore, it is possible to provide the dramatic benefit being better than conventional numerical fluid system.Field programmability significantly can improve the turnaround time of LOC design, LOC can also be made to design and rise to application level, is manually optimizing the burden in biologicall test, hardware design consuming time, expensive test and maintenance program to alleviate LOC designer.
Summary of the invention
A kind of field-programmable chip lab (FPLOC) device adopting Microelectrode array architecture is disclosed herein, comprise: a. base plate, comprise the array of the multiple microelectrodes be placed on the top surface of substrate, described multiple microelectrode is covered by dielectric layer, wherein each described microelectrode is connected at least one earth element in ground structure, the top of described dielectric layer and described earth element is provided with hydrophobic layer, to generate the hydrophobic surface with drop; B. field-programmable architectures, for a group configuration electrode of programming, to produce microfluid component and layout with selected shape and size; And c.FPLOC functional block, comprising: I/O port; Sample preparation unit; Droplet manipulation unit; Detecting unit; And system control unit.
In another embodiment, a kind of FPLOC device of CMOS technology manufactured goods that adopts comprises: a.CMOS system control block, comprising: controller block, for providing processor unit, memory headroom, interface circuit and software programmability; Chip layout block, for stored configuration electrode configuration data and FPLOC layout information and data; Droplet position map, for storing the physical location of drop; With fluid-operated manager, for described layout information, described droplet position map and the FPLOC application from described controller block being translated into the physical stimulus of drop; And b. many fluid logic blocks, comprising: a microelectrode, be positioned on the top surface of CMOS substrate; A memory map datum memory cell, for keeping the excitation information of described microelectrode; And control circuit block, for managing control logic.
In yet, a kind of FPLOC device of thin film transistor (TFT) TFT technology manufactured goods that adopts comprises: a.TFT system block, comprising: controller block, for providing processor unit, memory headroom, interface circuit and software programmability; Chip layout block, for stored configuration electrode configuration data and FPLOC layout information and data; Droplet position map, for storing the physical location of drop; With fluid-operated manager, for the data applied from described layout information, described droplet position map and FPLOC being translated into the physics drop excited data for encouraging microelectrode, described FPLOC application from described controller block, wherein said physics drop excited data comprise with mode frame by frame send to active matrix block to configuration electrode in groups, excitation and remove excitation; And b. active matrix block, comprising: for the active matrix panel of each microelectrode of independent drive, comprise grid bus, source bus line, thin film transistor (TFT), holding capacitor and microelectrode; Active matrix controller, comprises source electrode driver and gate drivers, for by driving data is sent to driving chip, utilizes the data from TFT system control block to carry out drive TFT array; With DC/DC converter, for applying driving voltage to described source electrode driver and described gate drivers.
In yet, a kind of method of programming from bottom to top and design FPLOC device comprises: a. wipes the internal memory of FPLOC; B. configuration has the microfluid component of a group configuration electrode of selected shape and size, a described group configuration electrode is included in the multiple microelectrodes arranged in the form of an array in field-programmable architectures, and described microfluid component comprises liquid reservoir, electrode, mixing chamber, detection window, discarded object reservoir, droplet path and appointed function electrode; C. the physical allocation of described microfluid component is configured; And d. is designed for the microfluidic procedures of sample preparation, droplet manipulation and detection.
In yet, a kind of method of programming from top to bottom and design FPLOC device comprises: a. is by the function of hardware description language design FPLOC; B. ordering chart model is produced according to hardware description language; C. simulation is performed with the function verifying FPLOC by hardware description language; D. utilize system level to synthesize according to described ordering chart model and produce concrete implementation; E. by from microfluidic module storehouse and from the design data of design specification be input to synthesis process in; F. the mapped file of measurement operation of core Resources on Chip, the timetable file of measurement operation and the Built-in Self Test file from synthesis process is produced; G. the input of design specification is utilized to perform the synthesis of geometry level, to produce the two-dimensional physical design of biochip; H. design according to the two-dimensional physical of the biochip being combined with concrete physical message, produce 3-D geometric model, described concrete physical message is from described microfluidic module storehouse; I. by using 3-D geometric model to perform physical level simulation and design verification; And FPLOC design is loaded in blank FPLOC by j..
In yet, a kind of method of the FPLOC of design storehouse comprises: a. simulates the microfluidic procedures of being write by hardware description language functional module by creating test table describes, described hardware description language comprises VHDL or Verilog, and described test table forms test macro and for simulating described system and observed result; B. by Compositing Engine, described functional module description is mapped to wire list; C. described wire list is translated into gate level description; D. described gate level description is simulated; E. propagation delay is added to described wire list by physical analogy; And f. is by having the wire list of described propagation delay, run whole system simulation.
In another embodiment, EWOD Microelectrode array architecture of the present invention adopts the concept of " dot matrix printing machine ", wherein, multiple microelectrode (such as " point ") in groups and can be excited simultaneously/remove excitation with the electrode forming various shape and size, to meet the requirement of the fluid-operated function in application on the scene.
In another embodiment, all EWOD microfluid components can be produced by microelectrode, and these microfluid components include, but is not limited to liquid reservoir, electrode, mixing chamber, droplet path etc.Further, the LOC physical layout for the position of I/O port, liquid reservoir, electrode, path and electrode network all realizes by configuration microelectrode.
In another embodiment, except configuration electrode in order to perform typical microfluidic operation conventional control except, the determination control sequence of microelectrode may be provided in the microfluidic procedures of advanced person when handling drop.
In another embodiment, the droplet manipulation method based on EWOD Microelectrode array architecture can comprise: produce drop; Conveying drop; Cutting drop; And mixing drop.
Disclose the various embodiments of FPLOC.In one embodiment, the design of FPLOC is based on EWOD Microelectrode array architecture.FPLOC can be programmed by dynamically field according to different application and function, and all electrodes be wherein made up of a lot of microelectrode are by Software for Design and reconfigure.After configuration or reconfiguring, similar with the general plotting of the LOC system based on EWOD, realizing by control and steering electrode based on the fluid-operated of EWOD technology in LOC design.
In another embodiment, the electrode of the various shape and size of FPLOC system such as liquid reservoir, electrode, mixing chamber, droplet path etc. by software programming or can both reconfigure, to meet the requirement of the operating function in application on the scene.
In addition, software programming or reconfigure can perform the FPLOC physical layout of the position to input port, liquid reservoir, electrode, path and electrode network.
In yet, rudimentary microfluidic procedures is encapsulated into during application layer presents by FPLOC, so that designer pays close attention to senior application.Microelectrode in order to perform specifically fluid-operated configuration data and excitation control sequence produced as library item order and tested, wherein FPLOC designer can select described library item order to combine its microfluidic applications.
In another embodiment, the design handling the EWOD Microelectrode array architecture of drop can based on coplanar structure, and wherein EWOD excitation can occur in the veneer configuration without top board.
In yet, the design handling the EWOD Microelectrode array architecture of drop can adopt biplane construction, wherein arranges top top board in systems in which.
Although disclose multiple embodiment, but other embodiment of the present invention also will become apparent for one of ordinary skill in the art after studying detailed description hereafter, and described detailed description illustrate and describes illustrative embodiments of the present invention.To recognize, under the condition not departing from the spirit and scope of the present invention, the present invention can have multiple remodeling in many aspects.Correspondingly, drawings and detailed description should be regarded as illustrative rather than restrictive in nature.
Accompanying drawing explanation
Figure 1A is the viewgraph of cross-section that conventional sandwiched EWOD system is shown substantially.
Figure 1B is the top view of the conventional EWOD substantially illustrated in two-dimensional array of electrodes.
Fig. 2 is the figure of the biplane DEP device for handling dielectric drop.
Fig. 3 is the figure that microelectrode array is shown, the configuration electrode (configured-electrode) wherein in microelectrode array can be configured to various shape and size.
Fig. 4 A is the figure of the LOC layout utilizing Microelectrode array architecture.
Fig. 4 B is the figure of the structure of conventional physical etch.
Fig. 4 C is the figure of configuration electrode, illustrated therein is the amplifier section of liquid reservoir (reservoir) and configuration electrode.
Fig. 5 A shows the array of multiple square microelectrode, and one of them microelectrode is highlighted.
Fig. 5 B shows the array of multiple hexagon microelectrode, and one of them microelectrode is highlighted.
Fig. 5 C shows the array of the multiple square microelectrode be arranged in wall brick (wall-brick) layout, and one of them microelectrode is highlighted.
Fig. 6 A shows mixed plate structure, and wherein mixed plate structure can be controlled as and switch microelectrode structure between plane modes and biplane mode.
Fig. 6 B shows grounded screen (ground grid) microelectrode coplanar structure.
Fig. 6 C shows the FPLOC microelectrode coplanar structure that another has ground pad.
Fig. 6 D shows the FPLOC microelectrode coplanar structure that another has ground pad able to programme.
Fig. 7 is the figure that hybrid system structure is shown, wherein hybrid system structure has dismountable, adjustable and transparent top board, in order to adapt to drop size and the volume of most wide region.
Fig. 8 is the figure of five base function blocks illustrated needed for FPLOC.
Fig. 9 A, 9B, 9C and 9D show and utilize another hinged passive lid adjustable to carry out load sample.
Figure 10 illustrates the figure detecting I/O port.
Figure 11 A and 11B shows FPLOC and utilizes the permanent Display Technique of field-programmable to show test results or other important messages.
Figure 12 A shows drop and suspended particulate by the top view utilizing square configuration electrode and striped configuration electrode excitation respectively by EWOD and DEP.
Figure 12 B and 12C illustrates the high-frequency signal being from left to right applied to striped configuration electrode; By DEP particle is driven into the viewgraph of cross-section on right side at the inhomogeneous field of drop internal.
Figure 12 D is shown and is applied on square configuration electrode to be produced the low frequency signal with two sub-drops of variable grain concentration by EWOD.
Figure 13 shows another embodiment of the FPLOC sample preparation utilizing point technology such as drop.
Figure 14 A and 14B shows sample that self-regulation loads or the reactant ability relative to the position of liquid reservoir.
Figure 15 shows an embodiment of FPLOC drop production process.
Figure 16 shows the concrete drop production process being called " drop decile ".
Figure 17 is the figure of the conveying of the drop that FPLOC is shown.
Figure 18 is the figure of the drop route that FPLOC is shown.
Figure 19 A, 19B and 19C are the figure that the temporary bridge process conveying drop utilizing FPLOC is shown.
Figure 20 A, 20B and 20C are the figure illustrating that electrodes series encourages.
Figure 21 A, 21B and 21C are the figure of the drop cutting that FPLOC is shown.
Figure 22 A, 22B and 22C are the figure of the precise cutting of the drop that FPLOC is shown.
Figure 23 A, 23B and 23C are the figure of the diagonal cutting of the drop that FPLOC is shown.
Figure 24 A, 24B and 24C show the drop cutting process on the open surface of FPLOC.
Figure 25 is the figure that the fine heating element be integrated in the substrate of FPLOC is shown.
Figure 26 A and 26B is the figure of basic merging/mixing that FPLOC is shown.
Figure 27 A, 27B and 27C are the figure of the effective mixed process illustrated by the droplet manipulation implemented that moves in order to the uneven geometry of acceleration mixing.
Figure 28 A and 28B shows for accelerating the uneven toward complex mixers of droplets mixing.
Figure 29 is the figure of the fluid circulation blender illustrated based on EWOD Microelectrode array architecture.
Figure 30 A-30F is the figure that multilayer blender is shown, wherein multilayer blender is particularly useful for the situation of low aspect ratio (< 1).
Figure 31 is the figure that the sensing apparatus illustrating based on CMOS technology is integrated in FPLOC.
Figure 32 is the block diagram of the grading software structure illustrated for FPLOC.
Figure 33 is the block diagram that prototype for FPLOC and test system configurations are shown.
Figure 34 A shows the desktop machine configuration of FPLOC application.
Figure 34 B shows the portable machine configuration of FPLOC application.
Figure 34 C shows the free-standing biochip configuration of FPLOC application.
Figure 35 utilizes standard CMOS manufacturing process to manufacture the block diagram of FPLOC.
Figure 36 shows the electrical design of the FLB array based on standard CMOS manufacturing technology.
Figure 37 shows the viewgraph of cross-section of the FLB array manufactured goods based on standard CMOS manufacturing technology.
Figure 38 A utilizes thin film transistor (TFT) (TFT) array fabrication process to manufacture the block diagram of FPLOC.
Figure 38 B shows the block diagram of active matrix block (AMB).
Figure 38 C is the top view of the microelectrode array based on tft array.
Figure 38 D illustrates the viewgraph of cross-section based on the FPLOC manufactured goods of TFT technology in biplane construction.
Figure 39 A shows the blank FPLOC before any programming or configuration.
Figure 39 B shows the example of the design of configuration LOC.
Figure 40 shows the flow chart of top-down nano-fabrication method for FPLOC design and programming.
Figure 41 A, 41B and 41C are shown to be encouraged by Continuous Flow and produce liquid.
Figure 41 D and 41E is shown to be encouraged by Continuous Flow and cuts liquid.
Figure 42 A, 42B and 42C are shown to be encouraged by Continuous Flow and merge/mixing material.
Detailed description of the invention
Show conventional electricity in figure ia and soak calculus thought structure (only in order to illustrative object, illustrating with reduced size).Digital micro-fluid device based on EWOD comprises two glass plates be parallel to each other 120 and 121.Base plate 121 comprises the patterned array of independent controllable electrodes 130, and top board 120 is coated with continuous print ground electrode 140.Material preferably by such as tin indium oxide (ITO) and so on forms electrode, makes it in thin layer, have the assemblage characteristic of electric conductivity and light transmission.The dielectric insulator 170 (such as Parylene C) being coated with the hydrophobic membrane 160 of such as polytetrafluoroethylene (PTFE) AF and so on is added on plate, to reduce wettability of the surface and to be increased in the electric capacity between drop and control electrode.Drop 150 containing biochemical samples and the filling media clip of such as silicone oil or air and so between the plates, are filling the conveying of medium inside to contribute to drop 150.In order to mobile drop 150, apply control voltage to the electrode 180 being adjacent to drop, the electrode simultaneously immediately below drop 150 is removed excitation.
