CN102671722A - Field-programmable lab-on-a-chip based on microelectrode array architecture - Google Patents

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

Field-programmable chip lab based on the microelectrode array structure

The cross reference of related application

The application incorporates the associating pending trial U.S. Patent application No. that the name of submitting on February 17th, 2011 is called " Droplet Manipulations on EWOD Microelectrode Array Architecture " into through the mode of reference 13,029,137, on February 17th, 2011 name submitted to be called the associating pending trial U.S. Patent application No. of " Field-Programmable Lab-on-a-Chip and Droplet Manipulations Based on EWOD Micro-Electrode Array Architecture " 13,029,138And the name of submission on February 17th, 2011 is called the associating pending trial 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 adopt field-programmable chip lab (FPLOC) system of microelectrode array structure.

FPLOC can be used for microfluidic applications by field programming, these microfluidic applications include, but is not limited to based on drop microfluidic procedures, based on continuous microfluidic procedures, based on the power on excitation (actuation) of wetting (EWOD) or of medium based on the excitation of (dielectrophoresis) DEP.

FPLOC is similar to field programmable gate array (FPGA) through utilization structure provides solution more easily for the LOC designer.Compare with exclusive hardwired solution, the field-programmable microfluidic platforms is realized the LOC design through software programming under the condition that need not complicated hardware design and encapsulation technology, and this provides the advantage that significantly is superior to other platform.FPLOC can realize that different application specific systems (mensuration) is just as utilizing the clearly FPGA of sign, large-scale production and encapsulation with the mode of simple and flexible.As a result, in the microfluid field through utilizing the semicon industry experience to can be implemented in Time To Market, large-scale production, fault-tolerance, advantage and a lot of other advantages aspect low-cost.

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 the manipulation of the micro fluid in microlitre arrives the millilambda scope usually.The use that is used to implement the plane fluid means of low capacity chemistry is proposed by AC first, and for this notion, the biochemist has used term " the total chemical analysis system of miniaturization " (μ TAS).Adopted the base fluids principle of μ TAS from the more and more researchers of a lot of subjects beyond the biochemistry, as a kind of mode of developing the recent studies on instrument that chemistry and biology uses.In order to reflect this scope of having expanded, except μ TAS, often use the more term of broad sense " microfluid " and " chip lab (LOC) " now.

First generation micro-fluidic technologies is based on the manipulation of the continuous liquid stream of the passage of the microfabrication of flowing through.The excitation of flow of liquid realizes by external pressure source, integrated mechanical micropump or by electric structure.Continuous-flow system can satisfy the needs that the simple biochemistries of a lot of clearly definition are used, but they are inappropriate for the flexibility that needs high level or complicated fluid actuated more complicated task.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 be handled in passage or on substrate, moving.Through utilizing the drop of discrete unit volume, the microfluid function can be reduced to one group of basic operation that repeats, and, moves the fluid of a unit under the situation of a unit that is.In document, proposed much to be used to handle the method for microfluid drop.These technology can be classified into chemistry, calorifics, acoustics and electrical method.In all methods, received extensive concern in recent years in order to the electrical method that encourages drop.

In the microfluidic device based on drop, liquid is clipped between two parallel-plates and with the form of drop and carries.Microfluid system based on drop provides lot of advantages: they have low power consumption and need be such as the mechanical component pump or the valve.In recent years, the microfluid system based on drop has been widely used in the multiple application such as hybrid analysis thing and reactant, analysing biomolecules and manipulation particle.In the digital micro-fluid system, medium powers on wetting (EWOD) and liquid dielectrophoresis (LDEP) is two kinds of main mechanism that are used to distribute and handle drop.EWOD and LDEP adopt electromechanical power to control drop.The EWOD micro-system is generally used for producing, carries, cuts and merges drop.In these systems, drop be clipped between two parallel-plates and be energized and unexcited electrode between the effect of wetability difference under be energized.In the LDEP micro-system, drop places on the coplanar electrodes.When applying voltage, liquid becomes polarizable, and flows towards the zone of highfield intensity more.Difference between LDEP and the EWOD incentive mechanism is driving voltage and frequency.In the EWOD excitation, apply common DC or low frequency AC voltage, and LDEP needs higher driving voltage (200-300Vrms) and higher frequency (50-200kHz) less than 100V.

Medium powers on, and wetting (EWOD) is one of modal electrical method.Digital micro-fluid such as chip lab (LOC) typically refers to and utilizes the drop of EWOD technology to handle.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 ground electrode.Preferably the material through 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 that is coated with hydrophobic membrane is added on the plate, with reduce wetting of surfaces property and be increased in drop and control electrode between electric capacity.Contain the drop of biochemical samples and fill media clip between plate, drop is inner mobile at the filling media simultaneously.In order to move drop, apply control voltage to the electrode that is adjacent to drop, the electrode under drop is removed excitation simultaneously.

In recent years, LDEP has also attracted widely to pay close attention to, because it is easy to implement and can distribute and handle the minimum drop that is raised to the picoliter scope from millimicro.Liquid D EP excitation is defined as towards the zone of higher electric-field intensity and attracts polarizable liquid to pile (liquid mass).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 have optimized liquid D EP liquid droplet distribution, and on coplanar electrodes, have produced the picoliter drop.The effect of surface-coated and reported with the relevant key factor of reliable excitation of the liquid D EP that uses coplanar electrodes.People such as Fan change coplane LDEP electrode into two parallel LDEP electrodes.The LDEP device of parallel construction is adopted by micro-mixer, and is integrated with the EWOD micro-system.Carry, division and merge the dielectric drop and realize by the DEP in parallel-plate (biplane) device, its with the fluid of digital micro-fluid from the range expansion of only conduction and water-based to containing non-conductive scope.The biplane DEP of dielectric drop excitation realizes through between parallel pole, applying voltage, and the liquid dielectric drop pump that will have relative high dielectric constant through DEP is to the zone with relatively low dielectric constant (for example air).

Disadvantageously be that the conventional LOC system of the employing EWOD technology of being set up so far still highly is exclusively used in certain applications.Current LOC system depends on manual control to a great extent and does biologicall test with optimizing.In addition, current application in the LOC system and function are consuming time, and need expensive hardware designs, test and maintenance program.Disadvantage about these systems is " hardwired " electrode." hardwired " is meant the shape, size, position of electrode and physically is subject to the structure of permanent etch about the electrical wiring track of electrode controller.In case electrode is produced, no matter what their function is, their shape, size, position and track just can not change.Therefore, this means with respect to the high disposable engineering cost of LOC design and shipment after limited update functions or the local ability that reconfigures LOC partly.

This area exists handles the needs of the system and method for manpower that the generation microfluid system is associated and cost to being used to reduce with utilizing drop.This area expectation makes the LOC design rise to application layer, is manually optimizing biologicall test, hardware designs consuming time, the test of costliness and the burden aspect the maintenance program to alleviate the LOC designer.

This area exists handles the needs of the system and method for manpower that the generation microfluid system is associated and cost to being used to reduce with utilizing drop.The microelectrode array structure technology can provide field-programmable property, and wherein the electrode of LOC and integral layout can be software programmables.If its (being stored in the nonvolatile memory such as ROM) firmware of microfluidic device or embedded system can " in the field " be modified; Maybe device is returned its manufacturer and need not disassembling apparatus, then can be described as field-programmable or existing field-programmable.The characteristic that this expects often very much is used to replace required expense and the turnaround time of firmware problematic or that degenerate because this can reduce.Ability, the part of update functions reconfigures the design of part and will advantage be provided for plurality of applications with respect to the lower disposable engineering cost of LOC design after the shipment.

In addition, based on the microelectrode array structure of novelty, can significantly improve the technology of the manipulation drop in the LOC system.Aspect the advanced person's in generation, conveying, mixing and the cutting process of EWOD microelectrode array structure drop manipulation, the invention provides various embodiments.

Can believe, adopt the field-programmable chip lab (FPLOC) of microelectrode array structure, therefore the dramatic benefit that is superior to conventional digital fluid system can be provided owing to have based on field should be used for dynamically the programming ability of new LOC system.The field-programmable performance is enough significantly improved the turnaround time of LOC design, can also make the LOC design rise to application level, is manually optimizing biologicall test, hardware designs consuming time, the test of costliness and the burden aspect the maintenance program to alleviate the LOC designer.

Summary of the invention

Herein disclosed is a kind of field-programmable chip lab (FPLOC) device that adopts the microelectrode array structure; Comprise: a. base plate; The array that comprises a plurality of microelectrodes on the top surface that places substrate, said a plurality of microelectrodes are covered by dielectric layer, and wherein each said microelectrode is connected at least one earth element in the ground structure; Top at said dielectric layer and said earth element is provided with hydrophobic layer, has the hydrophobic surface of drop with generation; B. field-programmable architectures, the configuration set electrode that is used to programme is so that produce microfluid component and layout with selected shape and size; And the c.FPLOC functional block, comprising: the I/O port; The sample preparation unit; The drop actuation unit; Detecting unit; And system control unit.

In another embodiment, a kind of FPLOC device of the CMOS of employing technology manufactured goods comprises: the a.CMOS system control block comprises: controller block is used to provide processor unit, memory headroom, interface circuit and software programming ability; The chip layout piece is used for stored configuration electrode configuration data and FPLOC layout information and data; The drop situational map, the physical location that is used to store drop; With fluid-operated manager, be used for using the physical stimulus that is translated into drop with said layout information, said drop situational map and from the FPLOC of said controller block; And many fluid logic pieces of b., comprising: a microelectrode is positioned on the top surface of CMOS substrate; A memory map datum memory cell is used to keep the excitation information of said microelectrode; And the control circuit piece, be used to manage control logic.

In another embodiment, a kind of FPLOC device of thin film transistor (TFT) TFT technology manufactured goods that adopts comprises: the a.TFT system block comprises: controller block is used to provide processor unit, memory headroom, interface circuit and software programming ability; The chip layout piece is used for stored configuration electrode configuration data and FPLOC layout information and data; The drop situational map, the physical location that is used to store drop; With fluid-operated manager; Be used for and be translated into the physics drop excited data that is used to encourage microelectrode from the data that said layout information, said drop situational map and FPLOC use; Said FPLOC uses from said controller block, wherein said physics drop excited data comprise with the mode by frame send to the active matrix piece to configured electrodes in groups, excitation and remove excitation; And b. active matrix piece, comprising: be used 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; The active matrix controller comprises source electrode driver and gate drivers, is used for through driving data is sent to chip for driving, is used to come the drive TFT array from the data of TFT system control block; With the DC/DC converter, be used for applying driving voltage to said source electrode driver and said gate drivers.

In another embodiment, a kind of method of programming from bottom to top and designing the FPLOC device comprises: a. wipes the internal memory of FPLOC; B. configuration has the microfluid component of a configuration set electrode of selected shape and size; A said configuration set electrode is included in a plurality of microelectrodes of arranging with array format in the field-programmable architectures, and said microfluid component comprises liquid reservoir, electrode, mixing chamber, detection window, discarded object reservoir, droplet path and appointed function electrode; C. dispose the physical allocation of said microfluid component; And d. is designed for sample preparation, drop is handled and the microfluidic procedures of detection.

In another embodiment, a kind of method of programming from top to bottom and designing the FPLOC device comprises: a. is through the function of hardware description language design FPLOC; B. produce the ordering chart model according to hardware description language; C. carry out the function of simulation through hardware description language with checking FPLOC; D. utilize the system level to synthesize according to said ordering chart model and produce concrete implementation; E. will be input in synthetic the processing from the microfluid module library with from the design data of design specification; F. produce the measurement operation of resource on the chip mapped file, measurement operation the timetable file and from the synthetic Built-in Self Test file of handling; G. utilize the input execution geometry level of design specification synthetic, to produce the two-dimentional physical Design of biochip; H. according to the two-dimentional physical Design that is combined with the biochip of concrete physical message, produce 3-D geometric model, said concrete physical message is from said microfluid module library; I. through using 3-D geometric model to carry out physical level simulation and design verification; And j. is loaded into the FPLOC design among the blank FPLOC.

In another embodiment; The method in a kind of FPLOC of design storehouse comprises: a. simulates the functional module description of the microfluidic procedures of being write by hardware description language through creating test table; Said hardware description language comprises VHDL or Verilog, and said test table constitutes test macro and is used to simulate said system and observed result; B. through Compositing Engine said functional module is described and be mapped to wire list; C. said wire list is translated into gate level description; D. simulate said gate level description; E. add propagation delay to said wire list through physical analogy; And f. is through having the wire list of said propagation delay, the operation whole system simulation.

In another embodiment; EWOD microelectrode array structure of the present invention adopts the notion of " dot matrix printing machine "; Wherein, A plurality of microelectrodes (for example " point ") in groups and can be by excitation/removal simultaneously excitation to form different shape and electrodes sized, so that satisfy the requirement of the fluid-operated function in the 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.And, all can realize through the configuration microelectrode for the LOC physical layout of the position of I/O port, liquid reservoir, electrode, path and electrode network.

In another embodiment, except the routine in order to carry out typical microfluidic procedures of configured electrodes was controlled, definite control sequence of microelectrode can be provided at the advanced person's when handling drop microfluidic procedures.

In another embodiment, the drop method of operating based on EWOD microelectrode array structure can comprise: produce drop; Carry drop; The cutting drop; And mixing drop.

The various embodiments of FPLOC are disclosed.In one embodiment, the design of FPLOC is based on EWOD microelectrode array structure.FPLOC can wherein can and be reconfigured through the software design by all electrodes that a lot of microelectrodes constitute according to different application and the dynamically programming of function quilt.After configuration or reconfiguring, similar with general plotting based on the LOC system of EWOD, can realize through control and steering electrode in the LOC design based on the fluid-operated of EWOD technology.

In another embodiment, the different shape of FPLOC system and electrodes sized can both or reconfigure through software programming such as liquid reservoir, electrode, mixing chamber, droplet path etc., to satisfy the requirement of the operating function in the application on the scene.

In addition, software programming or reconfigure the FPLOC physical layout that to carry out the position of input port, liquid reservoir, electrode, path and electrode network.

In another embodiment, FPLOC is encapsulated into rudimentary microfluidic procedures during application layer appears, so that the designer pays close attention to senior application.Being produced and test as the library item order with excitation control sequence in order to carry out concrete fluid-operated configuration data of microelectrode, wherein the FPLOC designer can select said library item order and make up its microfluidic applications.

In another embodiment, the EWOD microelectrode array structure Design of handling drop can be based on coplanar structure, and wherein the EWOD excitation can occur in the veneer configuration with top board.

In another embodiment, the EWOD microelectrode array structure Design of handling drop can adopt biplane construction, and the top top board wherein is set in system.

Although disclose a plurality of embodiments; It is obvious that but other embodiment of the present invention also will become after the detailed description of research hereinafter for one of ordinary skill in the art, and said detailed description illustrates and described illustrative embodiments of the present invention.To recognize that under the condition that does not break away from the spirit and scope of the present invention, the present invention can have multiple remodeling in many aspects.Correspondingly, accompanying drawing be described in detail in should be regarded as in nature illustrative rather than restrictive.

Description of drawings

Figure 1A is the viewgraph of cross-section that the conventional EWOD system that inserts and puts is shown substantially.

Figure 1B is the top view that is illustrated in the conventional EWOD on the two-dimensional array of electrodes substantially.

Fig. 2 is the figure that is used to handle the biplane DEP device of dielectric drop.

Fig. 3 is the figure that microelectrode array is shown, and wherein the configured electrodes in the microelectrode array (configured-electrode) can be configured to different shape and size.

Fig. 4 A is the figure that utilizes the LOC layout of microelectrode array structure.

Fig. 4 B is the figure of the structure of conventional physical etch.

Fig. 4 C is the figure of configured electrodes, wherein shows the amplifier section of liquid reservoir (reservoir) and configured electrodes.

Fig. 5 A shows the array of a plurality of square microelectrodes, and one of them microelectrode is shown by outstanding.

Fig. 5 B shows the array of a plurality of hexagon microelectrodes, and one of them microelectrode is shown by outstanding.

Fig. 5 C shows the array that is arranged in a plurality of square microelectrodes in wall brick (wall-brick) layout, and one of them microelectrode is shown by outstanding.

Fig. 6 A shows the mixed plate structure, and wherein the mixed plate structure can be controlled as and between coplane pattern and biplane mode, switch the microelectrode structure.

Fig. 6 B shows grounded screen (ground grid) microelectrode coplanar structure.

Fig. 6 C shows another FPLOC microelectrode coplanar structure with ground pad.

Fig. 6 D shows another FPLOC microelectrode coplanar structure with ground pad able to programme.

Fig. 7 is the figure that the hybrid system structure is shown, and wherein the hybrid system structure has dismountable, adjustable and transparent top board, in order to adapt to the drop size and the volume of wide region.

Fig. 8 is the figure that five required base function blocks of FPLOC are shown.

Fig. 9 A, 9B, 9C and 9D show and utilize adjustable another hinged passive lid to come load sample.

Figure 10 illustrates the figure that detects the I/O port.

Figure 11 A and 11B show FPLOC and utilize 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 that utilizes square configuration electrode and striped configuration electrode excitation respectively through EWOD and DEP.

Figure 12 B and 12C illustrate the high-frequency signal that from left to right is applied to the striped configuration electrode; Through DEP particle is driven into the viewgraph of cross-section on right side at the inner inhomogeneous field of drop.

Figure 12 D shows and is applied on the square configuration electrode to produce the low frequency signal of two sub-drops with variable grain concentration through EWOD.

Figure 13 shows another embodiment of the FPLOC sample preparation of technology such as the branch that utilizes drop.

Figure 14 A and 14B show sample that self-regulation loads or the reactant ability with respect to the position of liquid reservoir.

Figure 15 shows an embodiment of FPLOC drop production process.

Figure 16 shows the concrete drop production process that is called " drop five equilibrium ".

Figure 17 is the figure of conveying that the drop of FPLOC is shown.

Figure 18 is the figure that the drop route of FPLOC is shown.

Figure 19 A, 19B and 19C illustrate the temporary bridge that utilizes FPLOC to handle the figure that carries drop.

Figure 20 A, 20B and 20C are the figure that the electrodes series excitation is shown.

Figure 21 A, 21B and 21C are the figure that the drop cutting of FPLOC is shown.

Figure 22 A, 22B and 22C are the figure of accurate cutting that the drop of FPLOC is shown.

Figure 23 A, 23B and 23C are the figure of diagonal cutting that the drop of 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 in the substrate that is integrated into FPLOC is shown.

Figure 26 A and 26B are the figure that basic merging/mixing of FPLOC is shown.

Figure 27 A, 27B and 27C are the figure that effective mixed process of handling through the drop of implementing in order to inhomogeneous how much motions of quickening to mix is shown.

Figure 28 A and 28B show and are used to quicken the inhomogeneous past complex mixers that drop mixes.

Figure 29 is the figure that illustrates based on the fluid circulation blender of EWOD microelectrode array structure.

Figure 30 A-30F is the figure that the multilayer blender is shown, and wherein the multilayer blender is particularly useful for the situation of low aspect ratio (＜1).

Figure 31 is that the sensing apparatus that illustrates based on the CMOS technology is integrated into the figure among the FPLOC.

Figure 32 is the block diagram that the grading software structure that is used for FPLOC is shown.

Figure 33 illustrates the prototype that is used for FPLOC and the block diagram of test system configurations.

Figure 34 A shows the desktop machine configuration that FPLOC uses.

Figure 34 B shows the portable machine configuration that FPLOC uses.

Figure 34 C shows the free-standing biochip configuration that FPLOC uses.

Figure 35 utilizes the standard CMOS manufacturing process to make the block diagram of FPLOC.

Figure 36 shows the electrical design based on the FLB array of standard CMOS manufacturing technology.

Figure 37 shows the viewgraph of cross-section based on the FLB array manufactured goods of standard CMOS manufacturing technology.

Figure 38 A utilizes thin film transistor (TFT) (TFT) array fabrication process to make the block diagram of FPLOC.

Figure 38 B shows the block diagram of active matrix piece (AMB).

Figure 38 C is based on the top view of the microelectrode array of tft array.

Figure 38 D is the viewgraph of cross-section that is illustrated in the biplane construction based on the FPLOC manufactured goods of TFT technology.

Figure 39 A shows the blank FPLOC before any programming or configuration.

Figure 39 B shows the instance of the design of configuration LOC.

Figure 40 shows the flow chart of the method for designing from top to bottom that is used for FPLOC design and programming.

Figure 41 A, 41B and 41C show to encourage through Continuous Flow and produce liquid.

Figure 41 D and 41E show to encourage through Continuous Flow and cut liquid.

Figure 42 A, 42B and 42C show to encourage through Continuous Flow and merge/mixing material.

The specific embodiment

Conventional electric wetting little exciter structure (be merely illustrative purpose, illustrated with reduced size) has been shown in Figure 1A.Digital micro-fluid device based on EWOD comprises two glass plates that are 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 ground electrode 140.Preferably form electrode, make it in thin layer, have the assemblage characteristic of electric conductivity and light transmission through the material such as tin indium oxide (ITO).(for example Parylene C) adds on the plate with the dielectric insulator 170 that is coated with the hydrophobic membrane 160 such as polytetrafluoroethylene (PTFE) AF, with reduce wetting of surfaces property and be increased in drop and control electrode between electric capacity.Contain the drop 150 of biochemical samples and the filling media clip such as silicone oil or air between plate, filling the inner conveying of media to help drop 150.In order to move drop 150, apply control voltage to the electrode that is adjacent to drop 180, the electrode under drop 150 is removed excitation simultaneously.

Figure 1B is the top view that is illustrated in the conventional EWOD on the two-dimensional array of electrodes 190 substantially.Drop 150 moves to the electrode 180 that is energized from electrode 130.Electrode 180 black in color show and are applied with control voltage.The EWOD effect makes electric charge accumulate in drop/insulator interface, causes on the gap between adjacent electrode 130 and 180 135, producing interfacial tension gradient, realizes the conveying of drop 150 thus.Through changing current potential, the wetting next drop that moves the millilambda volume along this electrode wires of electricity capable of using along linear array.Can control the speed of drop through in the scope of 0-90V, regulating control voltage, and drop can move with speed up to 20cm/ s.Drop 151 and 152 also can be carried under clock voltage control with the pattern that the user limits through two-dimensional array of electrodes under the condition that need not micropump and miniature valve.

LOC device based on EWOD utilizes the interfacial tension gradient on the gap between the adjacent electrode to encourage drop.The design of electrode comprises intended shape, size and each two gaps between electrodes of each electrode.In the LOC layout designs based on EWOD, droplet path is made up of a plurality of electrodes of the zones of different that connects LOC usually.These electrodes can be used for course of conveying, also can be used for other more complicated operations such as mixing and cutting process in drop is handled.

In one embodiment, can structure as shown in Figure 2 be used to handle the biplane DEP device of dielectric drop.The a plurality of microelectrodes 261 of patterning on base substrate 245.Each configured electrodes 260 comprises a plurality of microelectrodes 261.Top board 240 comprises the reference electrode 220 that is 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 the drop 250 and the surface of solids, this helps reproducible drop to handle and eliminate the dielectric fluid residue of operating period.Clearance height or drop thickness 270 are confirmed by the thickness of sept.Apply voltage through driving between the microelectrode reference electrode 220 and one, with dielectric drop pump to the microelectrode that is in foment, shown in the arrow among Fig. 2.In clearance height is test dielectric drop (decane dielectric drop (350V in the parallel-plate device of 150mm _DC), hexadecane dielectric drop (470V _DC) and silicone oil dielectric drop (250V _DC)) excitation.The polarity of the dc voltage that is applied drives not influence to drop, and simultaneously, the AC signal that reaches the 1kHz frequency through test successfully encourages the dielectric drop.

Difference between LDEP and the EWOD incentive mechanism is driving voltage and frequency.Therefore shared physics biplane electrode structure and configuration are feasible between EWOD and DEP.Usually in EWOD excitation, apply usually DC or low frequency AC voltage less than 100V, preferably driving voltage at DC to the scope of the AC of 10kHz and less than 150V; And LDEP needs higher driving voltage (200-300Vrms) and higher frequency (50-200kHz), preferably driving voltage at 50kHz to the scope of the AC of 200kHz and have 100-300Vrms.In the description of this invention, will utilize the EWOD technology to explain embodiment of the present invention hereinafter, but in most of the cases through appropriate change driving voltage and frequency, the DEP excitation is also contained in the present invention.

The present invention has adopted the notion of " dot matrix printing machine ", that is, each microelectrode in the microelectrode array structure is " point " that can be used for forming all microfluid components.In other words, each microelectrode in the microelectrode array can be configured to form various microfluid components with different shape and size.According to client's demand, a plurality of microelectrodes can be regarded as (grouped) in groups and can be encouraged simultaneously to form different electrodes and to carry out " point " of microfluidic procedures." excitation " refers to electrode and applies required voltage, thereby the EWOD effect makes electric charge accumulate in drop/insulator interface, causes on the gap between the adjacent electrode, producing interfacial tension gradient, realizes the conveying of drop thus; Perhaps the DEP effect makes liquid become polarizable and flows towards the zone than highfield intensity." remove excitation " and refer to the voltage that removal is applied to electrode.

Fig. 3 shows an embodiment based on the FPLOC of microelectrode array structure of the present invention.In this embodiment, microelectrode array 300 comprises a plurality of (30 * 23) same microelectrode 310.This microelectrode array 300 is based on standard microelectrode standard (being expressed as microelectrode 310 here) and is independent of final LOC and uses with the manufacturing technology of concrete microfluidic procedures standard and make.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 the expectation LOC in.As shown in Figure 3, each configured electrodes 320 comprises 100 microelectrodes 310 (i.e. 10 * 10 microelectrodes)." configured electrodes " refers to 10 * 10 microelectrodes 310 and combines with as Integrated electrode 320, and will be together by excitation simultaneously or remove excitation.As a rule, configuration data is stored in the nonvolatile memory (such as ROM), and can " in the field " be modified, and maybe device is returned its manufacturer and need not disassembling apparatus.Fig. 3 shows drop 350 and is positioned at center configuration electrode 320.

As shown in Figure 3, the size and dimension of configured electrodes of the present invention can design based on application need.The size of the volume of drop 350 and electrode 320 is proportional.In other words, through the size of control electrode 320, the volume of drop 350 also is limited to adapt with the design size with electrode 320, can control the volume of drop thus.The example of the configured electrodes 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 can come the difformity of configured electrodes through utilizing microelectrode array.Although electrode 320 is square, electrode 330 is the rectangles that comprise 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 through the FPLOC whole LOC design of programming, shown in Fig. 4 A, being shaped as of the configured electrodes of transport path 440, detection window 450 and mixing chamber 460 is square.Liquid reservoir 430 is large scale configured electrodes of confirming shape.Discarded object reservoir 420 is quadrangles.

Fig. 4 B and 4C show the amplified version of the liquid reservoir 430 among Fig. 4 A.Fig. 4 B shows the liquid reservoir structure 431 of the physical etch of making through conventional EWOD-LOC system.Its assembly is shown as the liquid reservoir 431 of permanent etch and the electrode 471 of four permanent etch.Compare with Fig. 4 B (conventional design), Fig. 4 C shows a programming LOC structure, and it has the configuration liquid reservoir 432 and the electrode in groups 472 of similar size.Configuration liquid reservoir 432 can be made to make this liquid reservoir assembly through a plurality of microelectrodes 411 being combined into desired size and shape.Electrode 472 in groups comprises 4 * 4 microelectrodes 411.

After the shape and size of having set required microfluid component, also it is important to set the position of microfluid component and how these microfluid components are linked together as circuit or network.Fig. 4 A shows the residing physical location of these microfluid components and how these microfluid components link together to be used as function LOC.These microfluid components are: configured electrodes 470, liquid reservoir 430, discarded object reservoir 420, mixing chamber 460, detection window 450 and the transport path 440 that connects the zones of different of LOC.If field-programmable LOC then after layout designs, has some untapped microelectrodes 410.After FPLOC fully was up to the standards, the designer can attempt the hardwired version to practice thrift cost, and untapped then microelectrode 410 can be removed.

The shape of the microelectrode among the FPLOC can physically realize in a different manner.In an embodiment of the invention, Fig. 5 A shows the array of a plurality of square microelectrodes, and one of them microelectrode is shown as 501 by outstanding.6 * 6 microelectrodes constitute configured electrodes 502.Fig. 5 A always has 3 * 2 configured electrodes.In another embodiment, Fig. 5 B shows the array of a plurality of hexagon microelectrodes, and one of them microelectrode is shown as 503 by outstanding.6 * 6 microelectrodes constitute configured electrodes 504, and 3 * 2 configured electrodes are arranged among Fig. 5 B.The interdigital edge of hexagon microelectrode has advantage when moving drop in the gap between configured electrodes.In another embodiment, Fig. 5 C shows the array that is arranged in a plurality of square microelectrodes in the wall brick layout, and one of them microelectrode is shown as 505 by outstanding.6 * 6 microelectrodes constitute configured electrodes 506, and 3 * 2 configured electrodes are arranged among Fig. 5 C.The interdigital edge of hexagon microelectrode has advantage when moving drop in the gap between configured electrodes, but this only occurs on the x axle.Also can realize the microelectrode of a lot of other shapes, and three kinds of shapes that are not limited only to here to be discussed.