Figure 1B is the top view of the conventional EWOD substantially illustrated in two-dimensional array of electrodes 190.Drop 150 moves to energized electrode 180 from electrode 130.Electrode 180 is applied with control voltage in black table is bright.EWOD effect makes charge buildup in drop/insulator interface, causes the gap 135 between adjacent electrode 130 and 180 produces interfacial tension gradient, realizes the conveying of drop 150 thus.By changing the current potential along linear array, the wetting drop moving millilambda volume along this electrode wires of electricity can be utilized.Control the speed of drop by regulable control voltage in the scope of 0-90V, and drop can move with the speed up to 20cm/s.Drop 151 and 152 also can under the condition without the need to micropump and miniature valve, the pattern conveying under clock voltage controls limited with user by two-dimensional array of electrodes.
LOC device based on EWOD utilizes the interfacial tension gradient on the gap between adjacent electrode to encourage drop.The design of electrode comprises the gap between the intended shape of each electrode, size and each two electrodes.Based in the LOC layout designs of EWOD, droplet path is made up of multiple electrodes of the zones of different connecting LOC usually.These electrodes can be used for course of conveying, also can be used for the mixing of other more complicated operation such as in droplet manipulation and cutting process.
In one embodiment, the biplane DEP device for handling dielectric drop can be built as shown in Figure 2.The multiple microelectrode 261 of patterning in base substrate 245.Each configuration electrode 260 comprises multiple microelectrode 261.Top board 240 comprises the reference electrode 220 be not patterned.One deck low-surface-energy material (such as polytetrafluoroethylene (PTFE)) 210 is coated on two plates, and to reduce the interfacial force between drop 250 and the surface of solids, this contributes to reproducible drop process and eliminates the dielectric fluid residue during operation.Clearance height or drop thickness 270 are determined by the thickness of sept.Voltage is applied, by dielectric drop pump on the microelectrode being in foment, as denoted by the arrows in fig. 2 by driving between microelectrode reference electrode 220 and one.Be in the parallel-plate arrangement of 150mm, test dielectric drop (decane dielectric drop (350V in clearance height
dC), hexadecane dielectric drop (470V
dC) and silicone oil dielectric drop (250V
dC)) excitation.The polarity of the D/C voltage applied drives not impact to drop, and meanwhile, the AC signal reaching 1kHz frequency after tested successfully encourages dielectric drop.
Difference between LDEP and EWOD incentive mechanism is driving voltage and frequency.Therefore between EWOD and DEP, shared physics biplane electrode structure and configuration are feasible.Usually, in EWOD excitation, apply usually to be less than DC or the low frequency AC voltage of 100V, preferably driving voltage the AC of DC to 10kHz scope and be less than 150V; And LDEP needs higher driving voltage (200-300Vrms) and higher frequency (50-200kHz), preferably driving voltage the AC of 50kHz to 200kHz scope and there is 100-300Vrms.In the hereafter description of this invention, EWOD technology will be utilized to explain embodiments of the present invention, but in most of the cases by suitably changing driving voltage and frequency, DEP excitation is also contained in the present invention.
Present invention employs the concept of " dot matrix printing machine ", that is, each microelectrode in Microelectrode array architecture can be used for forming all microfluid components " point ".In other words, each microelectrode in microelectrode array can be configured to form various microfluid component with different shape and size.According to the demand of client, multiple microelectrode can be regarded as (grouped) in groups and can be excited simultaneously to form Different electrodes and perform " point " of microfluidic procedures." excitation " refers to the voltage needed for electrode applying, thus EWOD effect makes charge buildup in drop/insulator interface, causes gap between adjacent electrodes produces interfacial tension gradient, realizes the conveying of drop thus; Or DEP effect makes liquid become polarizable and flows towards the region compared with highfield intensity." remove excitation " and refer to the voltage removed and be applied to electrode.
Fig. 3 shows an embodiment of the FPLOC based on Microelectrode array architecture of the present invention.In the present embodiment, microelectrode array 300 comprises multiple (30 × 23) same microelectrode 310.This microelectrode array 300 manufactures based on standard microelectrode specification (being expressed as microelectrode 310 here) and independent of the manufacturing technology of final LOC application and concrete microfluidic procedures specification.In other words, this microelectrode array 300 is " blank " or " pre-configured " FPLOC.Then, based on application need, this microelectrode array can be configured or software programming to expect LOC in.As shown in Figure 3, each configuration electrode 320 comprises 100 microelectrodes 310 (i.e. 10 × 10 microelectrodes)." configuration electrode " refers to 10 × 10 microelectrodes 310 and combines to be used as Integrated electrode 320, and will be excited simultaneously together or remove excitation.As a rule, configuration data is stored in nonvolatile memory (such as ROM), and can " in field " be modified, and returns its manufacturer without the need to disassembling apparatus or by device.Fig. 3 shows drop 350 and is positioned at center configuration electrode 320.
As shown in Figure 3, the present invention configure electrode size and dimension can based on application need and design.The volume of drop 350 and the size of electrode 320 proportional.In other words, by the size of control electrode 320, the volume of drop 350 is also limited, to adapt with the design size of electrode 320, can control the volume of drop thus.The example of the configuration electrode that size is controlled is electrode 320 and 340.Electrode 320 has the size of 10 × 10 microelectrodes, and electrode 340 has the size of 4 × 4 microelectrodes.Except the configuration of electrode size, also by utilizing microelectrode array to configure the difformity of electrode.Although electrode 320 is square, electrode 330 is the rectangles comprising 2 × 4 microelectrodes.Electrode 360 is the square of left side dentation, and electrode 370 is circular.
Along with the quantity of microelectrode increases, can be designed by the FPLOC whole LOC that programmes, as shown in Figure 4 A, the shape of the configuration electrode of transport path 440, detection window 450 and mixing chamber 460 is square.Liquid reservoir 430 is the large scale configuration electrodes determining shape.Discarded object reservoir 420 is quadrangles.
Fig. 4 B and 4C shows the amplified version of the liquid reservoir 430 in Fig. 4 A.Fig. 4 B shows the liquid reservoir structure 431 of the physical etch manufactured by conventional EWOD-LOC system.Its assembly is shown as the liquid reservoir 431 of permanent etch and the electrode 471 of four permanent etch.Compared with Fig. 4 B (conventional design), Fig. 4 C shows field programming LOC structure, and it has configuration liquid reservoir 432 and the electrode 472 in groups of similar size.Configuration liquid reservoir 432 is by being combined into desired size and shape manufactures to make this liquid reservoir assembly by multiple microelectrode 411.Electrode 472 in groups comprises 4 × 4 microelectrodes 411.
After the shape and size setting required microfluid component, also it is important the position of setting microfluid component and how these microfluid components linked together as circuit or network.Fig. 4 A shows physical location residing for these microfluid components and how these microfluid components link together to be used as function LOC.These microfluid components are: the transport path 440 of the zones of different of configuration electrode 470, liquid reservoir 430, discarded object reservoir 420, mixing chamber 460, detection window 450 and connection LOC.If field-programmable LOC, then after layout designs, have some untapped microelectrodes 410.After FPLOC is fully up to the standards, designer can attempt hardwired version with cost-saving, and then untapped microelectrode 410 can be removed.
The shape of the microelectrode in FPLOC can physically realize in a different manner.In an embodiment of the invention, Fig. 5 A shows the array of multiple square microelectrode, and one of them microelectrode highlighted be 501.6 × 6 microelectrodes form configuration electrode 502.Fig. 5 A always has 3 × 2 configuration electrodes.In another embodiment, Fig. 5 B shows the array of multiple hexagon microelectrode, and one of them microelectrode highlighted be 503.6 × 6 microelectrodes are formed in configuration electrode 504, Fig. 5 B has 3 × 2 to configure electrode.The interdigital edge of hexagon microelectrode has advantage when moving drop along the gap between configuration electrode.In yet, Fig. 5 C shows the array of the multiple square microelectrode be arranged in wall brick layout, and one of them microelectrode is highlighted is 505.6 × 6 microelectrodes are formed in configuration electrode 506, Fig. 5 C has 3 × 2 to configure electrode.The interdigital edge of hexagon microelectrode has advantage when moving drop along the gap between configuration electrode, but this only occurs in x-axis.Also can realize the microelectrode of other shape a lot, and be not limited only to three kinds of shapes discussed herein.
Conventional LOC design is based on biplane construction (it has the base plate comprising patterned electrodes array and the top board being coated with electrode continuously) or coplanar structure (wherein excitation can occur in the veneer configuration without top board).Co-planar designs can adapt to the drop of the different volumes size of more wide region, and not by the restriction of top board.Biplane construction has fixed interval (FI) between top board, and there is restriction in the drop of volume size adapting to wide region, but biplane construction provides more stable microfluidic procedures really.LOC device based on coplanar structure still can increase the passive top board for sealing test surface, to protect fluid-operated or to have the object in longer added preservation (shelf storage) life-span in order to relay testing medium.
In order to adapt to the application of the most wide region of FPLOC, in an embodiment of the invention, FPLOC device is based on mixed plate structure, and wherein excitation can occur in coplanar arrangement or biplane configuration.Fig. 6 A shows switch 610, and it can be controlled as and switch microelectrode structure between plane modes and biplane mode.In biplane mode, the electrode continuously 640 on cover plate 620 is connected to ground, grounded screen on battery lead plate 621 680 with disconnect.On the other hand, in plane modes, the grounded screen 680 on battery lead plate 621 is connected to ground, and ground electrode on cover plate 620 640 with disconnect.
In one embodiment, the coplanar microelectrode of the physics of shown in Fig. 6 A (630 and 680) can be grounded screen structure.Grounded screen structure illustrates in fig. 6b, and it has driving microelectrode 631, ground wire 681 and the gap between 631 and 681 615.When electrode is energized, microelectrode 631 is driven to be charged by DC or square wave driving voltage.Ground wire 681 is on identical plate with driving microelectrode 631 to realize coplanar structure.Gap 681 is in order to guarantee between 631 and 681 without vertically superposed.Two drops 651 and 652 of different size are shown in fig. 6b, and they are all fully overlapping with grounded screen 681 and adjacent microelectrode 631, and can effectively be handled.In another embodiment, coplanar grounded screen can not disconnect with ground, as long as extra ground connection can not bring any problem to biplane construction operation.
Fig. 6 C shows another embodiment of FPLOC microelectrode structure.Driving four angles place of microelectrode 632 to have ground pad 682, and there is gap 616 between 632 and 682.Replace the ground wire in the embodiment shown in Fig. 6 B, present embodiment uses ground pad to realize coplanar structure.This embodiment of the present invention make use of group's ground connection (group grounding), and ground pad, microelectrode ensure that reliable droplet manipulation with the consistent overlap of drop 653 thus.In addition, in another embodiment, coplanar grounded screen can not disconnect with ground, as long as extra ground connection can not bring any problem to biplane construction operation.
Fig. 6 D shows another embodiment of FPLOC microelectrode " configuration ground pad " coplanar structure.The plate identical with microelectrode do not have ground wire or ground pad.But some microelectrodes are used as ground pad to realize coplanar-electrode structure.Fig. 6 D shows 4 × 4 same square microelectrodes 633, has gap 617 between microelectrode.In the present embodiment, any one microelectrode 633 can be configured to by being physically connected as electrical ground and be used as ground electrode.In the present embodiment, the microelectrode at four angles is configured to ground electrode 683.In addition, field programmability and the dynamic-configuration of miniature microelectrode to " configuration electrode " and " configuration ground pad " provide higher flexibility and the granularity of Geng Gao.In order to illustrative object, ground microelectrode is programmed on four angles, but this is not fixing layout.Comprise the optimum that can be implemented to obtain droplet manipulation to the preliminary step of the change of ground electrode or exciting electrode.This " field-programmable " microelectrode ground structure is the mode the most flexibly of the mixed plate structure realizing FPLOC, but will higher driving voltage be needed to encourage drop.
In another embodiment, in the mixed structure of FPLOC, adopt dismountable, adjustable and transparent top board, to optimize the clearance distance between top board 710 as shown in Figure 7 and battery lead plate 720.Battery lead plate 720 is realized by Microelectrode array architecture technology, and the side view wherein for the configuration electrode of drop 730 comprises three microelectrodes (being shown as black).Configuration electrode for drop 740 comprises six microelectrodes, and the configuration electrode for drop 750 comprises 11 microelectrodes.Present embodiment is particularly useful in the application of such as FPLOC and so on.Although Microelectrode array architecture provides field programmability when configuring the shape and size of described configuration electrode, still highly needs can adapt to the system architecture of the most size of wide region and the drop of volume.This is because the size of the adaptable drop of FPLOC and the scope of volume wider, just can realize more application.The clearance distance optimized can be adjusted to the drop of applicable desired size.In the present invention, the gap of optimization realizes by three kinds of modes: first, and all drops can be handled under the condition not contacting top board 710.This mode is applied in coplanar structure usually.In the second way, all drops are handled by contact top board, and wherein drop is clipped between top board 710 and battery lead plate 720.The second way is applied in biplane construction usually.The third mode or hybrid mode incorporate the function of coplanar structure and the adjustable clearance between top cover 710 and coplanar battery lead plate 720.This hybrid mode can be used for providing the drop with most wide region.As shown in Figure 7, the drop 730 being positioned at gap can be handled with drop 740 under the condition not contacting top board 710.Drop 750 is handled as being clipped between top board 710 and battery lead plate 720.The invention is not restricted to EWOD Microelectrode array architecture technology, also can drop size can range of application can the confined battery lead plate being simultaneously applied to other routine.
In an embodiment of FPLOC800, FPLOC needs five base function blocks, as shown in Figure 8, comprises I/O port (810,811,812 and 813), sample preparation 820, droplet manipulation 830, detects 840 and Systematical control 850.In paragraph below the embodiment of five functional blocks of FPLOC will be disclosed in detail.
Input/output end port (810,811,812 and 813) is the interface between the external world and FPLOC800.In another embodiment, there are four kinds of input/output end ports of FPLOC, they are associated with following four functional blocks: sample input mouth 810, drop I/O port 811, detect I/O port 812 and Systematical control I/O port 813, as shown in Figure 8.
Sample input mouth (810 in Fig. 8): due to real world sample (microlitre) and chip lab (millilambda) greatest differences in ratio, the design of fluid inlet port is rich in challenge.Sample (825 in Fig. 8) and reactant (833 in Fig. 8) are loaded into interface LOC needed between microfluidic device and the external world.An embodiment of the invention, based on mixed plate structure, wherein can add lid after sample or reactant are loaded on FPLOC, thus do not need the input port fixed.Fig. 9 A is shown and is directly loaded on coplanar electrodes plate 970 by sample 950 by pin 960.The loading of sample need not be very accurate, because the position of liquid reservoir can dynamically regulate as required, to compensate physical loading deviation.Fig. 9 B represents place passive lid 980 after load sample 950.Fig. 9 C shows an embodiment of the invention, wherein has adjustable sept 930, to regulate the clearance height between cover plate 980 and battery lead plate 970 at four angles of FPLOC.Drop 950 presss from both sides between which.Fig. 9 D shows another embodiment of the present invention, and wherein FPLOC have employed articulated mounting 940 and connects cover plate 980 and battery lead plate 970, to facilitate load sample and reactant 950 and to realize better physical system integrated.
Drop I/O port (811 in Fig. 8): in an embodiment of the invention, reactant loader (833 in Fig. 8) is connected to FPLOC by drop I/O port.Discarded object (835 in Fig. 8) can be stored in the discarded object reservoir on FPLOC800, or washes away by discarded object port (811 in Fig. 8).
Detect I/O port (812 in Fig. 8): increasing research paper is being inquired into and will detected the technology being integrated into micro-fluid chip, especially those phase specific absorptivities or fluoroscopic examination better technology in size microminiaturization.But, some ripe and stable detection techniques, such as can comprise and use the optical detection (1035 in Figure 10) and magnetic nanoparticle detection (1036 in Figure 10) that video detects and LIF (LIF) is analyzed, will be difficult to be integrated in FPLOC.Due to steadiness, high s/n ratio and sensitivity, other method that optical detecting method is compared for LOC is still occupied an leading position.The easiest LOC platform intergration with soaking based on electricity of optical detection.Only need to make transparent by being arranged in all material region being used for optical detection being comprised top board 1020, base plate 1021, dielectric layer 1040 and 1070 and electrode 1090.Co-planar designs can adapt to, than above-mentioned more testing mechanism, thus add the flexibility of system development.In order to the object of external detection, use is detected I/O port (812 in Fig. 8) by us.Detect I/O port also can be used for optics sensing and feed back with the object of the quick liquid of control FPLOC inside motion.
Systematical control I/O port (813 in Fig. 8): in an embodiment of the invention, need Systematical control I/O port 813 to chip 851 of programming, show test results 852, carry out data management 853 and a lot of other system works, as shown in Figure 8.As required, the required peripheral assembly 854 of such as printer, USB storage or network interface and so on is connected to FPLOC by Systematical control I/O port.FPLOC is also connected to power supply by Systematical control I/O port, to provide required AC/DC electric power.
In an embodiment of the invention, FPLOC utilizes the permanent Display Technique of field-programmable to show test result as shown in Figure 11 A and 11B or other important messages, and does not need exterior display device.In Figure 11 A, when system is performing other microfluidic procedures by encouraging or remove excitation to microelectrode 1111, display ink framework 1110 be not touched.After completing test or target microfluidic procedures, the drop that black ink in Figure 11 B (or other color and liquid) framework 1114 produces moves to right positions, with display graphics or text.Two advantages of present embodiment are: (1) almost not used for showing test results or the extra charge of other message because for test or the electrode of other microfluidic procedures is used as display pixel; And (2) are even if electric power disconnects from calculus thought, display is also permanent, therefore can be used as test record.
Sample preparation (820 in Fig. 8): the theme in sample preparation will be isolate cell in whole blood, to obtain serum or blood plasma, and pre-sample concentration (pre-concentration).Pre-sample concentration becomes very important in the mensuration that molecule to be detected is quantitatively little.In order to first following two reasons complete Sample Dilution: in order to reduce the impact of interfering material, and in order to aggrandizement apparatus operation the range of linearity.So far, the various technology that have employed wide range such as utilize acoustics power, magnetic force, optical force, Capillary Electrophoresis (CE), dielectrophoresis (DEP) power etc. to come separating particles and cell.An embodiment of the invention are as shown in the top view of Figure 12 A, and wherein drop 1250 and suspended particulate utilize EWOD and DEP to be energized by square configuration electrode (1210,1211,1212 and 1213) and striped configuration electrode (1220,1221,1222,1223,1224,1225 and 1226) respectively." configuration (configured) " refers to that Figure 12 B and 12C is viewgraph of cross-section, wherein pass through from left to right (from 1220 to 1226) and apply high-frequency signal (VHF) 1230 at strip electrode, the inhomogeneous field 1256 of drop internal utilizes DEP particle to be driven into right side.By applying low frequency signal (VLF) 1235 in square-shaped electrode 1221 and 1222, EWOD is utilized to obtain two sub-drops 1251 and 1252 with variable grain concentration.As an example, when from left to right applying 2MHz and 60Vrms signal 1230 on one of strip electrode, attract particle by positivity DEP.After cell aggregation to the right side in drop, by applying 80Vrms and 1kHz on two square configuration electrodes, EWOD is utilized drop breakup to be become two sub-drops.As a result, by encouraging the strip electrode of from left to right simple subprogram, cell is aggregated (the sub-drop in right side 1251) or dilution (the sub-drop 1251 in left side), as indicated in fig. 12d.
Figure 13 shows another embodiment of the FPLOC sample preparation utilizing point technology such as drop.Sharing one of sample preparation steps is remove haemocyte from whole blood, to obtain the plasma for immunoassays.As shown in figure 13, point technology such as drop are utilized via microelectrode 1340, produce less drop (this drop is too little to such an extent as to some or arbitrary haemocyte 1380 can not be carried), then move droplet 1345 via undersized down suction 1370, expect drop 1350 to be formed.Droplet 1345 can move from liquid reservoir/drop 1360 through passage 1370 by the combination of point technology such as drop and small―gap suture 1370 effectively, to form larger drop 1350, stops haemocyte 1380 simultaneously.Here physical barriers is mainly used in helping point technology such as drop, and difformity besides a square can be adopted to produce less drop to utilize microelectrode.It is also not used as the main cause removing haemocyte.By utilizing point technology such as drop, this sample preparation invention can not only remove particle from drop, and can for the preparation of the drop of the suitable dimension of diagnostic test.
Droplet manipulation (830 in Fig. 8): in yet, all typical microfluidic operations are by configure and " the configuration electrode " of control FPLOC performs." microfluidic procedures " refers to any manipulation of the drop on FPLOC.Such as, microfluidic procedures can comprise: be loaded into by drop in FPLOC; From the one or more drop of source liquid droplet distribution; Division, separation or a segmentation drop are two or more drops; Drop is transported to another location along any direction from a position; By two or more droplet coalescences or be combined as single drop; Dilution drop; Mixing drop; Stir drop; By drop deformation; Drop is kept going up in position; Cultivate (incubating) drop; Arrange drop; Drop is transferred out FPLOC; Other microfluidic procedures as herein described; And/or above-mentioned any combination.
In yet, except FPLOC " configuration electrode " in order to perform typical microfluidic operation conventional control except, the concrete control sequence (sequence) of microelectrode can be provided in the microfluidic procedures of advanced person when handling drop.The microfluidic procedures of the advanced person of FPLOC can comprise: diagonally or along any direction carry drop; Temporary bridge technology is utilized to carry drop through physical clearance; Electrodes series is utilized to encourage conveying drop; Scrub residual drop (dead volume); Drop is being carried compared with when low driving voltage; With controlled low velocity conveying drop; Perform accurate cutting; Execution diagonal cuts; Perform coplanar cutting; Diagonally merge drop; Make drop deformation to accelerate mixing; Mixing velocity is improved toward complex mixers by uneven; Mixing velocity is improved by circulation blender; Mixing velocity is improved by multilayer blender; The microfluidic procedures of other advanced person as herein described; And/or above-mentioned any combination.
Fluid storage and drop produce: from port fluid storage in the reservoir.Liquid reservoir can on EWOD device with allow drop into and out of large electrode region form produce.Basic LOC minimumly should have three liquid reservoirs: one for sample load, one for reactant, one drips for collecting waste liquid, but this depends on application.The 4th liquid reservoir may be needed for calibrating solution (calibratingsolution).Each liquid reservoir should have in order to allow the independence producing drop or collect drop to control.
In another embodiment, FPLOC has sample that self-regulation loads or the reactant ability relative to the position of liquid reservoir.This means can avoid accurately locating the needs of input port and avoiding sample and reactant being delivered to through input port the difficulty operation of liquid reservoir.The sample that Figure 14 A shows loading is broken into drop 1420 and drop 1430, and they are not all accurately positioned at the top of liquid reservoir 1440.Drop 1420 does not even have any overlapping with liquid reservoir 1440.For the LOC of routine, be difficult to drop 1420 to be reoriented in liquid reservoir 1440.Even and if sample drop 1420 is loaded and deviate from liquid reservoir, by excitation provisional configuration electrode 1460 drop 1420 to be moved to the position overlapping with liquid reservoir 1440, this self-align embodiment of the present invention also can be realized.Subsequently excitation is removed to provisional configuration electrode 1460 and liquid reservoir 1440 is encouraged, so that sample is navigated in liquid reservoir exactly, as shown in Figure 14B.
Figure 15 represents an embodiment of FPLOC drop production process.Routinely, drop must be produced with the liquid reservoir 1530 of specialized shapes and superposed electrodes 1535.In the present invention, the shape of liquid reservoir 1530 can be square (square liquid reservoir 1515), and does not need superposed electrodes 1535.In another embodiment, the shape of liquid reservoir 1515 can be needed according to design by design microelectrode array and be other shape any.As shown in figure 15, the generation of drop refers to the process extruding drop 1550 from square liquid reservoir 1515.In order to start drop production process, first encouraging temporary electrode 1530 as retracting (pull-back) electrode, then encouraging another temporary electrode 1535 to extrude liquid.Subsequently, by encouraging the configuration electrode 1540 of adjacent sequence number, extrude liquid finger piece (liquid finger) from liquid reservoir 1515, final generation drop 1550.Each configuration electrode 1540 comprises 4 × 4 microelectrodes of configuration, is thus square.In the present invention, the size of configuration electrode 1540 from the scope of tens microns to several millimeters, but can be not limited thereto scope.The shape of configuration electrode can be square or other shape.In the present invention, liquid reservoir can be square, circular or other concrete shape.
Figure 16 shows the embodiment being called the concrete drop production process of " drop decile " of the present invention.Drop decile uses Microelectrode array architecture first to produce less drop 1615 by microelectrode or undersized configuration electrode from liquid reservoir 1610, then by stimulation arrangement electrode 1620, less drop 1615 is collected together, to form larger drop 1630.Routinely, drop size is similar to the size of electrode, there is not the more accurate mode controlling droplet size.In the present invention, drop decile can be used for realizing controlling more accurately droplet size.In addition, in an inverse manner, this technology can be used for can producing from drop 1630 volume that how many less drops 1615 measure larger drop 1630 by calculating, as shown in figure 16.
The conveying of drop: Figure 17 is the figure of the drop conveying embodiment that FPLOC is shown.As shown in the figure, the configuration electrode 1731 to 1739 that 9 adjacent is had.Each configuration electrode comprises 10 × 10 microelectrodes of configuration, is thus square.Drop 1750 is positioned at the top of center configuration electrode 1735.In the microfluid conveying operations of routine, drop 1750 can only encourage along north and south and east-west direction by configuring electrode 1735 under this square-shaped electrode is arranged.Such as, remove by stimulation arrangement electrode 1734 and to configuration electrode 1735 and encourage, drop will be made to move to configuration electrode 1734 from configuration electrode 1735.But this routine operation can not make drop 1735 diagonally move to any one configuration electrode 1731,1733,1737 or 1739 from configuration electrode 1735, because these four configuration electrodes and drop 1750 do not have physical overlap.The restriction that this drop does not cover four angles is always present in from the situation of typical droplet production process generation drop.In order to diagonally move drop, an embodiment of the invention are as preliminary step stimulation arrangement electrode 1760, then encourage the configuration electrode 1733 of expectation and excitation is removed to provisional configuration electrode 1760, thus drop 1750 diagonally can be moved in the configuration electrode 1733 of expectation.As shown in figure 17, based on the present invention, drop 1750 can move along all 8 directions in square-shaped electrode is arranged.In addition, the conveying of drop is not limited to 8 directions.If adjacent configuration electrode is in outside these 8 directions, then provisional configuration electrode still can be encouraged so that drop is transported to destination.
Drop route: routinely, LOC has to connect the different piece of LOC to carry the transport path electrode 440 of drop, as shown in Figure 4 A.In the present invention, an embodiment of the drop route of FPLOC there is no need for the fixing transport path carrying drop, as shown in figure 18.But utilize drop route that multiple drop is moved to destination from multiple original position simultaneously.Clearly, the route processing of FPLOC will be different from the microfluid design of routine and design more effective than conventional microfluid very much, because pass through the different microelectrode of excitation, substantially can move along any direction comprising diagonal.Drop 1850,1851 and 1852 is in their original position, as shown in figure 18.Drop 1850 and drop 1852 will mix at configuration electrode 1810 place, and drop 1851 will be transported to configuration electrode 1820.Different from traditional VLSI routing issue, except routed path is selected, the problem that biochip routing issue needs the drop time table of solution under the actual restriction applied by fluid properties and the sequential restriction of synthesizing result to arrange.If do not consider to pollute, then by selection schemer 1860, first drop 1851 is moved, and by selection schemer 1840, drop 1852 is moved.Here required it is considered that arrange the conveying sequential of drop 1851 and 1852, they can not be piled up while moving to their destination.If consider pollute, then 1851 can selection schemer 1861 to avoid any overlap on drop mobile alignment.In addition, for two drops 1850 and 1852 that will merge at configuration electrode 1810 place, must consider the sequential arranging drop excitation, therefore the length difference of route 1830 and route 1840 can become Consideration, thus has best mixed effect.When the application performed on FPLOC becomes increasingly complex, top-down design automation will be needed, to limit route and the sequential of the drop on FPLOC.After defining biologic medical microfluid function, utilize system level (architectural-level) synthesize to FPLOC resource microfluid function is provided and by microfluid functional mapping to encourage time step in.