Conventional LOC design is based on biplane construction (it has the base plate that comprises the patterned electrodes array and is coated with the top board of electrode continuously) or coplanar structure (wherein excitation can occur in the veneer configuration with top board).Co-planar designs can adapt to the more drop of the different volumes size of wide region, and does not receive the restriction of top board.Biplane construction has the fixed interval (FI) between top board, and aspect the drop of the volume size that adapts to wide region, has restriction, but biplane construction provides more stable microfluidic procedures really.Still can increase the passive top board that is used for the sealing test surface based on the LOC device of coplanar structure, to protect fluid-operated or in order to protect test media to have the purpose in the longer preservation of putting on the shelf (shelf storage) life-span.

In order to adapt to the wide range of applications of FPLOC, in an embodiment of the invention, the FPLOC device is based on the mixed plate structure, and wherein excitation can occur in coplanar arrangement or the biplane configuration.Fig. 6 A shows switch 610, and it can be controlled as and between coplane pattern and biplane mode, switch the microelectrode structure.In biplane mode, the electrode continuously 640 on cover plate 620 is connected to ground, and the grounded screen 680 on battery lead plate 621 is broken off with ground and being connected.On the other hand, in the coplane pattern, the grounded screen 680 on the battery lead plate 621 is connected to ground, and the ground electrode 640 on cover plate 620 is connected with the ground disconnection.

In one embodiment, the physics coplane microelectrode (630 and 680) shown in Fig. 6 A can be the grounded screen structure.The grounded screen structure is shown in Fig. 6 B, and it has microelectrode 631, ground wire 681 and the gap between 631 and 681 615 of driving.When electrode is energized, drive microelectrode 631 by DC or the charging of square wave driving voltage.Ground wire 681 is on the identical plate to realize coplanar structure with driving microelectrode 631.Gap 681 is no vertically superposed in order to guarantee between 631 and 681.At two drops 651 and 652 of different size shown in Fig. 6 B, they are all fully overlapping with grounded screen 681 and adjacent micro electrode 631, and can be handled effectively.In another embodiment, coplane grounded screen can not broken off with ground and being connected, as long as extra ground connection can not brought any problem to the biplane construction operation.

Fig. 6 C shows another embodiment of FPLOC microelectrode structure.Place, four angles driving microelectrode 632 has ground pad 682, and between 632 and 682, has gap 616.Replace the ground wire in the embodiment shown in Fig. 6 B, this embodiment uses ground pad to realize coplanar structure.This embodiment of the present invention has utilized group's ground connection (group grounding), and ground pad, microelectrode and drop 653 consistent overlapping guaranteed reliable drop operation thus.In addition, in another embodiment, coplane grounded screen can not broken off with ground and being connected, as long as extra ground connection can not brought any problem to the biplane construction operation.

Fig. 6 D shows another embodiment of FPLOC microelectrode " configuration ground pad " coplanar structure.On the plate identical, do not have ground wire or ground pad with microelectrode.But some microelectrodes are used as ground pad to realize coplanar-electrode structure.Fig. 6 D shows 4 * 4 same square microelectrodes 633, between microelectrode, has gap 617.In this embodiment, any microelectrode 633 can be configured to be used as ground electrode through physical connection for electrical ground connection.In this embodiment, the microelectrode at four angles is configured to ground electrode 683.In addition, field-programmable property and miniature microelectrode provide higher flexibility and the granularity of Geng Gao to the dynamic-configuration of " configured electrodes " and " configuration ground pad ".For illustrative purpose, the ground microelectrode is programmed on four angles, but this is not the layout of fixing.Comprise and to be implemented to obtain the optimum that drop is handled the interim step of the change of ground electrode or exciting electrode.This " field-programmable " microelectrode ground structure is the flexible way that realizes the mixed plate structure of FPLOC, but will need higher driving voltage 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 as shown in Figure 7 710 and battery lead plate 720.Battery lead plate 720 realizes that through the microelectrode array structure technology side view that wherein is used for the configured electrodes of drop 730 comprises three microelectrodes (being shown as black).The configured electrodes that is used for drop 740 comprises six microelectrodes, and the configured electrodes that is used for drop 750 comprises 11 microelectrodes.This embodiment is particularly useful in the application such as FPLOC.Although the microelectrode array structure provides field-programmable property when the shape and size of the said configured electrodes of configuration, still highly needs can adapt to the system architecture of drop of size and the volume of wide region.This is because the scope of the size of the adaptable drop of FPLOC and volume is wide more, just can realize more application.The clearance distance of optimizing can be adjusted to the drop that is fit to desired size.In the present invention, the gap of optimization can be realized through three kinds of modes: at first, all drops can be handled under the condition that does not contact top board 710.This mode is applied in the coplanar structure usually.In the second way, all drops can be handled through the contact top board, and wherein drop is clipped between top board 710 and the battery lead plate 720.The second way is applied in the biplane construction usually.The third mode or hybrid mode have merged the function of coplanar structure and the adjustable clearance between top cover 710 and coplane battery lead plate 720.This hybrid mode can be used for providing the drop with wide region.As shown in Figure 7, the drop 730 that is positioned at the gap can be handled under the condition that does not contact top board 710 with drop 740.Drop 750 is handled to being clipped between top board 710 and the battery lead plate 720.The invention is not restricted to EWOD microelectrode array structure technology, but also can confinedly be applied to other conventional battery lead plate simultaneously in the range of application of drop size.

In the embodiment of FPLOC800, FPLOC needs five base function blocks, and is as shown in Figure 8, comprises I/O port (810,811,812 and 813), sample preparation 820, drop manipulation 830, detection 840 and system's control 850.The embodiment of five functional blocks of FPLOC will be disclosed in the paragraph below in detail.

Input/output end port (810,811,812 and 813) is the interface between the world and the FPLOC800 externally.In another embodiment, have four kinds of input/output end ports of FPLOC, they are associated with following four functional blocks: sample input port 810, drop I/O port 811, detection I/O port 812 and the control I/O of system port 813, and as shown in Figure 8.

Sample input port (810 among Fig. 8): because real world sample (microlitre) and the greatest differences of chip lab (millilambda) on ratio, the design of fluid input port is rich in challenge.Sample (825 among Fig. 8) and reactant (833 among Fig. 8) are loaded into the interface that needs on the LOC between the microfluidic device and the external world.An embodiment of the invention are based on the mixed plate structure, wherein after sample or reactant are loaded on the FPLOC, can add lid, thereby the input port that need not fix.Fig. 9 A shows through pin 960 sample 950 directly is loaded on the coplanar electrodes plate 970.The loading of sample needn't be very accurate, because the position of liquid reservoir can dynamically regulate as required, with compensation physical loading deviation.Fig. 9 B places passive lid 980 after being illustrated in load sample 950.Fig. 9 C shows an embodiment of the invention, wherein at four angles of FPLOC adjustable sept 930 is arranged, to be adjusted in the clearance height between cover plate 980 and the battery lead plate 970.Drop 950 is clipped between them.Fig. 9 D shows another embodiment of the present invention, and wherein FPLOC has adopted articulated mounting 940 to connect cover plate 980 and battery lead plate 970, to make things convenient for load sample and reactant 950 and to realize that better physical system is integrated.

Drop I/O port (811 among Fig. 8): in an embodiment of the invention, reactant loading bin (833 among Fig. 8) is connected to FPLOC through drop I/O port.Discarded object (835 among Fig. 8) can be stored in the discarded object reservoir on the FPLOC800, perhaps can wash away through discarded object port (811 among Fig. 8).

Detect I/O port (812 among Fig. 8): increasing research paper is being inquired into technology, especially those phase specific absorptivities or the fluoroscopic examination better technology in the size microminiaturization that detection is integrated into micro-fluid chip.But some ripe and stable detection technology for example can comprise that the optical detection (1035 among Figure 10) and the magnetic nanoparticle that use Video Detection and LIF (LIF) to analyze detect (1036 among Figure 10), will be difficult to be integrated among the FPLOC.Because steadiness, high s/n ratio and sensitivity, optical detecting method is compared other method that is used for LOC and is still occupied an leading position.Optical detection is the most easily with integrated based on the wetting LOC platform of electricity.Only need to be arranged in the zone that is used for optical detection comprise top board 1020, base plate 1021, dielectric layer 1040 and 1070 and all material of electrode 1090 make transparent getting final product.Co-planar designs can adapt to than above-mentioned more testing mechanism, thereby has increased the flexibility of system development.For the purpose of external detection, we will use and detect I/O port (812 among Fig. 8).Detect the I/O port and also can be used for optics sensing and the purpose of feedback with the inner quick liquid motion of control FPLOC.

System control I/O port (813 among Fig. 8): in an embodiment of the invention, need the control I/O of system port 813 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 such as printer, USB storage or network interface can be controlled the I/O port through system and be connected to FPLOC.FPLOC also is connected to power supply through system's control I/O port, so that required AC/DC electric power to be provided.

In an embodiment of the invention, FPLOC utilizes the permanent Display Technique of field-programmable to show test result or other important messages shown in Figure 11 A and 11B, and does not need exterior display device.In Figure 11 A, when system is carrying out other microfluidic procedures through microelectrode 1111 being encouraged or removes excitation, show that ink framework 1110 is not contacted.After accomplishing test or target microfluidic procedures, the drop that the 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 this embodiment are: (1) almost is not used in and shows test results or the extra charge of other message because be used to test or the electrode of other microfluidic procedures as display pixel; And (2) even electric power breaks off from little driver, shows it also is nonvolatil, therefore can be used as test record.

Sample preparation (820 among Fig. 8): the theme in the sample preparation will be in whole blood, to isolate cell, obtaining serum or blood plasma, and sample pre-concentration (pre-concentration).The sample pre-concentration quantitatively becomes very important in seldom the mensuration at molecule to be detected.For following two reasons are at first accomplished sample dilution: in order to reduce the influence of interfering material, and for the range of linearity of aggrandizement apparatus operation.So far, the various technology that adopted wide range are such as utilizing acoustics power, magnetic force, optical force, Capillary Electrophoresis (CE), dielectrophoresis (DEP) power to wait separating particles and cell.An embodiment of the invention are shown in the top view of Figure 12 A, and wherein drop 1250 utilizes EWOD and DEP to be energized through square configuration electrode (1210,1211,1212 and 1213) and striped configuration electrode (1220,1221,1222,1223,1224,1225 and 1226) respectively with suspended particulate." configuration (configured) " is meant that Figure 12 B and 12C are viewgraph of cross-section; Wherein apply high-frequency signal (VHF) 1230 through from left to right (from 1220 to 1226) at strip electrode, the inner inhomogeneous field 1256 of drop utilizes DEP that particle is driven into the right side.Through on square-shaped electrode 1221 and 1222, applying low frequency signal (VLF) 1235, utilize EWOD to obtain two sub-drops 1251 and 1252 with variable grain concentration.As an example, when from left to right on one of strip electrode, applying 2MHz and 60Vrms signal 1230, attract particle through positivity DEP.After the right side of cell aggregation in drop,, utilize EWOD that drop is split into two sub-drops through on two square configuration electrodes, applying 80Vrms and 1kHz.As a result, through encouraging the from left to right strip electrode of single circulation, cell is assembled (the sub-drop 1251 in right side) or dilution (the sub-drop 1251 in left side), shown in Figure 12 D.

Figure 13 shows another embodiment of the FPLOC sample preparation of technology such as the branch that utilizes drop.One of shared sample preparation steps is from whole blood, to remove haemocyte, to obtain the plasma that is used for immunoassays.Shown in figure 13; Utilize branch technology such as drop via microelectrode 1340; Produce littler drop (to such an extent as to too little some or the arbitrary haemocyte 1380 of can not carrying of this drop), move droplet 1345 via undersized down suction 1370 then, to form expectation drop 1350.The combination in branches such as drop technology and little gap 1370 can be moved from liquid reservoir/drop 1360 droplet 1345 effectively through passage 1370, to form bigger drop 1350, stop haemocyte 1380 simultaneously.The physical barriers here is mainly used in technology such as the branch that helps drop, and can adopt the difformity except square to utilize microelectrode to produce littler drop.It is not as the main cause of removing haemocyte.Through utilizing branch such as drop technology, this sample preparation invention can not only be removed particle from drop, and can prepare the drop of the suitable dimension that is used for diagnostic test.

Drop is handled (830 among Fig. 8): in another embodiment, all typical microfluidic procedures can be carried out through configuration and control FPLOC " configured electrodes "." microfluidic procedures " refers to any manipulation of the drop on FPLOC.For example, microfluidic procedures can comprise: drop is loaded among the FPLOC; The one or more drops of liquid droplet distribution from the source; Dividing, separating or cut apart a drop is two or more drops; Drop is transported to another position along any direction from a position; Two or more drops are merged or are combined as single drop; Dilute droplets; Mix drop; Stir drop; With 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 another embodiment, except FPLOC " configured electrodes " in order to the routine control of carrying out typical microfluidic procedures, the concrete control sequence (sequence) of microelectrode can be provided at the advanced person's when handling drop microfluidic procedures.The advanced person's of FPLOC microfluidic procedures can comprise: carry drop along diagonal or along any direction; Utilize the temporary bridge technology to carry drop through physical clearance; Utilize the electrodes series excitation to carry drop; Scrub residual drop (dead volume); Under situation, carry drop than low driving voltage; Carry drop with controlled low velocity; Carry out accurate cutting; The cutting of execution diagonal; The cutting of execution coplane; Merge drop along diagonal; Make drop deformation to quicken mixing; Improve mixing velocity through inhomogeneous toward complex mixers; Improve mixing velocity through circulation blender; Improve mixing velocity through the multilayer blender; Other advanced microfluidic procedures as herein described; And/or above-mentioned any combination.

Fluid storage and drop produce: from the fluid storage of port in liquid reservoir.Liquid reservoir can be on the EWOD device with allow drop into and out of the form in large electrode zone produce.Basic LOC should minimumly have three liquid reservoirs: one is used for sample and loads, and one is used for reactant, and one is used to collect waste liquid and drips, but this depends on application.May need the 4th liquid reservoir to be used for calibration solutions (calibrating solution).Each liquid reservoir should have the independent control in order to allow producing drop or to collect drop.

In another embodiment, FPLOC has sample that self-regulation loads or the reactant ability with respect to the position of liquid reservoir.This means and to avoid the needs of accurate location input port and the difficulty operation of avoiding sample and reactant being delivered to liquid reservoir through input port.The sample that Figure 14 A shows loading is broken into drop 1420 and drop 1430, and they all accurately are not positioned at the top of liquid reservoir 1440.Drop 1420 even do not have any overlapping with liquid reservoir 1440.For the LOC of routine, be difficult to drop 1420 is reoriented in the liquid reservoir 1440.Even and sample drop 1420 is loaded and has departed from liquid reservoir, drop 1420 is moved to and liquid reservoir 1440 position overlapped, also can realize this self-align embodiment of the present invention through excitation provisional configuration electrode 1460.Subsequently provisional configuration electrode 1460 is removed and encouraged and liquid reservoir 1440 is encouraged, so that sample is navigated in the liquid reservoir exactly, shown in Figure 14 B.

Figure 15 representes an embodiment of FPLOC drop production process.Routinely, must produce drop with the liquid reservoir 1530 and the stacked electrode 1535 of special shape.In the present invention, the shape of liquid reservoir 1530 can be square (square liquid reservoir 1515), and does not need stacked electrode 1535.In another embodiment, the shape of liquid reservoir 1515 can be any other shape according to design demand through the design microelectrode array.Shown in figure 15, the generation of drop is meant the process of extruding drop 1550 from square liquid reservoir 1515.In order to start the drop production process, at first encourage interim electrode 1530 as retracting (pull-back) electrode, encourage another interim electrode 1535 with extruding liquid then.Subsequently,, extrude liquid finger piece (liquid finger), finally produce drop 1550 from liquid reservoir 1515 through the configured electrodes 1540 that encourages adjacent sequence number.Each configured electrodes 1540 comprises 4 * 4 microelectrodes of configuration, thereby is square.In the present invention, the size of configured electrodes 1540 can be from tens microns to several millimeters scope, but is not limited thereto scope.The shape of configured electrodes 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 of the concrete drop production process of of the present invention being called " drop five equilibrium ".The drop five equilibrium is to use the microelectrode array structure at first to produce littler drop 1615 through microelectrode or undersized configured electrodes from liquid reservoir 1610; Through stimulation arrangement electrode 1620 littler drop 1615 is collected in together then, to form bigger drop 1630.Routinely, drop size is similar to the size of electrode, does not have the more accurate way in order to the control droplet size.Among the present invention, the drop five equilibrium can be used for realizing the control more accurately to droplet size.In addition, with reverse manner, this technology can be used for can producing the volume what littler drops 1615 are measured bigger drop 1630 through calculating from drop 1630, and is shown in figure 16.

The conveying of drop: Figure 17 is the figure that the drop conveying embodiment of FPLOC is shown.As shown in the figure, 9 adjacent configured electrodes 1731 to 1739 are arranged.Each configured electrodes comprises 10 * 10 microelectrodes of configuration, thereby is square.Drop 1750 is positioned at the top of center configuration electrode 1735.In the microfluid conveying operations of routine, drop 1750 can only be encouraged by configured electrodes 1735 along north and south and east-west direction under this square-shaped electrode is provided with.For example, remove excitation, drop will be moved on the configured electrodes 1734 from configured electrodes 1735 through stimulation arrangement electrode 1734 and to configured electrodes 1735.But this routine operation can not make drop 1735 move to from configured electrodes 1735 along diagonal on any configured electrodes 1731,1733,1737 or 1739, because these four configured electrodes and drop 1750 do not have physical overlap.The restriction that this drop does not cover four angles always is present in from the situation of typical drop production process generation drop.In order to move drop along diagonal; An embodiment of the invention are as interim step stimulation arrangement electrode 1760; Encourage the configured electrodes 1733 of expectation then and provisional configuration electrode 1760 is removed excitation, thereby can drop 1750 be moved in the configured electrodes 1733 of expectation along diagonal.Shown in figure 17, based on the present invention, drop 1750 can move along all 8 directions in square-shaped electrode is provided with.In addition, the conveying of drop is not limited to 8 directions.If the disposed adjacent electrode is in outside these 8 directions, then still can encourage the provisional configuration electrode so that drop is transported to the destination.

The drop route: routinely, LOC has in order to the different piece that connects LOC to carry the transport path electrode 440 of drop, shown in Fig. 4 A.Among the present invention, an embodiment of the drop route of FPLOC need not be used to carry the fixedly transport path of drop, and is shown in figure 18.But utilize the drop route that a plurality of drops are moved to the destination simultaneously from a plurality of original positions.Clearly, the route of FPLOC is handled and will be different from very much conventional microfluid design and more more effective than conventional microfluid design, because through the different microelectrode of excitation, can move along any direction that comprises diagonal basically.Drop 1850,1851 and 1852 is in their original position, and is shown in figure 18.Drop 1850 will mix at configured electrodes 1810 places with drop 1852, and drop 1851 will be transported to configured electrodes 1820.Different with traditional VLSI routing issue, except routed path is selected, the biochip routing issue need solve the problem that the drop timetable under physical constraints that is applied by fluid properties and synthetic result's sequential restriction is arranged.If do not consider to pollute, then can make drop 1851 at first mobile, and can drop 1852 moved through selection schemer 1840 through selection schemer 1860.Here required consideration be the conveying sequential of arranging drop 1851 and 1852, make them when moving to their destination, can not pile up.If consider to pollute, then 1851 can selection schemer 1861 to avoid any overlapping on the drop mobile alignment.In addition, with 1852, must consider to arrange the sequential of drop excitation, so the length difference of route 1830 and route 1840 can become Consideration, thereby have the mixed effect of the best for two drops 1850 that will merge at configured electrodes 1810 places.When the application of on FPLOC, carrying out becomes increasingly complex, need top-down design automation, to limit the route and the sequential of the drop on the FPLOC.After having defined biologic medical microfluid function, utilizing system level (architectural-level) to synthesize to come to the FPLOC resource provides the microfluid function and the microfluid function is mapped in the time step of excitation.

Temporary bridge: the present invention utilize FPLOC to carry and another embodiment that is called " temporary bridge technology " of moving drop shown in Figure 19 A-19C.Drop cutting and evaporation make drop become too little sometimes, and drop can not be encouraged by electrode reliably.Figure 19 A representes by gap 1,960 two configured electrodes 1930 and 1940 separated from one another.Drop 1950 is positioned on the configured electrodes 1930 of left side.Gap 1960 between two configured electrodes 1930 and 1940 is enough wide, so that can isolate two configured electrodes 1930 and 1940, makes the drop 1950 that is positioned on the configured electrodes 1930 of left side can not contact next disposed adjacent electrode 1940.Figure 19 A shows in the drop of routine is carried, and drop 1950 moves failure usually from configured electrodes 1930 to configured electrodes 1940, because configured electrodes 1940 does not have in order 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 configured electrodes 1940 of expectation.In this process, the microelectrode that is covered by " dentation " zone 1970 is energized.Dentation configured electrodes 1970 local left side configured electrodes 1930, gap 1960 and the whole next configured electrodes 1940 of covering.Shown in Figure 19 B, " dentation " configured electrodes 1970 has physical overlap with drop 1950, and shown in Figure 19 B, the excitation of configured electrodes 1970 will make drop 1950 move at the top of configured electrodes 1970.Figure 19 C shows completion and carries to the drop of the configured electrodes 1940 of expectation.After drop 1950 moved to the configured electrodes 1970 of expectation, " dentation " configured electrodes 1970 was removed excitation, and next configured electrodes 1940 is energized, so that drop 1950 is arranged and navigated in the square configuration electrode 1940 of expectation.

Electrodes series excitation: the present invention utilizes FPLOC to carry and the another embodiment that moves drop is called " electrodes series excitation ".Drop cutting and evaporation make drop become too little sometimes, and drop can not be encouraged by electrode reliably.Shown in Figure 20 A, to such an extent as to drop 2050 becomes too little and do not have physical overlap less than electrode 2010 and with adjacent electrode 2011 sometimes.In this case, even electrode 2011 is energized, drop 2050 can not move in the electrode 2011 yet, and drop can glue in the system of staying.Wash away that sticking to stay a kind of effective means of drop be to utilize the electrodes series excitation.Exciting electrode is arranged to multiple row to carry out the electrodes series excitation, shown in Figure 20 B.Here, every row configured electrodes row 2020 comprise 1 * 10 microelectrode, and three row configured electrodes row are combined to carry out the electrodes series excitation, shown in the part that is labeled as black among Figure 20 B.The column width of acquiescence is a microelectrode, but depends on that application also can be other quantity.The most effectively the electrodes series excitation is to have one group of electrodes series, and its width is a bit larger tham the radius of drop.The reason why Here it is here combines three row.The length of row depends on application, and generally the longer the better.For disposing in order to this three row that move drop 2050, before the configured electrodes row 2022 of first place, configured electrodes row 2021 are energized, and the configured electrodes row of trailing 2022 are removed excitation.By this way, no matter the size of drop how, always three row configured electrodes row provide the contact wire of maximum effective length.As a result, drop can be effectively, move smoothly, because the capillary force on the drop is consistent and is maximized.Therefore, drop can move under the driving voltage more much lower than the driving voltage in the conventional drop operation.Kind electrode row Driving technique can be used for carrying drop through smoothly moving under much lower driving voltage.In addition, because the capillary force of the unanimity of this technology through advance the configured electrodes row with low speed, can realize the control to liquid drop speed (especially in the low speed situation).Experiment shows: under critical driving voltage, this level and smooth, the effective driving force of electrodes series excitation is more obvious.Observe: be lower than under 8Vp-p 1kHz square wave driving voltage and the condition in the gap of 80 μ m, in 10cSt silicone oil slowly but move DI water droplet (1.1mm diameter) reposefully.Length can be configured to the total length of LOC, makes the single of electrodes series excitation wash away all invalid drops (dead droplet) that can wash off among the LOC.Figure 20 C shows droplet 2050 and shifts out configured electrodes 2010.

Drop cutting: use three configured electrodes of FPLOC to cut drop.The present invention is used to carry out the embodiment of typical case's three electrode cutting of drop of FPLOC shown in Figure 21 A-21C.Use three configured electrodes, and drop to be cut is positioned at the top of internal configurations electrode 2111 shown in Figure 21 A and have with exterior arrangement electrode 2110 and 2112 and to overlap.During cutting, outside two configured electrodes 2110 and 2112 are energized, and internal configurations electrode 2111 is removed excitation, wetting outside two electrodes thereby drop 2150 expansions are come.Usually, the hydrophilic tensile drop that two exterior arrangement electrodes 2110 and 2112 cause, central simultaneously hydrophobic force is two sub-drops 2151 and 2152 with the liquid pinch off, shown in Figure 21 C.

Accurately cutting: the present invention in order to an embodiment of the accurate cutting that realizes being similar to three electrode cutting shown in Figure 22 A-22C.Accurately cutting also originates in the top that drop to be cut is positioned at the internal configurations electrode.But replace to use outside two configured electrodes 2210 and 2212 to cut drop, utilize the electrodes series exciting technique slowly but firmly spur drop 2250, shown in Figure 22 A towards configured electrodes 2210 and 2212.Here, use two group of 5 row configured electrodes row 2215 and 2216 (in Figure 22 A, being labeled as black) to draw back drop.Figure 22 B shows through once advancing microelectrode row, makes that two arrays of electrodes row group keeps moving with being separated.The hydrophilic tensile drop that two arrays of electrodes row group 2215 and 2216 causes.When electrodes series group 2215 and 2216 arrived configured electrodes 2210 with 2212 outer rim, all configured electrodes were listed as and are removed excitation, and configured electrodes 2210 and 2212 is energized, to be two sub-drops 2251 and 2252 with the liquid pinch off, shown in Figure 22 C.

The diagonal cutting: Figure 23 A-23C shows the present invention in order to carry out the embodiment of diagonal cutting.Diagonal cutting originates in drop to be cut is moved on the provisional configuration electrode 2312, and wherein provisional configuration electrode 2312 is positioned at the center of the engagement angle (joint corner) of four configured electrodes 2310,2311,2313 and 2314.After drop was positioned at the center of engagement angle of four configured electrodes fully, provisional configuration electrode 2312 was removed excitation, and configured electrodes 2310 is energized with configured electrodes 2311, and drop 2350 is stretched in the liquid column, shown in Figure 23 B.In order to be two sub-drops with the liquid pinch off, need the interior angle of configured electrodes 2310 and 2311 be removed excitation, produce necessary hydrophobic force with middle part at drop 2350.Figure 23 C shows L shaped provisional configuration electrode 2315 and 2316 and is energized, and makes with further stretching drop only to have thin neck therebetween, and it is two sub-drops 2351 and 2352 that the hydrophobic force at the middle part helps drop 2350 pinch ofves subsequently.At last, configured electrodes 2310 and 2311 is by excitation once more, with drop 2351 and 2352 centralized positionings in configured electrodes 2310 and 2311, shown in Figure 23 D.

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 the configured electrodes 2440 of left side.Drop 2450 will be cut into two sub-drops 2470, shown in Figure 24 C.The drop cutting process roughly comprises following two processes.At first, through 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 " approaching " liquid column typically refers to the liquid column that has less than the width of initial liquid-drop diameter.Next, the configured electrodes 2440 and 2420 of two preliminary elections of excitation navigates in these two configured electrodes 2440 and 2420, shown in Figure 24 C with cutting drop 2470 and with its center.The key of coplane cutting is between drop and outside two configured electrodes, to have enough overlapping, cuts to carry out so that have the curvature that enough capillary forces overcome drop.In one embodiment, when liquid column 2460 is cut into a plurality of drop owing to the hydrodynamic force unstability, passive cutting takes place.In another embodiment, passive and active cutting is all adopted by the present invention.When drop is drawn into thin liquid column, capable of usingly initial drop is broken into two littler drops by power or active force.When utilizing, very important to the liquid column length calculation by power.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, configured electrodes 2440 and 2420 is by excitation normally, so that drop is navigated in the configured electrodes of expectation.In another embodiment, passive or active cutting process carries out under the open surface structure of FPLOC.Figure 24 C shows and when drop 2450 is cut into two drops 2470, accomplishes cutting.

Mix, cultivate and reaction: hybrid analysis thing and reactant are the committed steps when realizing FPLOC.Drop is used as virtual mixing chamber, and through carrying drop to mix along electrod-array.The ability of mixing material has greatly been improved output apace when utilizing Minimum Area.Yet along with the approaching sub-millilambda epoch of microfluidic device, the volume flow rate of reduction and low-down Reynolds (Reynolds) number cause being difficult to realize the mixing to this liquid with rational markers (time scale).Improved mixing is based on two principles: produce the ability of eddy current with this small size, perhaps alternatively, produce multilayer to realize the ability of rapid mixing via diffusion.

Sometimes also need incubation step at elevated temperatures, for example be used for PCR and amplify.In the embodiment of FPLOC shown in figure 25, drop 2550 is placed on fine heating element 2530 tops that are integrated in the substrate 2521.Also set up heater control/monitor 2532, and it is integrated among the FPLOC through the CMOS manufacturing technology.

The present invention is used to carry out the embodiment of basic merging or married operation of FPLOC 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 " are used interchangeably, in order to represent the combination of two or more drops.This is because merge the mixing fully of composition that two drops always directly or immediately do not cause the drop of initially-separate.In Figure 26 A, two drops 2650 and 2651 initially are positioned on configured electrodes 2610 and 2612, and are separated by at least one configured electrodes 2611 therebetween.Two drops 2650 and 2651 and configured electrodes 2611 at least all have and overlap.Shown in Figure 26 B; Outside two configured electrodes 2610 and 2612 are removed excitation, and the center configuration electrode is energized, and drop 2650 and 2651 draws along center configuration electrode 2611 each other thus; To be merged into a bigger drop 2653, shown in the arrow among Figure 26 B.