Temporary bridge: the present invention utilize FPLOC carry and mobile drop be called that another embodiment of " temporary bridge technology " is as shown in Figure 19 A-19C.Drop cutting and evaporation make drop become too little sometimes, and drop reliably can not be encouraged by electrode.Figure 19 A represents by gap 1,960 two configuration electrodes 1930 and 1940 separated from one another.Drop 1950 is positioned on left side configuration electrode 1930.Gap 1960 between two configuration electrodes 1930 and 1940 is enough wide, can isolate two configuration electrodes 1930 and 1940, makes the drop 1950 be positioned on left side configuration electrode 1930 can not contact next adjacent configuration electrode 1940.Figure 19 A shows in the drop conveying of routine, and drop 1950 is from configuration electrode 1930 to the failure usually of the movement configuration electrode 1940, because configuration electrode 1940 does not have to change its capillary physical overlap with drop 1950.The drop 1950 that Figure 19 B shows from Figure 19 A is transported in the configuration electrode 1940 of expectation.In this process, the microelectrode covered by " dentation " region 1970 is energized.Electrode 1930, gap 1960 and whole next one configuration electrode 1940 is configured on the left of dentation configuration electrode 1970 local complexity.As shown in Figure 19 B, " dentation " configures electrode 1970 and has physical overlap with drop 1950, and as shown in Figure 19 B, the top making drop 1950 at configuration electrode 1970 is moved by the excitation of configuration electrode 1970.Figure 19 C has shown the drop conveying to the configuration electrode 1940 expected.After drop 1950 moves to the configuration electrode 1970 of expectation, " dentation " configures electrode 1970 and is removed excitation, and next configuration electrode 1940 is energized, so that drop 1950 is arranged and to be navigated in the square configuration electrode 1940 of expectation.
Electrodes series encourages: the present invention utilizes FPLOC to carry and the another embodiment of mobile drop is called " electrodes series excitation ".Drop cutting and evaporation make drop become too little sometimes, and drop reliably can not be encouraged by electrode.As shown in FIG. 20 A, drop 2050 becomes too little to such an extent as to is less than electrode 2010 and does not have physical overlap with adjacent electrode 2011 sometimes.In this case, even if electrode 2011 is energized, drop 2050 also can not move in electrode 2011, and drop can glue and stay in systems in which.Washing away to glue stays a kind of effective means of drop to be utilize electrodes series to encourage.Exciting electrode is arranged to multiple row to perform electrodes series excitation, as shown in fig. 20b.Here, often row configuration electrodes series 2020 comprises 1 × 10 microelectrode, and three row configuration electrodes series combine to perform electrodes series excitation, as be labeled as black in Figure 20 B part shown in.The column width of acquiescence is a microelectrode, but depends on that application also can be other quantity.The most effective electrodes series excitation has one group of electrodes series, and its width is a bit larger tham the radius of drop.Why Here it is arranges three the reason combined here.The length of row depends on application, and the longer the better under normal circumstances.For this three row configurations in order to mobile drop 2050, before the configuration electrodes series 2022 of first place, configuration electrodes series 2021 is energized, and the configuration electrodes series 2022 of trailing is removed excitation.By this way, no matter the size of drop how, always three row configuration electrodes series are to provide the contact wire of maximum effective length.As a result, drop can effectively, smoothly move, because the capillary force on drop is consistent and is maximized.Therefore, drop can move under the driving voltage more much lower than the driving voltage in Conventional drop operation.This electrodes series actuation techniques can be used for carrying drop by the level and smooth movement under much lower driving voltage.In addition, due to the consistent capillary force of this technology, by with low-speed propulsion configuration electrodes series, the control to liquid drop speed (especially in low speed situation) can be realized.Experiment shows: under critical driving voltage, and this level and smooth, the effective driving force of electrodes series excitation is more obvious.Observe: lower than 8Vp-p 1kHz square wave driving voltage and under the condition in the gap of 80 μm, in 10cSt silicone oil slowly but move DI water droplet (1.1mm diameter) reposefully.Length can be configured to the total length of LOC, and the single that electrodes series is encouraged washes away all invalid drop (dead droplet) that can wash off in LOC.Figure 20 C shows droplet 2050 and shifts out configuration electrode 2010.
Drop cuts: use three of FPLOC configuration electrodes to cut drop.The present invention is for performing an embodiment of typical case three electrode cutting of the drop of FPLOC as shown in Figure 21 A-21C.Use three to configure electrodes, and the top having with exterior arrangement electrode 2110 and 2112 that drop to be cut is positioned at inner configuration electrode 2111 as illustrated in fig. 21 partly overlap.During cutting, two outside configuration electrodes 2110 and 2112 are energized, and inner configuration electrode 2111 is removed excitation, and drop 2150 expansion is come thus wetting outside two electrodes.Typically, the hydrophilic power stretching drop that two exterior arrangement electrodes 2110 and 2112 cause, liquid pinch off is two sub-drops 2151 and 2152 by the hydrophobic force of central authorities simultaneously, as shown in fig. 21 c.
Precise cutting: the present invention is similar to an embodiment of the precise cutting of three electrode cutting as shown in Figure 22 A-22C in order to realization.Precise cutting also originates in the top that drop to be cut is positioned at inner configuration electrode.But replacing using two outside configuration electrodes 2210 and 2212 to cut drop, utilizing electrodes series exciting technique towards configuring electrode 2210 and 2212 slowly but firmly pull drop 2250, as shown in fig. 22.Here, two group of 5 row configuration electrodes series 2215 and 2216 (being labeled as black in Figure 22 A) is used to pull open drop.Figure 22 B shows by once advancing microelectrode row, makes two arrays of electrodes row group keep moving separately.The hydrophilic power stretching drop that two arrays of electrodes row group 2215 and 2216 causes.When electrodes series group 2215 and 2216 arrives the outer rim of configuration electrode 2210 and 2212, all configuration electrodes series are removed excitation, and it is energized to configure electrode 2210 and 2212, by liquid pinch off to be two sub-drops 2251 and 2252, as shown in fig. 22 c.
Diagonal cuts: Figure 23 A-23C shows the present invention in order to perform the embodiment of diagonal cutting.Diagonal cutting originates in and moves on provisional configuration electrode 2312 by drop to be cut, and wherein provisional configuration electrode 2312 is positioned at the center of the engagement angle (joint corner) of four configuration electrodes 2310,2311,2313 and 2314.After drop is positioned at the center of the engagement angle of four configuration electrodes completely, provisional configuration electrode 2312 is removed excitation, and configures electrode 2310 and configure electrode 2311 energized, and drop 2350 is stretched in liquid column, as shown in fig. 23b.In order to be two sub-drops by liquid pinch off, need the interior angle of configuration electrode 2310 and 2311 to be removed excitation, to produce necessary hydrophobic force at the middle part of drop 2350.Figure 23 C shows L shape provisional configuration electrode 2315 and 2316 and is energized, and make only have thin neck therebetween with the drop that stretches further, the hydrophobic force at middle part contributes to being two sub-drops 2351 and 2352 by drop 2350 pinch off subsequently.Finally, configuration electrode 2310 and 2311 again encouraged, with by drop 2351 and 2352 centralized positioning to configuration electrode 2310 and 2311 in, as shown in fig. 23d.
Figure 24 A-24C shows the drop cutting process on the open surface of FPLOC.Figure 24 A shows drop 2450 and is positioned on left side configuration electrode 2440.Drop 2450 will be cut into two sub-drops 2470, as shown in Figure 24 C.Drop cutting process roughly comprises two processes below.First, by stimulation arrangement electrode 2430 under suitable voltage, drop 2450 to be cut is stretched as thin liquid column 2460.This can find out from Figure 24 B.This " thin " liquid column typically refers to the liquid column with the width being less than initial droplet diameter.Next, the configuration electrode 2440 and 2420 of excitation two preliminary elections, navigates in these two configuration electrodes 2440 and 2420 to cut drop 2470 Bing Jiangqi center, as shown in Figure 24 C.The key of coplanar cutting be two in drop and outside configure to have between electrode enough overlapping, there is enough capillary forces to overcome the curvature of drop to perform cutting.In one embodiment, when liquid column 2460 is cut into multiple drop due to hydrodynamic force unstability, there is passive cutting.In another embodiment, passive and active cutting is all adopted by the present invention.While drop is drawn into thin liquid column, can utilizes and initial droplet is broken into two less drops by power or active force.When utilizing by power, very important to the calculating of liquid column length.When utilizing active force, the length of optimization is unimportant.No matter be passive cutting or initiatively cutting, at the final step of cutting process, configuration electrode 2440 and 2420 is normally encouraged, to be navigated to by drop in the configuration electrode of expectation.In another embodiment, passive or active cutting process carries out under the open surface structure of FPLOC.Figure 24 C shows and completes cutting when drop 2450 is cut into two drops 2470.
Mixing, cultivation and reaction: hybrid analysis thing and reactant are committed steps when realizing FPLOC.Drop is used as virtual mixing chamber, and by mixing along electrod-array conveying drop.While utilizing Minimum Area, the ability of mixing material significantly improves output rapidly.But along with microfluidic device is close to the sub-millilambda epoch, the volume flow rate of reduction and low-down Reynolds (Reynolds) number cause being difficult to the mixing of rational markers (time scale) realization to this liquid.The mixing improved is based on two principles: the ability producing eddy current with this small size, or alternatively, produces multilayer to realize the ability of rapid mixing via diffusion.
Sometimes also need incubation step at elevated temperatures, such as, amplify for PCR.In an embodiment of FPLOC as shown in figure 25, drop 2550 is placed on above the fine heating element 2530 that is integrated in substrate 2521.Also set up heater control/monitor 2532 by CMOS manufacturing technology, and be integrated in FPLOC.
The present invention is for an embodiment of the basic merging or married operation that perform FPLOC as shown in Figure 26 A-26B, and wherein two drops 2650 and 2651 are combined into single drop 2653.In the present invention, term " merging " and " mixing " use interchangeably, in order to represent the combination of two or more drops.This is because merging two drops always directly or immediately do not cause the mixing completely of the composition of the drop of initially-separate.In Figure 26 A, two drops 2650 and 2651 are initially located on configuration electrode 2610 and 2612, and are separated by least one configuration electrode 2611 therebetween.Two drops 2650 and 2651 and configuration electrode 2611 at least all have and partly overlap.As shown in fig. 26b, two outside configuration electrodes 2610 and 2612 are removed excitation, and center configuration electrode is energized, and drop 2650 and 2651 draws mutually along center configuration electrode 2611 thus, to be merged into a larger drop 2653, as shown in the arrow in Figure 26 B.
Figure 27 A-27C shows the effective mixed process being implemented droplet manipulation by the uneven geometry motion of the eddy current in order to produce FPLOC.By stimulation arrangement electrode 2751 and 2771, drop 2750 and 2770 is out of shape, as shown in figure 27b; Make drop 2750 uprise thus, make drop 2770 become fat.Then, center configuration electrode 2760 is energized, to move in mixed configuration electrode 2760 (being labeled as black) by drop 2750 and 2770, as seen in fig. 27 c.In Figure 27 B, black region represents that two energized configuration electrodes 2751 and 2771 not only make two drops 2750 and 2770 be out of shape, and is drawn in center configuration electrode 2760 their local.The level and smooth mixing that this interim incentive step shown in Figure 27 B also contributes to two drops is mobile.Black region in Figure 27 B-27C and the shape of deformed droplet are only illustrative object.In the present invention, these shapes can be any type as required.
Figure 28 A and 28B shows the microelectrode array blender for improvement of mixing velocity.In one embodiment, uneven past complex mixers can be used to accelerate droplets mixing.This is by encouraging one group of microelectrode to produce irreversible pattern to realize, and the symmetry of wherein irreversible pattern collapses two circulation are to improve mixing velocity.Original state is shown in Figure 28 A, and wherein drop 2850 comprises sample and reactant, and is positioned at the top of configuration electrode 2840.First step for uneven reciprocal mixing is that stimulation arrangement electrode 2860 is to make drop 2850 towards the direction of arrow distortion shown in Figure 28 B.Then, configuration electrode 2860 is removed excitation, and it is energized so that drop is withdrawn into the initial position shown in Figure 28 A to configure electrode 2840.Reciprocal mixing can perform repeatedly, to realize the mixed effect optimized.In addition, the configuration electrode 2840 in Figure 28 A and 28B and the shape of deformed droplet are only illustrative object.In the present invention, these shapes can be the design of any type, as long as they have the ability producing eddy current, or alternatively, have the ability producing multilayer.
In the another embodiment of the mixed process based on PFLOC drop, Figure 29 shows the circulation blender for improvement of mixing velocity.This is by encouraging the sequence of less microelectrode group to produce irreversible horizontal cyclic to realize, and wherein irreversible horizontal cyclic destroys the symmetry of perpendicular layers circulation to accelerate mixing.An embodiment is as shown in figure 29 formed to surround eight of drop 2990 configurations electrode (2910,2920,2930,2940,2950,2960,2970 and 2980), then stimulation arrangement electrode sequentially one by one in a circulating manner.Such as, as first step, the time period that configuration electrode 2910 is energized shorter, change to cause surface tension and produce circulation towards configuration electrode 2910 in the inside of drop 2990.Next, configuration electrode 2910 is removed excitation, encourages next adjacent configuration electrode 2920 subsequently.By whole eight configuration electrode (2910 to 2980) repetitive cycling process of motivation, to produce horizontal cyclic in drop 2990 inside.The excitation of this circular flow can perform repeatedly as required.In addition, circular flow can clockwise, counterclockwise or the incompatible execution of alternatively mixing of these two kinds of modes, to realize best mixed effect.In addition, the shape configuring electrode 2910 to 2980 and circulation is only illustrative object.In the present invention, this circulation mixing can be the design of any type, as long as they have the ability producing eddy current, or alternatively, has the ability producing multilayer.