Figure 27 A-27C shows through inhomogeneous how much motions in order to the eddy current that produces FPLOC and implements effective mixed process that drop is handled.Through stimulation arrangement electrode 2751 and 2771, make drop 2750 and 2770 distortion, shown in Figure 27 B; Drop 2750 is uprised, make drop 2770 become fat.Then, center configuration electrode 2760 is energized, so that drop 2750 and 2770 is moved in the mixed configuration electrode 2760 (being labeled as black), shown in Figure 27 C.In Figure 27 B, black region representes that two configured electrodes that are energized 2751 and 2771 not only make two drops 2750 and 2770 distortion, and their parts are drawn in the center configuration electrode 2760.This interim incentive step shown in Figure 27 B also helps the level and smooth mixing of two drops to move.Black region among Figure 27 B-27C is merely illustrative purpose with the shape of distortion drop.In the present invention, these shapes can be any type as required.

Figure 28 A and 28B show the microelectrode array blender that is used to improve mixing velocity.In one embodiment, can use inhomogeneous past complex mixers to quicken drop mixes.This can realize that wherein irreversible pattern has destroyed the symmetry of two circulations to improve mixing velocity through encouraging one group of microelectrode to produce irreversible pattern.Original state is shown in Figure 28 A, and wherein drop 2850 comprises sample and reactant, and is positioned at the top of configured electrodes 2840.First step that is used for inhomogeneous reciprocal mixing is a stimulation arrangement electrode 2860 so that drop 2850 is out of shape towards the direction of arrow shown in Figure 28 B.Then, configured electrodes 2860 is removed excitation, and configured electrodes 2840 is energized drop is withdrawn into the initial position shown in Figure 28 A.Back and forth mixing can be carried out repeatedly, with the mixed effect of realizing optimizing.In addition, the configured electrodes among Figure 28 A and the 28B 2840 is merely illustrative purpose with the shape of distortion drop.In the present invention, these shapes can be the design of any type, as long as they have the ability that produces eddy current, or alternatively, have the ability that produces multilayer.

In the another embodiment based on the mixed process of PFLOC drop, Figure 29 shows the circulation blender that is used to improve mixing velocity.This can realize that wherein irreversible horizontal cyclic has been destroyed the symmetry of perpendicular layers circulation to quicken mixing through the sequence of the littler microelectrode group of excitation to produce irreversible horizontal cyclic.An embodiment shown in figure 29 is eight configured electrodes (2910,2920,2930,2940,2950,2960,2970 and 2980) of form surrounding drop 2990, then with the mode of circulation stimulation arrangement electrode one by one sequentially.For example, as first step, configured electrodes 2910 is energized the short time period, to cause surface tension to change and to produce circulation towards configured electrodes 2910 in the inside of drop 2990.Next, configured electrodes 2910 is removed excitation, encourages next disposed adjacent electrode 2920 subsequently.Through whole eight configured electrodes (2910 to 2980) repetitive cycling process of motivation, to produce horizontal cyclic in drop 2990 inside.This circular flow excitation can be carried out repeatedly as required.In addition, circular flow can be clockwise, counterclockwise or the incompatible execution of alternatively mixing of this dual mode, to realize the The Best Mixed effect.In addition, the shape of configured electrodes 2910 to 2980 and circulation is merely illustrative purpose.In the present invention, it can be the design of any kind that this circulation mixes, as long as they have the ability that produces eddy current, or alternatively, has the ability that produces multilayer.

The multilayer blender: the present invention with small size (2 * 2 configured electrodes) but effectively blender produce multilayer can be shown in Figure 30 A-30F with an embodiment that quickens to mix.This multilayer blender is particularly useful for the situation of low aspect ratio (＜1).Aspect ratio is meant the ratio of gap and electrode size between battery lead plate and the earth plate.Low aspect ratio means and more is difficult at the inner eddy current that produces of drop, thereby the ability of generation multilayer becomes more important.In this concrete blender, utilize diagonal to mix and the diagonal cutting.In Figure 30 A, mix with white drop 3050 at configured electrodes 3011 places at the black drop 3051 at configured electrodes 3014 places.Provisional configuration electrode 3010 will become mixing chamber, and will be energized to draw in drop 3051 and 3050.Mix in order to start multilayer, first step is to merge two drops along diagonal.The diagonal that drop merges can be 45 degree or 135 degree, but the direction of diagonal cutting subsequently need be perpendicular to union operation.Figure 30 B representes that merging for the first time becomes black and white drop 3052 with drop 3050 with drop 3051.Because low reynolds number and low aspect ratio, drop 3052 has merely based on the static mixing of diffusion, and it causes long incorporation time, so drop is shown as the half the white that is, half the is black.Second step is to carry out the diagonal cutting that mixes to be 90 degree with initial diagonal to drop 3052, shown in Figure 30 C.When provisional configuration electrode 3010 is removed excitation, configured electrodes 3012 and 3013 and other provisional configuration electrode be energized, so that drop 3052 is cut into two sub-drops 3053 and 3054 along diagonal, shown in Figure 30 C.Discuss in the details paragraph in front of diagonal cutting.Because low composite rate, therefore two sub-drops 3053 keep black/white lamination with identical orientation with 3054 after the diagonal cutting.Then, the 3rd step that multilayer is mixed is that two drops are moved back on the initial configured electrodes, and diagonal mixes and cutting to repeat.In Figure 30 D, drop 3054 moves on the configured electrodes 3011 from configured electrodes 3012, and drop 3053 moves on the configured electrodes 3014 from configured electrodes 3013.What need consideration is the merging of when drop 3053 and 3054 moves, avoiding them.Configured electrodes 3012 and 3013 removed excitation and the simple drop of configured electrodes 3011 and 3014 excitations is moved dirigibility can cause two drops generation physics when moving to contact, so latter two drop may combine.Therefore, provisional configuration electrode 3015 and 3016 need at first be energized, and between two drops, to produce the protection zone, merges in order to when move their destination, to prevent anything unexpected at two drops.After drop 3053 and 3054 moves in configured electrodes 3016 and 3015, forward two drops are moved in configured electrodes 3011 and 3014 straight.Three steps of first step to the can repeat, to produce the multilayer in order to the necessary amount that quickens to mix.As repeating from first step to the drop Figure 30 D 3053 and 3054 is merged the results become drop 3055 along diagonal, Figure 30 E shows four layers of drop 3055.Figure 30 F shows eight layers of drop 3056 that after another circulation of having experienced three steps of first step to the of mixing from multilayer, obtain.

Detect (840 among Fig. 8): send one of in the following manner detection signal usually: research tape label and the not competitiveness combination of the analyte of tape label; Use is exclusively used in the molecule of the tape label of solid phase assays thing; Form sandwich assay; Or carry out enzyme linked immunosorbent assay (ELISA) (ELISA), wherein add the organized enzyme substrate when joining the analyte reciprocation, to change color or fluorescence with enzyme.Increasing research paper is being inquired into technology, especially those phase specific absorptivities or the fluoroscopic examination better technology in the size microminiaturization that detection is integrated into micro-fluid chip.An embodiment of the invention are based on the CMOS technology sensing apparatus are integrated among the FPLOC; Shown in figure 31, wherein sensor (3130,3131 and 3132) can be provided with base plate 3121, top board 3120, drop 3150&3151, sensor probe 3180 and microelectrode 3130 explicitly.Usually measure drop 3150 based on the integrated electronic position flowmeter sensor 3130 of the potential measurement executable operations under the no current situation through sensor probe 3180.Usually the ampere meter sensor 3132 that is utilized in the electric current executable operations that produces when applying current potential between two electrodes is shown as through sensor probe 3181 measures drop 3151.Impedometer sensor 3131 has been integrated in the base plate 3121, with catalytic reaction or specific bond albumen, the agglutinin of keeping watch on enzyme, the biomolecule identification incident that receives master, nucleic acid, full cell, antibody or antibody related substances.Detecting the I/O port also can be used for the optics sensing and feeds back the purpose with the inner quick liquid motion of control FPLOC.

System control (850 among Fig. 8): it is shown in figure 32 that the present invention is used for an embodiment of FPLOC system control block.The major function of system control block is to realize the field-programmable ability of FPLOC.From the angle of software and hardware, the digital programmable ability of FPLOC is existed the requirement of different brackets.Figure 32 representes the grading software structure of FPLOC.Field programming management (FPM) software 3210 is the software of lowermost layer, and layout/network that it is configured to FLB microfluid component and is used for microfluid component is to form FPLOC.Microfluidic procedures programming management (MOPM) 3220 softwares are functions of rising one-level (one level up), and are fluid-operated in order to control and supervisor micro.This step has set how microfluidic procedures will be carried out and the order of microfluidic procedures in FPLOC.For the user who wants to pay close attention to application, they can utilize the microfluidic element of a group of predefined and empirical tests and utilize the advantage of the programmability of convection cell operation sequencing, accomplish the whole design of FPLOC.For the more senior user of the advantage of the flexible structure of wanting to optimize the whole design of FPLOC and utilize FPLOC, they can directly set up microfluid component and direct programming microfluidic procedures.FPM software and MOPM software all are the software of FPLOC chip-scale.System management 3230 is the special-purpose application-level functions that require of management application, it comprise system partitioning and integrated 3231, detect 3232, data management 3233 and peripheral assembly management 3234.

System partitioning and integrated (3231 among Figure 32): the general trend of commercial device has become makes simple disposable apparatus, and they are designed to carry out interface with the more expensive box that holds required control electronic device, reactant supply, detector and programming and are connected.Thereby microfluidic device possibly only carry out one group of limited operation, such as liquid conveying, separation or sensing.This device has been used once thereby has been dropped then.This complexity also produced to system element possibly separate with separately which be disposable, which is the demand that can utilize again, to reduce the cost of whole solution.

Detect and storage/demonstration (3232 among Figure 32): especially, will need CPU ability and software for the mensuration of simultaneous a plurality of quantitative measurments.During this process, also will need some to measure calibration.After obtaining the mensuration result, need define and realize like how concrete form demonstration, report and store data.

At least have several different possible system configuration and be used for FPLOC: (1) prototype and test system configurations; (2) desktop machine configuration; (3) portable machine configuration; And (4) free-standing biochip configuration.

An embodiment of prototype and test system configurations that is used for FPLOC is shown in figure 33.Fundamentally, prototype and test system configurations provide the instrument of a kind of technology evaluation and exploitation, use so that the researcher realizes its micro-fluidic technologies quickly and efficiently under the proof of conceptual system level prototype environment.Prototype and test system configurations are that opening relatively and user are accessible, and it is via providing the standard interface between standard module functional block and these pieces to implement.The functional block of prototype and test system configurations is shown in Figure 33.Prototype and test system configurations comprise: the fluid interface 3340 that is used for the fluid pumping; In order to the fixing fixture 3350 of FPLOC3360; Be used to provide 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 be used to control the PC3310 with the analysis chip function.Then, prototype and test system configurations are provided for hardware, software driver, chip layout, design review (check) (DR) and the field-programmable property of FPLOC prototype, thereby the notion that is implemented in the microfluid proves (proof-of-concept) research.Prototype and test system configurations possibly support to be used for two main tool of the optical characterisation of microfluid media: Video Detection and LIF analysis (LIF).Video capability is the photographic recording that is used for the function of microfluidic procedures.Provide user interface to come via computer control pump, flowmeter, pressure sensor and LIF analysis (LIF) unit.Prototype and test system configurations comprise the host PC of supporting these functions.Be connected realization with USB with being connected of this central actuator computer through RS-232.

With reference to Figure 34 A, in some embodiments of desktop machine configuration, the FPLOC that programming is provided is as the test organisms chip 3410 with desktop assembly 3415.The groove 3416 that Figure 34 A shows the outward appearance of desktop assembly 3415 and is used to insert the FPLOC3410 of programming.In desktop assembly 3415, comprise the built-in detecting sensor, device control button 3418 and the display 3417 that are used for the sensing test result.

With reference to Figure 34 B, in another embodiment of portable machine configuration, the FPLOC that programming is provided is as the test organisms chip 3420 with mancarried device 3425.The groove 3426 that Figure 34 B shows the outward appearance of mancarried device 3425 and is used to insert the FPLOC3420 of programming.In mancarried device 3425, comprise the built-in detecting sensor, device control button 3428 and the display 3427 that are used for the sensing test result.The portability of FPLOC of the present invention helps in the various places of wide regions such as clinic, operating room, emergency ward, small test chamber and is being used under critical situations, bringing the medical center (point-of-care) in field of the quick diagnosis of very fast turnaround time maybe to need point (point-of-need) to use.

Figure 34 C shows another embodiment of free-standing biochip configuration, and the FPLOC that programming wherein is provided is as free-standing biochip 3430.The sample collection device 3439 that Figure 34 C shows the outward appearance of free-standing biochip 3430 and is used for sample is collected chip.Be used for the detecting sensor of sensing test result, the reactant and the system control unit of preloaded all is integrated into chip.Through using microelectrode array, site of deployment permanent Display Technique able to programme shows test results 3437.In addition, even because the chip outage, result displayed can not disappear yet, and therefore can be used for test record.The disposable cheaply invention of the extensive manufacturing shown in Figure 34 C can help in the various places of wide regions such as clinic, operating room, emergency ward, small test chamber and be used under critical situations, bringing the medical center in field of the quick diagnosis of very fast turnaround time maybe need put use.

The embodiment of data management and transfer (3233 among Figure 32): FPLOC is to use emerging information technology, and it allows the different technologies configuration of FPLOC to be connected to the healthcare information system necessarily.Need the FPLOC design of communication in order to: (1) but make the access of FPLOC analyzer self-information system; (2) organize all data of obtaining in many ways through standardized format; (3) allow FPLOC easy use for unprofessional user; (4) keep different access grades, to avoid unauthorized manipulation to this sensitive data.

Other peripheral assembly (3234 among Figure 32): in another embodiment of FPLOC system configuration, should consider other peripheral assembly such as the low profile thermal printer, use under the situation with the hard copy immediately of measuring the result at needs.Perhaps consider and can the determination data of storage be transported to LAB or the USB storage of other database to be used to handle.Bar code scanner also is the popular existing POCT device that is used for management sample.Before networked capabilities can be integrated in the system, the ability of networking with wired connection or wireless connections also was regarded as communication peripheral assembly function.

In some embodiments of making FPLOC, depend on application need, the bottom manufacturing technology that is used for FPLOC can be based on the technology of semiconductor, thin film transistor (TFT) (TFT) array, PCB, plastics or paper.Standard CMOS and TFT manufacturing technology are preferred technology.

Through utilizing a embodiment that the standard CMOS manufacturing process makes FPLOC shown in the block diagram of Figure 35.Two main pieces of FPLOC are system control block 3550 and fluid logic piece (FLB) 3510.Under the normal condition, according to the restriction of application and manufacturing technology, system only needs a system control block 3550, but needs a plurality of FLB3510.

Microelectrode array is realized through the FLB that links together with the daisy chain mode.The quantity of FLB is by using and mainly being confirmed by the restriction of manufacturing technology.FLB comprises high drive microelectrode 3530, (one bit) memory map datum 3520 and a control circuit 3540.High drive microelectrode 3530 is to be energized so that encourage the physics microelectrode of drop through applying necessary voltage.One bit memory map datum 3520 keeps the logical value of the excitation of microelectrodes, and typically, " 1 " representative encourages microelectrode and " 0 " representative is removed excitation to microelectrode.Control circuit 3540 is managed control logics and is formed the daisy chain structure of FLB.

System's control 3550 comprises four main pieces: controller 3560, chip layout 3570, drop situational map 3580 and fluid-operated manager 3590.Controller 3560 is CPU, and has necessary memory headroom, interface circuit and software programming ability.Depend on manufacturing technology, controller 3560 can be integrated the part as manufactured goods, perhaps can be attached external device (ED).Chip layout piece 3570 is configuration data and FPLOC layout information and memory of data of stored configuration electrode.Drop situational map 3580 reflects the physical location of the drop on the FPLOC.Through excitation " configured electrodes " sequence, fluid-operated manager 3590 is with layout information, drop situational map and come the FPLOC of self-controller 3560 to use the physical stimulus that is translated into drop enforcement.

In one embodiment, FPLOC provides field-programmable property, makes that the electrode of LOC and integral layout all can be through software programmings.If its (being stored in the nonvolatile memory such as ROM) firmware of microfluidic device or embedded system can " in the field " be modified; Maybe device is returned its manufacturer and need not disassembling apparatus, then can be described as field-programmable or existing field-programmable.The field-programmable property of FPLOC or software configuration realize with FLB3510 through system's control 3550.The shape and size design of electrode and FPLOC layout information and data are stored in the nonvolatile memory of chip layout piece 3570 inside, and are shown in figure 35.The information that is energized electrode that comprises interim electrode is stored in the nonvolatile memory in the drop situational map 3580.Then, software configuration data passes to each microelectrode 3530 through a bit memory map datum 3520.(grouping) in groups of one group of microelectrode, excitation, remove the in fact arranged for executing through FLB3510 of excitation.In addition, all FLB3510 are that software is attachable, and physically are being the integrated form of monolithic that standard fabrication technique capable of using is made.

Figure 36 shows an embodiment of the electrical design of FLB array 3600, and wherein FLB array 3600 comprises based on a lot of FLB3620s of standard CMOS manufacturing technology with the daisy chain configuration.Daisy chain is the wire laying mode that in the electricity engineering design, uses.The size of microelectrode continue to dwindle and the quantity sustainable growth of microelectrode in, interconnection will be index and increase, to such an extent as to and the too complicated scale that can not management system that will become.Through utilizing the daisy chain mode, simplified the connection between each FLB3620, and the interconnection of FLB will be can increase along with the quantity of FLB and increase, can realize extendible and more succinct layout designs thus.Each FLB3620 comprises storage device (such as d type flip flop 3610) that is used to store excitation information and the high-tension circuit that is used to encourage microelectrode 3630.When applying signal VIN, according to the output valve of trigger 3610, microelectrode 3630 will be energized or remove excitation.SQ signal controlling square wave rather than stable state DC are applied to microelectrode.Before the excitation microelectrode array, load the value of trigger 3620 through the clock among the data-signal ED.A storage device such as d type flip flop 3610 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) have been used.Bottom is a substrate 3760, and the layer above it is a control circuit layer 3750.Control circuit, trigger and high-voltage drive are included in the zone that is arranged in 3751 under microelectrode 3740 and 3770.The three-layer metal layer is used to make microelectrode 3740,3770 and ground wire 3730.The top view of this electrode and ground configurations is shown in Fig. 5 A.The microelectrode 3740 that utilizes voltage to use to be energized, and microelectrode 3770 is for use.The top of microelectrode is a dielectric layer 3710.In this 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 wetting of surfaces property.If watch, only can see microelectrode array, and can not see the circuit that is hidden in below the microelectrode from the top.This self-contained microelectrode structure is the key that when making FLB, has high extensibility.

Through utilizing another embodiment that thin film transistor (TFT) (TFT) array fabrication process makes PFLOC shown in the block diagram among Figure 38 A.Two main pieces are system control block 3850 and active matrix piece (AMB) 3800.System control block 3850 comprises four main pieces: controller 3860, chip layout 3870, drop situational map 3880 and fluid-operated manager 3890.Controller 3860 is CPU, and has necessary memory headroom, interface circuit and software programming ability.Chip layout piece 3870 is configuration data and LOC layout information and memory of data of stored configuration electrode.Drop situational map 3880 reflects the physical location of the drop on the LOC.Through excitation " configured electrodes " sequence, fluid-operated manager 3890 is with layout information, drop situational map and come the LOC of self-controller 3860 to use the physical stimulus that is translated into drop enforcement.

In one embodiment, the configuration of the field-programmable property of LOC or software is realized by system's control 3850.Controller 3860 is CPU, and has necessary memory headroom, interface circuit and software programming ability.Depend on manufacturing technology, controller can be integrated the part as manufactured goods, perhaps can be attached external device (ED).The shape and size design of electrode and LOC layout information and data are stored in the nonvolatile memory of chip layout piece 3870 inside, shown in Figure 38 A.The drop situational map reflects the physical location of the drop on the FPLOC.The information that is energized electrode that comprises interim electrode is stored in the nonvolatile memory in the drop situational map 3880.Fluid-operated manager 3890 is with layout information, drop situational map and come the FPLOC of self-controller to use the physical stimulus that is translated into through encouraging " configured electrodes " sequence that drop is implemented.Then, to configured electrodes in groups, excitation and the data of removing excitation send to active matrix piece (AMB) 3800 with the mode by frame.

In another embodiment, AMB3800 comprises five main pieces: active matrix panel 3810, source electrode driver 3820, gate drivers 3825, DC/DC converter 3840 and AM controller 3830, and shown in Figure 38 B.In active matrix panel 3810, on the basis of sharing, use grid bus 3815 and source bus line 3814, but each microelectrode 3812 is addressable for separately with two suitable contact pads of row end through selecting to be positioned at capable end, shown in Figure 38 B.Switching device uses the transistor of being processed by the film of deposition (therefore being called thin film transistor (TFT) (TFT) 3811).The tft array substrate comprises TFT3811, holding capacitor 3813, microelectrode 3812 and interconnection wiring 3814 and 3815.A set of bond pad is made in each end in grid bus 3815 and data signal bus 3814, with attached source electrode driver IC3820 and gate drivers IC.AM controller 3830 is used to pass through drive circuit unit drive TFT array from the data 3831 of system's control 3850, and wherein drive circuit unit comprises that one group of LCD drives LC (LDI) chip 3820 and 3825.DC power supply 3841 is applied to DC/DC converter 3840, and DC/DC converter 3840 applies positive pulse through grid bus 3815 to grid, with conducting TFT.Holding capacitor is recharged, and the rising of the voltage level on the microelectrode 3812 reaches the voltage level that is applied to source bus line 3814.The major function of holding capacitor 3813 is the voltage that keeps on the microelectrode, till applying next signal voltage.

In one embodiment, based on the top view of the microelectrode array of tft array shown in Figure 38 C.Microelectrode 3812, TFT3811 and holding capacitor 3813 are shown in the typical TFT LCD layout.In another embodiment, realize the hexagon tft array layout shown in Fig. 4 B, with the collision in minimizing and the relatively large gap 3816 between the adjacent micro electrode.

In another embodiment, the FPLOC manufactured goods based on the TFT technology are in the biplane construction shown in Figure 38 D.TFT3803 makes on the glass substrate with microelectrode 3,804 3801, and adds the dielectric insulator 3806 that is coated with hydrophobic membrane 3805, with reduction wetting of surfaces property, and is increased in the electric capacity between drop and the microelectrode.On top board 3802, except the electrode continuously 3808 that is coated with hydrophobic membrane 3805, the black matrix" (BM) 3807 that maybe be also need be processed by opaque metal in order to block a-Si TFT, makes it avoid the irradiation of veiling glare.

Before any programming or configuration, blank FPLOC will look like that kind shown in Figure 39 A.It has the matrix of FLB (fluid logic piece) 3910, and each FLB is can be combined in together also by the microelectrode that encourages simultaneously physically.The various embodiments of blank FPLOC of programming comprise at least: (1) is programmed process from bottom to top manually; And (2) method for designing from top to bottom.

Programme the embodiment of FPLOC shown in Figure 39 A and 39B through utilizing manually programmed process from bottom to top.Before any programming or configuration, blank FPLOC3901 can be shown in Figure 39 A.This blank FPLOC3901 comprises array, the control 3920 of FPLOC system and the I/O interface 3930 of a plurality of FLB3910.In an embodiment of the invention, the quantity of I/O interface 3930 can be single or a plurality of according to design demand.In another embodiment, the placement location of I/O interface 3930 and FPLOC system control 3920 can be positioned at FLB3910 array the below or on same chip the array (shown in Figure 39 A) of next-door neighbour FLB3910.FPLOC system control 3920 provides system partitioning, configuration, control, management and other system related functions.I/O interface 3930 be provided at connect with the programming chip between FPLOC and the external device (ED), show test results, the function of calibration and 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 that leads to the power supply that FPLOC power supply station is needed.First design procedure of FPLOC (or first degree work) is that the integral layout to physical location, size and dimension and the FPLOC of all microfluid components (such as liquid reservoir, Mixed Zone, surveyed area and transport path) manually carries out the field programming.Figure 39 B shows blank FPLOC3901 is programmed with an embodiment of the design 3902 that realizes configuration LOC.This configuration LOC3902 has the microfluid component that comprises 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 that connects FPLOC.After the layout designs of FPLOC, in Figure 39 B, also there are some untapped microelectrodes 3910.Second step of design FPLOC is the microfluidic procedures of definition chip.Basic fluid-operated comprising: produce drop, conveying, cutting and mixing.Discuss like the paragraph of front, can realize more advanced fluid-operated based on the microelectrode array structure.The designer of FPLOC can select to use the basis to set up piece FLB and set up and comprise fluid-operated whole FPLOC.But for the convenience of designer design and for design that can spread F PLOC, the application layer that high expectations is used for microfluidic procedures appears.

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 that is provided by the biochip user.For the behavior (behavior) that defines FPLOC, the user provides the schematic design as the hardware description language (HDL) of " high-level language description " 4012 or conduct " ordering chart model " 4015." ordering chart model " 4015 can be from producing in order to " the high-level language description " 4012 of describing this mensuration agreement.This model can be used for carrying out " behavioral scaling simulation " 4013 to verify senior measurement function.HDL table is more suitable for working with large scale structure, because can specify them through numeral, and need not with hand each part that draws.Yet schematically catalogue can realize that easier design is visual.At this one deck, the purposes of definition application-level functions and LOC.Next, utilize " the system level is synthetic " 4020 according to the concrete implementation of ordering chart model generation." microfluid module library " 4021 also is provided the input of handling as synthetic with " design specification " 4022.This module library is similar to the standard cell lines storehouse of in based on the VLSI of cell design, using, and comprises the different microfluid functional modules such as blender and memory cell.Compact model is used for different microfluid functional modules and the parameter such as the operation duration of width, length and device simulation or laboratory experiment.In addition, some design specifications also have been endowed priori (priori), for example, and the combination of the upper limit of the upper limit of deadline, chip area size and not reconfigurable resource (such as liquid reservoir on the chip/distribution port and integrated optics detector).Synthetic handle mapping (or mapped file), the timetable of measurement operation 4023 (or timetable file) and the Built-in Self Test (BIST) (or Built-in Self Test file) 4025 that 4020 output comprises measurement operation resource 4042 to the chip.Then, through the input of design specification, geometry level synthetic 4030 takes place on geometry level 4032.Synthetic processing attempts to find the design point that not only meets the input standard but also can optimize the expectation of some factors of quality (such as performance and area).After synthetic, the two-dimentional physical Design 4033 of biochip (being that module is placed and route) 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 carrying out physical level simulation 4045 and rudimentary design verification 4050.After physical verification, the FPLOC design can be loaded among the blank FPLOC.

From schematically/the HDL source file disposes to actual FPLOC: in one embodiment, source file is fed to the software that is suitable for the FPLOC design, wherein will be through file of different generating step.Then, this document is shifted the external memory devices of giving FPLOC or similar EEPROM through serial line interface (JTAG).

Modal HDL is VHDL and Verilog, although having made effort aspect the complexity that reduces the HDL design, compare the assembler language that is equal to, has improved level of abstraction through introducing alternative language.Graphical programming language also capable of using (such as American National instrument LabVIEW) makes the FPLOC add-on module can be used for orientation and programming FPLOC hardware.The graphical programming language mode has greatly been simplified the FPLOC programmed process.

In another embodiment, in order to simplify the design of the complication system among the FPLOC, the FPLOC design process is quickened in the storehouse with the predefine sophisticated functions of optimizing to be tested capable of using.These predefined microfluid storehouses can be the advanced microfluidic procedures such as " diagonal cutting " or " showing ' OK ' with x:y ".In typical design cycle, the FPLOC application developer will multistage simulation design in whole design process.Initially, the description of carrying out with VHDL or Verilog is simulated in order to the test table of simulation system and observed result through creating.Then, at Compositing Engine with design map after wire list, wire list is translated into gate level description, wherein repeats simulation and synthesizes to confirm zero defect ground.At last, design in FPLOC, at this moment can add propagation delay, and through these values being returned note (back-annotated) to wire list, whole system simulation is moved once more by layout.