Multilayer blender: the present invention is with small size (2 × 2 configuration electrodes) but effective blender generation multilayer can as shown in Figure 30 A-30F with the embodiment accelerating to mix.This multilayer blender is particularly useful for the situation of low aspect ratio (< 1).Aspect ratio refers to the ratio of gap between battery lead plate and earth plate and electrode size.Low aspect ratio means and is more difficult to produce eddy current at drop internal, and the ability thus producing multilayer becomes more important.In this concrete blender, diagonal is utilized to mix and diagonal cutting.In Figure 30 A, mix with at the white drop 3050 configuring electrode 3011 place at the black drop 3051 at configuration electrode 3014 place.Provisional configuration electrode 3010 will become mixing chamber, and by energized to draw in drop 3051 and 3050.In order to start multilayer mixing, first step diagonally merges two drops.The diagonal of droplet coalescence can be 45 degree or 135 degree, but the direction of diagonal cutting subsequently needs perpendicular to union operation.Figure 30 B represents becomes black and white drop 3052 by drop 3051 and drop 3050 first time merging.Due to low reynolds number and low aspect ratio, drop 3052 has merely based on the static mixing of diffusion, and it causes longer incorporation time, and therefore drop is shown as half for white, and half is black.Second step will perform the diagonal mixed in 90 degree with initial diagonal to drop 3052 to cut, as shown in Figure 30 C.While provisional configuration electrode 3010 is removed excitation, configuration electrode 3012 and 3013 and other provisional configuration electrode are energized, drop 3052 diagonally to be cut into two sub-drops 3053 and 3054, as shown in Figure 30 C.Discuss in the paragraph of the details that diagonal cuts above.Due to low composite rate, therefore two sub-drops 3053 keep black/white lamination with identical orientation with 3054 after diagonal cutting.Then, the 3rd step of multilayer mixing is moved back on initial configuration electrode by two drops, to repeat diagonal mixing and cutting.In Figure 30 D, drop 3054 moves to configuration electrode 3011 from configuration electrode 3012, and drop 3053 moves to configuration electrode 3014 from configuration electrode 3013.It is envisaged that avoid their merging while drop 3053 and 3054 movement.Remove excitation to configuration electrode 3012 and 3013 and may cause two drops, while movement, physical contact occurs to the simple drop mobile operating that configuration electrode 3011 and 3014 encourages, so latter two drop may combine.Therefore, provisional configuration electrode 3015 and 3016 needs first to be energized, to produce protection zone between two drops, in order at two drops towards preventing any surprisingly to merge while their destination movement.After drop 3053 and 3054 moves in configuration electrode 3016 and 3015, forward two drops are moved to straight in configuration electrode 3011 and 3014.First step can repeat to the 3rd step, to produce the multilayer of the necessary amount in order to accelerate mixing.As repetition from first step to the drop 3053 and 3054 Figure 30 D diagonally being merged the result becoming drop 3055, Figure 30 E shows four layers of drop 3055.Figure 30 F shows the eight layers of drop 3056 obtained after experienced by another circulation from first step of multilayer mixing to the 3rd step.
Detect (840 in Fig. 8): usually one of in the following manner send detection signal: the competitive binding of research tape label and not the analysis thing of tape label; Use the molecule being exclusively used in the tape label of solid phase assays thing; Form sandwich assay; Or perform enzyme linked immunosorbent assay (ELISA) (ELISA), wherein add organized enzyme substrate to change color or fluorescence when joining analyze thing reciprocation with enzyme.Increasing research paper is being inquired into and will detected the technology being integrated into micro-fluid chip, especially those phase specific absorptivities or fluoroscopic examination better technology in size microminiaturization.An embodiment of the invention are integrated in FPLOC based on CMOS technology by sensing apparatus, as shown in figure 31, wherein sensor (3130,3131 and 3132) can be arranged explicitly with base plate 3121, top board 3120, drop 3150 & 3151, sensor probe 3180 and microelectrode 3130.Usually the integrated electronic position flowmeter sensor 3130 based on the potential measurement executable operations in no current situation measures drop 3150 by sensor probe 3180.The ampere meter sensor 3132 of the electric current executable operations that usual utilization produces when applying current potential is between two electrodes shown as measuring drop 3151 by sensor probe 3181.Impedance meter sensors 3131 has been integrated in base plate 3121, to monitor the biomolecule identification event of the catalytic reaction of enzyme or Specific binding proteins, agglutinin, acceptor, nucleic acid, full cell, antibody or antibody related substances.Detect I/O port also can be used for optics sensing and feed back with the object of the quick liquid of control FPLOC inside motion.
Systematical control (850 in Fig. 8): the present invention is used for an embodiment of FPLOC system control block as shown in figure 32.The major function of system control block is the field-programmable ability realizing FPLOC.From the angle of software and hardware, the digital programmable ability of FPLOC is existed to the requirement of different brackets.Figure 32 represents the grading software structure of FPLOC.Field programming management (FPM) software 3210 is the software of lowermost layer, and FLB is configured to microfluid component and is used in the layout/network of microfluid component, to form FPLOC by it.Microfluidic procedures programming management (MOPM) 3220 software is the function of going up one level (one levelup), in order to control and management microfluidic procedures.This step sets microfluidic procedures and by how performs in FPLOC and the order of microfluidic procedures.For wanting to pay close attention to the user of application, they can utilize the microfluidic element of one group of predefined and empirical tests and utilize the advantage to the programmability of fluid-operated sequence, complete the whole design of FPLOC.For wanting to optimize the whole design of FPLOC and for the more senior user utilizing the advantage of the flexible structure of FPLOC, they directly can set up microfluid component and Direct Programming microfluidic procedures.FPM software and MOPM software are all the software of FPLOC chip-scale.System management 3230 is application-level functions that management application specific requires, it comprise system partitioning and integrated 3231, detect 3232, data management 3233 and peripheral assembly management 3234.
System partitioning and integrated (3231 in Figure 32): the general trend of commercial device has become and manufactures simple disposable apparatus, they be designed to hold required control electronic device, reactant supply, detector and programming more expensive box carry out interface and be connected.Thus microfluidic device only may perform limited one group of operation, such as Liquid transfer, separation or sensing.Then this device is employed and is once thus dropped.This complexity also create to system element may separate with separately which be disposable, which is recycling demand, to reduce the cost of whole solution.
Detect and data storage/display (3232 in Figure 32): especially for the mensuration of simultaneous multiple quantitative measurment, CPU ability and software will be needed.During this process, some also will be needed to measure calibration.After acquisition measurement result, how needs definition and realization are shown in a particular format, report and store data.
At least there is several different possible system configuration for FPLOC:(1) prototype and test system configurations; (2) desktop machine configuration; (3) portable machine configuration; And (4) free-standing biochip configuration.
For the prototype of FPLOC and test system configurations an embodiment as shown in figure 33.Fundamentally, prototype and test system configurations provide the instrument of a kind of technology evaluation and exploitation, realize its micro-fluidic technologies in order to make researcher quickly and efficiently under the proof of conceptual system level prototype environment.Prototype and test system configurations are that opposing open and user are accessible, and it is implemented via the standard interface provided between standard module functional block and these blocks.The functional block of prototype and test system configurations is shown in Figure 33.Prototype and test system configurations comprise: for the fluid interface 3340 of fluid pumping; In order to the fixture 3350 of fixing FPLOC3360; For providing the driver subsystem 3320 of auxiliary actuator (function generator 3321 and high-voltage amplifier 3322) and data management A-D card 3323; FPGA plate 3330; Optical module 3370; And for controlling the PC3310 with analysis chip function.Then, prototype and test system configurations are provided for the hardware of FPLOC prototype, software driver, chip layout, design review (check) (DR) and field programmability, thus the concept realized in microfluid proves that (proof-of-concept) studies.Prototype and test system configurations may support two main tool of the optical characterisation for microfluid medium: video detects and LIF analysis (LIF).Video capability is the photographic recording of the function for microfluidic procedures.User interface is provided to come via computer control pump, flowmeter, pressure sensor and LIF analysis (LIF) unit.Prototype and test system configurations comprise the host PC supporting these functions.To be connected by RS-232 and USB with the connection of this central actuator computer and realize.
With reference to Figure 34 A, in some embodiments of desktop machine configuration, provide the test organisms chip 3410 of the FPLOC of programming as having desktop assembly 3415.Figure 34 A shows the outward appearance of desktop assembly 3415 and the groove 3416 for the FPLOC3410 that inserts programming.Built-in detecting sensor, device control button 3418 and the display 3417 for sensing test result is comprised at desktop assembly 3415.
With reference to Figure 34 B, in another embodiment of portable machine configuration, provide the test organisms chip 3420 of the FPLOC of programming as having mancarried device 3425.Figure 34 B shows the outward appearance of mancarried device 3425 and the groove 3426 for the FPLOC3420 that inserts programming.Built-in detecting sensor, device control button 3428 and the display 3427 for sensing test result is comprised at mancarried device 3425.The portability of FPLOC of the present invention to contribute in the various places of the wide regions such as clinic, operating room, emergency ward, small-size laboratory and for bringing the medical center in the field of the quick diagnosis of very fast turnaround time (point-of-care) or need point (point-of-need) to use under critical situations.
Figure 34 C shows another embodiment of free-standing biochip configuration, wherein provides the FPLOC of programming as free-standing biochip 3430.Figure 34 C show free-standing biochip 3430 outward appearance and for by sample collection to the sample collection device 3439 in chip.All be integrated in chip for sensing the detecting sensor of test result, the reactant of preloaded and system control unit.By using microelectrode array, site of deployment permanent Display Technique able to programme shows test results 3437.In addition, even if due to powering down chips, the result of display also can not disappear, and therefore can be used for test record.The disposable invention of the low cost of extensive manufacture as shown in figure 34 c can to contribute in the various places of the wide regions such as clinic, operating room, emergency ward, small-size laboratory and for the medical center in the field of the quick diagnosis of very fast turnaround time or needs point can be brought under critical situations to use.
An embodiment of data management and transfer (3233 in Figure 32): FPLOC uses emerging information technology, and it allows the configuration of the different technologies of FPLOC to be connected to healthcare information system necessarily.Need FPLOC communication scheme in order to: (1) makes FPLOC analyzer self-information system access; (2) all data obtained in many ways are organized by standardized format; (3) FPLOC easy use for unprofessional user is allowed; (4) different access grades is kept, to avoid handling the unauthorized of this sensitive data.
Other peripheral assembly (3234 in Figure 32): in another embodiment of FPLOC system configuration, should consider other peripheral assembly of such as low profile thermal printer and so on, to use when the hard copy immediately needing measurement result.Or consider the determination data of storage to be transported to LAB or other database USB storage for process.Bar code scanner is also the popular existing POCT device for management sample.Before networked capabilities can be integrated in system, be also regarded as communication signal assembly function with the ability of wired connection or wireless connections networking.
In some embodiments manufacturing FPLOC, depend on application needs, the bottom manufacturing technology for FPLOC can be the technology of based semiconductor, thin film transistor (TFT) (TFT) array, PCB, plastics or paper.Standard CMOS and TFT manufacturing technology are preferred technology.
An embodiment of FPLOC is manufactured as shown in the block diagram of Figure 35 by utilizing standard CMOS manufacturing process.Two main piece of FPLOC is system control block 3550 and fluid logic block (FLB) 3510.Under normal circumstances, according to application and the restriction of manufacturing technology, system only needs a system control block 3550, but needs multiple FLB3510.
Microelectrode array is realized by the FLB linked together with daisy chain fashion.The quantity of FLB is by applying and mainly being determined by the restriction of manufacturing technology.A FLB comprises high drive microelectrode 3530, (one bit) memory map datum 3520 and control circuit 3540.High drive microelectrode 3530 is energized to encourage the physics microelectrode of drop by applying necessary voltage.One bit memory map datum 3520 keeps the logical value of the excitation of microelectrode, and typically, " 1 " representative encourages microelectrode and " 0 " representative removes excitation to microelectrode.Control circuit 3540 manages control logic and forms the daisy chain architecture of FLB.
Systematical control 3550 comprises four main piece: controller 3560, chip layout 3570, droplet position map 3580 and fluid-operated manager 3590.Controller 3560 is CPU, and has necessary memory headroom, interface circuit and software programmability.Depend on manufacturing technology, controller 3560 can by an integrated part as manufactured goods, or can be the external device (ED) of attachment.Chip layout block 3570 is the configuration data of stored configuration electrode and the memory of FPLOC layout information and data.Droplet position map 3580 reflects the physical location of the drop on FPLOC.By excitation " configuration electrode " sequence, fluid-operated manager 3590 by layout information, droplet position map and come self-controller 3560 FPLOC application be translated into drop implement physical stimulus.
In one embodiment, FPLOC provides field programmability, makes the electrode of LOC and integral layout all by software programming.If microfluidic device or its (being stored in the nonvolatile memory of such as ROM and so on) firmware of embedded system can " in field " be modified, and without the need to disassembling apparatus or device to be returned its manufacturer, then can be described as field-programmable or existing field-programmable.The field programmability of FPLOC or software merit rating are realized by Systematical control 3550 and FLB3510.The shape and size design of electrode and FPLOC layout information and data are stored in the nonvolatile memory of chip layout block 3570 inside, as shown in figure 35.The information comprising the energized electrode of temporary electrode is stored in the nonvolatile memory in droplet position map 3580.Then, software configuration data passes to each microelectrode 3530 by a bit memory map datum 3520.(grouping) in groups, excitation, the removal excitation of one group of microelectrode perform actually by the configuration of FLB3510.In addition, all FLB3510 are that software is attachable, and are the single-chip integration form of usable criterion manufacturing technology manufacture physically.