In various embodiments, replace microfluidic procedures based on drop, EWOD microelectrode array structure can be carried out the Continuous Flow microfluidic procedures.The continuous microflow body operates in the control very simple, but the very effective mode of implementing microfluidic procedures can be provided.Figure 41 A-C shows from liquid reservoir 4110 and produces the liquid 4130 of confirming volume.Shown in Figure 41 A, thin microelectrode line has formed 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 the target configuration electrode 4160 from liquid reservoir.4130 express liquids flow to the configured electrodes 4160 from bridge.Here bridge is a microelectrode line.The configuration of this bridge has Continuous Flow and based on the characteristics of the system of drop.Its channelled all advantage, that is, in case the bridge configured electrodes is energized, liquid just will flow through it, and need not excitation sequential and speed are carried out extra control and consideration.It also has all advantages based on the system of drop simultaneously, that is, in case bridge 4115 is removed excitation, then all liquid all will be pulled back to liquid reservoir or target configuration electrode 4160, and in passage, not have residual drop.In case target configuration electrode 4160 is filled, then bridge 4115 is removed excitation, cutting off from the liquid 4130 of liquid reservoir 4110, shown in Figure 41 B.It is automation that the liquid of configured electrodes 4160 fills up, that is, in case all microelectrodes of bridge and configured electrodes are filled up by liquid, then will stop from liquid reservoir 4110 trickles, so the SECO of this process is unimportant.Can come accurately to control the generation of liquid 4130 through the breakpoint that encourages suitable microelectrode 4160 and bridge.Shown in Figure 41 B, then bridge is removed excitation through at first microelectrode 4116 being removed excitation, liquid 4130 breaks off from liquid reservoir 4110.This process will guarantee that the most of liquid that forms bridge will be pulled back to liquid reservoir 4110, and the quantity of the microelectrode that liquid 4130 will be through configured electrodes 4160 is accurately controlled.In Figure 41 B, configured electrodes 4160 comprises 10 * 10 microelectrodes.Other size and dimension of definable configured electrodes is to produce the different liquid size and dimension.Figure 41 C shows the disappearance of liquid bridge, and produces liquid 4130 through excitation liquid reservoir 4110 and configured electrodes 4160.

In one embodiment, the identical production process of liquid capable of using cuts into two seed liquid with liquid, shown in Figure 41 D.After configured electrodes 4160 was removed excitation, bridge configured electrodes 4117 was energized with target configuration electrode 4171, and liquid is from bridge flows to 4170 zone.Bridge configured electrodes 4117 is removed excitation, then configured electrodes 4161 and 4171 is encouraged, make liquid rupture and form two seed liquid 4170 and 4130, shown in Figure 41 E.As long as the size of configured electrodes 4161 and 4171 is calculated as desired size in advance, this cutting process just can produce two seed liquid of different size.

In another embodiment, Figure 42 A-C shows the mixed process of implementing through the Continuous Flow microfluidic procedures.Figure 42 A shows through excitation bridge 4215 and 4225 and stimulation arrangement electrode 4216 and 4226, and liquid flows to the mixing chamber 4230 through bridge from liquid reservoir 4210 and 4220.Here, the liquid that is associated with configured electrodes 4216 and 4226 is changing so that carry out better mixing in shape, and the size of liquid is also different so that carry out mixed (ratio mixing) in addition.Between configured electrodes 4216 and 4226, has the gap, to prevent too early mixing.In case liquid has filled up configured electrodes 4216 and 4226, then configured electrodes 4230 (10 * 10 microelectrodes) is energized, and two kinds of liquid are with mixed, shown in Figure 42 B.Then, two bridge electrodes are removed excitation, 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 with accurate way; (2) cutting: liquid 4216 is cut off with liquid 4210, and liquid 4226 is cut off with liquid 4220; (3) carry: bridge 4215 and 4225 is transported to mixing chamber with liquid; And mix (4): liquid 4216 and 4226 mixes at 4230 places.Clearly, this Continuous Flow technology not only can be in order to carrying out all microfluidic procedures, and can carry out with accurate way more, because the resolution ratio of precision depends on the small size microelectrode.

Although described the present invention with reference to preferred implementation, the those skilled in the art will recognize, under the condition that does not break away from the spirit and scope of the present invention, can make various changes in form and details.

Claims (73)

1. one kind is adopted the field-programmable chip lab (FPLOC) of microelectrode array structure to install, and comprising:

A. base plate; The array that comprises a plurality of microelectrodes on the top surface that places substrate; Said a plurality of microelectrode is covered by dielectric layer; Wherein each said microelectrode is connected at least one earth element in the ground structure, is provided with hydrophobic layer at the top of said dielectric layer and said earth element, has the hydrophobic surface of drop with generation;

B. field-programmable architectures, the configuration set electrode that is used to programme is so that produce microfluid component and layout with selected shape and size; And

The c.FPLOC functional block comprises: the I/O port; The sample preparation unit; The drop actuation unit; Detecting unit; And system control unit.

2. device as claimed in claim 1, wherein the configured electrodes in said field-programmable architectures comprises: first configured electrodes comprises a plurality of microelectrodes of arranging with array format; And at least one second disposed adjacent electrode adjacent with said first configured electrodes; Drop places the top of said first configured electrodes and a part of overlapping with the said second disposed adjacent electrode.

3. device as claimed in claim 1; Wherein said FPLOC functional block is carried out following steps: be used for one or more selected configured electrodes are encouraged and remove the driving voltage of excitation through sequentially applying; Thereby, handle the one or more drops between a plurality of configured electrodes sequentially to encourage/to remove excitation excitation drop to move along selected route to selected configured electrodes.

4. device as claimed in claim 3, wherein said FPLOC functional block is carried out following steps: handle the quantity of the microelectrode of said configured electrodes, roughly to control the size and dimension of drop.

5. device as claimed in claim 2, wherein said configured electrodes comprises at least one microelectrode.

6. device as claimed in claim 5, wherein the microfluid component of the configuration set electrode in said field-programmable architectures comprises: liquid reservoir, electrode, mixing chamber, detection window, discarded object reservoir, droplet path and appointed function electrode.

7. device as claimed in claim 6, 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.

8. device as claimed in claim 1; Wherein said FPLOC functional block is carried out following steps: first configured electrodes is removed excitation; And the second disposed adjacent electrode encouraged, so that drop is moved on the said second disposed adjacent electrode from said first configured electrodes.

9. device as claimed in claim 8; Wherein said FPLOC functional block is carried out through using three configured electrodes to divide the step of drop; Wherein in that to be in the drop that loads on first configured electrodes at center roughly overlapping with two second disposed adjacent electrodes, and saidly comprise through the step of using three configured electrodes to divide drop:

A. configuration comprises two provisional configuration electrodes of many microelectrode lines, and said many microelectrode lines cover the drop that loads on said first configured electrodes;

B. encourage said two provisional configuration electrodes;

C. encourage line by line moving, and to removing excitation, with roughly towards said two second disposed adjacent electrodes pulling drop with the immediate line in center towards said two second disposed adjacent electrodes; And

D. said two provisional configuration electrodes are removed excitation, and said two second disposed adjacent electrodes are encouraged.

10. device as claimed in claim 8; Wherein said FPLOC functional block is carried out through using three configured electrodes to divide the step of drop; Wherein drop is loaded on first configured electrodes that is in the center; And two disposed adjacent electrodes are not overlapping with drop, saidly comprise through the step of using three configured electrodes to divide drop:

A. configuration comprises two provisional configuration electrodes of many microelectrode lines, and said many microelectrode lines cover the drop that loads on said first configured electrodes;

B. encourage said two provisional configuration electrodes;

C. encourage line by line moving, and to removing excitation, with roughly towards said two second disposed adjacent electrodes pulling drop with the immediate line in center towards said two second disposed adjacent electrodes; And

D. said two provisional configuration electrodes are removed excitation, and said two second disposed adjacent electrodes are encouraged.

11. device as claimed in claim 8; Wherein said FPLOC functional block is carried out through using three configured electrodes to divide the step of drop; Wherein in that to be in drop and two second disposed adjacent electrodes of being provided with on first configured electrodes at center partly overlapping, saidly comprise through the step of using three configured electrodes to divide drop:

A. said first configured electrodes is removed excitation; And

B. encourage said two second disposed adjacent electrodes, roughly to spur and to cut drop.

12. device as claimed in claim 11, wherein said FPLOC functional block are carried out along the step of diagonal division drop, comprising:

A. drop is arranged on said first configured electrodes;

B. said first configured electrodes is removed excitation, and to encouraging with two overlapping second disposed adjacent electrodes of arranging along diagonal of said first configured electrodes, to spur drops towards said two second disposed adjacent electrodes of arranging along diagonal; And

C. excitation is removed in the overlapping region between said first configured electrodes and said two the second disposed adjacent electrodes of arranging along diagonal, being two sub-drops with the drop pinch off.

13. device as claimed in claim 8, wherein said FPLOC functional block is carried out the step in the said liquid reservoir is returned in the drop reorientation, comprising:

A. produce the provisional configuration electrode, wherein said provisional configuration electrode and said liquid reservoir a part of overlapping, and the part of drop is not overlapping with said liquid reservoir;

B. said provisional configuration electrode is encouraged,, make drop and said liquid reservoir overlapping at least in part to drag drop; And

C. said provisional configuration electrode is removed excitation, and said liquid reservoir is encouraged, so that drop is roughly moved in the said liquid reservoir.

14. device as claimed in claim 1, wherein said FPLOC functional block is carried out following steps: the adjacent configured electrodes of configuration third phase, make the adjacent configured electrodes of said third phase not with first configured electrodes on drop overlapping.

15. device as claimed in claim 14, the adjacent configured electrodes of wherein said third phase comprises a plurality of microelectrodes of arranging with array format.

16. device as claimed in claim 15, wherein said FPLOC functional block is carried out the step that the drop diagonal moves, and further comprises:

A. produce provisional configuration electrode and the adjacent configured electrodes of generation third phase overlapping with a part of drop;

B. through said first configured electrodes being removed excitation and said provisional configuration electrode being encouraged, drop is transported to from said first configured electrodes along diagonal on the adjacent configured electrodes of said third phase; And

C. said provisional configuration electrode is removed excitation, and the adjacent configured electrodes of said third phase is encouraged.

17. device as claimed in claim 14, wherein said FPLOC functional block is carried out the step that moves drop along all directions, comprising:

A. produce provisional configuration electrode and the adjacent configured electrodes of generation third phase overlapping with a part of drop;

B. through said first configured electrodes being removed excitation and said provisional configuration electrode being encouraged, drop is transported on the adjacent configured electrodes of said third phase from said first configured electrodes; And

C. said provisional configuration electrode is removed excitation, and the adjacent configured electrodes of said third phase is encouraged.

18. device as claimed in claim 8, wherein said FPLOC functional block is carried out the step of coplane division, comprising:

A. configuration and the overlapping thin-belt type provisional configuration electrode of drop;

B. said first configured electrodes is removed excitation, and said thin-belt type provisional configuration electrode is encouraged;

C. said provisional configuration electrode is removed excitation; And

D. said first configured electrodes and the said second disposed adjacent electrode are encouraged.

19. device as claimed in claim 8; Wherein said FPLOC functional block is carried out through using three configured electrodes that two drops are merged to step together; Wherein two first configured electrodes are by the said second disposed adjacent electrode separation, and are said through using three configured electrodes that the step that two drops merge to is together comprised:

A. said two first configured electrodes are removed excitation; And

B. the second disposed adjacent electrode that mediates is encouraged.

20. device as claimed in claim 19, wherein said FPLOC functional block is carried out the step that distortion mixes, and comprising:

A. produce two provisional configuration electrodes, to change the shape of two drops;

B. said two first configured electrodes are removed excitation, and said two provisional configuration electrodes are encouraged; And

C. said two provisional configuration electrodes are removed excitation, and the second disposed adjacent electrode that mediates is encouraged.

21. device as claimed in claim 8, wherein said FPLOC functional block are carried out through changing droplet profile and are quickened the step in the inner mixing of drop, comprising:

A. produce the provisional configuration electrode, to change the shape of drop;

B. said first configured electrodes is removed excitation, and said provisional configuration electrode is encouraged;

C. said provisional configuration electrode is removed excitation, and said first configured electrodes is encouraged; And

D. repeat removal excitation and excitation to said provisional configuration electrode and said first configured electrodes.

22. device as claimed in claim 8, wherein said FPLOC functional block are carried out through quicken the step in the inner mixing of drop in the drop inner loop, comprising:

A. produce a plurality of provisional configuration electrodes that surround drop; And

B. next ground encourages and removes excitation to each said provisional configuration electrode along clockwise direction, in shuttling movement, to mix drop.

23. device as claimed in claim 22, wherein said FPLOC functional block is carried out following steps: along counter clockwise direction one next ground each said provisional configuration electrode is encouraged and remove excitation.

24. device as claimed in claim 8, wherein said FPLOC functional block are carried out the step of the multilayer mixing that produces drop, comprising:

A. dispose the configured electrodes of 2 * 2 arrays, be included in two first configured electrodes on first diagonal position;

B. produce the provisional configuration electrode at the center of the configured electrodes that is positioned at said 2 * 2 arrays;

C. said provisional configuration electrode is encouraged, to merge two first drops from said two first configured electrodes;

D. said provisional configuration electrode is removed excitation, and two configured electrodes on second diagonal position are encouraged;

E. said provisional configuration electrode is removed excitation, drop is cut into two second drops;

F. through two extra provisional configuration electrodes are encouraged said two second drops are carried back first configured electrodes on said first diagonal position; Then said two extra provisional configuration electrodes are removed and encouraged and two first configured electrodes on said first diagonal position are encouraged, carry to accomplish;

G. said provisional configuration electrode is encouraged, to merge two second drops from said two first configured electrodes; And

H. repeating diagonal division, conveying and diagonal merges.

25. device as claimed in claim 8, wherein said FPLOC functional block is carried out the step that produces drop, comprising:

A. in said liquid reservoir, dispose the first provisional configuration electrode;

B. from the adjacent configured electrodes line of liquid reservoir configuration that is mounted with liquid;

C. produce with said liquid reservoir in the second overlapping and overlapping provisional configuration electrode of liquid with nearest disposed adjacent electrode;

D. the said first provisional configuration electrode is encouraged;

E. the said second provisional configuration electrode is encouraged, and nearest disposed adjacent electrode is encouraged;

F. the said second provisional configuration electrode is removed excitation; And

G. the back disposed adjacent electrode in the line sequence is encouraged, and the last disposed adjacent electrode that is energized is removed excitation, till producing drop.

26. device as claimed in claim 8, wherein said FPLOC functional block is carried out through utilizing the step of branch technique for generating drops such as drop, comprising:

A. produce the target configuration electrode that is used to expect drop size;

B. from the liquid reservoir configuration small size disposed adjacent electrode wires that is mounted with liquid, said liquid is connected to said target configuration electrode, and the two ends of wherein said small size disposed adjacent electrode wires and said liquid reservoir and said target configuration electrode are overlapping;

C. said target configuration electrode is encouraged;

D. along the path from the liquid reservoir side to said target configuration electrode, next ground encourages and removes excitation to each the small size disposed adjacent electrode that sequentially is mounted with little five equilibrium drop; And

E. repeat the excitation of small size disposed adjacent electrode and remove the excitation order, in said target configuration electrode, to produce the drop of expectation.

27. device as claimed in claim 26, wherein said FPLOC functional block is carried out the step of the quantity of calculating said little five equilibrium drop in advance.