Figure 36 shows an embodiment of the electrical design of FLB array 3600, and wherein FLB array 3600 comprises a lot of FLB3620 configured with daisy chain based on standard CMOS manufacturing technology.Daisy chain is the wire laying mode used in electricity engineering design.To reduce and while the quantity sustainable growth of microelectrode at the scales of microelectrode, interconnection will exponentially property increase, and will become too complicated to such an extent as to can not the scale of management system.By utilizing daisy chain fashion, simplify the connection between each FLB3620, and the interconnection of FLB can not increase along with the quantity of FLB and increase, and can realize extendible and more succinct layout designs thus.Each FLB3620 comprises storage device (such as d type flip flop 3610) for storing excitation information and for encouraging the high-tension circuit of microelectrode 3630.When applying signal VIN, according to the output valve of trigger 3610, microelectrode 3630 will be energized or remove excitation.SQ signal controls square wave instead of stable state DC is applied to microelectrode.Before excitation microelectrode array, loaded the value of trigger 3620 by the clock in data-signal ED.A storage device of such as d type flip flop 3610 and so on also can be other flip-flop design or other data-storage applications.
Figure 37 shows the cross section of FLB array manufactured goods.In one embodiment, three-layer metal layer and one polyethylene layer (poly layer) is employed.Bottom is substrate 3760, and the layer above it is control circuitry layer 3750.Control circuit, trigger and high-voltage drive are included in the region being arranged in 3751 immediately below microelectrode 3740 and 3770.Three-layer metal layer is for making microelectrode 3740,3770 and ground wire 3730.The top view of this electrode and ground configurations as shown in Figure 5A.Utilize voltage to apply energized microelectrode 3740, and microelectrode 3770 is stand-by.The top of microelectrode is dielectric layer 3710.In the present embodiment, ground wire 3730 is not covered by dielectric layer 3710, to reduce required driving voltage.Topmost, be coated with hydrophobic membrane 3720 to reduce wettability of the surface.If from top viewing, only can microelectrode array be seen, and can not see the circuit be hidden in below microelectrode.This self-contained microelectrode structure is the key when manufacturing FLB with high extensibility.
Another embodiment of PFLOC is manufactured as shown in the block diagram in Figure 38 A by utilizing thin film transistor (TFT) (TFT) array fabrication process.Two main piece is system control block 3850 and active matrix block (AMB) 3800.System control block 3850 comprises four main piece: controller 3860, chip layout 3870, droplet position map 3880 and fluid-operated manager 3890.Controller 3860 is CPU, and has necessary memory headroom, interface circuit and software programmability.Chip layout block 3870 is the configuration data of stored configuration electrode and the memory of LOC layout information and data.Droplet position map 3880 reflects the physical location of the drop on LOC.By excitation " configuration electrode " sequence, fluid-operated manager 3890 by layout information, droplet position map and come self-controller 3860 LOC application be translated into drop implement physical stimulus.
In one embodiment, the field programmability of LOC or software merit rating are realized by Systematical control 3850.Controller 3860 is CPU, and has necessary memory headroom, interface circuit and software programmability.Depend on manufacturing technology, controller can by an integrated part as manufactured goods, or can be the external device (ED) of attachment.The shape and size design of electrode and LOC layout information and data are stored in the nonvolatile memory of chip layout block 3870 inside, as shown in fig. 38 a.Droplet position map reflects the physical location of the drop on FPLOC.The information comprising the energized electrode of temporary electrode is stored in the nonvolatile memory in droplet position map 3880.Fluid-operated manager 3890 by layout information, droplet position map and come self-controller FPLOC application be translated into by excitation " configuration electrode " sequence pair drop implement physical stimulus.Then, to configuration electrode in groups, excitation and remove excitation data send to active matrix block (AMB) 3800 in mode frame by frame.
In another embodiment, AMB3800 comprises five main piece: active matrix panel 3810, source electrode driver 3820, gate drivers 3825, DC/DC converter 3840 and AM controller 3830, as shown in fig. 38b.In active matrix panel 3810, the basis of sharing uses grid bus 3815 and source bus line 3814, but each microelectrode 3812 is by selecting be positioned at row end and arrange two suitable contact pads of end and be addressable separately, as shown in fig. 38b.Switching device uses the transistor (being therefore called thin film transistor (TFT) (TFT) 3811) be made up of the film depositing.Tft array substrate comprises TFT3811, holding capacitor 3813, microelectrode 3812 and interconnection wiring 3814 and 3815.One group of bond pad is manufactured, to be attached source electrode driver IC3820 and gate drivers IC in each end of grid bus 3815 and data signal bus 3814.AM controller 3830 utilizes data 3831 from Systematical control 3850 by drive circuit unit drive TFT array, and wherein drive circuit unit comprises one group of LCD and drives LC (LDI) chip 3820 and 3825.DC power supply 3841 is applied to DC/DC converter 3840, DC/DC converter 3840 and applies positive pulse, with conducting TFT by grid bus 3815 to grid.Holding capacitor is charged, and the voltage level rising on microelectrode 3812 reaches the voltage level being applied to source bus line 3814.The major function of holding capacitor 3813 keeps the voltage on microelectrode, until apply next signal voltage.
In one embodiment, based on the top view of the microelectrode array of tft array as shown in Figure 38 C.Microelectrode 3812, TFT3811 and holding capacitor 3813 is shown in typical TFT LCD layout.In another embodiment, hexagon tft array layout is as shown in Figure 4 B realized, with the collision in the relatively large gap 3816 of reducing and between adjacent microelectrode.
In another embodiment, be in the such as biplane construction shown in Figure 38 D based on the FPLOC manufactured goods of TFT technology.TFT3803 manufactures in the glass substrate 3801 with microelectrode 3804, and adds the dielectric insulator 3806 being coated with hydrophobic membrane 3805, to reduce wettability of the surface, and is increased in the electric capacity between drop and microelectrode.On top board 3802, except the electrode continuously 3808 being coated with hydrophobic membrane 3805, also may need the black matrix" (BM) 3807 be made up of opaque metal, in order to block a-Si TFT, make it from the irradiation of veiling glare.
Before any programming or configuration, blank FPLOC will look like shown in Figure 39 A.It has the matrix of FLB (fluid logic block) 3910, and each FLB can be grouped together and the microelectrode be excited simultaneously.The various embodiments of blank FPLOC of programming at least comprise: (1) manually programmed process from bottom to top; And (2) top-down nano-fabrication method.
Programme the embodiment of FPLOC as shown in Figure 39 A and 39B by utilizing manually programmed process from bottom to top.Before any programming or configuration, blank FPLOC3901 can as shown in Figure 39 A.This blank FPLOC3901 comprises the array of multiple FLB3910, FPLOC Systematical control 3920 and I/O interface 3930.In an embodiment of the invention, the quantity of I/O interface 3930 can need for single or multiple according to design.In another embodiment, the placement location of I/O interface 3930 and FPLOC Systematical control 3920 can be the below of the array being positioned at FLB3910 or be close to the array (as shown in Figure 39 A) of FLB3910 on the same chip.FPLOC Systematical control 3920 provides system partitioning, configuration, control, management and other system related functions.I/O interface 3930 is provided in the chip that to carry out between FPLOC and external device (ED) connecting programming, show test results, calibrate and the function of data management.In another embodiment, I/O interface 3930 also can provide the connection to printer, USB storage device or network interface.I/O interface 3930 also provides the path led to the power supply that FPLOC power supply station needs.First design procedure (or first degree work) of FPLOC manually carries out field programming to the integral layout of physical location, size and dimension and the FPLOC of all microfluid components (such as liquid reservoir, Mixed Zone, surveyed area and transport path).Figure 39 B shows the embodiment programming to realize the design 3902 configuring LOC to blank FPLOC3901.This configuration LOC3902 has the microfluid component comprising electrode 3940 and liquid reservoir 3970, discarded object reservoir 3990, mixing chamber 3960, detection window 3950 and transport path 3980, and wherein transport path 3980 is made up of the electrode of the zones of different connecting FPLOC.After the layout designs of FPLOC, in Figure 39 B, also there are some untapped microelectrodes 3910.The second step of design FPLOC is the microfluidic procedures defining chip.Substantially fluid-operated comprises: produce drop, conveying, cutting and mixing.As paragraph above discussed, can to realize more advanced fluid-operated based on Microelectrode array architecture.The designer of FPLOC can set up and comprise fluid-operated whole FPLOC by choice for use Foundation block FLB.But in order to the convenience of designer's design and in order to can the design of spread F PLOC, the application layer that high expectations is used for microfluidic procedures presents.
FPLOC design and programming: at an embodiment, the top-down method for designing of FPLOC is shown in Figure 40.The top-down design of FPLOC originates in the biologicall test agreement 4010 provided by biochip user.In order to define the behavior (behavior) of FPLOC, user the is provided as hardware description language (HDL) of " high-level language description " 4012 or the schematic design as " ordering chart model " 4015." ordering chart model " 4015 can produce from " the high-level language description " 4012 in order to describe this mensuration agreement.This model can be used for performing " behavioral scaling simulation " 4013 to verify senior measurement function.HDL table is more suitable for working together with large scale structure, because can specify them by numeral, and without the need to drawing each part with hand.But it is visual that schematic catalogue can realize easier design.At this one deck, the purposes of definition application-level functions and LOC.Next, " synthesis of system level " 4020 is utilized to produce concrete implementation according to ordering chart model." microfluidic module storehouse " 4021 and " design specification " 4022 are also provided as the input of synthesis process.This module library, is similar to the standard cell lines storehouse used in the VLSI based on cell designs, comprises the different microfluid functional modules of such as blender and memory cell and so on.Compact model is used for the parameter of the operation duration of different microfluid functional modules and such as width, length and unit simulation or laboratory experiment and so on.In addition, some design specifications have also been endowed priori (priori), such as, the combination of the upper limit of deadline, the upper limit of chip area size and not reconfigurable resource (on such as chip liquid reservoir/distribution port and Integrated optical detectors).The output of synthesis process 4020 comprises the mapping (or mapped file) of measurement operation to core Resources on Chip 4042, the timetable (or timetable file) of measurement operation 4023 and Built-in Self Test (BIST) (or Built-in Self Test file) 4025.Then, by the input of design specification in geometry level 4032, there is geometry level synthesis 4030.Synthesis process attempts to find the design point of the expectation not only meeting input specification but also can optimize some factors of quality (such as performance and area).After composition, the two-dimensional physical design 4033 (namely module is placed and route) of biochip can combine with the concrete physical message from (being associated with some manufacturing technologies) module library, to obtain 3-D geometric model 4040.This model can be used for performing physical level simulation 4045 and rudimentary design verification 4050.After physical verification, FPLOC design can be loaded in blank FPLOC.
Configure from schematically/HDL source file to actual FPLOC: in one embodiment, source file is fed to the software being suitable for FPLOC design, wherein produces a file by by different steps.Then, this file is transferred to the external memory devices of FPLOC or similar EEPROM by serial line interface (JTAG).
Modal HDL is VHDL and Verilog, although made effort in the complexity reducing HDL design, having compared equivalent assembler language, improve level of abstraction by introducing alternative language.Also can utilize graphical programming language (such as American National instrument LabVIEW), make FPLOC add-on module can be used for orientation and programming FPLOC hardware.Graphical programming language mode greatly simplifies FPLOC programmed process.
In yet, in order to simplify the design of the complication system in FPLOC, the storehouse of predefined sophisticated functions that is tested and that optimize can be utilized to accelerate FPLOC design process.These predefined microfluid storehouses can be the advanced microfluidic procedures of such as " diagonal cutting " or " with x:y display ' OK ' " and so on.In typical design cycle, FPLOC application developer will multistage simulation design in whole design process.Initially, the establishment that is described through carried out with VHDL or Verilog is simulated in order to the test table of simulation system and observed result.Then, after Compositing Engine is by design map to wire list, wire list is translated into gate level description, wherein repeats simulation to confirm free of errors to synthesize.Finally, design by layout in FPLOC, at this moment can add propagation delay, and by these values being returned annotation (back-annotated) on wire list, whole system simulation runs again.
In various embodiments, replace the microfluidic procedures based on drop, EWOD Microelectrode array architecture can perform Continuous Flow microfluidic procedures.Continuous microflow body operates in control very simple, but can provide the very effective mode implementing microfluidic procedures.Figure 41 A-C shows and produces from liquid reservoir 4110 liquid 4130 determining volume.As shown in Figure 41 A, thin microelectrode line defines the bridge 4115 between target configuration electrode 4160 and liquid reservoir 4110.When bridge 4115 and target configuration electrode 4160 are energized, liquid is flow to target configuration electrode 4160 from liquid reservoir.4130 express liquids flow to configuration electrode 4160 from bridge.Here bridge is a microelectrode line.This bridge configuration has the feature of Continuous Flow and the system based on drop.It has all advantages of passage, that is, once bridge configuration electrode is energized, liquid just will be flowed by it, and without the need to additionally controlling excitation time order and speed and consider.It also has all advantages of the system based on drop simultaneously, that is, once bridge 4115 is removed excitation, then all liquid all will be pulled back to liquid reservoir or target configuration electrode 4160, and there is not residual drop in the channel.Once target configuration electrode 4160 is filled, then bridge 4115 is removed excitation, to be cut off by the liquid 4130 from liquid reservoir 4110, as shown in figure 41b.It is automation that the liquid of configuration electrode 4160 fills up, that is, once all microelectrodes of bridge and configuration electrode are filled up by liquid, then will stop from liquid reservoir 4110 trickle, therefore the SECO of this process is unimportant.By the generation encouraging the breakpoint of suitable microelectrode 4160 and bridge accurately to control liquid 4130.As shown in figure 41b, then remove excitation to bridge by first removing excitation to microelectrode 4116, liquid 4130 disconnects from liquid reservoir 4110.This process will guarantee that the most of liquid forming bridge will be pulled back to liquid reservoir 4110, and the quantity of the microelectrode by configuration electrode 4160 is accurately controlled by liquid 4130.In Figure 41 B, configuration electrode 4160 comprises 10 × 10 microelectrodes.Other size and dimension of definable configuration electrode is to produce different drop size and shape.Figure 41 C shows the disappearance of liquid bridge, and produces liquid 4130 by excitation liquid reservoir 4110 and configuration electrode 4160.
In one embodiment, the identical production process of liquid can be utilized liquid to be cut into two seed liquid, as shown in Figure 41 D.After removing excitation to configuration electrode 4160, bridge configuration electrode 4117 and target configuration electrode 4171 are energized, and liquid flows to the region of 4170 from bridge.Excitation is removed to bridge configuration electrode 4117, then configuration electrode 4161 and 4171 is encouraged, liquid is ruptured and forms two seed liquid 4170 and 4130, as shown in Figure 41 E.As long as the size of configuration electrode 4161 and 4171 is pre-calculated as desired size, this cutting process just can produce two seed liquid of different size.
In another embodiment, Figure 42 A-C shows the mixed process implemented by Continuous Flow microfluidic procedures.Figure 42 A shows by excitation bridge 4215 and 4225 and stimulation arrangement electrode 4216 and 4226, and liquid flows to mixing chamber 4230 from liquid reservoir 4210 and 4220 through bridge.Here, the liquid be associated with configuration electrode 4216 and 4226 changes better to mix in shape, and the size of liquid is also different to carry out ratio mixing (ratio mixing) in addition.Between configuration electrode 4216 and 4226, there is gap, to prevent too early mixing.Once liquid be filled with configuration electrode 4216 and 4226, then configure electrode 4230 (10 × 10 microelectrodes) be energized, two kinds of liquid by mixed, as shown in Figure 42 B.Then, two bridge electrodes are removed excitation, as shown in Figure 42 C.
In this simple mixing microfluidic procedures, in fact all basic microfluidic procedures are interpreted as: (1) produces: liquid 4216 and 4226 produces from liquid reservoir 4210 and 4220 in a precise manner; (2) cut: liquid 4216 is cut off with liquid 4210, liquid 4226 is cut off with liquid 4220; (3) carry: bridge 4215 and 4225 by Liquid transfer to mixing chamber; And (4) mixing: liquid 4216 and 4226 mixes at 4230 places.Clearly, this Continuous Flow technology not only in order to perform all microfluidic procedures, and can perform in a more accurate way, because the resolution ratio of precision depends on small size microelectrode.
Although describe the present invention with reference to preferred embodiment, those skilled in the art will recognize, can make various change in form and details under the condition not departing from the spirit and scope of the present invention.
Claims (57)
1. adopt field-programmable chip lab (FPLOC) device for Microelectrode array architecture, comprising:
A. base plate, comprise the array of the multiple microelectrodes be placed on the top surface of substrate, described multiple microelectrode is covered by dielectric layer, wherein each described microelectrode is connected at least one earth element in ground structure, the top of described dielectric layer and described earth element is provided with hydrophobic layer, to generate the hydrophobic surface with drop;
B. field-programmable architectures, for a group configuration electrode of programming, to produce microfluid component and layout with selected shape and size; And
C.FPLOC functional block, comprising: I/O port; Sample preparation unit; Droplet manipulation unit; Detecting unit; And system control unit,
Described system control unit comprises:
A. classification FPLOC chip-level software structure, comprising:
Field programming management software, for being configured to microfluid component by described microelectrode and being used in the layout/network of described microfluid component; With
Microfluidic procedures programming management software, for control and management microfluidic procedures; And
B. application system administrative unit, comprising:
System partitioning and integrated package, for separating described device;
Detect and displaying block, for obtaining, showing, report and storing measurement result;
Data management and transfer block, for attaching the device to external information system; With
For being connected to the peripheral management block of external system,
The microfluid component of the group configuration electrode wherein in described field-programmable architectures comprises: liquid reservoir, electrode, mixing chamber, detection window, discarded object reservoir, droplet path and appointed function electrode.
2. device as claimed in claim 1, the configuration electrode wherein in described field-programmable architectures comprises: the first configuration electrode, comprises the multiple microelectrodes arranged in the form of an array; And configure at least one adjacent second adjacent configuration electrode of electrode with described first; Drop is placed in the described first configuration top of electrode and overlapping with a part for described second adjacent configuration electrode.
3. device as claimed in claim 1, wherein said FPLOC functional block performs following steps: by being sequentially applied for the driving voltage encouraging and remove excitation to one or more selected configuration electrode, sequentially to encourage/to remove excitation to selected configuration electrode thus to encourage drop to move along selected route, handle the one or more drops between multiple configuration electrode.
4. device as claimed in claim 3, wherein said FPLOC functional block performs following steps: the quantity handling the microelectrode of described configuration electrode, to control the size and dimension of drop.
5. device as claimed in claim 2, wherein said configuration electrode comprises at least one microelectrode.
6. device as claimed in claim 1, the layout of wherein said microfluid component comprises: the physical allocation of input/output end port, liquid reservoir, electrode, mixing chamber, detection window, discarded object reservoir, droplet path and electrode network.
7. device as claimed in claim 1, wherein said FPLOC functional block performs following steps: remove excitation to the first configuration electrode, and the second adjacent configuration electrode is encouraged, so that drop is moved to described second adjacent configuration electrode from described first configuration electrode.
8. device as claimed in claim 7, wherein said FPLOC functional block performs the step by using three to configure electrode and divide drop, the drop wherein loaded on the first configuration electrode being in center is overlapping with two the second adjacent configuration electrodes, and the described step by using three configuration electrodes to divide drop comprises:
A. configuration comprises two provisional configuration electrodes of many microelectrode lines, and described many microelectrode lines cover the drop that described first configuration electrode loads;
B. described two provisional configuration electrodes are encouraged;
C. encourage to move towards described two the second adjacent configuration electrodes line by line, and encourage removing with the immediate line in center, to pull drop towards described two the second adjacent configuration electrodes; And
D. excitation is removed to described two provisional configuration electrodes, and described two the second adjacent configuration electrodes are encouraged.
9. device as claimed in claim 7, wherein said FPLOC functional block performs the step by using three to configure electrode and divide drop, wherein drop is loaded on the first configuration electrode at the center of being in, and two adjacent configuration electrodes are not overlapping with drop, the described step by using three configuration electrodes to divide drop comprises:
A. configuration comprises two provisional configuration electrodes of many microelectrode lines, and described many microelectrode lines cover the drop that described first configuration electrode loads;
B. described two provisional configuration electrodes are encouraged;
C. encourage to move towards described two the second adjacent configuration electrodes line by line, and encourage removing with the immediate line in center, to pull drop towards described two the second adjacent configuration electrodes; And
D. excitation is removed to described two provisional configuration electrodes, and described two the second adjacent configuration electrodes are encouraged.
10. device as claimed in claim 7, wherein said FPLOC functional block performs the step by using three to configure electrode and divide drop, the drop wherein arranged on the first configuration electrode being in center is overlapping with two the second adjacent configuration electrode part ground, and the described step by using three configuration electrodes to divide drop comprises:
A. excitation is removed to described first configuration electrode; And
B. described two the second adjacent configuration electrodes are encouraged, to pull and to cut drop.
11. devices as claimed in claim 10, wherein said FPLOC functional block performs the step diagonally dividing drop, comprising:
A. drop is arranged on described first configuration electrode;
B. excitation is removed to described first configuration electrode, and encourage with the described first two the second adjacent configuration electrodes diagonally arranged configuring electrode overlapping, pull drop with the diagonally arrange towards described two second adjacent configuration electrode; And
C. the overlapping region between described first configuration electrode and described two the second adjacent configuration electrodes diagonally arranged is removed and encouraged, being two sub-drops by drop pinch off.
12. devices as claimed in claim 7, the step in described liquid reservoir is returned in drop reorientation by wherein said FPLOC functional block execution, comprising:
A. produce provisional configuration electrode, wherein said provisional configuration electrode is overlapping with a part for described liquid reservoir, and a part for drop is not overlapping with described liquid reservoir;
B. described provisional configuration electrode is encouraged, to drag drop, make drop overlapping at least in part with described liquid reservoir; And
C. excitation is removed to described provisional configuration electrode, and described liquid reservoir is encouraged, so that drop is moved in described liquid reservoir.
13. devices as claimed in claim 1, wherein said FPLOC functional block performs following steps: configuration third phase neighbour configuration electrode, makes described third phase neighbour configuration electrode not overlapping with the drop that first configures on electrode.
14. devices as claimed in claim 13, wherein said third phase neighbour configuration electrode comprises the multiple microelectrodes arranged in the form of an array.
15. devices as claimed in claim 14, wherein said FPLOC functional block performs the step of drop diagonal movement, comprises further:
A. produce the provisional configuration electrode overlapping with a part of drop and produce third phase neighbour and configure electrode;
B. by removing excitation to described first configuration electrode and encourage described provisional configuration electrode, drop is diagonally transported to described third phase neighbour configuration electrode from described first configuration electrode; And
C. excitation is removed to described provisional configuration electrode, and described third phase neighbour configuration electrode is encouraged.
16. devices as claimed in claim 13, wherein said FPLOC functional block performs the step moving drop along all directions, comprising:
A. produce the provisional configuration electrode overlapping with a part of drop and produce third phase neighbour and configure electrode;
B. by removing excitation to described first configuration electrode and encourage described provisional configuration electrode, drop is transported to described third phase neighbour configuration electrode from described first configuration electrode; And
C. excitation is removed to described provisional configuration electrode, and described third phase neighbour configuration electrode is encouraged.
17. devices as claimed in claim 7, wherein said FPLOC functional block performs the step of coplanar division, comprising:
A. the thin-belt type provisional configuration electrode that configuration is overlapping with drop;
B. excitation is removed to described first configuration electrode, and described thin-belt type provisional configuration electrode is encouraged;
C. excitation is removed to described provisional configuration electrode; And
D. described first configuration electrode and described second adjacent configuration electrode are encouraged.
18. devices as claimed in claim 7, wherein said FPLOC functional block performs by using three to configure electrode by two droplet coalescences to step together, wherein two first configuration electrodes by described second adjacent configuration electrode separation, described by use three configuration electrode two droplet coalescences are comprised to step together:
A. excitation is removed to described two first configuration electrodes; And
B. the mediate second adjacent configuration electrode is encouraged.
19. devices as claimed in claim 18, wherein said FPLOC functional block performs the step of distortion mixing, comprising:
A. two provisional configuration electrodes are produced, to change the shape of two drops;
B. excitation is removed to described two first configuration electrodes, and described two provisional configuration electrodes are encouraged; And
C. excitation is removed to described two provisional configuration electrodes, and the mediate second adjacent configuration electrode is encouraged.
20. devices as claimed in claim 7, wherein said FPLOC functional block performs the step accelerating the mixing at drop internal by changing droplet profile, comprising:
A. provisional configuration electrode is produced, to change the shape of drop;
B. excitation is removed to described first configuration electrode, and described provisional configuration electrode is encouraged;
C. excitation is removed to described provisional configuration electrode, and described first configuration electrode is encouraged; And
D. repeat to encourage and excitation the removal of described provisional configuration electrode and described first configuration electrode.
21. devices as claimed in claim 7, wherein said FPLOC functional block performs the step by accelerating the mixing at drop internal in drop internal circulation, comprising:
A. the multiple provisional configuration electrodes surrounding drop are produced; And
B. one at a time each described provisional configuration electrode is encouraged and removes excitation, to mix drop in shuttling movement along clockwise direction.
22. devices as claimed in claim 21, wherein said FPLOC functional block performs following steps: encourage each described provisional configuration electrode and remove excitation one at a time in the counterclockwise direction.
23. devices as claimed in claim 7, wherein said FPLOC functional block performs the step of the multilayer mixing producing drop, comprising:
A. configure the configuration electrode of 2 × 2 arrays, be included in two first configuration electrodes on the first diagonal position;
B. the provisional configuration electrode being positioned at the center of the configuration electrode of described 2 × 2 arrays is produced;
C. described provisional configuration electrode is encouraged, to merge two the first drops from described two first configuration electrodes;
D. excitation is removed to described provisional configuration electrode, and the configuration electrode of two on the second diagonal position is encouraged;
E. excitation is removed, drop to be cut into two the second drops to described provisional configuration electrode;
F. by encouraging two extra provisional configuration electrodes, described two the second drops are transmitted back to the first configuration electrode on described first diagonal position, then excitation is removed to described two extra provisional configuration electrodes and two first configuration electrodes on described first diagonal position are encouraged, to complete conveying;
G. described provisional configuration electrode is encouraged, to merge two the second drops from described two first configuration electrodes; And
H. repeat diagonal division, conveying and diagonal to merge.
24. devices as claimed in claim 7, wherein said FPLOC functional block performs the step producing drop, comprising:
A. in described liquid reservoir, the first provisional configuration electrode is configured;
B. an adjacent configuration electrode wires is configured from the liquid reservoir being mounted with liquid;
C. the second overlapping with the liquid in described liquid reservoir and overlapping with nearest adjacent configuration electrode provisional configuration electrode is produced;
D. described first provisional configuration electrode is encouraged;
E. described second provisional configuration electrode is encouraged, and nearest adjacent configuration electrode is encouraged;
F. excitation is removed to described second provisional configuration electrode; And
G. the rear adjacent configuration electrode in line sequence is encouraged, and excitation is removed, until produce drop to last energized adjacent configuration electrode.
25. devices as claimed in claim 7, wherein said FPLOC functional block performs the step by utilizing point technology such as drop to produce drop, comprising:
A. the target configuration electrode for expecting drop size is produced;
B. from the adjacent configuration electrode wires of liquid reservoir configuration small size being mounted with liquid, described liquid is connected to described target configuration electrode, and the two ends of wherein said small size adjacent configuration electrode wires are overlapping with described liquid reservoir and described target configuration electrode;
C. described target configuration electrode is encouraged;
D. along from liquid reservoir side to the path of described target configuration electrode, one at a time the adjacent configuration electrode of each small size being sequentially mounted with micro-decile drop is encouraged and removes excitation; And
E. repeat the excitation of the adjacent configuration electrode of small size and remove excitation order, to produce the drop of expectation in described target configuration electrode.