28. device as claimed in claim 8, wherein said FPLOC functional block are carried out through utilizing branch technology such as drop to calculate to be loaded in the step of the volume of the drop on said first configured electrodes, comprising:

A. produce the stored configuration electrode;

B. at the internal configurations provisional configuration electrode of said first configured electrodes;

C. from first configured electrodes configuration small size disposed adjacent electrode wires that is mounted with the drop that is connected with said stored configuration electrode, the two ends of wherein said small size disposed adjacent electrode wires and said first configured electrodes and said stored configuration electrode are overlapping;

D. said provisional configuration electrode is encouraged;

E. said stored configuration electrode is encouraged;

F. along the path from the first configured electrodes side to said stored configuration electrode, next ground encourages and removes excitation to each the small size disposed adjacent electrode that sequentially is mounted with little five equilibrium drop; And

G. repeat the excitation of small size disposed adjacent electrode and remove the excitation order, to calculate the sum of said little five equilibrium drop.

29. device as claimed in claim 14, wherein said FPLOC functional block are carried out the step that bridge joint between the adjacent configured electrodes of the third phase that utilizes said first configured electrodes and align with said first configured electrodes moves drop, comprising:

A. produce the bridge configured electrodes, said bridge configured electrodes comprises adjacent configured electrodes of said third phase and the extension bridge areas as there overlapping with drop;

B. said first configured electrodes is removed excitation, and said bridge configured electrodes is encouraged; And

C. said bridge configured electrodes is removed excitation, and the adjacent configured electrodes of said third phase is encouraged.

30. device as claimed in claim 8, wherein said FPLOC functional block are carried out through utilizing the row excitation to move the step of drop, comprising:

A. configuration comprises the row configured electrodes of multiple row microelectrode; And

B. through the son of said row configured electrodes row being encouraged and remove excitation, wash away the drop on the said row configured electrodes along target direction.

31. device as claimed in claim 8, wherein said FPLOC functional block is carried out the step of washing away the residual drop on the electrode surface, comprising:

A. configuring arrange configured electrodes, said row configured electrodes comprise the multiple row microelectrode and have the length that covers all residual drops; And

B. through the son of said row configured electrodes row being encouraged and remove excitation, wash away all the residual drops on the said row configured electrodes along target direction.

32. device as claimed in claim 8, wherein said liquid reservoir is mounted with liquid.

33. device as claimed in claim 32, wherein said FPLOC functional block is carried out through utilizing Continuous Flow to produce the step of the liquid of difformity and size, comprising:

A. configuration is used for the target configuration electrode of desirable for liquid size and dimension;

B. dispose the bridge configured electrodes, said bridge configured electrodes comprises the microelectrode line and is connected to said liquid reservoir and said target configuration electrode;

C. said bridge configured electrodes and said target configuration electrode are encouraged; And

D. through at first to said bridge configured electrodes, remove excitation with one group of nearest microelectrode of said target configuration electrode, come said bridge configured electrodes is removed excitation.

34. device as claimed in claim 32, wherein said FPLOC functional block can be carried out through utilizing Continuous Flow to compare the step that liquid is split into two seed liquid with controlled size and division, comprising:

A. configuration and the overlapping first target configuration electrode of liquid with predefined first sub-liquid size and dimension;

B. configuration has the second target configuration electrode of the predefined second sub-liquid size and dimension;

C. dispose the bridge configured electrodes, said bridge configured electrodes comprises the microelectrode line and is connected to the said first target configuration electrode and the said second target configuration electrode;

D. said bridge configured electrodes and the said second target configuration electrode are encouraged;

E. said bridge configured electrodes is removed excitation; And

F. the said first target configuration electrode is encouraged.

35. device as claimed in claim 32, wherein said FPLOC functional block are carried out through utilizing Continuous Flow recently to merge the step of two kinds of liquid with controlled size, shape and merging, comprising:

A. dispose the mixed configuration electrode;

B. configuration and the overlapping first target configuration electrode and the second target configuration electrode of said mixed configuration electrode;

C. dispose the first bridge configured electrodes, the said first bridge configured electrodes comprises the microelectrode line and is connected to the said first target configuration electrode and first fluid supply;

D. dispose the second bridge configured electrodes, the said second bridge configured electrodes comprises the microelectrode line and is connected to the said second target configuration electrode and second fluid supply;

E. the said first bridge configured electrodes and the said second bridge configured electrodes and the said first target configuration electrode and the said second target configuration electrode are encouraged;

F. said first bridge configured electrodes and the said second bridge configured electrodes are removed excitation; And

G. said mixed configuration electrode is encouraged.

36. device as claimed in claim 1, wherein said ground structure is made on the top board of biplane construction, and said top board has the gap above the base plate and between said top board and said base plate.

37. device as claimed in claim 1, wherein said ground structure are the coplanar structure that has passive top cover or do not have top cover.

38. device as claimed in claim 1, wherein said ground structure are the coplanar structure with grounded screen.

39. device as claimed in claim 1, wherein said ground structure are the coplanar structure with ground pad.

40. device as claimed in claim 1, wherein said ground structure are the coplanar structure with ground pad of programming.

41. device as claimed in claim 1, but wherein said ground structure is for utilizing the mixed structure of selector switch with biplane construction and coplane textural association.

42. device as claimed in claim 8, wherein said FPLOC functional block is carried out liquid is loaded into the step in the said liquid reservoir, comprising:

A. liquid is loaded on the coplanar structure; And

B. on liquid, place passive lid.

43. device as claimed in claim 1; Wherein utilize the clearance distance regulon that drop is clipped between top board and the base plate; Said clearance distance regulon is used to adapt to drop wide region, that have different size, and wherein said clearance distance regulon can be carried out following steps:

A. be configured in the height of the clearance distance between said top board and the said base plate;

B. dispose the size of said configured electrodes, the size with the control drop makes drop contact said top board and said base plate;

C. dispose the size of said configured electrodes, the size with the control drop makes drop only contact said base plate.

44. device as claimed in claim 1, wherein said microelectrode can with array format be arranged as circular, square, hexagon is cellular or folded brick shape.

45. device as claimed in claim 1, wherein said I/O port comprises:

A. drop I/O port unit;

B. detect the I/O port unit; And

C. system controls the I/O port unit.

46. device as claimed in claim 45, the drop I/O port unit in the wherein said I/O port comprises:

A. the sample I/O port unit that is used for load sample;

B. be used for carrying out the reactant I/O port unit that interface is connected with the reactant loading bin; And

C. be used to wash away the discarded object I/O port unit of discarded object.

47. detecting with Video Detection, LIF analysis (LIF) and magnetic nanoparticle, device as claimed in claim 45, wherein said detection I/O port unit be connected.

48. device as claimed in claim 45, the wherein said control I/O of system port unit is connected to the external unit that comprises processor, display unit, printer, USB storage, network interface, power supply.

49. device as claimed in claim 1, wherein sample preparation can be carried out in the sample preparation unit in said FPLOC functional block, comprises the steps:

A. configuration comprises the square configuration electrode and the striped configuration electrode of a plurality of microelectrodes;

B. edge direction from left to right applies the DEP driving voltage on said striped configuration electrode; And

C. on said square configuration electrode, apply the EWOD driving voltage, drop is cut into two sub-drops with variable grain concentration.

50. device as claimed in claim 1, wherein the sample preparation unit in said FPLOC functional block comprises the narrow passage with the barrier material that is attached to top board, and wherein said sample preparation unit can prepare sample, comprises the steps:

A. encourage microelectrode, producing the micro-dimension drop, can not load bearing grain to such an extent as to said micro-dimension drop is too little;

B. through said narrow passage said micro-dimension drop is moved to the position of expectation, simultaneously particle is waited behind;

C. repeat moving of said micro-dimension drop, till the drop that produces desired size.

51. device as claimed in claim 8 also comprises the drop routing infrastructure that realizes through the configured electrodes among the excitation FPLOC, said drop routing infrastructure can be carried out following steps:

A. dispose at least one routed path that is used to carry drop and comprises a plurality of configured electrodes;

B. with the excitation of each routed path of sequence selection of order with remove the sequential of excitation; And

C. the selected configured electrodes to said routed path encourages and removes excitation.

52. device as claimed in claim 1, wherein fine heating element is integrated in the substrate of said device, can be in order under selected temperature, to heat drop.

53. device as claimed in claim 1, wherein the detecting unit in said FPLOC functional block comprises the sensing apparatus that is integrated in the said substrate, and said sensing apparatus comprises potentiometric pick-up, ampere meter sensor or impedometer sensor.

54. device as claimed in claim 1, wherein the system control unit in said FPLOC functional block comprises:

A. classification FPLOC chip-scale software configuration comprises: a programming management software is used for layout/network that said microelectrode is configured to microfluid component and is used for said microfluid component; With microfluidic procedures programming management software, it is fluid-operated to be used for control and supervisor micro; And

B. application system administrative unit, comprising: system partitioning and integrated package are used to separate said device; Detect and displaying block, be used to obtain, show, report and storing measurement result; Data management and transfer block are used to attach the device to the external information system; With the peripheral management block that is used to be connected to external system.

55. device as claimed in claim 54 can be configured to prototype and test macro structure.

56. device as claimed in claim 54 can be configured to the desktop machine structure.

57. device as claimed in claim 54 can be configured to the portable machine structure.

58. device as claimed in claim 54 can be configured to free-standing biochip structure.

59. a FPLOC device that adopts CMOS technology manufactured goods comprises:

The a.CMOS system control block comprises: controller block is used to provide processor unit, memory headroom, interface circuit and software programming ability; The chip layout piece is used for stored configuration electrode configuration data and FPLOC layout information and data; The drop situational map, the physical location that is used to store drop; With fluid-operated manager, be used for using the physical stimulus that is translated into drop with said layout information, said drop situational map and from the FPLOC of said controller block; And

B. many fluid logic pieces, each fluid logic piece comprises: a microelectrode is positioned on the top surface of CMOS substrate; A memory map datum memory cell is used to keep the excitation information of said microelectrode; And the control circuit piece, be used to manage control logic.

60. device as claimed in claim 59, the control circuit piece of wherein said a plurality of fluid logic pieces links together with the daisy chain structure.

61. device as claimed in claim 59, the microelectrode of wherein said fluid logic piece can be energized through applying driving voltage.

62. device as claimed in claim 59, the memory map datum memory cell of wherein said fluid logic piece were loaded with data before excitation.

63. device as claimed in claim 59, the manufactured goods of the fluid logic piece of wherein said FPLOC device comprise:

A. metal layer at top is used to form microelectrode and ground structure;

B. the second layer below said metal layer at top comprises said control circuit piece, said memory map datum memory cell and the high-voltage drive that is used to encourage said microelectrode; And

C. base substrate.

64. like the described device of claim 63, wherein said control circuit piece, said memory map datum memory cell and said high-voltage drive are included in the zone under the corresponding microelectrode.

65. a FPLOC device that adopts thin film transistor (TFT) TFT technology manufactured goods comprises:

The a.TFT system block comprises: controller block is used to provide processor unit, memory headroom, interface circuit and software programming ability; The chip layout piece is used for stored configuration electrode configuration data and FPLOC layout information and data; The drop situational map, the physical location that is used to store drop; With fluid-operated manager, be used for the data of using from said layout information, said drop situational map and FPLOC are translated into the physics drop excited data that is used to encourage microelectrode, said FPLOC uses from said controller block; Wherein said physics drop excited data comprise with send to by the mode of frame the active matrix piece, to configured electrodes carry out in groups, excitation and remove the data of excitation; And

B. active matrix piece, comprising: be used for the active matrix panel of each microelectrode of independent drive, this active matrix panel comprises grid bus, source bus line, thin film transistor (TFT), holding capacitor and microelectrode; The active matrix controller comprises source electrode driver and gate drivers, is used for through driving data is sent to chip for driving, is used to come the drive TFT array from the data of TFT system control block; With the DC/DC converter, be used for applying driving voltage to said source electrode driver and said gate drivers.

66. like the described device of claim 65, wherein said FPLOC device comprises hexagon tft array layout.

67. like the described device of claim 65, wherein said FPLOC device comprises biplane construction, said biplane construction comprises:

A. the glass substrate that has microelectrode;

B. be coated with the dielectric insulator of hydrophobic membrane;

C. be coated with the electrode continuously of hydrophobic membrane; And

D. the black matrix" of processing by opaque metal.

68. the method for programming from bottom to top and designing the FPLOC device comprises:

A. wipe the internal memory of FPLOC;

B. configuration has the microfluid component of a configuration set electrode of selected shape and size; A said configuration set electrode is included in a plurality of microelectrodes of arranging with array format in the field-programmable architectures, and said microfluid component comprises liquid reservoir, electrode, mixing chamber, detection window, discarded object reservoir, droplet path and appointed function electrode;

C. dispose the physical allocation of said microfluid component; And

D. the microfluidic procedures that is designed for sample preparation, drop manipulation and detects.

69. the method for programming from top to bottom and designing the FPLOC device comprises:

A. design the function of FPLOC through hardware description language;

B. produce the ordering chart model according to hardware description language;

C. carry out the function of simulation through hardware description language with checking FPLOC;

D. utilize the system level to synthesize according to said ordering chart model and produce concrete implementation;

E. will be input in synthetic the processing from the microfluid module library with from the design data of design specification;

F. produce the measurement operation of resource on the chip mapped file, measurement operation the timetable file and from the synthetic Built-in Self Test file of handling;

G. utilize the input execution geometry level of design specification synthetic, to produce the two-dimentional physical Design of biochip;

H. according to the two-dimentional physical Design that is combined with the biochip of concrete physical message, produce 3-D geometric model, said concrete physical message is from said microfluid module library;

I. through using 3-D geometric model to carry out physical level simulation and design verification; And

J. the FPLOC design is loaded among the blank FPLOC.

70. like the described method of claim 69, wherein step j is loaded into the FPLOC design among the blank FPLOC and comprises:

A. according to top-down programming and the design of FPLOC, obtain the mapped file of the measurement operation of resource on the chip and the timetable file of measurement operation;

B. said file is shifted to FPLOC through serial line interface (JTAG) and perhaps said file is shifted to external memory devices.

71. a method that designs the FPLOC storehouse comprises:

A. simulate the functional module description of the microfluidic procedures of writing through creating test table by hardware description language; Said hardware description language comprises VHDL or Verilog, and said test table constitutes test macro and is used to simulate said system and observed result;

B. through Compositing Engine said functional module is described and be mapped to wire list;

C. said wire list is translated into gate level description;

D. simulate said gate level description;

E. add propagation delay to said wire list through physical analogy; And

F. through having the wire list of said propagation delay, the operation whole system simulation.

72. device as claimed in claim 3, said device are the EWOD device, wherein driving voltage at DC to the scope of the AC of 10kHz and less than 150V.

73. device as claimed in claim 3, said device are the DEP device, wherein driving voltage at 50kHz to the scope of the AC of 200kHz and have 100-300Vrms.

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