26. devices as claimed in claim 25, wherein said FPLOC functional block performs the step precalculating the quantity of described micro-decile drop.
27. devices as claimed in claim 7, wherein said FPLOC functional block performs the step being loaded in the volume of the drop on described first configuration electrode by utilizing point technology such as drop to calculate, and comprising:
A. stored configuration electrode is produced;
B. at the inside configuration provisional configuration electrode of described first configuration electrode;
C. configure electrode with first of the drop of described stored configuration Electrode connection configure the adjacent configuration electrode wires of small size from being mounted with, the two ends and described first of wherein said small size adjacent configuration electrode wires configure electrode and described stored configuration electrode is overlapping;
D. described provisional configuration electrode is encouraged;
E. described stored configuration electrode is encouraged;
F. along from the first configuration electrode side to the path of described stored configuration electrode, one at a time the adjacent configuration electrode of each small size being sequentially mounted with micro-decile drop is encouraged and removes excitation; And
G. repeat the excitation of the adjacent configuration electrode of small size and remove excitation order, to calculate the sum of described micro-decile drop.
28. devices as claimed in claim 13, wherein said FPLOC functional block performs and utilizes described first configuration electrode and configure that third phase that electrode aligns is adjacent configures bridge joint between electrode to move the step of drop with described first, comprising:
A. produce bridge configuration electrode, described bridge configuration electrode comprises described third phase neighbour configuration electrode and the extension bridge areas as there overlapping with drop;
B. excitation is removed to described first configuration electrode, and described bridge configuration electrode is encouraged; And
C. excitation is removed to described bridge configuration electrode, and described third phase neighbour configuration electrode is encouraged.
29. devices as claimed in claim 7, wherein said FPLOC functional block performs the step by utilizing row excitation to move drop, comprising:
A. configuration comprises the row configuration electrode of multiple row microelectrode; And
B. by encouraging along target direction the son row that described row configure electrode and remove excitation, the drop on described row configuration electrode is washed away.
30. devices as claimed in claim 7, wherein said FPLOC functional block performs the step of the residual drop washed away on electrode surface, comprising:
A. configuration row configuration electrode, described row configuration electrode comprises multiple row microelectrode and has the length covering all residual drops; And
B. by encouraging along target direction the son row that described row configure electrode and remove excitation, all residual drop on described row configuration electrode is washed away.
31. devices as claimed in claim 7, wherein said liquid reservoir is mounted with liquid.
32. devices as claimed in claim 31, wherein said FPLOC functional block performs the step by utilizing Continuous Flow to produce the liquid of difformity and size, comprising:
A. the target configuration electrode of desirable for liquid size and dimension is configured for;
B. configure bridge configuration electrode, described bridge configuration electrode comprises microelectrode line and is connected to described liquid reservoir and described target configuration electrode;
C. described bridge configuration electrode and described target configuration electrode are encouraged; And
D. removed by one group of that first configure electrode to described bridge, nearest with described target configuration electrode microelectrode and encourage, come to remove excitation to described bridge configuration electrode.
33. devices as claimed in claim 31, wherein said FPLOC functional block can perform by utilizing Continuous Flow with controlled size and the step divided than liquid being split into two seed liquid, comprising:
A. the first object with predefined first sub-drop size and shape that configuration is overlapping with liquid configures electrode;
B. configuration has the second target configuration electrode of predefined second sub-drop size and shape;
C. configure bridge configuration electrode, described bridge configuration electrode comprises microelectrode line and is connected to described first object configuration electrode and described second target configuration electrode;
D. described bridge configuration electrode and described second target configuration electrode are encouraged;
E. excitation is removed to described bridge configuration electrode; And
F. described first object configuration electrode is encouraged.
34. devices as claimed in claim 31, wherein said FPLOC functional block performs by utilizing Continuous Flow with controlled size, shape and merging than the step merging two kinds of liquid, comprising:
A. mixed configuration electrode is configured;
B. configure the first object overlapping with described mixed configuration electrode and configure electrode and the second target configuration electrode;
C. configure the first bridge configuration electrode, described first bridge configuration electrode comprises microelectrode line and is connected to described first object configuration electrode and first liquid source;
D. configure the second bridge configuration electrode, described second bridge configuration electrode comprises microelectrode line and is connected to described second target configuration electrode and second liquid source;
E. configure electrode and described first object configuration electrode and described second target configuration electrode to described first bridge configuration electrode and described second bridge to encourage;
F. excitation is removed to described first bridge configuration electrode and described second bridge configuration electrode; And
G. described mixed configuration electrode is encouraged.
35. devices as claimed in claim 1, wherein said ground structure manufactures on the top board of biplane construction, and described top board is above base plate and have gap between described top board and described base plate.
36. devices as claimed in claim 1, wherein said ground structure is the coplanar structure having passive top cover or do not have top cover.
37. devices as claimed in claim 1, wherein said ground structure is the coplanar structure with grounded screen.
38. devices as claimed in claim 1, wherein said ground structure is the coplanar structure with ground pad.
39. devices as claimed in claim 1, wherein said ground structure is the coplanar structure of the ground pad with programming.
40. devices as claimed in claim 1, wherein said ground structure be utilize can selector switch by the mixed structure of biplane construction and coplanar textural association.
41. devices as claimed in claim 7, liquid containing to the step in described liquid reservoir, comprises by wherein said FPLOC functional block execution:
A. by liquid containing in coplanar structure; And
B. on liquid, passive lid is placed.
42. devices as claimed in claim 1, clearance distance regulon is wherein utilized to be clipped between top board and base plate by drop, described clearance distance regulon for adapt to wide region, the drop with different size, wherein said clearance distance regulon can perform following steps:
A. the height of the clearance distance between described top board and described base plate is configured in;
B. configure the size of described configuration electrode, to control the size of drop, make top board described in drop contact and described base plate;
C. configure the size of described configuration electrode, to control the size of drop, make drop only contact described base plate.
43. devices as claimed in claim 1, wherein said microelectrode can be arranged as circle in the form of an array, square, hexagon is cellular or folded brick shape.
44. devices as claimed in claim 1, wherein said I/O port comprises:
A. drop I/O port unit;
B. I/O port unit is detected; And
C. Systematical control I/O port unit.
45. devices as claimed in claim 44, the drop I/O port unit in wherein said I/O port comprises:
A. for the sample I/O port unit of load sample;
B. for carrying out with reactant loader the reactant I/O port unit that interface is connected; And
C. for washing away the discarded object I/O port unit of discarded object.
46. devices as claimed in claim 44, wherein said detection I/O port unit detects with video, LIF analysis (LIF) and magnetic nanoparticle detect and be connected.
47. devices as claimed in claim 44, wherein said Systematical control I/O port unit is connected to the external unit comprising processor, display unit, printer, USB storage, network interface, power supply.
48. devices as claimed in claim 1, the sample preparation unit wherein in described FPLOC functional block can perform sample preparation, comprises the steps:
A. configuration comprises square configuration electrode and the striped configuration electrode of multiple microelectrode;
B. on described striped configuration electrode, DEP driving voltage is applied along direction from left to right; And
C. on described square configuration electrode, EWOD driving voltage is applied, drop to be cut into two sub-drops with variable grain concentration.
49. devices as claimed in claim 1, the sample preparation unit wherein in described FPLOC functional block comprises the narrow passage with the barrier material being attached to top board, and wherein said sample preparation unit can prepare sample, comprises the steps:
A. encourage microelectrode, to produce micro-dimension drop, described micro-dimension drop is too little to such an extent as to can not load bearing grain;
B. through described narrow passage, described micro-dimension drop is moved to the position of expectation, particle is waited behind simultaneously;
C. the movement of described micro-dimension drop is repeated, until produce the drop of desired size.
50. devices as claimed in claim 7, also comprise the drop routing infrastructure realized by the configuration electrode in excitation FPLOC, described drop routing infrastructure can perform following steps:
A. be configured for and carry drop and at least one routed path comprising multiple configuration electrode;
B. with the excitation of each routed path of sequence selection of order and the sequential removing excitation; And
C. the selected configuration electrode of described routed path is encouraged and removes excitation.
51. devices as claimed in claim 1, wherein fine heating element is integrated in the substrate of described device, can in order to heat drop under selected temperature.
52. devices as claimed in claim 1, the detecting unit wherein in described FPLOC functional block comprises the sensing apparatus be integrated in described substrate, and described sensing apparatus comprises potentiometric pick-up, ampere meter sensor or impedance meter sensors.
53. devices as claimed in claim 1, can be configured to prototype and test macro structure.
54. devices as claimed in claim 1, can be configured to desktop machine structure.
55. devices as claimed in claim 1, can be configured to portable machine structure.
56. devices as claimed in claim 1, can be configured to free-standing biochip structure.
57. 1 kinds of methods of programming from bottom to top and designing FPLOC device, comprising:
A. the internal memory of FPLOC is wiped;
B. configuration has the microfluid component of a group configuration electrode of selected shape and size, a described group configuration electrode is included in the multiple microelectrodes arranged in the form of an array in field-programmable architectures, and described microfluid component comprises liquid reservoir, electrode, mixing chamber, detection window, discarded object reservoir, droplet path and appointed function electrode;
C. the physical allocation of described microfluid component is configured; And
D. the microfluidic procedures of sample preparation, droplet manipulation and detection is designed for.
Priority Applications (3)
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| TW101105387A TWI515831B (en) | 2011-02-17 | 2012-02-17 | Microelectrode array architecture |
| TW101105386A TWI510296B (en) | 2011-02-17 | 2012-02-17 | Droplet manipulations on ewod microelectrode array architecture |
| TW101105384A TWI510295B (en) | 2011-02-17 | 2012-02-17 | Field-programmable lab-on-a-chip and droplet manipulations based on ewod micro-electrode array architecture |
Applications Claiming Priority (6)
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| US13/029,137 | 2011-02-17 | ||
| US13/029,137 US8834695B2 (en) | 2010-03-09 | 2011-02-17 | Droplet manipulations on EWOD microelectrode array architecture |
| US13/029,138 | 2011-02-17 | ||
| US13/029,140 US8815070B2 (en) | 2010-03-09 | 2011-02-17 | Microelectrode array architecture |
| US13/029,140 | 2011-02-17 | ||
| US13/029,138 US8685325B2 (en) | 2010-03-09 | 2011-02-17 | Field-programmable lab-on-a-chip based on microelectrode array architecture |
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| DE102012021933B4 (en) * | 2012-11-09 | 2015-12-31 | Airbus Defence and Space GmbH | Optical pH sensor |
| WO2014135232A1 (en) * | 2013-03-04 | 2014-09-12 | Tecan Trading Ag | Manipulating the size of liquid droplets in digital microfluidics |
| CN104321141B (en) * | 2013-05-23 | 2017-09-22 | 泰肯贸易股份公司 | Digital micro-fluid system with interconvertible PCB |
| CN106933142A (en) * | 2017-02-24 | 2017-07-07 | 华南师范大学 | A kind of Microfluidic droplet alignment system and method based on electrowetting |
| US10330920B2 (en) * | 2017-04-04 | 2019-06-25 | Sharp Life Science (Eu) Limited | Droplet actuation method for a microfluidic device |
| US10697986B2 (en) * | 2017-06-23 | 2020-06-30 | International Business Machines Corporation | Microfluidic device with programmable verification features |
| CN107754962B (en) * | 2017-11-22 | 2020-09-18 | 南方科技大学 | A digital microfluidic droplet driving device and driving method |
| CN109261234B (en) * | 2018-11-23 | 2021-03-23 | 京东方科技集团股份有限公司 | Microfluidic chip and analysis device |
| US10870114B2 (en) * | 2019-03-11 | 2020-12-22 | Sharp Life Science (Eu) Limited | EWOD cartridge position sensing when docked in EWOD instrument |
| CN109894167B (en) * | 2019-03-25 | 2021-09-28 | 上海天马微电子有限公司 | Micro-fluidic chip |
| CN109870801B (en) * | 2019-03-28 | 2021-08-06 | 上海天马微电子有限公司 | Electrowetting panel and analysis device |
| US11524297B2 (en) | 2019-12-03 | 2022-12-13 | Sharp Life Science (Eu) Limited | Method of concentrating particles in a liquid droplet using an EWOD device with sensing apparatus |
| CN113811389B (en) * | 2020-02-28 | 2023-04-11 | 京东方科技集团股份有限公司 | Micro-fluidic chip and micro-fluidic system |
| CN111220309B (en) * | 2020-03-27 | 2020-07-21 | 广东省计量科学研究院（华南国家计量测试中心） | Force source device for micro-nano force measurement and implementation method thereof |
| CN114336511A (en) * | 2020-09-30 | 2022-04-12 | 富佳生技股份有限公司 | Dielectric wetting device and circuit detection method thereof |
| US20240238781A1 (en) * | 2021-10-27 | 2024-07-18 | Beijing Boe Sensor Technology Co., Ltd. | Digital Microfluidics Chip and Drive Method thereof, and Digital Microfluidics Apparatus |
| CN114177958B (en) * | 2021-12-09 | 2023-05-09 | 华南师范大学 | A high-throughput uniform droplet array preparation method and microstructure array chip |
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| WO2006081558A2 (en) * | 2005-01-28 | 2006-08-03 | Duke University | Apparatuses and methods for manipulating droplets on a printed circuit board |
| ITBO20050481A1 (en) * | 2005-07-19 | 2007-01-20 | Silicon Biosystems S R L | METHOD AND APPARATUS FOR THE HANDLING AND / OR IDENTIFICATION OF PARTICLES |
| US7815871B2 (en) * | 2006-04-18 | 2010-10-19 | Advanced Liquid Logic, Inc. | Droplet microactuator system |
| WO2008147568A1 (en) * | 2007-05-24 | 2008-12-04 | Digital Biosystems | Electrowetting based digital microfluidics |
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